Show YAML
name: com_Gastroesophageal_Reflux_Disease__Irritable_Bowel_Syndrome
creation_date: "2026-08-27T00:00:00Z"
curation_status: CANDIDATE
notes: >-
Curated from the candidate directional edge K21 -> K58 in
`projects/COMORBIDITIES.md` (female, phase 1.0, genetic FDR 2.10e-04, GO
enrichment dominated by cAMP/cGMP phosphodiesterase terms). That Disease
Trajectories edge is a prioritization pointer, not evidence, and the
mechanistic and causal content of this entry rests entirely on the
literature cited below.
Directionality is A_BEFORE_B on the strength of a two-sample Mendelian
randomization study that found genetic liability to GERD raises IBS risk with
no reverse effect. That asymmetry is worth taking seriously precisely because
the naive expectation for two disorders of gut-brain interaction is a
symmetric overlap, and the community-survey data below indeed show
co-occurrence without ordering.
What this entry does not claim: that the reflux itself inflames the colon.
Both mechanisms curated here are indirect — a shared central pain-processing
trait, and an iatrogenic route through acid suppression. A direct
oesophagus-to-bowel mechanism has not been established, and the entry should
not be read as asserting one.
disease_a:
slug: Gastroesophageal_Reflux_Disease
preferred_term: gastroesophageal reflux disease
term:
id: MONDO:0007186
label: gastroesophageal reflux disease
disease_b:
slug: Irritable_Bowel_Syndrome
preferred_term: irritable bowel syndrome
term:
id: MONDO:0005052
label: irritable bowel syndrome
directionality: A_BEFORE_B
effect_direction: RISK
hypotheses:
- description: >-
A shared trait of amplified visceral pain processing, rather than a shared
lesion, links the two conditions: the same central sensitization and
symptom-reporting tendency that makes oesophageal acid exposure
symptomatic makes normal colonic distension painful. The community-survey
evidence supports this indirectly but pointedly — what best distinguished
people with both conditions from people with reflux alone was not a more
severe reflux measure but a higher somatization score, and from people with
IBS alone, frequent abdominal pain. On this account the overlap group is
defined by how visceral signals are processed centrally.
evidence:
- reference: PMID:17635380
reference_title: "Overlap of gastro-oesophageal reflux disease and irritable bowel syndrome: prevalence and risk factors in the general population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "An additional predictor of irritable bowel syndrome-GERD overlap vs. GERD alone was higher somatization (OR 1.7, 1.1-2.4)"
explanation: >-
Somatization, a marker of amplified symptom processing, is what separates
the overlap group from reflux-only disease, supporting a central rather
than luminal explanation for the overlap.
- reference: PMID:17635380
reference_title: "Overlap of gastro-oesophageal reflux disease and irritable bowel syndrome: prevalence and risk factors in the general population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Predictors of irritable bowel syndrome-GERD overlap vs. irritable bowel syndrome alone, and separately, GERD alone, were insomnia (OR 1.3, 95% CI: 1.06-1.70; OR 1.5, 95% CI: 1.13-1.90, respectively) and frequent abdominal pain (OR 3.9, 2.2-6.7; OR 1.8, 1.02-3.2, respectively)."
explanation: >-
Insomnia and pain frequency — both gut-brain-axis rather than
mucosal variables — predict the overlap phenotype against either
condition alone.
- description: >-
A treatment-mediated route: long-term acid suppression, the standard
management of GERD, raises intragastric pH and alters the intraluminal
environment, and proton pump inhibitor use is associated with roughly
doubled odds of small intestinal bacterial overgrowth. SIBO produces
bloating, distension and altered bowel habit that satisfy IBS symptom
criteria, so part of the directed GERD-to-IBS association may be iatrogenic
rather than a property of reflux disease itself. This is a plausible
contributor, not a demonstrated pathway: the cited meta-analysis measures
SIBO, not IBS, and its association held only for the aspirate-culture
diagnostic subgroup and not for breath testing.
evidence:
- reference: PMID:23270866
reference_title: "Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The pooled OR of SIBO in PPI users vs nonusers was 2.282 (95% confidence interval [CI], 1.238-4.205)."
explanation: >-
Quantifies the acid-suppression-to-overgrowth step of this route.
Indirect because the outcome measured is SIBO rather than IBS, leaving the
final step of the proposed pathway untested.
- reference: PMID:23270866
reference_title: "Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "PPI use statistically was associated with SIBO risk, but only when the diagnosis was made by a highly accurate test (duodenal or jejunal aspirate culture)."
explanation: >-
Records the authors' own restriction of the finding to one diagnostic
modality, which is why this mechanism is curated as a contributor rather
than an established pathway.
association_signals:
- source: LITERATURE
method: COMPUTATIONAL_INFERENCE
population: >-
Two-sample Mendelian randomization on European-ancestry GWAS summary
statistics: GERD (129,080 cases) as exposure, IBS (4,605 cases) as outcome,
inverse-variance weighted with sensitivity analyses, plus the reverse
analysis.
directionality: A_BEFORE_B
effect_direction: RISK
mapping_notes: >-
Mendelian randomization estimates the effect of lifelong genetic liability
to GERD, not of prevalent reflux disease, and it cannot separate a direct
effect from one mediated by GERD treatment. The reverse arm is
underpowered relative to the forward arm (6 instruments versus 74), so the
null it reports is weaker evidence than the positive forward estimate.
statistics:
metrics:
- metric_type: OR
metric_value: 1.375
metric_ci_lower: 1.164
metric_ci_upper: 1.624
notes: >-
Effect of genetic liability to GERD on IBS risk, 74 instruments.
- metric_type: OR
metric_value: 0.996
metric_ci_lower: 0.960
metric_ci_upper: 1.034
notes: >-
Reverse direction, IBS liability on GERD risk, 6 instruments; null,
which is the basis for recording this pair as directed rather than
BIDIRECTIONAL.
evidence:
- reference: PMID:38601073
reference_title: "Causal association of gastroesophageal reflux disease on irritable bowel syndrome: a two-sample Mendelian randomization study."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "We found a significant association of GERD with IBS (NSNP = 74; OR: 1.375; 95% CI: 1.164-1.624; p < 0.001)."
explanation: >-
Genetic-instrument estimate of the forward effect, the strongest
available support for the directed reading of this pair.
- reference: PMID:38601073
reference_title: "Causal association of gastroesophageal reflux disease on irritable bowel syndrome: a two-sample Mendelian randomization study."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Reverse MR analysis showed no evidence of a causal association for IBS with GERD (NSNP = 6; OR: 0.996; 95% CI: 0.960-1.034; p = 0.845)."
explanation: >-
The null reverse estimate is what distinguishes this from a symmetric
overlap and supports A_BEFORE_B over BIDIRECTIONAL.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: >-
Population-based cross-sectional survey of Olmsted County, Minnesota
residents aged 30-95 (2,298 questionnaires returned, 55% response); IBS by
Rome III, GERD by weekly or more frequent heartburn and/or acid
regurgitation.
directionality: SAME_TIME
effect_direction: RISK
mapping_notes: >-
Cross-sectional, so it establishes non-chance co-occurrence and its
magnitude but carries no temporal information; the directionality recorded
on this signal is deliberately SAME_TIME even though the entry as a whole
is A_BEFORE_B on the Mendelian randomization evidence. Both conditions are
symptom-defined by questionnaire rather than by endoscopy or physician
diagnosis.
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 3.0
notes: >-
Percentage of men with both conditions, against 15% GERD alone and 5%
IBS alone; in women 4% overlap against 14% and 10%.
evidence:
- reference: PMID:17635380
reference_title: "Overlap of gastro-oesophageal reflux disease and irritable bowel syndrome: prevalence and risk factors in the general population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Irritable bowel syndrome and GERD occurred together more commonly than expected by chance; the prevalence of irritable bowel syndrome-GERD overlap, GERD alone and irritable bowel syndrome alone were 3%, 15% and 5% in men, and 4%, 14% and 10% in women, respectively."
explanation: >-
Establishes that the co-occurrence exceeds chance in an unselected
community population and quantifies the overlap by sex.
- source: DISEASE_TRAJECTORIES
method: EHR_TEMPORAL_COMORBIDITY
signal_disorder_a_id: ICD10:K21
signal_disorder_b_id: ICD10:K58
population: Austrian hospital stays (EHR-derived)
demographics:
sex: FEMALE
directionality: A_BEFORE_B
a_before_b: 1.0
b_before_a: 0.0
same_time: 0.0
mapping_notes: >-
ICD10:K21 is gastro-oesophageal reflux disease and ICD10:K58 irritable
bowel syndrome, so the code-to-concept mapping is direct. The reported
genetic overlap FDR for the pair is 2.10e-04 and the GO enrichment is
dominated by cAMP/cGMP phosphodiesterase terms; individual GO identifiers
and per-term FDRs are not recorded here because the underlying Disease
Trajectories export is not committed to this repository.
notes: >-
Values transcribed from the candidate-edge table in
`projects/COMORBIDITIES.md`, which derived them from the distraj phase and
genetic-FDR dictionaries. Recorded as the provenance of this curation task;
it is a prioritization signal and carries no independent evidential weight
here.