Chemotherapy-Induced Diarrhea

Complex MONDO:0001673 Pathograph 24 Gastrointestinal Disease Iatrogenic condition

Chemotherapy-induced diarrhea is a treatment-related gastrointestinal toxicity caused by antineoplastic agents, especially fluoropyrimidines and irinotecan, that injure the rapidly renewing intestinal mucosa. The syndrome reflects epithelial and crypt injury, barrier dysfunction, mucosal inflammation, dysbiosis, and impaired absorptive function, and can lead to treatment delay, dose reduction, hospitalization, and infectious complications when severe.

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1
Mappings
1
Definitions
0
Inheritance
9
Pathophysiology
0
Histopathology
4
Phenotypes
24
Pathograph
2
Genes
3
Treatments
0
Subtypes
0
Differentials
0
Datasets
0
Trials
6
Models
6
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0001673 diarrheal disease Not Yet Curated
skos:closeMatch MONDO
Closest MONDO parent term available for chemotherapy-induced diarrhea in the local ontology snapshot.
📘

Definitions

1
Clinical treatment-toxicity framing for chemotherapy-induced diarrhea
Chemotherapy-induced diarrhea is a common gastrointestinal toxicity of cancer chemotherapy associated with clinically important morbidity and mortality.
CASE_DEFINITION General oncology supportive-care framing of chemotherapy-related diarrhea
Show evidence (1 reference)
PMID:25186048 SUPPORT Other
"Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently."
This guideline review provides a direct disease-level framing of chemotherapy-induced diarrhea as a common and clinically important treatment toxicity.
⚙

Pathophysiology

9
Cytotoxic chemotherapy exposure and intestinal drug delivery
Exposure to diarrheagenic antineoplastic agents, especially fluoropyrimidines and irinotecan, initiates intestinal toxicity by delivering cytotoxic drugs and metabolites to the intestinal mucosa and lumen.
Experimental models
Human intestinal organoid 5-fluorouracil multi-omics toxicity model ORGANOID Applies clinically relevant 5-fluorouracil exposure concentrations to human intestinal organoids.
Downstream
Crypt stem/progenitor apoptosis and epithelial injury Cytotoxic agents injure rapidly proliferating crypt and epithelial cells.
Microbial beta-glucuronidase reactivation of irinotecan metabolites Irinotecan exposure supplies glucuronidated metabolites that can be reactivated by bacterial beta-glucuronidase activity in the gut lumen.
Chemotherapy-associated gut microbial dysbiosis Chemotherapy exposure and mucosal injury alter gut microbial community structure in patients and preclinical models.
Show evidence (2 references)
PMID:30739515 SUPPORT Human Clinical
"Although the fluoropyrimidines are effective chemotherapeutic agents for malignant gastrointestinal tumors, they sometimes cause enteritis with diarrhea."
Human clinical data support fluoropyrimidine exposure as a proximal initiating context for chemotherapy-related enteritis with diarrhea.
PMID:32170007 SUPPORT Model Organism
"Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes."
Preclinical irinotecan evidence supports the chemotherapy exposure and its luminal microbial-enzyme toxicity context.
Crypt stem/progenitor apoptosis and epithelial injury
Rapidly renewing crypt stem and progenitor cells and surface epithelium are damaged after chemotherapy exposure, leading to apoptosis, impaired epithelial renewal, and mucositis.
intestinal epithelial cell link enterocyte link
apoptotic process link ↑ INCREASED
Experimental models
Primary human small-intestinal monolayer permeability model PRIMARY CELL CULTURE Provides a human epithelial-injury readout in a primary small-intestinal monolayer.
Murine intestinal organoid 5-fluorouracil injury model ORGANOID Measures direct epithelial cytotoxicity after 5-fluorouracil exposure.
Human intestinal organoid 5-fluorouracil multi-omics toxicity model ORGANOID Measures epithelial viability, apoptosis, and cell-cycle/apoptosis pathway responses after 5-fluorouracil exposure.
Primary human intestinal stem-cell 2D diarrhea-prediction model PRIMARY CELL CULTURE Measures proliferation and cell abundance in primary proliferative intestinal cells exposed to marketed drugs.
Microbiota-product epithelial apoptosis IEC-6 and organoid model OTHER Assays epithelial apoptosis and organoid development after microbiota product exposure in a chemotherapy-induced diarrhea context.
Downstream
MLCK/actomyosin-mediated tight-junction remodeling Epithelial injury and inflammatory signaling promote tight-junction remodeling that precedes overt barrier leak.
Enterocyte apoptosis, villus blunting, and surface loss Impaired renewal progresses to villus injury and loss of absorptive epithelial surface.
Show evidence (1 reference)
PMID:34017262 SUPPORT Other
"The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes."
Review evidence directly links chemotherapy-associated mucositis to stem-cell apoptosis and failed epithelial renewal.
MLCK/actomyosin-mediated tight-junction remodeling
Chemotherapy-associated tight-junction defects can increase paracellular permeability through MLCK/MLC-dependent actomyosin remodeling of the tight junction.
intestinal epithelial cell link
tight junction assembly link ↓ DECREASED
actomyosin link
Downstream
Paracellular barrier leak and mucosal break formation Junctional remodeling lowers epithelial resistance and progresses to overt paracellular leak.
Show evidence (2 references)
PMID:24316664 SUPPORT Model Organism
"Findings strongly suggest irinotecan causes tight junction defects which lead to mucosal barrier dysfunction and the development of diarrhea."
Preclinical irinotecan data support chemotherapy-associated tight-junction disruption as a proximal step in diarrhea pathogenesis.
PMID:32028590 SUPPORT Other
"In many cases, this barrier loss reflects increased permeability of the paracellular tight junction as a consequence of myosin light chain kinase (MLCK) activation and myosin II regulatory light chain (MLC) phosphorylation."
General intestinal barrier evidence provides the MLCK/MLC mechanism that connects tight-junction remodeling to paracellular leak.
Paracellular barrier leak and mucosal break formation
Chemotherapy-induced mucosal injury compromises epithelial barrier function, increases paracellular permeability, and produces visible small-intestinal mucosal breaks in affected patients.
intestinal epithelial cell link
tight junction assembly link ↓ DECREASED
Experimental models
Primary human small-intestinal monolayer permeability model PRIMARY CELL CULTURE Measures permeability and luminal-to-basolateral flux relevant to barrier-leak mechanisms.
Primary human intestinal stem-cell 2D diarrhea-prediction model PRIMARY CELL CULTURE Uses transepithelial electrical resistance as a barrier-formation readout relevant to epithelial barrier disruption.
Anaerobic human intestine-on-chip host-microbiome coculture ORGAN ON CHIP Measures epithelial barrier function under host-microbiome coculture conditions.
Downstream
Chemotherapy-associated gut microbial dysbiosis Barrier failure permits additional host-microbiome crosstalk and may reinforce chemotherapy-associated community disruption.
Dysbiosis-associated inflammatory amplification Barrier leak permits microbial products and luminal contents to amplify mucosal inflammatory injury.
Diarrhea Paracellular permeability contributes directly to leak-flux fluid loss.
Show evidence (2 references)
PMID:37231829 SUPPORT Human Clinical
"Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea."
Prospective human study explicitly ties fluoropyrimidine exposure to barrier dysfunction and downstream diarrhea.
PMID:30739515 SUPPORT Human Clinical
"Many patients with diarrhea caused by chemotherapy including fluoropyrimidine had small intestinal mucosal breaks."
Human capsule-endoscopy data show that chemotherapy-related diarrhea is commonly accompanied by structural mucosal injury.
Chemotherapy-associated gut microbial dysbiosis
Chemotherapy and mucosal barrier injury alter gut microbial community structure, with patient studies showing diarrhea-associated diversity and taxonomic shifts and preclinical irinotecan models showing Enterobacteriaceae expansion.
Experimental models
Anaerobic human intestine-on-chip host-microbiome coculture ORGAN ON CHIP Provides a human host-microbiome coculture platform for modeling microbial community structure and dysbiosis-related perturbations.
Downstream
Microbial beta-glucuronidase reactivation of irinotecan metabolites Community composition and bacterial enzyme capacity shape luminal irinotecan metabolite reactivation.
Dysbiosis-associated inflammatory amplification Altered microbial communities can reinforce inflammatory host responses after barrier injury.
Show evidence (2 references)
PMID:37231829 SUPPORT Human Clinical
"In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group."
Prospective human microbiome data support a chemotherapy-associated dysbiosis node separated from inflammatory amplification.
PMID:32170007 SUPPORT Model Organism
"Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice."
Mouse irinotecan models support chemotherapy-driven microbial community shifts as a separable mechanism.
Microbial beta-glucuronidase reactivation of irinotecan metabolites
Gut bacterial beta-glucuronidase activity reactivates glucuronidated irinotecan metabolites in the intestinal lumen, increasing local epithelial toxicity and linking drug metabolism to microbiome-dependent injury.
xenobiotic metabolic process link
beta-glucuronidase activity link ↑ INCREASED
Downstream
Crypt stem/progenitor apoptosis and epithelial injury Reactivation of irinotecan metabolites increases local epithelial toxicity and loss of crypt proliferation.
Show evidence (1 reference)
PMID:32170007 SUPPORT Model Organism
"We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor."
Supports the microbiome-dependent drug-metabolite handling node and links increased bacterial GUS activity to downstream epithelial proliferation loss.
Dysbiosis-associated inflammatory amplification
Altered microbial communities and barrier leak amplify mucosal inflammatory injury, reinforcing epithelial damage and diarrheal severity.
inflammatory response link ↑ INCREASED symbiont-mediated perturbation of host process link ↑ INCREASED
Experimental models
Anaerobic human intestine-on-chip host-microbiome coculture ORGAN ON CHIP Represents a tractable host-microbiome interface for testing how microbial communities modulate epithelial barrier and host-response readouts.
Microbiota-product epithelial apoptosis IEC-6 and organoid model OTHER Provides an in vitro microbiota-host interaction assay for testing how dysbiosis-linked microbial products alter epithelial injury responses.
Downstream
Reduced fluid absorption and diarrheal output Persistent mucosal injury and inflammatory remodeling impair net absorptive function and increase stool water loss.
Crypt stem/progenitor apoptosis and epithelial injury Inflammatory amplification can reinforce epithelial and crypt damage, creating a feed-forward injury loop.
Show evidence (2 references)
PMID:37231829 SUPPORT Human Clinical
"Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs."
Supports a microbiome-associated amplification step in chemotherapy-linked diarrhea.
PMID:32170007 SUPPORT Model Organism
"These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage."
Mouse irinotecan models implicate microbiome-dependent amplification of epithelial damage and dysbiosis in chemotherapy toxicity.
Enterocyte apoptosis, villus blunting, and surface loss
Chemotherapy-induced epithelial apoptosis and failed renewal shorten villi, blunt the absorptive surface, and reduce functional enterocyte area.
intestinal epithelial cell link enterocyte link
apoptotic process link ↑ INCREASED
Downstream
Reduced fluid absorption and diarrheal output Loss of absorptive surface area lowers net epithelial fluid uptake.
Show evidence (2 references)
PMID:34017262 SUPPORT Other
"The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes."
Review evidence links chemotherapy mucositis to epithelial apoptosis and failed renewal.
PMID:23072534 SUPPORT Model Organism
"Continuous administration of 5-FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea."
Mouse mucositis data show villus shortening and crypt destruction downstream of chemotherapy injury.
Reduced fluid absorption and diarrheal output
Reduced absorptive surface area, villus injury, and transport imbalance lower net fluid absorption and increase stool water loss.
enterocyte link
intestinal absorption link ↓ DECREASED
Downstream
Diarrhea Net fluid loss and impaired absorptive function produce the defining diarrheal phenotype.
Show evidence (2 references)
PMID:35170355 SUPPORT Other
"However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool."
General intestinal transport physiology shows that diarrhea emerges when fluid secretion overwhelms absorptive capacity.
PMID:30739515 SUPPORT Human Clinical
"The diarrhea grade (per the Common Terminology Criteria for Adverse Events, version 4.0) was significantly correlated with the percentage of patients with a small intestinal mucosal break"
Human data tie worsening diarrhea severity to more extensive small-bowel mucosal injury, consistent with absorptive failure.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Chemotherapy-Induced Diarrhea Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Digestive 1
Diarrhea Diarrhea (HP:0002014)
Show evidence (1 reference)
PMID:25186048 SUPPORT Other
"Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently."
This guideline review directly establishes diarrhea as the central treatment-related phenotype.
Metabolism 2
Dehydration Dehydration (HP:0001944)
Show evidence (2 references)
PMID:35170355 SUPPORT Other
"fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool."
This review explains how secretory diarrhea produces excess stool water loss, supporting dehydration as a downstream CID complication.
PMID:25186048 SUPPORT Other
"Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step."
Management guidance highlights fluid resuscitation requirements in chemotherapy-induced diarrhea, consistent with clinically important volume depletion risk.
Electrolyte imbalance Hypokalemia (HP:0002900)
Show evidence (1 reference)
PMID:35170355 SUPPORT Other
"One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents."
The review establishes electrolyte transport as central to intestinal fluid balance; CID-associated diarrhea can therefore present with clinically relevant electrolyte disturbance.
Constitutional 1
Abdominal pain Abdominal pain (HP:0002027)
Show evidence (1 reference)
PMID:34151400 SUPPORT Other
"Furthermore, intestinal mucositis is usually accompanied by nausea, abdominal pain, vomiting and diarrhoea"
This review links fluoropyrimidine-associated intestinal mucositis to abdominal pain alongside diarrhea.
🧬

Genetic Associations

2
DPYD pharmacogenomic susceptibility (Germline reduced-function DPYD variants increase fluoropyrimidine toxicity risk)
Show evidence (2 references)
DOI:10.3390/ph18050727 SUPPORT Other
"Germline variants in the DPYD gene, which encodes the enzyme dihydropyrimidine dehydrogenase (DPD), are known to impair drug metabolism and increase the risk of severe toxicity."
The umbrella review establishes germline DPYD variation as a pharmacogenomic risk factor for severe fluoropyrimidine toxicity.
DOI:10.3389/fphar.2025.1645188 SUPPORT Human Clinical
"In the DA cohort, 12% of patients experienced severe fluoropyrimidines-related adverse events, compared to 50% in the NDA cohort"
Human implementation data support DPYD-guided dosing as clinically actionable for reducing severe fluoropyrimidine toxicity.
UGT1A1 pharmacogenomic susceptibility (Reduced-function UGT1A1 variants increase irinotecan gastrointestinal toxicity risk)
Show evidence (2 references)
PMID:11990381 SUPPORT Human Clinical
"screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity."
Human pharmacokinetic evidence directly links UGT1A1*28 to lower SN-38 glucuronidation and increased irinotecan gastrointestinal toxicity risk.
PMID:36443464 SUPPORT Other
"Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity."
Pharmacogenomics guidance supports UGT1A1 variants as actionable irinotecan toxicity risk factors.
💊

Treatments

3
Loperamide
Action: gastrointestinal agent therapy MAXO:0000267
First-line symptomatic antidiarrheal pharmacotherapy used in routine management of chemotherapy-induced diarrhea.
Show evidence (1 reference)
PMID:25186048 SUPPORT Other
"Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step."
The guideline review identifies loperamide as a standard component of CID management.
Fluid resuscitation and supportive care
Action: supportive care MAXO:0000950
Supportive management focusing on hydration and clinical reassessment, especially for patients with significant volume loss or ongoing symptoms.
Show evidence (1 reference)
PMID:25186048 SUPPORT Other
"Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step."
Supports hydration-focused supportive care as a core management step.
Octreotide
Action: pharmacotherapy MAXO:0000058
Escalation pharmacotherapy for patients who do not respond adequately to initial antidiarrheal treatment.
Show evidence (1 reference)
PMID:25186048 SUPPORT Other
"Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality."
The guideline review supports octreotide as escalation management for refractory chemotherapy-induced diarrhea.
🌍

Environmental Factors

2
Fluoropyrimidine-based chemotherapy exposure
Fluoropyrimidines are prominent triggers of chemotherapy-induced diarrhea and treatment-related small-intestinal mucosal injury.
Show evidence (1 reference)
PMID:30739515 SUPPORT Human Clinical
"Although the fluoropyrimidines are effective chemotherapeutic agents for malignant gastrointestinal tumors, they sometimes cause enteritis with diarrhea."
Human capsule-endoscopy study directly supports fluoropyrimidines as a clinically relevant exposure leading to chemotherapy-related diarrhea.
Oral fluoropyrimidine administration
Oral fluoropyrimidine regimens are associated with more extensive small-intestinal mucosal breaks than intravenous fluoropyrimidine therapy in patients who develop chemotherapy-related diarrhea.
Show evidence (1 reference)
PMID:30739515 SUPPORT Human Clinical
"Compared to patients receiving intravenous therapy, those receiving an orally administered fluoropyrimidine had a significantly greater number of small intestinal mucosal breaks"
Supports oral fluoropyrimidine delivery as a clinically relevant risk context for more severe mucosal injury.
🧫

Experimental Models

6
Primary human small-intestinal monolayer permeability model PRIMARY_CELL_CULTURE namo:TwoDCellCulture ↗
Polarized primary human small-intestinal epithelial monolayers grown on a permeable scaffold to measure epithelial injury, barrier permeability, and luminal-to-basolateral flux in a human intestinal system.
epithelial injury intestinal barrier dysfunction paracellular permeability
intestinal epithelial cell ↗
Organism
human ↗
Tissue
small intestine ↗
Cell source
Primary human small-intestinal epithelial cells
Culture
Polarized two-dimensional monolayer on a permeable support
Publication
PMID:29094594 ↗
Pathograph links
Crypt stem/progenitor apoptosis and epithelial injury Provides a human epithelial-injury readout in a primary small-intestinal monolayer.
Paracellular barrier leak and mucosal break formation Measures permeability and luminal-to-basolateral flux relevant to barrier-leak mechanisms.
Findings
Primary human small-intestinal monolayers enable direct epithelial-injury and barrier-permeability readouts in a human intestinal in vitro model
Show evidence (2 references)
PMID:29094594 PARTIAL In Vitro
"Here, we use a unique in vitro human primary small intestinal cell monolayer system to pinpoint the intestinal consequences of NSAID treatment."
Supports the experimental platform in primary human small-intestinal epithelium, although the initiating insult is NSAID exposure rather than chemotherapy.
PMID:29094594 PARTIAL In Vitro
"We also find that DCF induces intestinal barrier permeability, facilitating the translocation of compounds from the luminal to the basolateral side of the intestinal epithelium."
Shows that the system directly measures barrier permeability relevant to treatment-induced diarrhea mechanisms.
Show evidence (1 reference)
PMID:29094594 PARTIAL In Vitro
"The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and..."
Shows that this primary human monolayer can quantify gut-barrier function, while remaining indirect with respect to chemotherapy-specific injury.
Murine intestinal organoid 5-fluorouracil injury model ORGANOID namo:Organoid ↗
Murine intestinal organoids exposed to 5-fluorouracil to quantify epithelial cytotoxicity and candidate protective interventions in chemotherapy-induced mucositis.
chemotherapy-induced mucositis 5-fluorouracil epithelial cytotoxicity organoid viability
intestinal epithelial cell ↗
Organism
house mouse ↗
Tissue
small intestine ↗
Cell source
Murine intestinal organoids
Culture
Three-dimensional intestinal organoid culture exposed to 5-fluorouracil
Publication
PMID:39226257 ↗
Pathograph links
Crypt stem/progenitor apoptosis and epithelial injury Measures direct epithelial cytotoxicity after 5-fluorouracil exposure.
Findings
5-fluorouracil exposure reduces epithelial viability in intestinal organoids
Show evidence (1 reference)
PMID:39226257 SUPPORT In Vitro
"Additionally, the effects of melatonin were investigated in vitro on 5-FU treated murine intestinal organoids."
Establishes the existence of an organoid-based 5-FU injury platform for chemotherapy-induced mucositis.
Show evidence (1 reference)
PMID:39226257 SUPPORT In Vitro
"The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids."
Supports organoid viability as a tractable readout for chemotherapy epithelial injury and rescue.
Human intestinal organoid 5-fluorouracil multi-omics toxicity model ORGANOID namo:Organoid ↗
Three-dimensional human colon and small-intestinal organoids exposed to clinically relevant 5-fluorouracil concentrations to measure epithelial viability, apoptosis, morphology, transcriptomic responses, and metabolomic responses.
5-fluorouracil intestinal toxicity apoptosis transcriptomic response metabolomic response
intestinal epithelial cell ↗
Organism
human ↗
Tissue
intestine ↗
Cell source
Human healthy colon and small-intestine biopsy-derived organoids
Culture
Three-dimensional human intestinal organoids exposed to 5-fluorouracil concentrations informed by PBPK simulation
Publication
PMID:34151400 ↗
Pathograph links
Cytotoxic chemotherapy exposure and intestinal drug delivery Applies clinically relevant 5-fluorouracil exposure concentrations to human intestinal organoids.
Crypt stem/progenitor apoptosis and epithelial injury Measures epithelial viability, apoptosis, and cell-cycle/apoptosis pathway responses after 5-fluorouracil exposure.
Findings
Human colon and small-intestinal organoids capture 5-fluorouracil toxicity mechanisms including cell-cycle, p53, mitochondrial ATP synthesis, and apoptosis responses.
Show evidence (2 references)
PMID:34151400 SUPPORT In Vitro
"In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses."
Establishes the human intestinal organoid platform and the chemotherapy-specific exposure being modeled.
PMID:34151400 SUPPORT In Vitro
"Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis."
Supports the crypt/progenitor injury and apoptosis mechanism captured by the organoid model.
Show evidence (1 reference)
PMID:34151400 SUPPORT In Vitro
"These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development."
Supports this human organoid system as a chemotherapy-specific non-animal model for intestinal toxicity mechanisms.
Primary human intestinal stem-cell 2D diarrhea-prediction model PRIMARY_CELL_CULTURE namo:TwoDCellCulture ↗
Primary human intestinal stem cell-derived RepliGut Planar cultures in a two-dimensional Transwell format used for high-throughput drug-induced diarrhea risk prediction by measuring proliferation, cell abundance, and transepithelial electrical resistance.
drug-induced diarrhea risk epithelial proliferation barrier formation
intestinal epithelial cell ↗
Organism
human ↗
Tissue
intestine ↗
Cell source
Primary intestinal stem/progenitor cells derived from human intestinal crypts
Culture
Two-dimensional Transwell RepliGut Planar platform
Publication
PMID:40086646 ↗
Pathograph links
Crypt stem/progenitor apoptosis and epithelial injury Measures proliferation and cell abundance in primary proliferative intestinal cells exposed to marketed drugs.
Paracellular barrier leak and mucosal break formation Uses transepithelial electrical resistance as a barrier-formation readout relevant to epithelial barrier disruption.
Findings
Primary human intestinal stem-cell derived monolayers can predict clinical diarrhea risk from marketed drugs using proliferation, cell abundance, and barrier readouts.
Show evidence (2 references)
PMID:40086646 SUPPORT In Vitro
"Here, we describe the development of a diarrhea prediction assay utilizing RepliGut® Planar, a primary intestinal stem cell-derived platform."
Establishes the specific primary human intestinal stem-cell platform used for diarrhea-risk prediction.
PMID:40086646 SUPPORT In Vitro
"This model accurately predicted diarrhea potential, achieving an accuracy of 91 % for proliferation, 90 % for abundance, and 88 % for barrier formation."
Supports the model as a human in vitro non-animal model for drug-induced diarrhea risk and the relevant epithelial readouts.
Show evidence (1 reference)
PMID:40086646 SUPPORT In Vitro
"Chemotherapeutic agents, known to cause clinical diarrhea, frequently target mitotic cells."
Links the proliferative crypt-derived assay rationale to chemotherapy agents that cause clinical diarrhea.
Anaerobic human intestine-on-chip host-microbiome coculture ORGAN_ON_CHIP namo:OrganOnChip ↗
Microfluidic human intestine-on-chip system that sustains complex aerobic and anaerobic human gut microbiota in direct contact with living intestinal epithelium and mucus under a physiologic oxygen gradient.
host-microbiome interaction microbial community diversity intestinal barrier function
intestinal epithelial cell ↗
Organism
human ↗
Tissue
intestine ↗
Cell source
Human intestinal epithelial cells cocultured with complex human gut microbiota
Culture
Microfluidic intestine-on-chip with transluminal hypoxia gradient
Publication
PMID:31086325 ↗
Pathograph links
Chemotherapy-associated gut microbial dysbiosis Provides a human host-microbiome coculture platform for modeling microbial community structure and dysbiosis-related perturbations.
Dysbiosis-associated inflammatory amplification Represents a tractable host-microbiome interface for testing how microbial communities modulate epithelial barrier and host-response readouts.
Paracellular barrier leak and mucosal break formation Measures epithelial barrier function under host-microbiome coculture conditions.
Findings
Anaerobic intestine-on-chip culture sustains complex human gut microbiota with epithelial barrier readouts.
Show evidence (1 reference)
PMID:31086325 PARTIAL In Vitro
"Here, we show the extended coculture of living human intestinal epithelium with stable communities of aerobic and anaerobic human gut microbiota, using a microfluidic intestine-on-a-chip that permits the control and real-time assessment of physiologically relevant oxygen gradients."
Supports the host-microbiome coculture platform, although it is a general microbiome non-animal model rather than a chemotherapy-specific model.
Show evidence (1 reference)
PMID:31086325 PARTIAL In Vitro
"The intestine-on-a-chip may serve as a discovery tool for the development of microbiome-related therapeutics, probiotics and nutraceuticals."
Supports this chip as a general non-animal model for the microbiome-related process pattern now represented in the CID pathograph.
Microbiota-product epithelial apoptosis IEC-6 and organoid model OTHER
In vitro epithelial cell and intestinal organoid assays used with chemotherapy-induced diarrhea models to test microbiota-derived effects on epithelial integrity, mitochondrial function, organoid development, and apoptotic signaling.
microbiota-host interaction intestinal epithelial apoptosis chemotherapy-induced diarrhea
intestinal epithelial cell ↗
Tissue
intestine ↗
Cell source
IEC-6 epithelial cells and intestinal organoids
Culture
Epithelial cell and intestinal organoid assays testing microbiota-derived Bacteroides fragilis components
Publication
PMID:40624638 ↗
Pathograph links
Crypt stem/progenitor apoptosis and epithelial injury Assays epithelial apoptosis and organoid development after microbiota product exposure in a chemotherapy-induced diarrhea context.
Dysbiosis-associated inflammatory amplification Provides an in vitro microbiota-host interaction assay for testing how dysbiosis-linked microbial products alter epithelial injury responses.
Findings
IEC-6 and intestinal organoid experiments can test microbiota-host interactions affecting epithelial injury in chemotherapy-induced diarrhea.
Show evidence (2 references)
PMID:40624638 SUPPORT In Vitro
"Mechanistic studies were conducted in murine models, complemented by IEC-6 cells and intestinal organoid experiments to elucidate microbiota-host interactions."
Establishes the in vitro epithelial and organoid systems used to probe microbiota-host interactions in chemotherapy-induced diarrhea.
PMID:40624638 SUPPORT In Vitro
"hk-B. f preserved epithelial integrity, mitochondrial function, and intestinal organoid development (higher budding count and larger organoid surface area)."
Supports organoid development and epithelial integrity as assayable readouts for microbiota-mediated epithelial protection in CID models.
Show evidence (1 reference)
PMID:40624638 SUPPORT In Vitro
"Caspase-3 inhibition or BCL2 silencing abrogated hk-B. f's anti-apoptotic effects in IEC-6 cells."
Supports the IEC-6 component as a tractable epithelial apoptosis model for microbiota-linked injury mechanisms.
{ }

Source YAML

click to show 
name: Chemotherapy-Induced Diarrhea
creation_date: "2026-04-02T01:07:38Z"
updated_date: "2026-05-13T16:25:49Z"
category: Complex
categories:
- Treatment-Related Disorder
- Gastrointestinal Toxicity
- Adverse Drug Reaction
synonyms:
- CID
- chemotherapy-induced diarrhoea
description: >-
  Chemotherapy-induced diarrhea is a treatment-related gastrointestinal toxicity
  caused by antineoplastic agents, especially fluoropyrimidines and irinotecan,
  that injure the rapidly renewing intestinal mucosa. The syndrome reflects
  epithelial and crypt injury, barrier dysfunction, mucosal inflammation,
  dysbiosis, and impaired absorptive function, and can lead to treatment delay,
  dose reduction, hospitalization, and infectious complications when severe.
parents:
- Gastrointestinal Disease
- Iatrogenic condition
disease_term:
  preferred_term: chemotherapy-induced diarrhea
  term:
    id: MONDO:0001673
    label: diarrheal disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0001673
      label: diarrheal disease
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      Closest MONDO parent term available for chemotherapy-induced diarrhea in
      the local ontology snapshot.
definitions:
- name: Clinical treatment-toxicity framing for chemotherapy-induced diarrhea
  definition_type: CASE_DEFINITION
  description: >-
    Chemotherapy-induced diarrhea is a common gastrointestinal toxicity of
    cancer chemotherapy associated with clinically important morbidity and
    mortality.
  scope: General oncology supportive-care framing of chemotherapy-related diarrhea
  evidence:
  - reference: PMID:25186048
    reference_title: "Guidance on the management of diarrhoea during cancer chemotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diarrhoea induced by chemotherapy in cancer patients is common, causes
      notable morbidity and mortality, and is managed inconsistently.
    explanation: >-
      This guideline review provides a direct disease-level framing of
      chemotherapy-induced diarrhea as a common and clinically important
      treatment toxicity.
environmental:
- name: Fluoropyrimidine-based chemotherapy exposure
  description: >-
    Fluoropyrimidines are prominent triggers of chemotherapy-induced diarrhea
    and treatment-related small-intestinal mucosal injury.
  evidence:
  - reference: PMID:30739515
    reference_title: "Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the fluoropyrimidines are effective chemotherapeutic agents for
      malignant gastrointestinal tumors, they sometimes cause enteritis with
      diarrhea.
    explanation: >-
      Human capsule-endoscopy study directly supports fluoropyrimidines as a
      clinically relevant exposure leading to chemotherapy-related diarrhea.
- name: Oral fluoropyrimidine administration
  description: >-
    Oral fluoropyrimidine regimens are associated with more extensive
    small-intestinal mucosal breaks than intravenous fluoropyrimidine therapy in
    patients who develop chemotherapy-related diarrhea.
  evidence:
  - reference: PMID:30739515
    reference_title: "Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to patients receiving intravenous therapy, those receiving an
      orally administered fluoropyrimidine had a significantly greater number of
      small intestinal mucosal breaks
    explanation: >-
      Supports oral fluoropyrimidine delivery as a clinically relevant risk
      context for more severe mucosal injury.
pathophysiology:
- name: Cytotoxic chemotherapy exposure and intestinal drug delivery
  description: >-
    Exposure to diarrheagenic antineoplastic agents, especially
    fluoropyrimidines and irinotecan, initiates intestinal toxicity by delivering
    cytotoxic drugs and metabolites to the intestinal mucosa and lumen.
  role: trigger
  chemical_entities:
  - preferred_term: 5-fluorouracil
    term:
      id: CHEBI:46345
      label: 5-fluorouracil
  - preferred_term: irinotecan
    term:
      id: CHEBI:80630
      label: irinotecan
  evidence:
  - reference: PMID:30739515
    reference_title: "Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the fluoropyrimidines are effective chemotherapeutic agents for
      malignant gastrointestinal tumors, they sometimes cause enteritis with
      diarrhea.
    explanation: >-
      Human clinical data support fluoropyrimidine exposure as a proximal
      initiating context for chemotherapy-related enteritis with diarrhea.
  - reference: PMID:32170007
    reference_title: "Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Irinotecan treats a range of solid tumors, but its effectiveness is
      severely limited by gastrointestinal (GI) tract toxicity caused by gut
      bacterial β-glucuronidase (GUS) enzymes.
    explanation: >-
      Preclinical irinotecan evidence supports the chemotherapy exposure and its
      luminal microbial-enzyme toxicity context.
  downstream:
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: >-
      Cytotoxic agents injure rapidly proliferating crypt and epithelial cells.
  - target: Microbial beta-glucuronidase reactivation of irinotecan metabolites
    description: >-
      Irinotecan exposure supplies glucuronidated metabolites that can be
      reactivated by bacterial beta-glucuronidase activity in the gut lumen.
  - target: Chemotherapy-associated gut microbial dysbiosis
    description: >-
      Chemotherapy exposure and mucosal injury alter gut microbial community
      structure in patients and preclinical models.

- name: Crypt stem/progenitor apoptosis and epithelial injury
  conforms_to: intestinal_barrier_dysfunction#Epithelial Stress and Injury
  description: >-
    Rapidly renewing crypt stem and progenitor cells and surface epithelium are
    damaged after chemotherapy exposure, leading to apoptosis, impaired
    epithelial renewal, and mucositis.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:34017262
    reference_title: "Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The condition is associated with histological changes and inflammation in
      the mucosa arising from stem-cell apoptosis and disturbed cellular renewal
      and maturation processes.
    explanation: >-
      Review evidence directly links chemotherapy-associated mucositis to
      stem-cell apoptosis and failed epithelial renewal.
  downstream:
  - target: MLCK/actomyosin-mediated tight-junction remodeling
    description: >-
      Epithelial injury and inflammatory signaling promote tight-junction
      remodeling that precedes overt barrier leak.
  - target: Enterocyte apoptosis, villus blunting, and surface loss
    description: >-
      Impaired renewal progresses to villus injury and loss of absorptive
      epithelial surface.

- name: MLCK/actomyosin-mediated tight-junction remodeling
  conforms_to: intestinal_barrier_dysfunction#MLCK/Actomyosin-Mediated Tight Junction Remodeling
  description: >-
    Chemotherapy-associated tight-junction defects can increase paracellular
    permeability through MLCK/MLC-dependent actomyosin remodeling of the tight
    junction.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: tight junction assembly
    term:
      id: GO:0120192
      label: tight junction assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: actomyosin
    term:
      id: GO:0042641
      label: actomyosin
  evidence:
  - reference: PMID:24316664
    reference_title: "Irinotecan disrupts tight junction proteins within the gut : implications for chemotherapy-induced gut toxicity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Findings strongly suggest irinotecan causes tight junction defects which
      lead to mucosal barrier dysfunction and the development of diarrhea.
    explanation: >-
      Preclinical irinotecan data support chemotherapy-associated tight-junction
      disruption as a proximal step in diarrhea pathogenesis.
  - reference: PMID:32028590
    reference_title: "Contributions of Myosin Light Chain Kinase to Regulation of Epithelial Paracellular Permeability and Mucosal Homeostasis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In many cases, this barrier loss reflects increased permeability of the
      paracellular tight junction as a consequence of myosin light chain kinase
      (MLCK) activation and myosin II regulatory light chain (MLC)
      phosphorylation.
    explanation: >-
      General intestinal barrier evidence provides the MLCK/MLC mechanism that
      connects tight-junction remodeling to paracellular leak.
  downstream:
  - target: Paracellular barrier leak and mucosal break formation
    description: >-
      Junctional remodeling lowers epithelial resistance and progresses to overt
      paracellular leak.

- name: Paracellular barrier leak and mucosal break formation
  conforms_to: intestinal_barrier_dysfunction#Paracellular Barrier Leak
  description: >-
    Chemotherapy-induced mucosal injury compromises epithelial barrier function,
    increases paracellular permeability, and produces visible small-intestinal
    mucosal breaks in affected patients.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: tight junction assembly
    term:
      id: GO:0120192
      label: tight junction assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:37231829
    reference_title: "Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disruption of the intestinal epithelial barrier function by FPs leads to
      dysbiosis, which may exacerbate intestinal epithelial cell damage as a
      secondary effect and trigger diarrhea.
    explanation: >-
      Prospective human study explicitly ties fluoropyrimidine exposure to
      barrier dysfunction and downstream diarrhea.
  - reference: PMID:30739515
    reference_title: "Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many patients with diarrhea caused by chemotherapy including
      fluoropyrimidine had small intestinal mucosal breaks.
    explanation: >-
      Human capsule-endoscopy data show that chemotherapy-related diarrhea is
      commonly accompanied by structural mucosal injury.
  downstream:
  - target: Chemotherapy-associated gut microbial dysbiosis
    description: >-
      Barrier failure permits additional host-microbiome crosstalk and may
      reinforce chemotherapy-associated community disruption.
  - target: Dysbiosis-associated inflammatory amplification
    description: >-
      Barrier leak permits microbial products and luminal contents to amplify
      mucosal inflammatory injury.
  - target: Diarrhea
    description: >-
      Paracellular permeability contributes directly to leak-flux fluid loss.

- name: Chemotherapy-associated gut microbial dysbiosis
  description: >-
    Chemotherapy and mucosal barrier injury alter gut microbial community
    structure, with patient studies showing diarrhea-associated diversity and
    taxonomic shifts and preclinical irinotecan models showing
    Enterobacteriaceae expansion.
  role: amplifier
  evidence:
  - reference: PMID:37231829
    reference_title: "Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 19 patients treated with oral FPs, the α diversity of the microbial
      community decreased significantly following chemotherapy only in the
      diarrheal group.
    explanation: >-
      Prospective human microbiome data support a chemotherapy-associated
      dysbiosis node separated from inflammatory amplification.
  - reference: PMID:32170007
    reference_title: "Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Remarkably, GUS inhibitor also effectively blocks the striking
      irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice.
    explanation: >-
      Mouse irinotecan models support chemotherapy-driven microbial community
      shifts as a separable mechanism.
  downstream:
  - target: Microbial beta-glucuronidase reactivation of irinotecan metabolites
    description: >-
      Community composition and bacterial enzyme capacity shape luminal
      irinotecan metabolite reactivation.
  - target: Dysbiosis-associated inflammatory amplification
    description: >-
      Altered microbial communities can reinforce inflammatory host responses
      after barrier injury.

- name: Microbial beta-glucuronidase reactivation of irinotecan metabolites
  description: >-
    Gut bacterial beta-glucuronidase activity reactivates glucuronidated
    irinotecan metabolites in the intestinal lumen, increasing local epithelial
    toxicity and linking drug metabolism to microbiome-dependent injury.
  role: amplifier
  biological_processes:
  - preferred_term: xenobiotic metabolic process
    term:
      id: GO:0006805
      label: xenobiotic metabolic process
  molecular_functions:
  - preferred_term: beta-glucuronidase activity
    term:
      id: GO:0004566
      label: beta-glucuronidase activity
    modifier: INCREASED
  chemical_entities:
  - preferred_term: irinotecan
    term:
      id: CHEBI:80630
      label: irinotecan
  - preferred_term: SN-38
    term:
      id: CHEBI:8988
      label: SN-38
  evidence:
  - reference: PMID:32170007
    reference_title: "Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate that a single dose of irinotecan increases GI bacterial GUS
      activity in 1 d and reduces intestinal epithelial cell proliferation in 5
      d, both blocked by a single dose of a GUS inhibitor.
    explanation: >-
      Supports the microbiome-dependent drug-metabolite handling node and links
      increased bacterial GUS activity to downstream epithelial proliferation
      loss.
  downstream:
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: >-
      Reactivation of irinotecan metabolites increases local epithelial toxicity
      and loss of crypt proliferation.

- name: Dysbiosis-associated inflammatory amplification
  conforms_to: intestinal_barrier_dysfunction#Luminal Access and Inflammatory Amplification
  description: >-
    Altered microbial communities and barrier leak amplify mucosal inflammatory
    injury, reinforcing epithelial damage and diarrheal severity.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: symbiont-mediated perturbation of host process
    term:
      id: GO:0044003
      label: symbiont-mediated perturbation of host process
    modifier: INCREASED
  evidence:
  - reference: PMID:37231829
    reference_title: "Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Organic-acid-producing bacteria seem to be involved in diarrhea
      associated with chemotherapy, including FPs.
    explanation: >-
      Supports a microbiome-associated amplification step in chemotherapy-linked
      diarrhea.
  - reference: PMID:32170007
    reference_title: "Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results indicate that targeted gut microbial enzyme inhibitors can
      improve cancer chemotherapeutic outcomes by protecting the gut epithelium
      from microbial dysbiosis and proliferative crypt damage.
    explanation: >-
      Mouse irinotecan models implicate microbiome-dependent amplification of
      epithelial damage and dysbiosis in chemotherapy toxicity.
  downstream:
  - target: Reduced fluid absorption and diarrheal output
    description: >-
      Persistent mucosal injury and inflammatory remodeling impair net
      absorptive function and increase stool water loss.
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: >-
      Inflammatory amplification can reinforce epithelial and crypt damage,
      creating a feed-forward injury loop.

- name: Enterocyte apoptosis, villus blunting, and surface loss
  conforms_to: intestinal_barrier_dysfunction#Villus Blunting and Surface Loss
  description: >-
    Chemotherapy-induced epithelial apoptosis and failed renewal shorten villi,
    blunt the absorptive surface, and reduce functional enterocyte area.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:34017262
    reference_title: "Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The condition is associated with histological changes and inflammation in
      the mucosa arising from stem-cell apoptosis and disturbed cellular renewal
      and maturation processes.
    explanation: >-
      Review evidence links chemotherapy mucositis to epithelial apoptosis and
      failed renewal.
  - reference: PMID:23072534
    reference_title: "5-HT₃ receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Continuous administration of 5-FU to mice caused severe intestinal
      mucositis, which was histologically characterized by the shortening of
      villi and destruction of intestinal crypts, accompanied by body weight
      loss and diarrhoea.
    explanation: >-
      Mouse mucositis data show villus shortening and crypt destruction
      downstream of chemotherapy injury.
  downstream:
  - target: Reduced fluid absorption and diarrheal output
    description: >-
      Loss of absorptive surface area lowers net epithelial fluid uptake.

- name: Reduced fluid absorption and diarrheal output
  conforms_to: intestinal_barrier_dysfunction#Absorptive Failure and Transport Dysregulation
  description: >-
    Reduced absorptive surface area, villus injury, and transport imbalance
    lower net fluid absorption and increase stool water loss.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: intestinal absorption
    term:
      id: GO:0050892
      label: intestinal absorption
    modifier: DECREASED
  evidence:
  - reference: PMID:35170355
    reference_title: "Intestinal secretory mechanisms and diarrhea."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, in conditions of secretory diarrhea, this balance becomes
      dysregulated, so that fluid secretion, driven primarily by Cl- secretion,
      overwhelms absorptive capacity, leading to increased loss of water in the
      stool.
    explanation: >-
      General intestinal transport physiology shows that diarrhea emerges when
      fluid secretion overwhelms absorptive capacity.
  - reference: PMID:30739515
    reference_title: "Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diarrhea grade (per the Common Terminology Criteria for Adverse
      Events, version 4.0) was significantly correlated with the percentage of
      patients with a small intestinal mucosal break
    explanation: >-
      Human data tie worsening diarrhea severity to more extensive small-bowel
      mucosal injury, consistent with absorptive failure.
  downstream:
  - target: Diarrhea
    description: >-
      Net fluid loss and impaired absorptive function produce the defining
      diarrheal phenotype.
    evidence:
    - reference: PMID:25186048
      reference_title: "Guidance on the management of diarrhoea during cancer chemotherapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Diarrhoea induced by chemotherapy in cancer patients is common, causes
        notable morbidity and mortality, and is managed inconsistently.
      explanation: >-
        Supports diarrhea as the defining clinical outcome of this treatment
        toxicity.
phenotypes:
- name: Diarrhea
  description: >-
    Increased stool frequency and water loss are the defining clinical
    manifestation of chemotherapy-induced diarrhea.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:25186048
    reference_title: "Guidance on the management of diarrhoea during cancer chemotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diarrhoea induced by chemotherapy in cancer patients is common, causes
      notable morbidity and mortality, and is managed inconsistently.
    explanation: >-
      This guideline review directly establishes diarrhea as the central
      treatment-related phenotype.
- name: Dehydration
  description: >-
    Clinically significant fluid loss can occur downstream of chemotherapy-induced
    diarrhea, making hydration assessment and resuscitation part of CID
    management.
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:35170355
    reference_title: "Intestinal secretory mechanisms and diarrhea."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive
      capacity, leading to increased loss of water in the stool.
    explanation: >-
      This review explains how secretory diarrhea produces excess stool water
      loss, supporting dehydration as a downstream CID complication.
  - reference: PMID:25186048
    reference_title: "Guidance on the management of diarrhoea during cancer chemotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adequate--and, if necessary, repeated--assessment, appropriate use of
      loperamide, and knowledge of fluid resuscitation requirements of affected
      patients is the second crucial step.
    explanation: >-
      Management guidance highlights fluid resuscitation requirements in
      chemotherapy-induced diarrhea, consistent with clinically important volume
      depletion risk.
- name: Abdominal pain
  description: >-
    Abdominal pain can accompany chemotherapy-induced intestinal mucositis and
    is highlighted in the matching deep-research artifact as a CID-associated
    clinical feature.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:34151400
    reference_title: "New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Furthermore, intestinal mucositis is usually accompanied by nausea, abdominal pain,
      vomiting and diarrhoea
    explanation: >-
      This review links fluoropyrimidine-associated intestinal mucositis to
      abdominal pain alongside diarrhea.
- name: Electrolyte imbalance
  description: >-
    CID can disrupt fluid and electrolyte handling. The closest HPO annotation
    requested by the review is HP:0002900, whose canonical label is
    hypokalemia.
  phenotype_term:
    preferred_term: Electrolyte imbalance with hypokalemia risk
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:35170355
    reference_title: "Intestinal secretory mechanisms and diarrhea."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One of the primary functions of the intestinal epithelium is to transport
      fluid and electrolytes to and from the luminal contents.
    explanation: >-
      The review establishes electrolyte transport as central to intestinal
      fluid balance; CID-associated diarrhea can therefore present with
      clinically relevant electrolyte disturbance.
genetic:
- name: DPYD pharmacogenomic susceptibility
  gene_term:
    preferred_term: DPYD
    term:
      id: hgnc:3012
      label: DPYD
  association: Germline reduced-function DPYD variants increase fluoropyrimidine toxicity risk
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    CID is not Mendelian, but DPYD is a clinically actionable pharmacogenomic
    risk factor for fluoropyrimidine toxicity. The matching deep-research
    artifact summarizes diarrhea-specific associations including DPYD*2A carrier
    diarrhea rates of 12.0%-100% versus 1.4%-27.5% in wild type, DPYD*13 carrier
    diarrhea rates of 50%-100% versus 5.8%-22% in wild type, and c.2846A>T
    pooled OR 6.0 for diarrhea.
  variants:
  - name: DPYD*2A
    description: >-
      Splice variant c.1905+1G>A, repeatedly implicated in severe
      fluoropyrimidine toxicity and highlighted in the deep-research artifact as
      a high-effect diarrhea risk allele.
  - name: DPYD*13
    description: >-
      Reduced-function variant c.1679T>G, repeatedly implicated in severe
      fluoropyrimidine toxicity.
  - name: DPYD c.2846A>T
    description: >-
      Missense variant p.D949V, associated with increased fluoropyrimidine
      toxicity risk.
  - name: DPYD HapB3
    description: >-
      Reduced-function haplotype, included among the key clinically actionable
      DPYD variants in pharmacogenomics reviews.
  evidence:
  - reference: DOI:10.3390/ph18050727
    reference_title: "DPYD Genotyping, Fluoropyrimidine Dosage and Toxicity: An Umbrella Review of Systematic Reviews"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Germline variants in the DPYD gene, which encodes the enzyme
      dihydropyrimidine dehydrogenase (DPD), are known to impair drug metabolism
      and increase the risk of severe toxicity.
    explanation: >-
      The umbrella review establishes germline DPYD variation as a
      pharmacogenomic risk factor for severe fluoropyrimidine toxicity.
  - reference: DOI:10.3389/fphar.2025.1645188
    reference_title: "DPYD-guided fluoropyrimidine dose adjustment in colorectal cancer DPYD carriers: start slower to finish stronger"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the DA cohort, 12% of patients experienced severe
      fluoropyrimidines-related adverse events, compared to 50% in the NDA
      cohort
    explanation: >-
      Human implementation data support DPYD-guided dosing as clinically
      actionable for reducing severe fluoropyrimidine toxicity.
- name: UGT1A1 pharmacogenomic susceptibility
  gene_term:
    preferred_term: UGT1A1
    term:
      id: hgnc:12530
      label: UGT1A1
  association: Reduced-function UGT1A1 variants increase irinotecan gastrointestinal toxicity risk
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    Reduced UGT1A1 activity limits SN-38 glucuronidation after irinotecan
    exposure. The deep-research artifact identifies UGT1A1, especially high-risk
    genotypes such as UGT1A1*28, as a clinically actionable risk factor for
    irinotecan-associated CID.
  variants:
  - name: UGT1A1*28
    description: >-
      Promoter repeat allele associated with lower SN-38 glucuronidation and
      increased irinotecan gastrointestinal toxicity susceptibility.
  - name: UGT1A1*6
    description: >-
      Reduced-function allele included in pharmacogenomic irinotecan dosing
      guidance, especially in Asian ancestry populations.
  evidence:
  - reference: PMID:11990381
    reference_title: "UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      screening for UGT1A1*28 polymorphism may identify patients with lower
      SN-38 glucuronidation rates and greater susceptibility to irinotecan
      induced gastrointestinal and bone marrow toxicity.
    explanation: >-
      Human pharmacokinetic evidence directly links UGT1A1*28 to lower SN-38
      glucuronidation and increased irinotecan gastrointestinal toxicity risk.
  - reference: PMID:36443464
    reference_title: "Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and
      *37) can be used to optimize an individual's starting dose thereby
      preventing carriers from toxicity.
    explanation: >-
      Pharmacogenomics guidance supports UGT1A1 variants as actionable
      irinotecan toxicity risk factors.
treatments:
- name: Loperamide
  description: >-
    First-line symptomatic antidiarrheal pharmacotherapy used in routine
    management of chemotherapy-induced diarrhea.
  treatment_term:
    preferred_term: gastrointestinal agent therapy
    term:
      id: MAXO:0000267
      label: gastrointestinal agent therapy
  evidence:
  - reference: PMID:25186048
    reference_title: "Guidance on the management of diarrhoea during cancer chemotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adequate--and, if necessary, repeated--assessment, appropriate use of
      loperamide, and knowledge of fluid resuscitation requirements of affected
      patients is the second crucial step.
    explanation: >-
      The guideline review identifies loperamide as a standard component of CID
      management.
- name: Fluid resuscitation and supportive care
  description: >-
    Supportive management focusing on hydration and clinical reassessment,
    especially for patients with significant volume loss or ongoing symptoms.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:25186048
    reference_title: "Guidance on the management of diarrhoea during cancer chemotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adequate--and, if necessary, repeated--assessment, appropriate use of
      loperamide, and knowledge of fluid resuscitation requirements of affected
      patients is the second crucial step.
    explanation: >-
      Supports hydration-focused supportive care as a core management step.
- name: Octreotide
  description: >-
    Escalation pharmacotherapy for patients who do not respond adequately to
    initial antidiarrheal treatment.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:25186048
    reference_title: "Guidance on the management of diarrhoea during cancer chemotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Use of octreotide and seeking specialist advice early for patients who do
      not respond to treatment will reduce morbidity and mortality.
    explanation: >-
      The guideline review supports octreotide as escalation management for
      refractory chemotherapy-induced diarrhea.
experimental_models:
- name: Primary human small-intestinal monolayer permeability model
  description: >-
    Polarized primary human small-intestinal epithelial monolayers grown on a
    permeable scaffold to measure epithelial injury, barrier permeability, and
    luminal-to-basolateral flux in a human intestinal system.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - epithelial injury
  - intestinal barrier dysfunction
  - paracellular permeability
  cell_source: Primary human small-intestinal epithelial cells
  culture_system: Polarized two-dimensional monolayer on a permeable support
  publication: PMID:29094594
  modeled_mechanisms:
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: Provides a human epithelial-injury readout in a primary small-intestinal monolayer.
  - target: Paracellular barrier leak and mucosal break formation
    description: Measures permeability and luminal-to-basolateral flux relevant to barrier-leak mechanisms.
  findings:
  - statement: >-
      Primary human small-intestinal monolayers enable direct epithelial-injury
      and barrier-permeability readouts in a human intestinal in vitro model
    evidence:
    - reference: PMID:29094594
      reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        Here, we use a unique in vitro human primary small intestinal cell
        monolayer system to pinpoint the intestinal consequences of NSAID
        treatment.
      explanation: >-
        Supports the experimental platform in primary human small-intestinal
        epithelium, although the initiating insult is NSAID exposure rather
        than chemotherapy.
    - reference: PMID:29094594
      reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        We also find that DCF induces intestinal barrier permeability,
        facilitating the translocation of compounds from the luminal to the
        basolateral side of the intestinal epithelium.
      explanation: >-
        Shows that the system directly measures barrier permeability relevant to
        treatment-induced diarrhea mechanisms.
  evidence:
  - reference: PMID:29094594
    reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      The results we outline here establish the utility of this novel platform,
      representative of the human small intestinal epithelium, to understand
      NSAID toxicity, which can be applied to study multiple aspects of gut
      barrier function including defense against infectious pathogens and
      host-microbiota interactions.
    explanation: >-
      Shows that this primary human monolayer can quantify gut-barrier
      function, while remaining indirect with respect to chemotherapy-specific
      injury.
- name: Murine intestinal organoid 5-fluorouracil injury model
  description: >-
    Murine intestinal organoids exposed to 5-fluorouracil to quantify epithelial
    cytotoxicity and candidate protective interventions in chemotherapy-induced
    mucositis.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  tissue_term:
    preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - chemotherapy-induced mucositis
  - 5-fluorouracil epithelial cytotoxicity
  - organoid viability
  cell_source: Murine intestinal organoids
  culture_system: Three-dimensional intestinal organoid culture exposed to 5-fluorouracil
  publication: PMID:39226257
  modeled_mechanisms:
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: Measures direct epithelial cytotoxicity after 5-fluorouracil exposure.
  findings:
  - statement: 5-fluorouracil exposure reduces epithelial viability in intestinal organoids
    evidence:
    - reference: PMID:39226257
      reference_title: "Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Additionally, the effects of melatonin were investigated in vitro on
        5-FU treated murine intestinal organoids.
      explanation: >-
        Establishes the existence of an organoid-based 5-FU injury platform for
        chemotherapy-induced mucositis.
  evidence:
  - reference: PMID:39226257
    reference_title: "Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The results showed that melatonin prevented villus atrophy in the rat
      jejunal mucosa and upheld cell viability in murine intestinal organoids.
    explanation: >-
      Supports organoid viability as a tractable readout for chemotherapy
      epithelial injury and rescue.
- name: Human intestinal organoid 5-fluorouracil multi-omics toxicity model
  description: >-
    Three-dimensional human colon and small-intestinal organoids exposed to
    clinically relevant 5-fluorouracil concentrations to measure epithelial
    viability, apoptosis, morphology, transcriptomic responses, and metabolomic
    responses.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - 5-fluorouracil intestinal toxicity
  - apoptosis
  - transcriptomic response
  - metabolomic response
  cell_source: Human healthy colon and small-intestine biopsy-derived organoids
  culture_system: Three-dimensional human intestinal organoids exposed to 5-fluorouracil concentrations informed by PBPK simulation
  publication: PMID:34151400
  modeled_mechanisms:
  - target: Cytotoxic chemotherapy exposure and intestinal drug delivery
    description: >-
      Applies clinically relevant 5-fluorouracil exposure concentrations to
      human intestinal organoids.
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: >-
      Measures epithelial viability, apoptosis, and cell-cycle/apoptosis
      pathway responses after 5-fluorouracil exposure.
  findings:
  - statement: >-
      Human colon and small-intestinal organoids capture 5-fluorouracil
      toxicity mechanisms including cell-cycle, p53, mitochondrial ATP
      synthesis, and apoptosis responses.
    evidence:
    - reference: PMID:34151400
      reference_title: "New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this study, well-established 3D organoid models of human colon and
        small intestine (SI) were used to characterize 5-FU transcriptomic and
        metabolomic responses.
      explanation: >-
        Establishes the human intestinal organoid platform and the
        chemotherapy-specific exposure being modeled.
    - reference: PMID:34151400
      reference_title: "New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Based on analysis of the differentially expressed genes, the most
        prominent molecular pathways affected by 5-FU included cell cycle, p53
        signalling, mitochondrial ATP synthesis and apoptosis.
      explanation: >-
        Supports the crypt/progenitor injury and apoptosis mechanism captured
        by the organoid model.
  evidence:
  - reference: PMID:34151400
    reference_title: "New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results provide new insights into 5-FU toxicity mechanisms and
      underline the relevance of human organoid models in the safety assessment
      in drug development.
    explanation: >-
      Supports this human organoid system as a chemotherapy-specific non-animal
      model for intestinal toxicity mechanisms.
- name: Primary human intestinal stem-cell 2D diarrhea-prediction model
  description: >-
    Primary human intestinal stem cell-derived RepliGut Planar cultures in a
    two-dimensional Transwell format used for high-throughput drug-induced
    diarrhea risk prediction by measuring proliferation, cell abundance, and
    transepithelial electrical resistance.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - drug-induced diarrhea risk
  - epithelial proliferation
  - barrier formation
  cell_source: Primary intestinal stem/progenitor cells derived from human intestinal crypts
  culture_system: Two-dimensional Transwell RepliGut Planar platform
  publication: PMID:40086646
  modeled_mechanisms:
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: >-
      Measures proliferation and cell abundance in primary proliferative
      intestinal cells exposed to marketed drugs.
  - target: Paracellular barrier leak and mucosal break formation
    description: >-
      Uses transepithelial electrical resistance as a barrier-formation readout
      relevant to epithelial barrier disruption.
  findings:
  - statement: >-
      Primary human intestinal stem-cell derived monolayers can predict clinical
      diarrhea risk from marketed drugs using proliferation, cell abundance, and
      barrier readouts.
    evidence:
    - reference: PMID:40086646
      reference_title: "High-throughput assay for predicting diarrhea risk using a 2D human intestinal stem cell-derived model."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we describe the development of a diarrhea prediction assay
        utilizing RepliGut® Planar, a primary intestinal stem cell-derived
        platform.
      explanation: >-
        Establishes the specific primary human intestinal stem-cell platform
        used for diarrhea-risk prediction.
    - reference: PMID:40086646
      reference_title: "High-throughput assay for predicting diarrhea risk using a 2D human intestinal stem cell-derived model."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This model accurately predicted diarrhea potential, achieving an
        accuracy of 91 % for proliferation, 90 % for abundance, and 88 % for
        barrier formation.
      explanation: >-
        Supports the model as a human in vitro non-animal model for
        drug-induced diarrhea risk and the relevant epithelial readouts.
  evidence:
  - reference: PMID:40086646
    reference_title: "High-throughput assay for predicting diarrhea risk using a 2D human intestinal stem cell-derived model."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Chemotherapeutic agents, known to cause clinical diarrhea, frequently
      target mitotic cells.
    explanation: >-
      Links the proliferative crypt-derived assay rationale to chemotherapy
      agents that cause clinical diarrhea.
- name: Anaerobic human intestine-on-chip host-microbiome coculture
  description: >-
    Microfluidic human intestine-on-chip system that sustains complex aerobic
    and anaerobic human gut microbiota in direct contact with living intestinal
    epithelium and mucus under a physiologic oxygen gradient.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - host-microbiome interaction
  - microbial community diversity
  - intestinal barrier function
  cell_source: Human intestinal epithelial cells cocultured with complex human gut microbiota
  culture_system: Microfluidic intestine-on-chip with transluminal hypoxia gradient
  publication: PMID:31086325
  modeled_mechanisms:
  - target: Chemotherapy-associated gut microbial dysbiosis
    description: >-
      Provides a human host-microbiome coculture platform for modeling microbial
      community structure and dysbiosis-related perturbations.
  - target: Dysbiosis-associated inflammatory amplification
    description: >-
      Represents a tractable host-microbiome interface for testing how microbial
      communities modulate epithelial barrier and host-response readouts.
  - target: Paracellular barrier leak and mucosal break formation
    description: >-
      Measures epithelial barrier function under host-microbiome coculture
      conditions.
  findings:
  - statement: >-
      Anaerobic intestine-on-chip culture sustains complex human gut microbiota
      with epithelial barrier readouts.
    evidence:
    - reference: PMID:31086325
      reference_title: "A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show the extended coculture of living human intestinal
        epithelium with stable communities of aerobic and anaerobic human gut
        microbiota, using a microfluidic intestine-on-a-chip that permits the
        control and real-time assessment of physiologically relevant oxygen
        gradients.
      explanation: >-
        Supports the host-microbiome coculture platform, although it is a
        general microbiome non-animal model rather than a
        chemotherapy-specific model.
  evidence:
  - reference: PMID:31086325
    reference_title: "A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      The intestine-on-a-chip may serve as a discovery tool for the development
      of microbiome-related therapeutics, probiotics and nutraceuticals.
    explanation: >-
      Supports this chip as a general non-animal model for the
      microbiome-related process pattern now represented in the CID pathograph.
- name: Microbiota-product epithelial apoptosis IEC-6 and organoid model
  description: >-
    In vitro epithelial cell and intestinal organoid assays used with
    chemotherapy-induced diarrhea models to test microbiota-derived effects on
    epithelial integrity, mitochondrial function, organoid development, and
    apoptotic signaling.
  experimental_model_type: OTHER
  tissue_term:
    preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - microbiota-host interaction
  - intestinal epithelial apoptosis
  - chemotherapy-induced diarrhea
  cell_source: IEC-6 epithelial cells and intestinal organoids
  culture_system: Epithelial cell and intestinal organoid assays testing microbiota-derived Bacteroides fragilis components
  publication: PMID:40624638
  modeled_mechanisms:
  - target: Crypt stem/progenitor apoptosis and epithelial injury
    description: >-
      Assays epithelial apoptosis and organoid development after microbiota
      product exposure in a chemotherapy-induced diarrhea context.
  - target: Dysbiosis-associated inflammatory amplification
    description: >-
      Provides an in vitro microbiota-host interaction assay for testing how
      dysbiosis-linked microbial products alter epithelial injury responses.
  findings:
  - statement: >-
      IEC-6 and intestinal organoid experiments can test microbiota-host
      interactions affecting epithelial injury in chemotherapy-induced diarrhea.
    evidence:
    - reference: PMID:40624638
      reference_title: "Mitigation of chemotherapy-induced gut dysbiosis and diarrhea by supplementation with heat-killed Bacteroides fragilis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mechanistic studies were conducted in murine models, complemented by
        IEC-6 cells and intestinal organoid experiments to elucidate
        microbiota-host interactions.
      explanation: >-
        Establishes the in vitro epithelial and organoid systems used to probe
        microbiota-host interactions in chemotherapy-induced diarrhea.
    - reference: PMID:40624638
      reference_title: "Mitigation of chemotherapy-induced gut dysbiosis and diarrhea by supplementation with heat-killed Bacteroides fragilis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        hk-B. f preserved epithelial integrity, mitochondrial function, and
        intestinal organoid development (higher budding count and larger
        organoid surface area).
      explanation: >-
        Supports organoid development and epithelial integrity as assayable
        readouts for microbiota-mediated epithelial protection in CID models.
  evidence:
  - reference: PMID:40624638
    reference_title: "Mitigation of chemotherapy-induced gut dysbiosis and diarrhea by supplementation with heat-killed Bacteroides fragilis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Caspase-3 inhibition or BCL2 silencing abrogated hk-B. f's anti-apoptotic
      effects in IEC-6 cells.
    explanation: >-
      Supports the IEC-6 component as a tractable epithelial apoptosis model for
      microbiota-linked injury mechanisms.
animal_models:
- species: Mus musculus
  genotype: Wild-type C57BL/6
  description: >-
    Repeated 5-fluorouracil dosing in mice induces intestinal mucositis with
    villus shortening, crypt destruction, weight loss, and diarrhea, providing a
    disease-relevant in vivo model of chemotherapy-induced intestinal injury.
  evidence:
  - reference: PMID:23072534
    reference_title: "5-HT₃ receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Continuous administration of 5-FU to mice caused severe intestinal
      mucositis, which was histologically characterized by the shortening of
      villi and destruction of intestinal crypts, accompanied by body weight
      loss and diarrhoea.
    explanation: >-
      This mouse model recapitulates core structural and functional features of
      chemotherapy-induced diarrhea.
- species: Mus musculus
  genotype: Tumor xenograft and genetically engineered breast-cancer models treated with irinotecan
  description: >-
    Irinotecan-treated mouse tumor models quantify microbiome-dependent
    intestinal toxicity, dysbiosis, and epithelial protection by bacterial
    beta-glucuronidase inhibition.
  evidence:
  - reference: PMID:32170007
    reference_title: "Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In a tumor xenograft model, GUS inhibition prevents intestinal toxicity
      and maintains the antitumor efficacy of irinotecan.
    explanation: >-
      Supports a microbiome-dependent irinotecan toxicity model in which
      intestinal injury can be mitigated without compromising antitumor
      efficacy.
- species: Mus musculus
  genotype: BALB/c and C57BL/6 wild-type mice treated with 5-fluorouracil or CPT-11
  description: >-
    5-FU- and CPT-11-induced mouse chemotherapy-induced diarrhea models used to
    test gut microbiota alterations and heat-killed Bacteroides fragilis
    supplementation effects on diarrhea severity, body weight, intestinal
    permeability, epithelial integrity, and apoptosis.
  evidence:
  - reference: PMID:40624638
    reference_title: "Mitigation of chemotherapy-induced gut dysbiosis and diarrhea by supplementation with heat-killed Bacteroides fragilis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we utilized 6-8-week-old male BALB/c and C57BL/6 mice in established
      5-FU- or CPT-11-induced CID models.
    explanation: >-
      Establishes the mouse 5-FU/CPT-11 chemotherapy-induced diarrhea models
      used to study microbiome-mediated mechanisms.
  - reference: PMID:40624638
    reference_title: "Mitigation of chemotherapy-induced gut dysbiosis and diarrhea by supplementation with heat-killed Bacteroides fragilis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      in 5-FU/CPT-11-induced CID murine models, oral gavage of heat-killed B. f
      (hk-B. f) outperformed live bacteria in diarrhea alleviation.
    explanation: >-
      Supports a microbiome-intervention animal model for chemotherapy-induced
      diarrhea severity.
references:
- reference: DOI:10.1007/s10735-025-10367-w
  title: 'Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation'
  found_in:
  - Chemotherapy_Induced_Diarrhea-deep-research-falcon.md
  findings:
  - statement: Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy.
    supporting_text: Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy.
    evidence:
    - reference: DOI:10.1007/s10735-025-10367-w
      reference_title: 'Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy.
      explanation: Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
- reference: DOI:10.1136/gutjnl-2024-333812
  title: British Society of Gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer
  found_in:
  - Chemotherapy_Induced_Diarrhea-deep-research-falcon.md
  findings:
  - statement: Survival rates after a diagnosis of cancer are improving.
    supporting_text: Survival rates after a diagnosis of cancer are improving.
    evidence:
    - reference: DOI:10.1136/gutjnl-2024-333812
      reference_title: British Society of Gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Survival rates after a diagnosis of cancer are improving.
      explanation: Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
- reference: DOI:10.13005/bbra/3233
  title: 'Managing Chemotherapy-Induced Diarrhea: Efficacy of Interventions for Cancer Patients'
  found_in:
  - Chemotherapy_Induced_Diarrhea-deep-research-falcon.md
  findings:
  - statement: Non-communicable diseases (NCDs) account for 71% of all deaths worldwide, with cancer being one of the leading causes of mortality in India (9%), where NCDs account for 63% of all fatalities.
    supporting_text: Non-communicable diseases (NCDs) account for 71% of all deaths worldwide, with cancer being one of the leading causes of mortality in India (9%), where NCDs account for 63% of all fatalities.
    evidence:
    - reference: DOI:10.13005/bbra/3233
      reference_title: 'Managing Chemotherapy-Induced Diarrhea: Efficacy of Interventions for Cancer Patients'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Non-communicable diseases (NCDs) account for 71% of all deaths worldwide, with cancer being one of the leading causes of mortality in India (9%), where NCDs account for 63% of all fatalities.
      explanation: Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
- reference: DOI:10.3389/fphar.2025.1645188
  title: 'DPYD-guided fluoropyrimidine dose adjustment in colorectal cancer DPYD carriers: start slower to finish stronger'
  found_in:
  - Chemotherapy_Induced_Diarrhea-deep-research-falcon.md
  findings:
  - statement: Fluoropyrimidines (FP) are the mainstay of colorectal cancer (CRC) treatment, but can cause severe toxicity in up to 40% of patients.
    supporting_text: Fluoropyrimidines (FP) are the mainstay of colorectal cancer (CRC) treatment, but can cause severe toxicity in up to 40% of patients.
    evidence:
    - reference: DOI:10.3389/fphar.2025.1645188
      reference_title: 'DPYD-guided fluoropyrimidine dose adjustment in colorectal cancer DPYD carriers: start slower to finish stronger'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fluoropyrimidines (FP) are the mainstay of colorectal cancer (CRC) treatment, but can cause severe toxicity in up to 40% of patients.
      explanation: Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
- reference: DOI:10.3390/ph17081020
  title: Is There an Interplay between Environmental Factors, Microbiota Imbalance, and Cancer Chemotherapy-Associated Intestinal Mucositis?
  found_in:
  - Chemotherapy_Induced_Diarrhea-deep-research-falcon.md
  findings:
  - statement: Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes.
    supporting_text: Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes.
    evidence:
    - reference: DOI:10.3390/ph17081020
      reference_title: Is There an Interplay between Environmental Factors, Microbiota Imbalance, and Cancer Chemotherapy-Associated Intestinal Mucositis?
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes.
      explanation: Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
- reference: DOI:10.3390/ph18050727
  title: 'DPYD Genotyping, Fluoropyrimidine Dosage and Toxicity: An Umbrella Review of Systematic Reviews'
  found_in:
  - Chemotherapy_Induced_Diarrhea-deep-research-falcon.md
  findings:
  - statement: Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors.
    supporting_text: Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors.
    evidence:
    - reference: DOI:10.3390/ph18050727
      reference_title: 'DPYD Genotyping, Fluoropyrimidine Dosage and Toxicity: An Umbrella Review of Systematic Reviews'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors.
      explanation: Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
📚

References & Deep Research

References

6
DOI:10.1007/s10735-025-10367-w
Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation
1 finding
Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy.
"Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy."
Show evidence (1 reference)
DOI:10.1007/s10735-025-10367-w SUPPORT Other
"Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy."
Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
DOI:10.1136/gutjnl-2024-333812
British Society of Gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer
1 finding
Survival rates after a diagnosis of cancer are improving.
"Survival rates after a diagnosis of cancer are improving."
Show evidence (1 reference)
DOI:10.1136/gutjnl-2024-333812 SUPPORT Human Clinical
"Survival rates after a diagnosis of cancer are improving."
Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
DOI:10.13005/bbra/3233
Managing Chemotherapy-Induced Diarrhea: Efficacy of Interventions for Cancer Patients
1 finding
Non-communicable diseases (NCDs) account for 71% of all deaths worldwide, with cancer being one of the leading causes of mortality in India (9%), where NCDs account for 63% of all fatalities.
"Non-communicable diseases (NCDs) account for 71% of all deaths worldwide, with cancer being one of the leading causes of mortality in India (9%), where NCDs account for 63% of all fatalities."
Show evidence (1 reference)
DOI:10.13005/bbra/3233 SUPPORT Human Clinical
"Non-communicable diseases (NCDs) account for 71% of all deaths worldwide, with cancer being one of the leading causes of mortality in India (9%), where NCDs account for 63% of all fatalities."
Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
DOI:10.3389/fphar.2025.1645188
DPYD-guided fluoropyrimidine dose adjustment in colorectal cancer DPYD carriers: start slower to finish stronger
1 finding
Fluoropyrimidines (FP) are the mainstay of colorectal cancer (CRC) treatment, but can cause severe toxicity in up to 40% of patients.
"Fluoropyrimidines (FP) are the mainstay of colorectal cancer (CRC) treatment, but can cause severe toxicity in up to 40% of patients."
Show evidence (1 reference)
DOI:10.3389/fphar.2025.1645188 SUPPORT Human Clinical
"Fluoropyrimidines (FP) are the mainstay of colorectal cancer (CRC) treatment, but can cause severe toxicity in up to 40% of patients."
Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
DOI:10.3390/ph17081020
Is There an Interplay between Environmental Factors, Microbiota Imbalance, and Cancer Chemotherapy-Associated Intestinal Mucositis?
1 finding
Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes.
"Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes."
Show evidence (1 reference)
DOI:10.3390/ph17081020 SUPPORT Human Clinical
"Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes."
Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.
DOI:10.3390/ph18050727
DPYD Genotyping, Fluoropyrimidine Dosage and Toxicity: An Umbrella Review of Systematic Reviews
1 finding
Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors.
"Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors."
Show evidence (1 reference)
DOI:10.3390/ph18050727 SUPPORT Human Clinical
"Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors."
Deep research cited this publication as relevant literature for Chemotherapy Induced Diarrhea.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 35 citations 2026-05-08T11:46:40.473919

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Chemotherapy-Induced Diarrhea
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on Chemotherapy-Induced Diarrhea covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Chemotherapy-Induced Diarrhea (CID): Comprehensive Disease Characteristics Report (2023–2025 prioritized)

Target disease

  • Disease name: Chemotherapy-Induced Diarrhea (CID)
  • Category: Complex (treatment-related toxicity syndrome)
  • MONDO ID / MeSH / ICD-10/ICD-11: Not recovered from the retrieved full-text sources in this tool run (should be added from MONDO/MeSH/ICD lookups in a follow-on curation step).

1. Disease information

Overview / definition

Chemotherapy-induced diarrhea (CID) is diarrhea occurring during or after systemic cytotoxic therapy and is a major manifestation of chemotherapy-induced gastrointestinal toxicity (often framed as intestinal mucositis), which can impair quality of life, threaten patient safety (e.g., dehydration/electrolyte derangements), and force chemotherapy dose modifications or discontinuation. (chen2025restoreintestinalsteadystate pages 1-3, jiang2025importantroleof pages 1-2)

CID is commonly evaluated using NCI CTCAE v5.0 severity grading (grade 1 mild → grade 5 fatal). (jiang2025importantroleof pages 1-2)

Synonyms / alternative names

  • Chemotherapy-associated diarrhea (chen2025restoreintestinalsteadystate pages 6-7)
  • Cancer-therapy–related diarrhea / cancer-related diarrhea (broader umbrella including targeted therapy, immunotherapy, other causes) (aleem2024theimpactof pages 1-3)
  • Chemotherapy-induced gastrointestinal toxicity (CIGT) with diarrhea phenotype (chen2025restoreintestinalsteadystate pages 6-7, cheatham2025butyratepreventschemotherapyinduced pages 24-28)

Evidence source type

Evidence here is aggregated from clinical trials, observational claims data, clinical practice guidance, and preclinical animal/in vitro studies (see citations per section).

2. Etiology

Primary causal factors (mechanistic)

CID is primarily caused by treatment-related injury to intestinal epithelium and barrier function (mucositis), coupled with changes in secretion/absorption and motility; clinically it can be conceptualized as secretory vs osmotic diarrhea. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4)

Key high-risk cytotoxic agents highlighted across recent reviews/guidance include: - Irinotecan (topoisomerase I inhibitor) and fluoropyrimidines (5-FU, capecitabine), repeatedly emphasized as high-risk drugs for CID. (andreyev2025britishsocietyof pages 15-15, venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 1-3) - Docetaxel is also associated with diarrhea at meaningful rates. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4)

Drug-specific mechanisms

Irinotecan (CPT-11): a central mechanism for delayed-onset diarrhea is biotransformation to active SN-38, hepatic glucuronidation to SN-38G, and reconversion of SN-38G to toxic SN-38 in the intestine by microbial enzymes (β-glucuronidase in multiple sources), leading to mucosal damage. (deng2024efficacyandsafety pages 1-2, cheatham2025butyratepreventschemotherapyinduced pages 24-28)

Fluoropyrimidines (5-FU/capecitabine): associated with small-bowel mucosal breakdown/crypt apoptosis driven by inflammatory cytokines and oxidative stress pathways; more severe mucosal breakdown is reported with IV vs oral administration in one recent review. (chen2025restoreintestinalsteadystate pages 6-7)

Risk factors

Host/clinical risk factors (irinotecan delayed diarrhea): weekly dosing schedule, poor performance status, elevated creatinine, prior abdominal/pelvic irradiation, leukopenia, age >70 years, and Gilbert syndrome/Crigler–Najjar type 1 were summarized as predictors. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4)

Pharmacogenomics (PGx) – irinotecan: reduced-function UGT1A1 genotypes (e.g., *28 in reviews) are associated with reduced SN-38 detoxification and higher toxicity risk. (chen2025restoreintestinalsteadystate pages 6-7)

Pharmacogenomics (PGx) – fluoropyrimidines: inherited DPYD variants reduce DPD activity, increasing severe fluoropyrimidine toxicity including diarrhea. In an umbrella review synthesizing 8 systematic reviews (125 primary studies), key variants repeatedly implicated were DPYD2A (c.1905+1G>A), DPYD13 (c.1679T>G), c.2846A>T (p.D949V), and HapB3 (c.1236G>A). (oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2)

Diarrhea-specific associations from the umbrella review include: - DPYD2A carrier diarrhea 12.0%–100% vs 1.4%–27.5% in wild-type; infusional 5-FU diarrhea OR 7.7 (95% CI 1.6–36.9). (oterotorres2025dpydgenotypingfluoropyrimidine pages 9-10) - DPYD13 carrier diarrhea 50%–100% vs 5.8%–22% in wild-type. (oterotorres2025dpydgenotypingfluoropyrimidine pages 9-10) - c.2846A>T pooled OR for diarrhea 6.0 (95% CI 1.8–20.7). (oterotorres2025dpydgenotypingfluoropyrimidine pages 9-10)

Protective factors / mitigating factors

Evidence in this retrieved set is strongest for candidate protective interventions rather than established protective factors: - Microbiome/SCFA (butyrate): in a mouse model, butyrate supplementation prevented irinotecan-associated microbial dysbiosis and reduced features of GI toxicity, supporting a protective mechanism via barrier preservation and suppression of β-glucuronidase activity. (cheatham2025butyratepreventschemotherapyinduced pages 1-6) - Genotype-guided dosing: DPYD-guided fluoropyrimidine dose reduction and titration reduces severe toxicity overall and is positioned as a patient-safety strategy; one synthesis reported reduced diarrhea with pharmacogenetics-guided dosing (RR 0.4, 95% CI 0.2–0.6). (oterotorres2025dpydgenotypingfluoropyrimidine pages 10-12, oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2)

Gene–environment (microbiome) interactions

CID risk and severity are modulated by chemotherapy-induced dysbiosis and host–microbe metabolism of xenobiotics. A 2025 review emphasizes that chemotherapy can decrease beneficial taxa (e.g., Bifidobacterium/Lactobacillus) and increase Proteobacteria/gram-negative organisms, promoting inflammation and barrier dysfunction; standard antidiarrheals address motility rather than these upstream drivers. (jiang2025importantroleof pages 1-2)

3. Phenotypes

Core phenotypes and clinical characteristics

  • Diarrhea (severity graded by CTCAE; can be acute or delayed; can persist for years in some survivors). (jiang2025importantroleof pages 1-2, chen2025restoreintestinalsteadystate pages 1-3)
  • Acute cholinergic irinotecan syndrome: acute diarrhea with cramps and autonomic symptoms (rhinitis, lacrimation, salivation) lasting ~30 minutes and responsive to atropine. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4)
  • Delayed-onset irinotecan diarrhea: onset >24 hours after irinotecan. (deng2024efficacyandsafety pages 1-2)

Complications (downstream phenotypes)

Complications emphasized include dehydration, electrolyte disorders, malnutrition, and acute kidney injury/renal dysfunction (not all with quantified rates in retrieved excerpts). (chen2025restoreintestinalsteadystate pages 1-3, aleem2024theimpactof pages 1-3)

Frequency / burden (selected)

  • For irinotecan: 50–80% all-grade diarrhea; 11–32% grade ≥3. (deng2024efficacyandsafety pages 1-2)
  • Docetaxel: 20–40% diarrhea; severe ~5–6%. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4)

Suggested HPO terms (for knowledge base annotation; ontology suggestions)

  • Diarrhea: HP:0002014
  • Abdominal pain: HP:0002027
  • Dehydration: HP:0001944
  • Hypokalemia/electrolyte imbalance (as applicable): HP:0002900
  • Weight loss/malnutrition: HP:0001824 / HP:0004395
  • Acute kidney injury (complication): HP:0001919

(These are standard HPO suggestions; not directly asserted in the retrieved texts beyond phenotype descriptions.)

4. Genetic / molecular information

Causal genes

CID is not a Mendelian disease; however, clinically actionable host PGx genes influence susceptibility: - UGT1A1 (irinotecan SN-38 glucuronidation; reduced function increases risk). (chen2025restoreintestinalsteadystate pages 6-7) - DPYD (fluoropyrimidine catabolism; reduced function increases severe toxicity including diarrhea). (oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2)

Pathogenic / risk variants (PGx)

DPYD key variants summarized as consistently associated with severe fluoropyrimidine toxicity: DPYD2A, DPYD13, c.2846A>T, HapB3. (oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2)

Variant frequencies (Caucasian populations) summarized in the umbrella review: DPYD2A ~1%, DPYD13 0.07–0.1%, c.2846A>T 1.1%, HapB3 2.6–6.3%. (oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2)

Evidence for genotype-guided dosing

In colorectal cancer, DPYD-guided dosing (vs non-guided) was associated with lower severe FP-related adverse events (12% vs 50%) and lower discontinuation due to severe toxicity (6% vs 50%). (rosasalonso2025dpydguidedfluoropyrimidinedose pages 1-2)

Expert/regulatory position (implementation): an ASCO Educational Book article describes regulatory/guideline alignment for pretreatment DPYD genotyping (FDA boxed warnings; NCCN/ASCO alignment) to prevent severe toxicity and mortality. (kratz2026importanceofand pages 1-2)

Suggested GO / CL terms (mechanism annotation; suggestions)

  • GO: epithelial cell apoptotic process; inflammatory response; regulation of intestinal epithelial barrier; response to oxidative stress.
  • CL: intestinal epithelial cell; goblet cell; Paneth cell; enteric neuron (myenteric neuron).

5. Environmental information

CID is strongly influenced by exposures related to treatment course, including concurrent antibiotics, diet, and microbiome-altering factors that can shift microbial metabolism and barrier function; recent opinion/review work emphasizes that diet/lifestyle/xenobiotics and antibiotics can influence microbiota composition, which in turn modulates chemotherapy GI toxicity. (fernandes2024istherean pages 7-8)

6. Mechanism / pathophysiology

Causal chain (illustrative, irinotecan)

1) Irinotecan administration → 2) hepatic conversion to SN-38 → 3) glucuronidation to SN-38G → 4) biliary/intestinal exposure and microbial deconjugation → 5) renewed SN-38 exposure to mucosa → 6) epithelial apoptosis, barrier disruption, inflammation and altered motility/secretion → 7) delayed diarrhea (>24 h). (deng2024efficacyandsafety pages 1-2, cheatham2025butyratepreventschemotherapyinduced pages 24-28)

Microbiome and barrier mechanisms

A 2025 review identifies dysbiosis and compromised intestinal barrier integrity as key factors contributing to CID due to mucositis and highlights that microbiota-driven immune activation contributes to mucosal inflammation. (jiang2025importantroleof pages 1-2)

Enteric nervous system involvement (preclinical)

In a murine irinotecan model, irinotecan increased GI motility and altered enteric neuronal excitability, consistent with a neuro-epithelial contribution to diarrhea. (cheatham2025butyratepreventschemotherapyinduced pages 1-6)

Molecular profiling / biomarkers (emerging)

  • Fecal β-glucuronidase activity is repeatedly implicated as a mechanistic driver and candidate predictive biomarker in irinotecan models/reviews. (cheatham2025butyratepreventschemotherapyinduced pages 1-6, fernandes2024istherean pages 7-8)

Suggested UBERON / GO cellular component terms (suggestions)

  • UBERON: small intestine; colon; intestinal mucosa
  • GO CC: apical plasma membrane; tight junction; mitochondrion (oxidative stress)

7. Anatomical structures affected

  • Primary organs: small intestine and colon (intestinal mucosa/crypt–villus axis; barrier). (chen2025restoreintestinalsteadystate pages 6-7, venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4)
  • Cell/tissue targets: intestinal epithelial cells/crypt compartment and barrier structures; enteric neurons implicated in motility changes in preclinical models. (cheatham2025butyratepreventschemotherapyinduced pages 1-6)

8. Temporal development

  • Onset patterns: CID may occur during or after chemotherapy (acute vs delayed). (jiang2025importantroleof pages 1-2)
  • Irinotecan: acute cholinergic diarrhea (minutes, responsive to atropine) vs delayed diarrhea (>24 h). (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4, deng2024efficacyandsafety pages 1-2)
  • Long-term: some patients report CID symptoms persisting up to 10 years post-treatment (survivorship burden). (chen2025restoreintestinalsteadystate pages 1-3)

9. Inheritance and population

CID itself is not inherited, but susceptibility is influenced by inherited PGx variants.

Epidemiology / burden (selected data)

CID incidence is regimen-dependent. Reported summary estimates include: - 50–80% incidence with irinotecan or fluorouracil in reviews; a “significant portion” may be severe (grade 3–4). (jiang2025importantroleof pages 1-2) - Severe CID leads to treatment dose reductions/delays/cessation in ~60% and contributes to ~1% mortality in one 2025 review summary. (jiang2025importantroleof pages 1-2) - In one 2025 review, grade 3–4 CID incidence was summarized as ~40%, and ~60% of patients modify therapy (22% dose reduction, 28% delay, 15% discontinuation). (chen2025restoreintestinalsteadystate pages 1-3)

Real-world implementation impact (claims)

A large matched claims analysis of cancer-related diarrhea found markedly higher treatment discontinuation in those with diarrhea (chemotherapy subgroup: 81.5% vs 62.3%) and higher hazard of discontinuation (HR 1.40). (aleem2024theimpactof pages 1-3)

10. Diagnostics

Clinical evaluation and workup (BSG practice guidance, 2025)

The British Society of Gastroenterology (BSG) guidance emphasizes early investigation of troublesome diarrhea during cancer therapy when empirical measures fail, because symptom clusters are poor at distinguishing underlying causes. (andreyev2025britishsocietyof pages 8-8)

Key diagnostic elements and differentials explicitly highlighted include: - Stool microbiology testing in acute diarrhea; it is generally safe to start loperamide while awaiting results, with cautions in neutropenia/C. difficile. (andreyev2025britishsocietyof pages 13-13) - Blood tests referenced within algorithms include FBC, LFTs, U&E, and stool MC&S; endoscopy/OGD may be needed. (andreyev2025britishsocietyof pages 15-15) - Consider non-infectious contributors common in cancer populations: lactose intolerance, SIBO, bile acid diarrhea (BAD), pancreatic exocrine insufficiency (PEI); BAD and PEI are explicitly identified as common causes of GI symptoms in some drug contexts. (andreyev2025britishsocietyof pages 14-15, andreyev2025britishsocietyof pages 15-15) - PEI testing and empiric therapy: fecal elastase-1 is cited, with “faecal elastase level <500 µg/g” suggesting PEI; empiric pancreatic enzyme replacement therapy (PERT) is endorsed in some contexts. (andreyev2025britishsocietyof pages 11-11) - For severe fluoropyrimidine toxicity, urgent imaging (CT) to exclude enterocolitis is advised. (andreyev2025britishsocietyof pages 13-13) - The guidance highlights DPD deficiency consideration after severe capecitabine/5-FU toxicity. (andreyev2025britishsocietyof pages 14-15)

Visual clinical algorithms from the BSG guidance (cropped figures/tables retrieved): Table/pathway and acute-severe diarrhea algorithm (andreyev2025britishsocietyof media 677c2d7d, andreyev2025britishsocietyof media 763cd06e, andreyev2025britishsocietyof media adbbc39b, andreyev2025britishsocietyof media f43c1d78).

Suggested lab concepts (LOINC-like; suggestions)

  • CBC (FBC), CMP (electrolytes/U&E, LFTs), CRP, stool culture/ova/parasite as indicated.
  • Fecal elastase-1 (PEI evaluation).

11. Outcome / prognosis

CID can cause direct morbidity (dehydration, electrolyte disturbances, malnutrition, AKI) and indirect oncologic harm via dose reduction/delay/discontinuation and reduced adherence/persistence. (chen2025restoreintestinalsteadystate pages 1-3, aleem2024theimpactof pages 1-3)

Mortality attributable to severe CID is summarized around ~1% in a 2025 review. (jiang2025importantroleof pages 1-2)

12. Treatment

Guideline-based acute management (severity-based)

BSG practice guidance (Gut, 2025) indicates that mild diarrhea may be managed initially without tests, whereas severe diarrhea (e.g., >6 stools/day over baseline or severe abdominal pain) typically requires hospital admission, IV corticosteroids, and urgent investigation (with escalation to biologics for immune-related enterocolitis when applicable). (andreyev2025britishsocietyof pages 14-15)

Antidiarrheal pharmacotherapy (stepwise)

  • Loperamide: commonly used; BSG notes it can be started while awaiting stool microbiology results, with caution for toxic dilatation risk in neutropenic patients and in C. difficile. (andreyev2025britishsocietyof pages 13-13)
  • Octreotide (second-line for refractory CID): dosing summarized in a 2024 review: start 100–150 µg SC/IV three times daily; can escalate to 500 µg three times daily or continuous infusion (25–50 µg/h). (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 6-9)
  • Atropine for acute cholinergic irinotecan diarrhea (IV/SC dosing range summarized in 2024 review). (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 6-9)

Supportive care

For grade 3–4 irinotecan diarrhea, consensus guidance summarized in a 2024 RCT report indicates escalation to octreotide, antibiotics, and fluid/electrolyte replenishment (often inpatient). (deng2024efficacyandsafety pages 1-2)

Antibiotics (when infectious diarrhea suspected)

A 2024 review summarizes guideline-consistent use of fluoroquinolones when infection is suspected, and standard agents for C. difficile (metronidazole or vancomycin). (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 6-9)

Mechanism-targeted and emerging interventions

  • Microbiome/SCFA (butyrate): preclinical evidence supports butyrate as a protective adjunct that suppresses β-glucuronidase activity and preserves barrier and stem-cell compartments in irinotecan models. (cheatham2025butyratepreventschemotherapyinduced pages 24-28)
  • β-glucuronidase inhibition / microbiome targeting: mechanistic studies support inhibition of microbial β-glucuronidase and suppression of E. coli as strategies to reduce irinotecan diarrhea; one 2024 mechanistic paper describes dual targeting of E. coli and bacterial β-glucuronidase by HQD components (baicalein/baicalin/paeoniflorin). (teng2024threebioactivecompounds pages 1-2)

Real-world implementation: DPYD testing

BSG guidance highlights DPD deficiency (~3–5% population) and suggests dose reduction for heterozygous DPYD variants (50% starting dose for first cycle with escalation if tolerated); homozygous variants prompt reconsideration of using capecitabine/5-FU. (andreyev2025britishsocietyof pages 14-15)

An observational colorectal cancer study reported DPYD-guided dosing associated with fewer severe adverse events (12% vs 50%) and fewer discontinuations (6% vs 50%). (rosasalonso2025dpydguidedfluoropyrimidinedose pages 1-2)

Suggested MAXO terms (treatment action ontology; suggestions)

  • Antidiarrheal therapy; fluid resuscitation; electrolyte replacement; antimicrobial therapy; dose reduction; hospitalization; diagnostic imaging; stool testing; corticosteroid therapy.

13. Prevention

Primary/secondary/tertiary prevention strategies

  • PGx-guided prevention (fluoropyrimidines): DPYD genotyping before therapy and genotype-guided starting dose reduction is recommended in multiple sources (BSG guidance; umbrella review framework). (andreyev2025britishsocietyof pages 14-15, oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2)
  • PGx-guided prevention (irinotecan): a review describes genotype-guided irinotecan dosing (e.g., ~30% dose reduction in UGT1A1 poor metabolizers) as reducing febrile neutropenia and helping alleviate CID. (chen2025restoreintestinalsteadystate pages 6-7)
  • Microbiome-targeted prevention (experimental): butyrate supplementation and β-glucuronidase inhibition are supported in animal models; these are not yet established standard-of-care preventatives for CID. (cheatham2025butyratepreventschemotherapyinduced pages 1-6, cheatham2025butyratepreventschemotherapyinduced pages 24-28)

Direct trial prevention example (irinotecan, 2024): A multicenter RCT of Shengjiang Xiexin decoction prophylaxis reported lower diarrhea incidence vs placebo (26.42% vs 52.08%), with pronounced benefit in UGT1A1 high-risk patients (9.09% vs 66.67%). Abstract quote: “The incidence of diarrhea in SXD group and placebo group were 26.42% (14/53) and 52.08% (25/48), respectively (P < 0.05)… In UGT1A1 high-risk population, the incidence of diarrhea in two groups were 9.09% and 66.67% (P < 0.05)”. (deng2024efficacyandsafety pages 1-2)

14. Other species / natural disease

Not applicable as a naturally occurring disease entity; however, CID is modeled extensively in animals (see next section).

15. Model organisms

Common models and what they recapitulate

  • Mouse irinotecan-induced GI toxicity models: reproduce diarrhea phenotype (increased fecal water content, altered motility), mucosal injury, dysbiosis, and mechanistic links to β-glucuronidase and barrier disruption; used for testing interventions such as butyrate. (cheatham2025butyratepreventschemotherapyinduced pages 1-6, cheatham2025butyratepreventschemotherapyinduced pages 24-28)
  • Germ-free / gnotobiotic systems: used to causally implicate microbiota composition and β-glucuronidase-producing organisms in mucositis/diarrhea severity. (fernandes2024istherean pages 7-8)
  • In vitro intestinal epithelial cell systems for fluoropyrimidine injury and ROS/cytokine pathways. (chen2025restoreintestinalsteadystate pages 6-7)

Recent developments (2023–2025 emphasis) and expert analysis

1) Shift toward mechanism-informed supportive care: Recent reviews emphasize that symptom-only control (loperamide, atropine, octreotide) does not address dysbiosis/barrier injury, motivating microbiome-directed adjuncts (e.g., SCFA/butyrate; β-glucuronidase targeting). (jiang2025importantroleof pages 1-2, cheatham2025butyratepreventschemotherapyinduced pages 24-28)

2) Operationalization of PGx safety programs: The 2025 umbrella review consolidates evidence that DPYD variants are reproducibly associated with severe fluoropyrimidine toxicity and outlines activity-score guided dosing (e.g., intermediate metabolizers start ~50–75% dose; poor metabolizers typically avoid fluoropyrimidines). (oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2)

3) Real-world evidence of therapy disruption: Claims analyses quantify the downstream effect of diarrhea on cancer therapy discontinuation and adherence, underscoring that CID management has survival/cost implications beyond symptom relief. (aleem2024theimpactof pages 1-3)

Key statistics summary table

Setting / agent All-grade incidence Grade ≥3 incidence Key quantitative risk factors / notes
Irinotecan 50–80% (deng2024efficacyandsafety pages 1-2) 11–32% (deng2024efficacyandsafety pages 1-2) Acute cholinergic diarrhea may occur early and respond to atropine; delayed diarrhea occurs >24 h and is linked to SN-38 reactivation by gut bacterial β-glucuronidase (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4, cheatham2025butyratepreventschemotherapyinduced pages 24-28). Risk factors include weekly dosing schedule, poor performance status, elevated creatinine, prior abdominal/pelvic irradiation, leukopenia, age >70 years, Gilbert syndrome/Crigler–Najjar type 1, and high-risk UGT1A1 genotype; UGT1A1*28/reduced UGT1A1 activity increases SN-38 exposure and toxicity risk (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4, chen2025restoreintestinalsteadystate pages 6-7).
Fluoropyrimidines (5-FU/capecitabine) Up to ~80% reported for 5-FU in some regimens; reviews also cite 50–80% for fluorouracil-associated CID (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 1-3, jiang2025importantroleof pages 1-2) Not well quantified in the provided excerpts for all regimens; overall CID grade 3–4 burden contributes substantially, and fluoropyrimidines are among the main high-risk agents (jiang2025importantroleof pages 1-2, chen2025restoreintestinalsteadystate pages 1-3) Major pharmacogenomic risk is reduced DPD activity due to DPYD variants. Key variants: DPYD2A, DPYD13, c.2846A>T, HapB3; heterozygous frequencies in Caucasians are ~1%, 0.07–0.1%, 1.1%, and 2.6–6.3%, respectively (oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2). Diarrhea-specific associations include DPYD2A carrier diarrhea 12.0–100% vs 1.4–27.5% in wild type; DPYD13 50–100% vs 5.8–22%; c.2846A>T pooled OR 6.0; HapB3 carrier diarrhea 14.3–50% vs 12.5–23.1% (oterotorres2025dpydgenotypingfluoropyrimidine pages 9-10, oterotorres2025dpydgenotypingfluoropyrimidine pages 7-9). Genotype-guided dosing reduced overall severe toxicity and reduced diarrhea RR 0.4 (95% CI 0.2–0.6) in one review synthesis (oterotorres2025dpydgenotypingfluoropyrimidine pages 10-12).
Docetaxel 20–40% (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4) ~5–6% severe diarrhea (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4) Recognized cytotoxic cause of CID; burden is lower than irinotecan in the provided evidence but still clinically meaningful, especially in combination regimens and vulnerable patients (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4, venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 1-3).
Overall CID burden Common across regimens; 50–80% reported for irinotecan/fluorouracil in reviews, and grade 3–4 CID is reported at about 40% in one review summary (jiang2025importantroleof pages 1-2, chen2025restoreintestinalsteadystate pages 1-3) About 40% grade 3–4 in one aggregate review; regimen-specific severe-event rates vary widely (chen2025restoreintestinalsteadystate pages 1-3) Severe CID leads to dose reduction, delay, or discontinuation in ~60% of affected patients and is associated with ~1% mortality (jiang2025importantroleof pages 1-2). In a large claims study of cancer-related diarrhea, treatment discontinuation was higher with diarrhea: overall 82.4% vs 64.6%, chemotherapy subgroup 81.5% vs 62.3%, HR for discontinuation 1.40 (aleem2024theimpactof pages 1-3). Clinical complications include dehydration, electrolyte imbalance, malnutrition, and acute kidney injury (aleem2024theimpactof pages 1-3, chen2025restoreintestinalsteadystate pages 1-3).

Table: This table summarizes the best available quantitative data from the provided evidence for chemotherapy-induced diarrhea across major implicated agents. It highlights incidence, severe-event burden, and key clinical and pharmacogenomic risk factors relevant for disease characterization and supportive-care decision making.

Visual evidence (clinical algorithms)

  • BSG guidance includes visual algorithms for investigation and management of diarrhea during cancer treatment, including an acute severe diarrhea during chemotherapy algorithm and a table-based pathway for diarrhea workup. (andreyev2025britishsocietyof media 677c2d7d, andreyev2025britishsocietyof media 763cd06e, andreyev2025britishsocietyof media adbbc39b, andreyev2025britishsocietyof media f43c1d78)

Notes on PMID requirement

Many retrieved full texts in this run provided DOIs and journal metadata but not PubMed identifiers in the extracted evidence. Where PMIDs are required for a knowledge base, they should be added during a dedicated PubMed crosswalk step using DOI→PMID mapping.

References

  1. (chen2025restoreintestinalsteadystate pages 1-3): Miaoqi Chen, Yamao Li, and Peijun Chen. Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation. Journal of Molecular Histology, Mar 2025. URL: https://doi.org/10.1007/s10735-025-10367-w, doi:10.1007/s10735-025-10367-w. This article has 5 citations and is from a peer-reviewed journal.

  2. (jiang2025importantroleof pages 1-2): Wanrou Jiang, Yongjun Wu, Xiuyun He, Ling Jiang, Wanyi Zhang, Wenjuan Zheng, Min Hu, and Chaofu Zhu. Important role of intestinal microbiota in chemotherapy-induced diarrhea and therapeutics. Journal of Cancer, 16:648-659, Jan 2025. URL: https://doi.org/10.7150/jca.99421, doi:10.7150/jca.99421. This article has 9 citations and is from a peer-reviewed journal.

  3. (chen2025restoreintestinalsteadystate pages 6-7): Miaoqi Chen, Yamao Li, and Peijun Chen. Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation. Journal of Molecular Histology, Mar 2025. URL: https://doi.org/10.1007/s10735-025-10367-w, doi:10.1007/s10735-025-10367-w. This article has 5 citations and is from a peer-reviewed journal.

  4. (aleem2024theimpactof pages 1-3): Abdullah Aleem, Maya Charuni Sarihan, Pablo C. Okhuysen, Eric J. Roeland, Lee Schwartzberg, Yinghong Wang, and Pravin Chaturvedi. The impact of cancer-related diarrhea on changes in cancer therapy. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32 10:668, Sep 2024. URL: https://doi.org/10.1007/s00520-024-08871-y, doi:10.1007/s00520-024-08871-y. This article has 2 citations.

  5. (cheatham2025butyratepreventschemotherapyinduced pages 24-28): Stanley M. Cheatham, Zayd Rehman, Mahshid Arastonejad, Ryan Kane, Naeem Ahmad, Natalie Luffman, Hisashi Harada, Yuesheng Zhang, Katarzyna M. Tyc, David A. Gewirtz, and Hamid I. Akbarali. Butyrate prevents chemotherapy-induced gastrointestinal toxicity and microbial dysbiosis. Scientific Reports, Dec 2025. URL: https://doi.org/10.1038/s41598-025-30385-8, doi:10.1038/s41598-025-30385-8. This article has 1 citations and is from a peer-reviewed journal.

  6. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 3-4): N. Venkateswaramurthy, Aravindhan S, and Elavarasan P R. Managing chemotherapy-induced diarrhea: efficacy of interventions for cancer patients. Biosciences Biotechnology Research Asia, 21:391-404, Jul 2024. URL: https://doi.org/10.13005/bbra/3233, doi:10.13005/bbra/3233. This article has 9 citations.

  7. (andreyev2025britishsocietyof pages 15-15): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  8. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 1-3): N. Venkateswaramurthy, Aravindhan S, and Elavarasan P R. Managing chemotherapy-induced diarrhea: efficacy of interventions for cancer patients. Biosciences Biotechnology Research Asia, 21:391-404, Jul 2024. URL: https://doi.org/10.13005/bbra/3233, doi:10.13005/bbra/3233. This article has 9 citations.

  9. (deng2024efficacyandsafety pages 1-2): Chao Deng, Qing Liu, Meng Yang, Hui-juan Cui, Yang Ge, Qin Li, Shi-jie Zhu, Guo-wang Yang, Zhi-guo Zhang, Yu Gao, Yan-ni Lou, and Li-qun Jia. Efficacy and safety of shengjiang xiexin decoction on irinotecan-induced diarrhea in small cell lung cancer patients: a multicenter, randomized, double-blind, placebo-controlled trial. Chinese Medicine, Nov 2024. URL: https://doi.org/10.1186/s13020-024-01025-6, doi:10.1186/s13020-024-01025-6. This article has 4 citations.

  10. (oterotorres2025dpydgenotypingfluoropyrimidine pages 1-2): Sara Otero-Torres, Rosa Rodríguez-Mauriz, Eduard Fort-Casamartina, Ana Clopés-Estela, Francesc Soler-Rotllant, Sandra Fontanals-Martínez, and Olalla Montero-Pérez. Dpyd genotyping, fluoropyrimidine dosage and toxicity: an umbrella review of systematic reviews. Pharmaceuticals, 18:727, May 2025. URL: https://doi.org/10.3390/ph18050727, doi:10.3390/ph18050727. This article has 4 citations.

  11. (oterotorres2025dpydgenotypingfluoropyrimidine pages 9-10): Sara Otero-Torres, Rosa Rodríguez-Mauriz, Eduard Fort-Casamartina, Ana Clopés-Estela, Francesc Soler-Rotllant, Sandra Fontanals-Martínez, and Olalla Montero-Pérez. Dpyd genotyping, fluoropyrimidine dosage and toxicity: an umbrella review of systematic reviews. Pharmaceuticals, 18:727, May 2025. URL: https://doi.org/10.3390/ph18050727, doi:10.3390/ph18050727. This article has 4 citations.

  12. (cheatham2025butyratepreventschemotherapyinduced pages 1-6): Stanley M. Cheatham, Zayd Rehman, Mahshid Arastonejad, Ryan Kane, Naeem Ahmad, Natalie Luffman, Hisashi Harada, Yuesheng Zhang, Katarzyna M. Tyc, David A. Gewirtz, and Hamid I. Akbarali. Butyrate prevents chemotherapy-induced gastrointestinal toxicity and microbial dysbiosis. Scientific Reports, Dec 2025. URL: https://doi.org/10.1038/s41598-025-30385-8, doi:10.1038/s41598-025-30385-8. This article has 1 citations and is from a peer-reviewed journal.

  13. (oterotorres2025dpydgenotypingfluoropyrimidine pages 10-12): Sara Otero-Torres, Rosa Rodríguez-Mauriz, Eduard Fort-Casamartina, Ana Clopés-Estela, Francesc Soler-Rotllant, Sandra Fontanals-Martínez, and Olalla Montero-Pérez. Dpyd genotyping, fluoropyrimidine dosage and toxicity: an umbrella review of systematic reviews. Pharmaceuticals, 18:727, May 2025. URL: https://doi.org/10.3390/ph18050727, doi:10.3390/ph18050727. This article has 4 citations.

  14. (rosasalonso2025dpydguidedfluoropyrimidinedose pages 1-2): Rocío Rosas-Alonso, Nuria Rodríguez Salas, Pablo Perez Wert, Angela Hoyo, Susana Martin-López, Daniel Martínez-Pérez, Iciar Ruiz-Gutiérrez, Diego Jiménez-Bou, Jesús Peña, Pedro Arias, Ana Custodio, Itsaso Losantos-García, Alberto M. Borobia, Jaime Feliu, and Ismael Ghanem. Dpyd-guided fluoropyrimidine dose adjustment in colorectal cancer dpyd carriers: start slower to finish stronger. Frontiers in Pharmacology, Sep 2025. URL: https://doi.org/10.3389/fphar.2025.1645188, doi:10.3389/fphar.2025.1645188. This article has 1 citations.

  15. (kratz2026importanceofand pages 1-2): Jeremy Kratz, Karen Merritt, Jessica Jorgensen, Comfort Kanji, Luis Abel Quiñones, and Daniel L. Hertz. Importance of and strategies for implementing dpyd testing to prevent severe fluoropyrimidine chemotherapy toxicity in health care systems. American Society of Clinical Oncology Educational Book, Jun 2026. URL: https://doi.org/10.1200/edbk-26-521184, doi:10.1200/edbk-26-521184. This article has 0 citations.

  16. (fernandes2024istherean pages 7-8): Camila Fernandes, Mahara Coelho Crisostomo Miranda, Cássia Rodrigues Roque, Ana Lizeth Padilla Paguada, Carlos Adrian Rodrigues Mota, Katharine Gurgel Dias Florêncio, Anamaria Falcão Pereira, Deysi Viviana Tenazoa Wong, Reinaldo Barreto Oriá, and Roberto César Pereira Lima-Júnior. Is there an interplay between environmental factors, microbiota imbalance, and cancer chemotherapy-associated intestinal mucositis? Pharmaceuticals, 17:1020, Aug 2024. URL: https://doi.org/10.3390/ph17081020, doi:10.3390/ph17081020. This article has 14 citations.

  17. (andreyev2025britishsocietyof pages 8-8): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  18. (andreyev2025britishsocietyof pages 13-13): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  19. (andreyev2025britishsocietyof pages 14-15): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  20. (andreyev2025britishsocietyof pages 11-11): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  21. (andreyev2025britishsocietyof media 677c2d7d): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  22. (andreyev2025britishsocietyof media 763cd06e): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  23. (andreyev2025britishsocietyof media adbbc39b): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  24. (andreyev2025britishsocietyof media f43c1d78): Jervoise Andreyev, Richard Adams, Jan Bornschein, Mark Chapman, Dave Chuter, Sally Darnborough, Andrew Davies, Fiona Dignan, Clare Donnellan, Darren Fernandes, Robert Flavel, Georgina Giebner, Alexandra Gilbert, Fiona Huddy, Mohid Shakil S Khan, Pauline Leonard, Shameer Mehta, Ollie Minton, Christine Norton, Louise Payton, Gill McGuire, D Mark Pritchard, Claire Taylor, Susan Vyoral, Ana Wilson, and Linda Wedlake. British society of gastroenterology practice guidance on the management of acute and chronic gastrointestinal symptoms and complications as a result of treatment for cancer. Gut, 74:1040-1067, Mar 2025. URL: https://doi.org/10.1136/gutjnl-2024-333812, doi:10.1136/gutjnl-2024-333812. This article has 22 citations and is from a highest quality peer-reviewed journal.

  25. (venkateswaramurthy2024managingchemotherapyinduceddiarrhea pages 6-9): N. Venkateswaramurthy, Aravindhan S, and Elavarasan P R. Managing chemotherapy-induced diarrhea: efficacy of interventions for cancer patients. Biosciences Biotechnology Research Asia, 21:391-404, Jul 2024. URL: https://doi.org/10.13005/bbra/3233, doi:10.13005/bbra/3233. This article has 9 citations.

  26. (teng2024threebioactivecompounds pages 1-2): Xiaojun Teng, Bingxin Wu, Zuhui Liang, Lisheng Zhang, Maolin Yang, Zhongqiu Liu, Qi Liang, and Caiyan Wang. Three bioactive compounds from huangqin decoction ameliorate irinotecan-induced diarrhea via dual-targeting of escherichia coli and bacterial β-glucuronidase. Cell Biology and Toxicology, Oct 2024. URL: https://doi.org/10.1007/s10565-024-09922-0, doi:10.1007/s10565-024-09922-0. This article has 12 citations and is from a peer-reviewed journal.

  27. (oterotorres2025dpydgenotypingfluoropyrimidine pages 7-9): Sara Otero-Torres, Rosa Rodríguez-Mauriz, Eduard Fort-Casamartina, Ana Clopés-Estela, Francesc Soler-Rotllant, Sandra Fontanals-Martínez, and Olalla Montero-Pérez. Dpyd genotyping, fluoropyrimidine dosage and toxicity: an umbrella review of systematic reviews. Pharmaceuticals, 18:727, May 2025. URL: https://doi.org/10.3390/ph18050727, doi:10.3390/ph18050727. This article has 4 citations.