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Brain–gut axis and visceral hypersensitivity

TL;DR — Three decades of mechanistic work have produced a long list of reproducible abnormalities in IBS and no biomarker: peripheral (infection, microbiome, visceral hypersensitivity, permeability, low-grade mucosal immune activation, motility, serotonin, bile acid and carbohydrate handling) and central (psychological state, altered pain processing), acting together through the gut–brain axis (Nasser 2026, PMID 42462748). Visceral hypersensitivity is the most-measured of these and is present in roughly two-thirds of patients at an optimised barostat cut-off (63.5% of 126 IBS patients vs 6.6% of 30 controls at 26 mmHg / VAS ≥20 mm; Ludidi 2012, PMID 22591192) — meaning about a third of people with IBS are not hypersensitive by the standard test, and there was no significant difference between subtypes. The brain–gut relationship is genuinely bidirectional: in a 12-year population cohort, baseline anxiety predicted new-onset functional GI disorders (OR 1.11, 1.03–1.19) while baseline disorder predicted later anxiety and depression (Koloski 2012, PMID 22234979), and genetics supports shared pathways rather than one causing the other — genome-wide correlation of IBS with anxiety, neuroticism and depression rg > 0.5 across 53,400 cases (Eijsbouts 2021, PMID 34741163). Mechanistically the most concrete recent advance is the enterochromaffin-cell–afferent circuit: activating these cells is sufficient to produce persistent visceral hypersensitivity in mice even without inflammation, and the circuit is tonically engaged in females (Bayrer 2023, PMID 36949192), with an estrogen-responsive L-cell → PYY → EC-cell → serotonin pathway proposed as the cellular basis of the female predominance (Venkataraman 2025, PMID 41411420). The gap between mechanism and clinic remains almost total: as the 2026 review puts it, "more work is needed to translate most mechanisms into reliable tests able to identify specific targets for treatment" (Nasser 2026, PMID 42462748).

The current mechanistic map

The 2026 Lancet Gastroenterology & Hepatology review organises the field into peripheral, central and integrated mechanisms, and names the three that can currently be quantified with validated tests: abnormal bile acid metabolism, accelerated colonic transit, and psychological comorbidity (Nasser 2026, PMID 42462748). Everything else in the list below is measurable in research settings only.

Domain Mechanism Status
Peripheral Gastrointestinal infection Established cause in a subset — post-infectious-ibs
Peripheral Gut microbiome alteration Reproducible group differences, no validated test — microbiome
Peripheral Visceral hypersensitivity Present in ~2/3, no clinical assay (Ludidi 2012, PMID 22591192)
Peripheral Increased intestinal permeability Research measure (Vanuytsel 2023, PMID 36657961)
Peripheral Low-grade mucosal immune activation, mast cells Mechanistic evidence; one drug class tested (below)
Peripheral Abnormal motility / transit Quantifiable; accelerated colonic transit is one of three validated measures (Nasser 2026, PMID 42462748)
Peripheral Serotonin signalling Enterochromaffin-cell circuit now causally demonstrated in mice (Bayrer 2023, PMID 36949192)
Peripheral Bile acid metabolism Quantifiable and treatable — differential-diagnosis-and-exclusion
Peripheral Carbohydrate metabolism Basis of dietary therapy — dietary-therapy
Central Psychological health Quantifiable, bidirectional (Koloski 2012, PMID 22234979)
Central Altered central pain processing Imaging-level evidence (Zhao 2023, PMID 37942144)

Visceral hypersensitivity: what the barostat actually shows

  • Prevalence and cut-off. ROC analysis in 126 IBS patients and 30 healthy controls put the optimal discriminating threshold at 26 mmHg with VAS ≥20 mm, classifying 63.5% of IBS patients and 6.6% of controls as hypersensitive, with allodynia in 11% and no significant difference between IBS subtypes (Ludidi 2012, PMID 22591192). The corollary is that ~36% of patients meeting criteria for IBS are normosensitive on the standard test — a heterogeneity that no treatment trial has stratified on.
  • Protocol dependence. How hypersensitivity is classified, and how well it predicts symptom severity, depends on which barostat protocol is used (Josefsson 2022, PMID 36250370).
  • Temporal stability. Re-testing 26 IBS patients 8–12 years after an index barostat study found sensitivity broadly stable at group level but with individual fluctuation (Josefsson 2019, PMID 31012215).
  • Relation to symptoms. Rectal hypersensitivity relates to bloating and distension (Agrawal 2008, PMID 18455167) and to symptom reporting generally (Kuiken 2005, PMID 16011674), but the correlation is loose enough that hypersensitivity is a group-level marker, not an individual diagnostic.

The mucosal end of the circuit

  • Neuroplasticity. In 101 IBS patients versus 23 controls, the lamina propria area occupied by neuronal-specific-enolase-positive fibres was 57.7% greater and GAP-43-positive fibres 56.1% greater, with NGF staining density up 89.3% and NTRK1 protein up 64% (p<0.05). Mucosal supernatants from IBS biopsies induced more neuritogenesis in primary rat enteric neurons and more NGF-dependent sprouting in SH-SY5Y cells than control supernatants (Dothel 2015, PMID 25655556). This is a structural peripheral abnormality in a condition defined by the absence of structural abnormality.
  • Mast cells and histamine. Mucosal immune activation — particularly mast cells and eosinophils releasing nociceptive mediators that activate sensitised afferents — is the mechanistic core of the "immune-mediated" reframing of DGBI (Vanuytsel 2023, PMID 36657961). The therapeutic test of that hypothesis is the H1-receptor antagonist ebastine: in an open-label comparison in non-constipated IBS, 40 mg beat 20 mg for abdominal-pain response (≥30% reduction: 62% vs 32%, p=0.0014; ≥50%: 40% vs 12%, p=0.0010) and reduced diarrhoea severity (p=0.0334) (Pia 2026, PMID 41603723). This is dose-comparison, open-label evidence — not placebo-controlled — and is flagged as such.
  • Enterochromaffin cells. Optogenetic/chemogenetic manipulation showed EC cells are sufficient to elicit hypersensitivity to gut distension and necessary for sensitisation by the bacterial short-chain fatty acid isovalerate; prolonged EC activation produced persistent visceral hypersensitivity "even in the absence of an instigating inflammatory episode," and perturbing EC activity produced anxiety-like behaviour that normalised with serotonergic blockade. Sex differences were observed, indicating the EC-cell–mucosal-afferent circuit is tonically engaged in females (Bayrer 2023, PMID 36949192).
  • A cellular basis for the sex bias. Estrogen upregulates the short-chain-fatty-acid receptor Olfr78 on colonic PYY-expressing L cells, increasing PYY release and acetate sensitivity; PYY then acts on neighbouring EC cells via NPY1R to enhance serotonin release and gut pain (Venkataraman 2025, PMID 41411420). This is a mouse-level mechanism proposed to explain the ~1.5–3-fold female predominance seen epidemiologically (epidemiology-and-burden).

The central end

  • Structural and functional imaging. Meta-analysis of 12 whole-brain studies (194 IBS patients, 230 controls) found abnormal resting-state functional connectivity in left inferior parietal gyrus, left lingual gyrus, right angular gyrus, right precuneus, right amygdala, right median cingulate cortex and left hippocampus, plus grey-matter alterations across fusiform, inferior frontal, supramarginal, anterior cingulate, rectus, orbital, putamen, superior parietal and precuneus regions; left middle frontal gyrus, left orbital inferior frontal gyrus and right putamen overlapped between modalities (Zhao 2023, PMID 37942144). The authors note prior studies were "divergent" — this is a field with heterogeneous small samples, and none of these findings is diagnostic at individual level.
  • Stress physiology. Corticotropin-releasing factor signalling is the best-characterised stress pathway in animal models of visceral hypersensitivity and altered colonic motility (Fukudo 2013, PMID 24021863; Meerveld 2018, PMID 29291604; Nozu 2015, PMID 25962711). No CRF-targeting drug has an IBS indication.

Directionality: the bidirectional finding, three ways

Design Population Finding
12-year prospective population cohort 1,002 Australians followed from 1997; 217 new FGID, 82 new IBS, 45 new FD Baseline anxiety (not depression) predicted new-onset FGID at 12 years (OR 1.11, 1.03–1.19, p=0.006). Conversely, in those without elevated baseline anxiety/depression, having an FGID at baseline predicted higher anxiety (mean difference 0.76, p<0.001) and depression (0.30, p=0.01) at follow-up. For IBS specifically, baseline anxiety and depression predicted IBS at follow-up (Koloski 2012, PMID 22234979)
Birth cohort, adolescence → young adulthood 3,391 subjects, IBS at 16 (paediatric Rome III) and 24 years (adult Rome IV) EQ-5D index at 16 inversely associated with new-onset IBS at 24 (OR 0.1, 0.01–0.6); psychological distress at 16 positively associated (OR 1.6, 1.2–2.3); any abdominal-pain DGBI at 16 associated with new-onset psychological distress at 24 (OR 1.7, 1.2–2.5) (Sjölund 2024, PMID 37802270)
Genetics 53,400 IBS cases / 433,201 controls, replicated in 205,252 / 1,384,055 Six loci (NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3, BAG6); genome-wide correlation with anxiety, neuroticism and depression rg > 0.5; additional analyses "suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms" (Eijsbouts 2021, PMID 34741163)

The three designs converge on the same conclusion from different directions: the gut–brain relationship in IBS is not unidirectional psychosomatic causation, and the genetic evidence specifically argues against anxiety causing the abdominal symptoms.

Genetics

Study Design Result
Eijsbouts 2021, PMID 34741163 GWAS, UK Biobank + cohorts, replication in 23andMe 6 confirmed loci; implicated genes expressed in nervous system and/or associated with mood disorders
Holliday 2014, PMID 24797007 GWAS Two novel genomic regions reported
Huang 2025, PMID 39166955 Integrative genome-wide analyses, 845,492 individuals Susceptibility analysis (see source)
Gong 2023, PMID 36753304 Genome-wide pleiotropic analysis, GI tract diseases × psychiatric disorders Shared genetic architecture of the gut–brain axis
Díaz-Muñoz 2026, PMID 41558814 Genetic dissection of stool frequency Implicates vitamin B1 metabolism and other pathways in gut motility

Effect sizes at individual loci are small and no polygenic score is clinically usable; the value of the GWAS is directional (nervous-system genes, shared mood-disorder architecture) rather than predictive.

Early-life and environmental antecedents

A systematic review of 27 studies identified recurring risk factors: parental IBS, parental substance abuse, parental punishment and rejection; low birth weight; crowded living conditions in low-income families; childhood anxiety, depression or child abuse. Emotional warmth from a parent and being born to an older mother appeared protective (Low 2020, PMID 32989183). A three-level meta-analysis of childhood maltreatment and adult intestinal disorders has since been published (Ding 2026, PMID 42312593). Environmental exposures have also been implicated at population scale: in 546,246 US veterans, IBS was associated with service after September 2001 and with reported exposure to chemical and biological warfare agents and anti-nerve-agent pills (Gasperi 2026, PMID 41489281) — an association, not a demonstrated mechanism.

Why no biomarker has emerged

Three structural reasons, each supported:

  1. Every abnormality is a group difference with wide overlap. Hypersensitivity, the most robust, misclassifies ~36% of patients and 6.6% of controls at the optimal cut-off (Ludidi 2012, PMID 22591192).
  2. Candidate biomarkers have been tested against symptom criteria and lost. Eleven biomarkers "performed no better than symptom-based criteria" in a 22-study diagnostic meta-analysis (Sood 2015, PMID 26076071); a 2026 systematic review of serological and faecal markers reaches the field again (Burns 2026, PMID 41793943).
  3. The mechanisms are not mutually exclusive and probably co-occur in individuals, so a single-analyte test is the wrong instrument (Nasser 2026, PMID 42462748).

Open questions

  • What distinguishes the ~36% of criteria-positive patients who are not rectally hypersensitive (Ludidi 2012, PMID 22591192)? A targeted PubMed search on 2026-09-02 retrieved no treatment trial stratified by barostat status.
  • Does the enterochromaffin-cell circuit operate in humans as it does in mice, and is it druggable? The mouse evidence is causal and specific (Bayrer 2023, PMID 36949192; Venkataraman 2025, PMID 41411420); no human translation exists.
  • Is mucosal nerve-fibre sprouting (Dothel 2015, PMID 25655556) a cause, a consequence, or an epiphenomenon of chronic symptom load?
  • Does ebastine beat placebo at 40 mg? The dose comparison is open-label (Pia 2026, PMID 41603723) and the mast-cell hypothesis needs a properly controlled test.
  • If IBS and anxiety share pathogenic pathways (rg > 0.5; Eijsbouts 2021, PMID 34741163), why do gut–brain neuromodulators work at doses far below antidepressant doses (gut-brain-neuromodulators)?
  • Can the three quantifiable mechanisms (bile acid metabolism, colonic transit, psychological comorbidity) be combined into a treatment-allocation algorithm (Nasser 2026, PMID 42462748)? A targeted PubMed search on 2026-09-02 retrieved no prospective test of that combined allocation rule.
  • Which of the reported early-life risk factors is causal rather than confounded by familial reporting (Low 2020, PMID 32989183)?

References

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