Pathophysiology description (current understanding) IBS is a multifactorial DGBI characterized by altered bidirectional signaling across the gut–brain–microbiome axis. Core mechanisms include visceral hypersensitivity, mucosal immune activation with mast-cell mediators, epithelial barrier dysfunction, dysregulated enteroendocrine (serotonergic) signaling, altered microbial ecology and metabolites (e.g., SCFAs and bile acids), and central modulation of pain and affect. Contemporary reviews and transcriptomic studies in IBS (particularly IBS-D) show upregulation of immune/inflammatory and nociceptive pathways (including TRPV1), barrier-related changes, and mediator release that sensitizes enteric afferents and facilitates pain (hyperalgesia), while bile acid diarrhea (BAD) represents a defined mechanistic subset with FXR–FGF19 signaling disturbances and enhanced mucosal immune activation by dihydroxy bile acids (e.g., chenodeoxycholic, deoxycholic acids) (Camilleri & Boeckxstaens 2023, Gut, Oct 2023; https://doi.org/10.1136/gutjnl-2022-328515) (camilleri2023irritablebowelsyndrome pages 6-8). The brain–gut axis integrates psychosocial stress, HPA activation, and inflammatory mediators, with high psychiatric comorbidity and heightened central pain processing contributing to symptom severity (Shaikh et al. 2023, J Clin Med; https://doi.org/10.3390/jcm12072558) (shaikh2023irritablebowelsyndrome pages 4-5).
1) Core pathophysiology - Visceral hypersensitivity • IBS patients demonstrate lower pain thresholds to recto-colonic distension; transcriptomics in IBS-D highlight upregulation of TRPV1 and neurotransmission genes, consistent with hyperexcitability of visceral afferents (Camilleri & Boeckxstaens 2023, Gut) (camilleri2023irritablebowelsyndrome pages 6-8). • Clinical and experimental evidence links neurotrophins (e.g., BDNF), prostaglandins (PGE2), and mast-cell mediators to heightened nociception (McKevitt 2024, colonic mucosa gene-expression review) (mckevitt2024investigatinggeneexpression pages 24-27).
Immune activation and mast cells • Mucosal B cells/plasma cells and mast cells increase adjacent to nerves; augmented release of histamine, tryptase, and other mediators heightens neuronal excitability and visceral pain (Camilleri & Boeckxstaens 2023, Gut) (camilleri2023irritablebowelsyndrome pages 6-8). • Multiple studies report increased stool tryptase and localized mast-cell degranulation correlating with pain severity (McKevitt 2024; Mansilla et al. 2024, Nutrients; https://doi.org/10.3390/nu17010155) (mckevitt2024investigatinggeneexpression pages 20-24, mansilla2024exploringgutmicrobiota pages 2-4).
Epithelial barrier dysfunction • Increased permeability is documented in IBS, especially in BAD versus IBS-D without BAD; colonic and small-bowel segmental permeability can be inferred from timed urinary sugar probes (Camilleri & Boeckxstaens 2023, Gut) (camilleri2023irritablebowelsyndrome pages 6-8). • Barrier-protein transcripts and tight-junction remodeling are variably altered across IBS subtypes (OCLN/CLDN1 increases in IBS-C with greater integrity; loss in IBS-D), and innate-sensing TLRs are dysregulated (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 20-24).
Microbiome and metabolites • Dysbiosis with reduced beneficial taxa (e.g., Bifidobacterium, Faecalibacterium prausnitzii) and altered Firmicutes:Bacteroidetes balance are repeatedly observed, with mechanistic links to immune activation, oxidative stress, and permeability (Mansilla et al. 2024, Nutrients) (mansilla2024exploringgutmicrobiota pages 2-4). • SCFAs regulate epithelial transport, immune differentiation (e.g., Treg induction), and serotonergic gene expression (TPH1/SERT); butyrate can increase SERT in vitro, whereas acetate/propionate may decrease SERT expression; SCFAs also exert epigenetic effects (histone acetylation) modulating NF-κB/TNF-α (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 27-31).
Bile acids and FXR–FGF19/TGR5 signaling (particularly in IBS-D/BAD) • BAD denotes ~subset of IBS-D with increased fecal bile acids and reduced FXR–FGF19 feedback; mucosa exhibits greater immune activation, partly attributable to bile acid detergency (Camilleri & Boeckxstaens 2023, Gut) (camilleri2023irritablebowelsyndrome pages 6-8).
Serotonin pathway (enterochromaffin) • About 95% of 5-HT is produced in GI tissues; IBS shows altered expression of serotonergic genes (TPH1, SLC6A4/SERT, HTRs) and associations with bowel habit phenotypes (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 24-27). SCFAs can modulate TPH1/SERT (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 27-31).
Brain–gut axis and central modulation • Psychiatric comorbidity is frequent; stress and HPA activation (elevated IL-6/IL-8) can worsen gut symptoms via effects on motility, permeability, and nociception (Shaikh et al. 2023) (shaikh2023irritablebowelsyndrome pages 4-5).
2) Key molecular players - Genes/Proteins (HGNC) • TRPV1 (HGNC:12350): upregulated in IBS-D transcriptomes; mediator of nociceptive hypersensitivity (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). • CLDN family (e.g., CLDN1; HGNC:2045), OCLN (HGNC:8101), TJP1/ZO-1 (HGNC:11773): barrier integrity/remodeling in IBS subtypes (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 20-24). • SLC6A4 (SERT; HGNC:11050), TPH1 (HGNC:12016): serotonergic transport/synthesis altered in IBS; SCFAs modulate expression (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 27-31, mckevitt2024investigatinggeneexpression pages 24-27). • FXR/NR1H4 (HGNC:7965), FGF19 (HGNC:3680), GPBAR1/TGR5 (HGNC:4518): bile acid signaling implicated in BAD and IBS-D (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). • BDNF (HGNC:1033): linked to visceral pain and enteric signaling (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 24-27). • Immune mediators: TNF (HGNC:11892), IL6 (HGNC:6018), IL1B (HGNC:5992); increased cytokine activity associated with symptoms and stress (Shaikh 2023) (shaikh2023irritablebowelsyndrome pages 4-5); evidence for TNFSF15 and immune loci in IBS genetics (Camilleri & Jencks 2024) (camilleri2024pharmacogeneticsinibs pages 16-18).
Chemical entities (CHEBI) • SCFAs: acetate (CHEBI:15343), propionate (CHEBI:15986), butyrate (CHEBI:17148); immunoepithelial and epigenetic modulators (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 27-31). • Bile acids: chenodeoxycholic acid/CDCA (CHEBI:16755), deoxycholic acid/DCA (CHEBI:29807); mucosal irritants promoting BAD immune activation (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). • Histamine (CHEBI:18295) and tryptase (e.g., TPSAB1 gene product): mast-cell mediators linked to pain (Gut 2023; Mansilla 2024) (camilleri2023irritablebowelsyndrome pages 6-8, mansilla2024exploringgutmicrobiota pages 2-4).
Cell types (CL) • Enterochromaffin cells (CL:0000160), intestinal epithelial cells (CL:0002253), mucosal mast cells (CL:0000097), enteric neurons (CL:0000393) (mechanistic roles per Gut 2023; McKevitt 2024) (camilleri2023irritablebowelsyndrome pages 6-8, mckevitt2024investigatinggeneexpression pages 24-27).
Anatomical locations (UBERON) • Colon (UBERON:0001155), small intestine (UBERON:0002108), lamina propria (UBERON:0001969), enteric nervous system (UBERON:0001799) (Gut 2023; McKevitt 2024) (camilleri2023irritablebowelsyndrome pages 6-8, mckevitt2024investigatinggeneexpression pages 24-27).
3) Biological processes (GO terms) disrupted - Sensory perception of pain/visceral nociception (GO:0019233): TRPV1-mediated hypersensitivity (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Inflammatory response (GO:0006954) and mast-cell activation (GO:0045576): immune mediator release driving neuronal excitability (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Regulation of intestinal epithelial cell–cell adhesion (GO:0098609) and tight junction assembly (GO:0070830): barrier dysfunction in IBS subtypes/BAD (Gut 2023; McKevitt 2024) (camilleri2023irritablebowelsyndrome pages 6-8, mckevitt2024investigatinggeneexpression pages 20-24). - Serotonin metabolic process (GO:0042428) and monoamine transport (GO:0015844): altered EC signaling (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 24-27). - Bile acid mediated signaling pathway (GO:1905114): FXR–FGF19/TGR5 dysregulation in BAD/IBS-D (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Regulation of T cell differentiation, including Treg (GO:0045580): SCFA-driven immune modulation (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 27-31).
4) Cellular components (GO) - Tight junction (GO:0005923): ZO-1/TJP1, claudins, occludin localization changes (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 20-24). - Extracellular space (GO:0005615): mediator milieu (histamine, proteases, cytokines) sensitizing afferents (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Plasma membrane and ion channel complexes (GO:0005886; GO:1902495): TRPV1 and other nociceptive channels (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8).
5) Disease progression: sequence of events - Triggers (e.g., acute enteric infection, psychosocial stress) perturb microbiota and barrier integrity, increasing antigen exposure and activating mucosal immune cells (mast cells, B/plasma cells). Released mediators (histamine, tryptase, prostaglandins) and epithelial factors sensitize TRPV1-expressing afferents, producing visceral hypersensitivity. Concurrently, enteroendocrine serotonin signaling and bile acid pathways shape motility and secretion (IBS-D vs IBS-C). Central circuits (BGA) amplify pain and hypervigilance, reinforced by psychiatric comorbidities. In a subset (BAD), impaired FXR–FGF19 feedback increases colonic dihydroxy bile acids, further disrupting barrier and activating mucosal immunity (Camilleri & Boeckxstaens 2023; Shaikh 2023) (camilleri2023irritablebowelsyndrome pages 6-8, shaikh2023irritablebowelsyndrome pages 4-5).
6) Phenotypic manifestations (HP terms) and mechanistic links - Abdominal pain (HP:0002027) and visceral hyperalgesia (HP:0025387): TRPV1 upregulation, mast-cell mediator release, central sensitization (Gut 2023; McKevitt 2024) (camilleri2023irritablebowelsyndrome pages 6-8, mckevitt2024investigatinggeneexpression pages 24-27). - Diarrhea (HP:0002014) in IBS-D, including bile acid diarrhea: increased luminal bile acids with FXR–FGF19 dysregulation (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Constipation (HP:0002019) in IBS-C: altered serotonergic transport/synthesis and neuromuscular signaling (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 24-27). - Bloating and distension (HP:0003270): dysbiosis, fermentation, barrier permeability (Mansilla 2024; McKevitt 2024) (mansilla2024exploringgutmicrobiota pages 2-4, mckevitt2024investigatinggeneexpression pages 20-24). - Anxiety/depression comorbidity (HP:0000739/HP:0000716): BGA dysregulation and HPA-axis stress–inflammation link (Shaikh 2023) (shaikh2023irritablebowelsyndrome pages 4-5).
Genetics and ion channels - IBS is polygenic with modest heritability. Recent overviews emphasize immune-related loci (e.g., TNFSF15), motility/stool-frequency signals, and neuronal/neurotrophic pathways in ENS and pain modulation; these provide theoretical targets for precision therapeutics though clinical pharmacogenomic stratification remains limited to drug-metabolizing enzymes (e.g., CYP2D6/2C19) at present (Camilleri & Jencks 2024; Expert Opin Drug Metab Toxicol, May 2024; https://doi.org/10.1080/17425255.2024.2349716) (camilleri2024pharmacogeneticsinibs pages 16-18). - Ion-channel and nociceptive signaling (TRPV1) are consistently implicated in IBS-D hypersensitivity, with transcriptome-level upregulation and functional links to immune mediator exposure (Gut 2023) (camilleri2023irritablebowelsyndrome pages 6-8).
Brain–gut axis, neuroimaging, and psychiatric comorbidity - IBS shows high rates of anxiety/depression, with stress and inflammatory cytokines (IL-6, IL-8) linked to symptom exacerbation and altered motility/visceral pain processing—underscoring top-down modulation along the BGA (Shaikh 2023; Mar 2023; https://doi.org/10.3390/jcm12072558) (shaikh2023irritablebowelsyndrome pages 4-5).
Post-infectious IBS (PI-IBS) - Meta-analytic and narrative syntheses indicate an increased risk of PI-IBS (on the order of ~fourfold) following enteric infections, with persistent low-grade mucosal inflammation, immune activation (Th1/Th17 bias), and barrier defects proposed as drivers (Almonajjed et al. 2025, Medicina; https://doi.org/10.3390/medicina61010109) (almonajjed2025impactofmicrobiota pages 4-5).
Current applications and real-world implementations - Biomarker-guided care: BAD testing (serum C4/FGF19 where available; fecal bile acids) and empiric bile acid sequestrants or FXR-targeted approaches for IBS-D/BAD; mast-cell–directed strategies (e.g., non-sedating H1R antagonists) in patients with histamine-driven pain; barrier-directed nutrition and microbiota-modifying interventions (pre/probiotics, fiber) (Camilleri & Boeckxstaens 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Psychogastroenterology: integration of central neuromodulators and brain–gut behavioral therapies alongside diet/microbiome strategies given strong BGA contribution (Shaikh 2023) (shaikh2023irritablebowelsyndrome pages 4-5).
Expert opinions and analysis from authoritative sources - A state-of-the-art Gut review advocates individualized treatment guided by actionable mechanisms (transit abnormality, BAD, barrier dysfunction, immune activation/mast cells, microbiome) rather than symptom phenotype alone, citing multi-omics and mucosal transcriptomic evidence supporting immune–nociceptive–barrier triad in IBS-D and BAD (Camilleri & Boeckxstaens 2023, Gut) (camilleri2023irritablebowelsyndrome pages 6-8). - Pharmacogenetics perspective underscores that, while GWAS illuminate biological pathways (immune/ENS/motility), near-term precision medicine in IBS is more feasible via pharmacokinetic genotyping (e.g., CYP2D6/2C19 for central neuromodulators) and mechanism-targeted selection (Camilleri & Jencks 2024) (camilleri2024pharmacogeneticsinibs pages 16-18).
Relevant statistics and data (recent) - Transcriptomics: 181 genes (ascending colon) and 199 genes (rectosigmoid) differentially expressed in IBS-D vs controls, with upregulation of inflammation, TRPV1, neurotransmitter/receptor pathways; PI15/PI16 peptidase inhibitors reduced in IBS-D (Camilleri & Boeckxstaens 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Immune/neuronal proximity: Increased mast cells near nerves and mediator release linked to pain; proof-of-concept improvement with non-sedating H1 receptor antagonists (Camilleri & Boeckxstaens 2023) (camilleri2023irritablebowelsyndrome pages 6-8). - Psychiatric comorbidity: High prevalence of anxiety/depression in IBS cohorts and symptom exacerbation linked to stress cytokines (Shaikh 2023) (shaikh2023irritablebowelsyndrome pages 4-5). - Post-infectious risk: Approximately fourfold increased risk of IBS after enteric infection, with immune and barrier alterations persisting (Almonajjed 2025) (almonajjed2025impactofmicrobiota pages 4-5). - Serotonin and SCFAs: Butyrate upregulates SERT; acetate/propionate downregulate SERT in vitro; SCFAs promote Treg differentiation and modulate TNF/NF-κB signaling via epigenetic effects (McKevitt 2024) (mckevitt2024investigatinggeneexpression pages 27-31).
Evidence items (with PMIDs/DOIs/URLs; publication dates) - Camilleri M, Boeckxstaens G. Irritable bowel syndrome: treatment based on pathophysiology and biomarkers. Gut. 2023 Oct;72(3):590–599. doi:10.1136/gutjnl-2022-328515. URL: https://doi.org/10.1136/gutjnl-2022-328515 (mechanistic immune–barrier–TRPV1, BAD/FXR–FGF19, biomarker-guided therapy) (camilleri2023irritablebowelsyndrome pages 6-8). - Camilleri M, Jencks KJ. Pharmacogenetics in IBS: update and impact of GWAS studies in drug targets and metabolism. Expert Opin Drug Metab Toxicol. 2024 May;20(5):319–332. doi:10.1080/17425255.2024.2349716. URL: https://doi.org/10.1080/17425255.2024.2349716 (genetics, ENS mechanisms, translational precision medicine) (camilleri2024pharmacogeneticsinibs pages 16-18). - Shaikh SD et al. Irritable Bowel Syndrome and the Gut Microbiome: A Comprehensive Review. J Clin Med. 2023 Mar;12(7):2558. doi:10.3390/jcm12072558. URL: https://doi.org/10.3390/jcm12072558 (BGA, psychiatric comorbidity, stress–cytokine links) (shaikh2023irritablebowelsyndrome pages 4-5). - McKevitt EE. Investigating gene expression in the colonic mucosal tissue of individuals with disorders of gut–brain interaction. 2024 (preprint/unknown journal). Key mechanistic syntheses: barrier proteins (OCLN/CLDN1), TLRs, cytokines (TNF, IL-1β, IL-6), mast-cell activation (tryptase), serotonin pathway (TPH1/SLC6A4), neurotrophins (BDNF), SCFA modulation of SERT/TPH1 (mckevitt2024investigatinggeneexpression pages 20-24, mckevitt2024investigatinggeneexpression pages 27-31, mckevitt2024investigatinggeneexpression pages 24-27). - Mansilla MJG et al. Exploring Gut Microbiota Imbalance in IBS: Potential Therapeutic Effects of Probiotics and Their Metabolites. Nutrients. 2024 Dec;17(1):155. doi:10.3390/nu17010155. URL: https://doi.org/10.3390/nu17010155 (dysbiosis patterns; mast-cell correlates) (mansilla2024exploringgutmicrobiota pages 2-4). - Almonajjed MB et al. Impact of Microbiota on IBS Pathogenesis and Management: A Narrative Review. Medicina. 2025 Jan;61(1):109. doi:10.3390/medicina61010109. URL: https://doi.org/10.3390/medicina61010109 (PI-IBS risk, immune–barrier mechanisms) (almonajjed2025impactofmicrobiota pages 4-5).
Ontology-linked annotations (exemplars) - Genes/Proteins (HGNC): TRPV1; SLC6A4 (SERT); TPH1; NR1H4 (FXR); FGF19; GPBAR1 (TGR5); CLDN1; OCLN; TJP1; TNF; IL6; IL1B (camilleri2023irritablebowelsyndrome pages 6-8, camilleri2024pharmacogeneticsinibs pages 16-18, mckevitt2024investigatinggeneexpression pages 24-27, mckevitt2024investigatinggeneexpression pages 20-24, mckevitt2024investigatinggeneexpression pages 27-31). - Biological process (GO): inflammatory response (GO:0006954); bile acid mediated signaling (GO:1905114); serotonin metabolic process (GO:0042428); regulation of intestinal permeability (GO:1905499); sensory perception of pain (GO:0019233) (camilleri2023irritablebowelsyndrome pages 6-8, mckevitt2024investigatinggeneexpression pages 24-27). - Cellular component (GO): tight junction (GO:0005923); extracellular space (GO:0005615); ion channel complex (GO:1902495) (mckevitt2024investigatinggeneexpression pages 20-24, camilleri2023irritablebowelsyndrome pages 6-8). - Cell types (CL): mucosal mast cell (CL:0000097); enterochromaffin cell (CL:0000160); intestinal epithelial cell (CL:0002253); enteric neuron (CL:0000393) (camilleri2023irritablebowelsyndrome pages 6-8, mckevitt2024investigatinggeneexpression pages 24-27). - Anatomical locations (UBERON): colon (UBERON:0001155); small intestine (UBERON:0002108); lamina propria (UBERON:0001969); enteric nervous system (UBERON:0001799) (camilleri2023irritablebowelsyndrome pages 6-8, mckevitt2024investigatinggeneexpression pages 24-27). - Chemical entities (CHEBI): acetate (CHEBI:15343); propionate (CHEBI:15986); butyrate (CHEBI:17148); chenodeoxycholic acid (CHEBI:16755); deoxycholic acid (CHEBI:29807); histamine (CHEBI:18295) (mckevitt2024investigatinggeneexpression pages 27-31, camilleri2023irritablebowelsyndrome pages 6-8).
Notes and limitations - Where possible, 2023–2024 high-quality sources (Gut 2023; Expert Opin 2024) were prioritized. Some mechanistic syntheses (gene expression/SCFA–SERT modulation; PI-IBS estimate) derive from recent narrative/unknown-journal reviews; these highlight hypotheses needing continued validation. Neuroimaging- and subtype-specific genetic effect sizes were outside the scope of the retrieved evidence here and warrant further targeted review.
References
(camilleri2023irritablebowelsyndrome pages 6-8): Michael Camilleri and Guy Boeckxstaens. Irritable bowel syndrome: treatment based on pathophysiology and biomarkers. Gut, 72:590-599, Oct 2023. URL: https://doi.org/10.1136/gutjnl-2022-328515, doi:10.1136/gutjnl-2022-328515. This article has 99 citations and is from a highest quality peer-reviewed journal.
(shaikh2023irritablebowelsyndrome pages 4-5): Sofia D. Shaikh, Natalie Sun, Andrew Canakis, William Y. Park, and Horst Christian Weber. Irritable bowel syndrome and the gut microbiome: a comprehensive review. Journal of Clinical Medicine, 12:2558, Mar 2023. URL: https://doi.org/10.3390/jcm12072558, doi:10.3390/jcm12072558. This article has 146 citations and is from a poor quality or predatory journal.
(mckevitt2024investigatinggeneexpression pages 24-27): EE McKevitt. Investigating gene expression in the colonic mucosal tissue of individuals with disorders of gut-brain interaction. Unknown journal, 2024.
(mckevitt2024investigatinggeneexpression pages 20-24): EE McKevitt. Investigating gene expression in the colonic mucosal tissue of individuals with disorders of gut-brain interaction. Unknown journal, 2024.
(mansilla2024exploringgutmicrobiota pages 2-4): María José García Mansilla, María Jesús Rodríguez Sojo, Andrea Roxana Lista, Ciskey Vanessa Ayala Mosqueda, Antonio Jesús Ruiz Malagón, Julio Gálvez, Alba Rodríguez Nogales, and María José Rodríguez Sánchez. Exploring gut microbiota imbalance in irritable bowel syndrome: potential therapeutic effects of probiotics and their metabolites. Nutrients, 17:155, Dec 2024. URL: https://doi.org/10.3390/nu17010155, doi:10.3390/nu17010155. This article has 13 citations and is from a poor quality or predatory journal.
(mckevitt2024investigatinggeneexpression pages 27-31): EE McKevitt. Investigating gene expression in the colonic mucosal tissue of individuals with disorders of gut-brain interaction. Unknown journal, 2024.
(camilleri2024pharmacogeneticsinibs pages 16-18): Michael Camilleri and Kara J Jencks. Pharmacogenetics in ibs: update and impact of gwas studies in drug targets and metabolism. Expert Opinion on Drug Metabolism & Toxicology, 20:319-332, May 2024. URL: https://doi.org/10.1080/17425255.2024.2349716, doi:10.1080/17425255.2024.2349716. This article has 1 citations and is from a peer-reviewed journal.
(almonajjed2025impactofmicrobiota pages 4-5): Mhd Bashir Almonajjed, Mahdi Wardeh, Abdallah Atlagh, Abdulrahman Ismaiel, Stefan-Lucian Popa, Flaviu Rusu, and Dan L. Dumitrascu. Impact of microbiota on irritable bowel syndrome pathogenesis and management: a narrative review. Medicina, 61:109, Jan 2025. URL: https://doi.org/10.3390/medicina61010109, doi:10.3390/medicina61010109. This article has 10 citations and is from a poor quality or predatory journal.
name: Irritable Bowel Syndrome
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-17T21:53:14Z'
category: Complex
parents:
- Gastrointestinal Disease
disease_term:
preferred_term: irritable bowel syndrome
term:
id: MONDO:0005052
label: irritable bowel syndrome
pathophysiology:
- name: Visceral Hypersensitivity
description: >
Enhanced perception of normal gut sensations leads to pain and
discomfort. Lowered pain thresholds in response to balloon
distension. Central sensitization contributes.
biological_processes:
- preferred_term: Pain Perception
term:
id: GO:0048265
label: response to pain
evidence:
- reference: PMID:18252749
reference_title: "Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain."
supports: SUPPORT
snippet: "A significant 3.5-fold increase in median numbers of TRPV1-immunoreactive
fibres was found in biopsies from IBS patients compared with controls (p<0.0001)."
explanation: TRPV1-expressing sensory nerve fibers are significantly
increased in IBS, providing a molecular basis for visceral
hypersensitivity.
- reference: PMID:18252749
reference_title: "Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain."
supports: SUPPORT
snippet: "In multivariate regression analysis, only TRPV1-immuno-reactive fibres
(p = 0.005) and mast cells (p = 0.008) were significantly related to the abdominal
pain score."
explanation: TRPV1 nerve fiber density directly correlates with abdominal
pain severity in IBS patients.
- reference: PMID:17241857
reference_title: "Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome."
supports: SUPPORT
snippet: "Mediators from IBS patients, but not controls, markedly enhanced the
firing of mesenteric nerves (14.7 +/- 3.2 imp/sec vs 2.8 +/- 1.5 imp/sec; P
< .05) and stimulated mobilization of Ca(2+) in dorsal root ganglia neurons
(29% +/- 4% vs 11% +/- 4%; P < .05)."
explanation: Mucosal mediators from IBS patients directly excite visceral
sensory neurons, demonstrating a mechanism for visceral hypersensitivity.
- reference: PMID:17241857
reference_title: "Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome."
supports: SUPPORT
snippet: "On average, 64% of dorsal root ganglia responsive to mediators were
capsaicin-sensitive, known to mediate nociception."
explanation: The majority of sensory neurons activated by IBS mucosal
mediators are nociceptive, explaining the pain phenotype.
- name: Gut Dysmotility
description: >
Altered intestinal motility patterns with either accelerated
(diarrhea-predominant) or delayed (constipation-predominant)
transit. Abnormal colonic contractions.
biological_processes:
- preferred_term: Gut Motility
term:
id: GO:0030432
label: peristalsis
evidence:
- reference: PMID:15100164
reference_title: "Role of serotonin in the pathophysiology of the irritable bowel syndrome."
supports: SUPPORT
snippet: "5-HT release from enterochromaffin (EC) cells initiates peristaltic,
secretory, vasodilatory, vagal and nociceptive reflexes."
explanation: Serotonin from enterochromaffin cells is a key regulator of
intestinal motility and peristaltic reflexes.
- reference: PMID:15100164
reference_title: "Role of serotonin in the pathophysiology of the irritable bowel syndrome."
supports: SUPPORT
snippet: "5-HT directly and indirectly affects intestinal motor and secretory
function and abnormalities may lead to either constipation or diarrhea."
explanation: Dysregulated serotonin signaling can account for both IBS-D and
IBS-C subtypes through effects on motility.
- name: Gut-Brain Axis Dysfunction
description: >
Bidirectional communication between gut and brain is disrupted.
Stress and psychological factors modulate gut function through
autonomic and neuroendocrine pathways.
biological_processes:
- preferred_term: Nervous System Process
term:
id: GO:0050877
label: nervous system process
evidence:
- reference: PMID:37048642
reference_title: "Irritable Bowel Syndrome and the Gut Microbiome: A Comprehensive Review."
supports: SUPPORT
snippet: "Although the pathophysiology of IBS has not been fully elucidated, it
involves dysregulation of communication between the brain and gut (brain-gut
axis) which is associated with alterations in intestinal motility, gut permeability,
visceral hypersensitivity and gut microbiota composition."
explanation: The gut-brain axis is a central organizing principle in IBS
pathophysiology, integrating multiple dysfunctional mechanisms.
- reference: PMID:15100164
reference_title: "Role of serotonin in the pathophysiology of the irritable bowel syndrome."
supports: SUPPORT
snippet: "Ongoing, bidirectional brain-gut interactions involving 5-HT pathways
occur that significantly influence the effector systems."
explanation: Serotonin pathways mediate bidirectional brain-gut
communication in IBS.
- name: Intestinal Barrier Dysfunction
description: >
Increased intestinal permeability (leaky gut) allows translocation
of luminal antigens, triggering low-grade immune activation.
evidence:
- reference: PMID:17593135
reference_title: "Intestinal permeability and irritable bowel syndrome."
supports: SUPPORT
snippet: "While a subgroup of patients with IBS appears to have evidence of increased
intestinal permeability, improvements in the methods and validation are key
to further research in this field in order to better understand intestinal barrier
functions in IBS."
explanation: A subset of IBS patients demonstrate measurable increases in
intestinal permeability, though the exact prevalence varies by
methodology.
- reference: PMID:19595511
reference_title: "Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome."
supports: SUPPORT
snippet: "Approximately 39% of diarrhea-predominant IBS patients had increased
intestinal membrane permeability as measured by the lactulose/mannitol ratio."
explanation: Nearly 40% of IBS-D patients show objective evidence of barrier
dysfunction using validated permeability testing.
- reference: PMID:19595511
reference_title: "Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome."
supports: SUPPORT
snippet: "A subset of D-IBS patients had increased intestinal membrane permeability
that was associated with an increased FBDSI score and increased hypersensitivity
to visceral and thermal nociceptive pain stimuli."
explanation: Barrier dysfunction in IBS-D correlates with more severe
symptoms and heightened visceral sensitivity, linking permeability to
clinical phenotype.
- name: Immune Activation and Mast Cell Degranulation
description: >
Low-grade mucosal immune activation with increased mast cell density
and degranulation near enteric nerves. Mast cell mediators including
histamine and tryptase excite visceral sensory neurons, contributing
to pain and hypersensitivity.
biological_processes:
- preferred_term: Mast Cell Activation
term:
id: GO:0045576
label: mast cell activation
evidence:
- reference: PMID:17241857
reference_title: "Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome."
supports: SUPPORT
snippet: "IBS-dependent nerve firing and Ca(2+) mobilization were correlated with
the area of the colonic lamina propria occupied by mast cells (r = 0.74; P <
.01, and r = 0.78; P < .01, respectively)."
explanation: Mast cell density directly correlates with sensory neuron
activation in IBS, establishing a quantitative relationship.
- reference: PMID:17241857
reference_title: "Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome."
supports: SUPPORT
snippet: "Mucosal mast cell mediators from IBS patients excite rat nociceptive
visceral sensory nerves. These results provide new insights into the mechanism
underlying visceral hypersensitivity in IBS."
explanation: Mast cell mediators from IBS patients directly activate
nociceptive neurons, providing a mechanistic link to pain.
- reference: PMID:18252749
reference_title: "Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain."
supports: SUPPORT
snippet: "Substance P-immunoreactive fibres (p = 0.01), total nerve fibres (PGP9.5)
(p = 0.002), mast cells (c-kit) (p = 0.02) and lymphocytes (CD3) (p = 0.03)
were also significantly increased in the IBS group."
explanation: Both mast cells and immune cells are increased in IBS mucosa,
indicating low-grade immune activation.
- name: Microbiome Dysbiosis
description: >
Altered composition and function of gut microbiota may contribute
to symptoms. Post-infectious IBS follows gastroenteritis in
some patients.
biological_processes:
- preferred_term: Host-Microbiome Interaction
term:
id: GO:0044003
label: symbiont-mediated perturbation of host process
evidence:
- reference: PMID:37048642
reference_title: "Irritable Bowel Syndrome and the Gut Microbiome: A Comprehensive Review."
supports: SUPPORT
snippet: "It has a prevalence of 10 to 25% in the United States and has a high
disease burden, as evidenced by reduced quality of life, decreased work productivity
and increased healthcare utilization and costs."
explanation: IBS is a common disorder with substantial public health impact,
emphasizing the importance of understanding pathophysiological mechanisms
including microbiome alterations.
phenotypes:
- name: Abdominal Pain
category: Gastrointestinal
frequency: VERY_FREQUENT
diagnostic: true
notes: Related to defecation
phenotype_term:
preferred_term: Abdominal Pain
term:
id: HP:0002027
label: Abdominal pain
evidence:
- reference: PMID:18252749
reference_title: "Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain."
supports: SUPPORT
snippet: "Increased TRPV1 nerve fibres are observed in IBS, together with a low-grade
inflammatory response. The increased TRPV1 nerve fibres may contribute to visceral
hypersensitivity and pain in IBS, and provide a novel therapeutic target."
explanation: TRPV1-expressing nerve fibers are increased in IBS and directly
linked to abdominal pain severity.
- reference: PMID:17241857
reference_title: "Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome."
supports: SUPPORT
snippet: "IBS-dependent excitation of dorsal root ganglia was inhibited by histamine
H(1) receptor blockade and serine protease inactivation (inhibition of 51.7%;
P < .05 and 74.5%; P < .05; respectively)."
explanation: Mast cell mediators, particularly histamine and proteases,
directly excite nociceptive neurons to produce abdominal pain in IBS.
- name: Altered Bowel Habits
category: Gastrointestinal
frequency: VERY_FREQUENT
diagnostic: true
phenotype_term:
preferred_term: Abnormal Stool Pattern
term:
id: HP:0025085
label: Bloody diarrhea
- name: Bloating
category: Gastrointestinal
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Abdominal Distention
term:
id: HP:0003270
label: Abdominal distention
- name: Constipation
category: Gastrointestinal
frequency: FREQUENT
notes: IBS-C subtype
phenotype_term:
preferred_term: Constipation
term:
id: HP:0002019
label: Constipation
- name: Diarrhea
category: Gastrointestinal
frequency: FREQUENT
notes: IBS-D subtype
phenotype_term:
preferred_term: Diarrhea
term:
id: HP:0002014
label: Diarrhea
evidence:
- reference: PMID:19595511
reference_title: "Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome."
supports: SUPPORT
snippet: "Approximately 39% of diarrhea-predominant IBS patients had increased
intestinal membrane permeability as measured by the lactulose/mannitol ratio."
explanation: Increased intestinal permeability is present in a substantial
proportion of IBS-D patients and may contribute to diarrheal symptoms.
- reference: PMID:15100164
reference_title: "Role of serotonin in the pathophysiology of the irritable bowel syndrome."
supports: SUPPORT
snippet: "5-HT directly and indirectly affects intestinal motor and secretory
function and abnormalities may lead to either constipation or diarrhea."
explanation: Dysregulated serotonin signaling affects secretion and
motility, contributing to diarrhea in IBS-D.
- name: Fatigue
category: Systemic
frequency: FREQUENT
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
genetic:
- name: HTR3E
association: Risk Factor
notes: Serotonin receptor
- name: SCN5A
association: Risk Factor
notes: Sodium channel
environmental:
- name: Psychological Stress
notes: Major trigger for symptoms
- name: Dietary Triggers
notes: FODMAPs, gluten in some patients
- name: Gastroenteritis
notes: Post-infectious IBS
- name: Antibiotics
notes: May alter microbiome
- name: Early Life Stress
notes: May predispose to IBS
treatments:
- name: Dietary Modification
description: Low FODMAP diet effective in many patients.
- name: Antispasmodics
description: Dicyclomine, hyoscyamine for pain and cramping.
- name: Loperamide
description: For diarrhea-predominant IBS.
- name: Linaclotide
description: Guanylate cyclase agonist for IBS-C.
- name: Rifaximin
description: Non-absorbable antibiotic for IBS-D with bloating.
- name: Tricyclic Antidepressants
description: Low-dose for pain modulation.
- name: SSRIs
description: For patients with comorbid anxiety/depression.
- name: Probiotics
description: May help some patients.
- name: Cognitive Behavioral Therapy
description: Effective for gut-brain axis modulation.
datasets:
# Jejunal biopsy transcriptome in IBS-D
- accession: geo:GSE36701
title: Gene expression analysis of rectal mucosa in chronic irritable bowel
syndrome (IBS) compared to healthy volunteers (HV)
description: >-
Microarray analysis of jejunal mucosal biopsies from 53 IBS-D
(diarrhea-predominant) patients and 40 healthy volunteers to
identify differentially expressed genes related to intestinal
barrier function and visceral hypersensitivity.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: MICROARRAY
sample_types:
- preferred_term: jejunal mucosa biopsy
tissue_term:
preferred_term: jejunum
term:
id: UBERON:0002115
label: jejunum
sample_count: 93
conditions:
- IBS-D (diarrhea-predominant)
- healthy controls
platform: Affymetrix Human Genome U133 Plus 2.0 Array
notes: >-
Widely used IBS dataset for biomarker discovery. Key targets
identified include EGFR, VEGFA, BCL2L1, CASP9, MMP9, MAPK14.
# IBS-D pilot microarray study
- accession: geo:GSE14841
title: Expression data from healthy volunteers and IBS patients
description: >-
Microarray profiling of jejunal mucosal biopsies from 5 IBS-D
patients and 4 healthy volunteers as a pilot study to characterize
gene expression patterns in diarrhea-predominant IBS.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: MICROARRAY
sample_types:
- preferred_term: jejunal mucosa biopsy
tissue_term:
preferred_term: jejunum
term:
id: UBERON:0002115
label: jejunum
sample_count: 9
conditions:
- IBS-D (diarrhea-predominant)
- healthy controls
notes: >-
Smaller pilot dataset often combined with GSE36701 for meta-analysis.
Studies have identified 1257 differentially expressed genes between
IBS-D and controls.
# IBS gut microbiota 16S sequencing
- accession: bioproject:PRJNA566284
title: IBS gut microbiota and metabolome profiling
description: >-
16S rRNA gene sequencing of fecal samples from IBS patients and
healthy controls at Beijing Friendship Hospital to investigate
gut microbiota composition and identify potential biomarkers.
organism:
preferred_term: human gut metagenome
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: WGS
sample_types:
- preferred_term: fecal sample
tissue_term:
preferred_term: feces
term:
id: UBERON:0001988
label: feces
sample_count: 29
conditions:
- IBS patients
- healthy controls
notes: >-
Combined with metabolomics data to investigate mechanisms underlying
IBS through microbiologic and metabolomic profiling.
# American Gut Project IBS subset
- accession: mgnify:MGYS00000596
title: American Gut Project
description: >-
16S rRNA V4 region sequencing from the American Gut Project citizen
science initiative. Contains 942 IBS subjects (IBS-D, IBS-C, IBS-U
subtypes) matched with 942 non-IBS controls by age, gender, BMI,
geography, and dietary patterns.
organism:
preferred_term: human gut metagenome
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: WGS
sample_types:
- preferred_term: fecal sample
tissue_term:
preferred_term: feces
term:
id: UBERON:0001988
label: feces
sample_count: 1884
conditions:
- IBS-D (diarrhea-predominant)
- IBS-C (constipation-predominant)
- IBS-U (unclassified)
- healthy controls
publication: PMID:36573834
notes: >-
Large-scale microbiome study showing IBS-D and IBS-U have reduced
bacterial diversity (Shannon index). Identifies associations between
gut microbiota and depression in IBS subtypes. Bifidobacterium and
SCFA pathways reduced in IBS with depression
references:
- reference: DOI:10.1080/17425255.2024.2349716
title: 'Pharmacogenetics in IBS: update and impact of GWAS studies in drug targets
and metabolism'
findings: []
- reference: DOI:10.1136/gutjnl-2022-328515
title: 'Irritable bowel syndrome: treatment based on pathophysiology and biomarkers'
findings: []
- reference: DOI:10.3390/jcm12072558
title: 'Irritable Bowel Syndrome and the Gut Microbiome: A Comprehensive Review'
findings: []
- reference: DOI:10.3390/medicina61010109
title: 'Impact of Microbiota on Irritable Bowel Syndrome Pathogenesis and Management:
A Narrative Review'
findings: []
- reference: DOI:10.3390/nu17010155
title: 'Exploring Gut Microbiota Imbalance in Irritable Bowel Syndrome: Potential
Therapeutic Effects of Probiotics and Their Metabolites'
findings: []