Highlights

• • Endogenous phenethylamine (PEA) levels are significantly elevated in IBS-D mice and correlate with diarrhea severity.
• • Exogenous PEA exacerbates diarrhea phenotypes, intestinal inflammation, and barrier dysfunction.
• • PEA disrupts tight junction protein expression and promotes proinflammatory cytokine release in the colon.
• • Activation of the colonic TAAR1-PKC signaling pathway mediates PEA-induced pathological effects.
• • Pharmacological blockade of TAAR1 with EPPTB partially attenuates PEA-driven inflammation and barrier impairment.

Full link: https://thelimbic.com/gastroenterology/provocative-prof-nick-talley-lecture-headlines-ddw/?lightbox=true&type=thanks

"Australian neuro-gastroenterologist Professor Nick Talley was one of three luminaries to present the prestigious Josephine & Michael Camilleri lecture at Digestive Disease Week (DDW) 2026 in Chicago earlier this month.

Taking on the topic ‘State of the Art in Neurogastroenterology’, Professor Talley delved into the developments and controversies in gastroduodenal disorders, including some of his personal views on the terminology used and a word of caution against following the new Rome V criteria too strictly.

Here are some of the highlights from his talk.

Call to change disorder names

Professor Talley proposed replacing the term functional GI disorder (FGID) with the term neurogastrointestinal disorder (NGID) in line with research that now offered a better explanation of the underlying pathophysiological processes.

He also suggested dropping the term functional dyspepsia and instead using chronic dyspepsia, similar to the change from functional to chronic constipation by the Rome committee.

“I hate the word functional. I’m really sorry, I think it’s pejorative and it’s a problem. Is DGBI a problem as well? Some people have suggested it might be, although I think that remains to be determined, but functional is definitely a problem,” he told delegates in the packed theatre.

“So I think we need to sort out the terminology, and I would suggest we need to have experts, patients and a consensus on this in some fashion or another.”

Challenging the prevalence of DGBI

Professor Talley said according to the epidemiology work for the Rome IV criteria, about 40% of the world had a disorder of gut-brain interaction (DGBI).

He suggested there should be better classification of the severity of DGBIs.

“If you add those with sub-threshold, there’s another 30% who are affected. It’s abnormal to be normal. It’s got to be wrong. It cannot be right. We are misclassifying ‘so called’ mild disease as disease. It’s actually mild health, and we need to think about that. So I think we haven’t done enough,” he said.

Functional dyspepsia mortality question

On the prognosis of functional dyspepsia, Professor Talley said despite being “always taught” that functional dyspepsia had no increased mortality risk, disturbing data from a nationwide Taiwanese study suggested otherwise.

“What they found is, if you’ve got IBS or functional dyspepsia for that matter, you have an increased risk of psychiatric hospitalisation, increased risk of suicide, which we never talk about, and an all-cause mortality increase as well,” he said.

“And the other piece of disturbing data… although I think it needs replication, is that the safety of antidepressants that we do use in difficult functional dyspepsia and in difficult IBS has been recently challenged in this retrospective nationwide US cohort study, where antidepressants were associated with an increased all-cause mortality.

“This has got to be replicated. This is an important question. We need to know the answer to this, and we can’t forget this is the case.”

Does epigastric pain syndrome exist?

Despite epigastric pain syndrome (EPS) being listed in the new Rome V criteria, Professor Talley posed the “challenging thought” of whether it really existed after pointing out that epigastric pain itself was not necessarily a one disease syndrome.

Differential diagnoses of non-specific epigastric pain included coeliac disease, eosinophilic gastritis/duodenitis, infiltrative diseases, abdominal wall pain, metabolic and vascular diseases, but there were many more, he stressed.

“There are many diseases and disorders that can potentially induce epigastric pain. In fact, I don’t know of a study that has really carefully excluded almost everything we know that can cause epigastric pain and then come up with what’s left as epigastric pain syndrome. I even wonder if EPS exists,” he told delegates.

New syndrome on the block 

Professor Talley highlighted ‘inability to belch syndrome’ as a new syndrome in the gastroduodenal disorder section of Rome V. Its criteria includes a bothersome inability, or impaired ability to belch at least 3 days per week with no evidence of underlying major oesophageal diseases/dysfunction that could explain symptoms.

Symptoms include chest pain, gurgling noises in the chest, bloating, flatulence and epigastric pain. Prevalence is estimated to be about 3%.

Professor Talley said the syndrome could present with classic functional dyspepsia symptoms and could help explain some oesophageal and gastroduodenal syndromes. “That is new thinking, and I think it’s important to recognise, but you’ve got to test, you cannot diagnose this purely on clinical grounds,” he said.

“The rapid drinking challenge with sparkling water is one approach you can use, which seems very reasonable and has been published on and it does seem to differentiate. You can certainly use appropriate cutoffs to make a diagnosis.”

Dr Talley suggested inability to belch syndrome was most likely an unconscious learned behavior syndrome that was “totally curable” with Botox in a subset of patients – up to 90% in the literature, although he argued this value was “too high”.

However, he added that “really exciting” emerging approaches from unpublished data suggested patients could be taught to belch for relief without a procedure.

https://www.clinicalneuropsychiatry.org/download/why-the-polyvagal-theory-is-untenable-an-international-expert-evaluation-of-the-polyvagal-theory-and-commentary-upon-porges-s-w-2025-polyvagal-theory-current-status-clinical-applications-and/

"We maintain that an erroneous belief system regarding relationships between psychological states and neurophysiology may be harmful when presented as facts to healthcare providers, patients and their families. Moreover, implausible physiological explanations are neither helpful for psychotherapists nor for the credibility of psychology, psychotherapy, psychophysiology or other related fields within medicine and neuroscience."

“In sum, PVT proposes a line of argumentation that ignores the overwhelming scientific consensus. The proposal to use an inaccurate framework and unproven measures to guide treatment of diverse vulnerable groups in society is neither scientifically valid nor ethically acceptable. The PVT framework promotes mistaken ideas about how the human mind and nervous system function together and introduces new mental fictions and fantasies about the mind-body relationship, thus contributing to greater, rather than less, distance between lived experience of psychological states and perceptions of bodily functions. Furthermore, broad influence of this scientifically inaccurate theory is likely to hinder the development, integration and true understanding of valid neuroscience and physiology research in relation to psychology and the practice of psychotherapy.”

Overview

The Rome V diagnostic framework for disorders of gut-brain interaction (DGBI) rests on three operational pillars: a positive symptom-based diagnosis, a minimal investigation workup, and the use of standard endoscopy only to clarify atypical or alarm-feature cases. This framework is increasingly incompatible with what neurogastroenterology research has established over the past two decades. A 2021 review by Holland et al. in "Cellular and Molecular Life Sciences", examining the role of the enteric nervous system (ENS) in gastrointestinal disease etiology, makes this incompatibility explicit.

This post argues that the Rome V framework, as currently operationalised, systematically prevents the evaluation of some of the most mechanistically plausible pathologies in refractory IBS and FD, renders the "positive diagnosis" epistemically indefensible for refractory patients, and perpetuates a clinical communication that the evidence no longer supports.

What Rome V Actually Does

Rome V defines IBS as recurrent abdominal pain or discomfort at least one day per week in the last three months, associated with two or more of: change in stool frequency, change in stool form, or relation to defecation. The diagnostic process is explicitly symptom-based. Investigations are recommended only to exclude organic disease (IBD, celiac disease, colorectal cancer), not to evaluate plausible mechanisms.

The endoscopy recommended by Rome in ambiguous cases evaluates the mucosa and superficial submucosa. It identifies macroscopic inflammation, neoplasia, and vascular abnormalities. It does not reach the myenteric plexus, which is located in the external muscle layer. It does not evaluate interstitial cells of Cajal (ICC), muscularis macrophages (MMφ), myenteric ganglia, or submucosal neural architecture. These are not limitations of technique alone, but structural constraints of what standard endoscopy with mucosal biopsies is anatomically capable of assessing.

The Rome framework, taken at its word, operationalises the following implicit claim: that normal colonoscopy with mucosal biopsies, standard bloods, and symptom pattern recognition are sufficient to characterise a patient's gastrointestinal disorder. However, the ENS literature demonstrates that this claim is false for a subgroup of patients.

A review of ENS role in 'DGBIs' by Holland et al. (2021) and advances by Tornblom, Boeckxstaens, Pasricha

The review by Holland, Bhave, Bhave, and colleagues in Cellular and Molecular Life Sciences synthesises evidence for ENS involvement across enteric neuropathies, DGBI, IBD, and colorectal cancer. The section on DGBI is the most clinically consequential, precisely because it describes documented pathological findings in patients who would receive a Rome-based IBS or FD diagnosis and who would be told, in clinical practice, that "there is nothing there."

The paper documents the following in patients with IBS and FD:

- Lymphocytic infiltration of myenteric ganglia: inflammatory cell infiltration at the level of the enteric plexus, inaccessible to mucosal biopsy

- Autoantibodies against neural antigens: immunological markers of active attack on enteric neurons, not evaluated in any standard workup

- Defective muscularis macrophage maturation and altered numbers: directly relevant to ENS maintenance, given that MMφ are now established as the structural guardians of enteric neurons

- Periganglionar mast cell activation correlating directly with pain intensity: mechanistic link between immune activation and visceral hypersensitivity, again inaccessible to routine investigation

- Post-infectious neuronal remodelling: documented after *Campylobacter*, *Salmonella*, and other entero-invasive pathogens, with selective damage to glutamatergic myenteric neurons

- Increased mucosal nerve fibre density: structural neuroplasticity documented in IBS tissue

The paper is unambiguous about the diagnostic implications: "ENS defects are not simple to diagnose if ganglia are present; that is not to say that the presence of ganglia averts gastrointestinal anomalies." And further: "the disturbed gastrointestinal function in DGBIs could result from subtle alterations in ENS circuitry that have gone undetected in routine clinical diagnosis", assuming directly that the pathology relevant to IBS/FD is not detectable by the investigation Rome recommends.

In 2002, Törnblom and colleagues published full-thickness jejunal biopsies in patients with severe IBS. They found enteric neuropathy: neuronal degeneration, inflammatory infiltration of myenteric ganglia, and structural ENS damage. These were patients the clinical system had declared to have "no organic pathology." This paper was never systematically replicated, because no research group had the institutional incentive, the ethical approval infrastructure, and the freedom from Rome-paradigm institutional constraints to pursue it. What Törnblom et al. established is that the category IBS with normal investigations is not equivalent to IBS without enteric pathology, but assumes that enteric pathology was not looked for with adequate instruments.

More recently, Boeckxstaens and colleagues published in Nature in 2023 a demonstration that dedicated muscularis macrophages organise and maintain the ENS through a reciprocal TGF-β signalling axis. Depletion of these macrophages during critical developmental windows produces persistent dysmotility. Disruption of the ENS-MMφ dialogue results in enteric neurodegeneration. A 2025 review in Nature Immunology by the same group concludes that *"loss of neuron-associated macrophages or an alteration in their phenotype can contribute to enteric neurodegeneration in the gastrointestinal tract, causing motility disorders."

Pasricha and colleagues at Johns Hopkins had previously documented reduced ICC and altered CD206+ macrophages in patients with FD/gastroparesis and proposed a macrophage-driven cajalopathy as a unifying mechanism. Holland et al. note this directly, asking whether gastroparesis "can therefore be considered as a macrophage-driven cajalopathy" pending further confirmation.

The MMφ literature now constitutes a mechanistic chain from immune perturbation to ENS degeneration to motility dysfunction that is documented in human tissue. None of it is evaluated in the Rome diagnostic workup. There is no clinical test for MMφ phenotype or number in the muscularis. There is no pathway in any DGBI guideline that would lead a clinician to investigate this mechanism in a refractory patient.

Also, there's evidence that autoantibodies (markers of organic autoimmune disease) are present in patients with IBS diagnosis. For example, a 2024 review in Frontiers in Physiology documents multiple autoantibodies in IBS patients with pathogenic potential:

- Anti-neuronal enteric antibodies targeting myenteric plexus antigens: detected in a proportion of IBS patients with both nuclear and cytoplasmic staining patterns.

- Anti-CdtB and anti-vinculin (Pimentel et al.): produced by molecular mimicry after enteric infection, with anti-vinculin cross-reacting with ICC, constituting a mechanistic pathway from post-infectious trigger to ICC destruction.

- Antibodies against neuronal ion channels: potentially pathogenic for enteric neuronal function.

If a patient with peripheral neuropathy had autoantibodies against neuronal antigens, they would be investigated for autoimmune neuropathy, considered for immunosuppression, and referred to a specialist with expertise in autoimmune neurology, but a patient with IBS under Rome guidance with anti-neuronal enteric antibodies receives a symptom-based Rome diagnosis and is told their nervous system is intact.

Epistemic problems with symptom based diagnosis

Rome V explicitly positions the IBS diagnosis as "positive" rather than exclusionary. This framing has important clinical consequences that are rarely examined.

A positive diagnosis implies that the diagnostic process characterises the patient's condition. In IBS, the diagnostic process characterises the symptom pattern. It does not characterise the mechanism. Given what Holland et al. document about lymphocytic myenteric infiltration, autoantibodies, defective macrophages, and post-infectious neuronal remodelling, none of which is evaluated under Rome guidance, the "positive diagnosis" is better described as a diagnosis of investigative incompleteness dressed as diagnostic certainty.

Holland et al. conclude their section with the observation that *"it is plausible that in this way particular gastrointestinal disorders now labeled as functional will eventually be identified as enteric neuropathies."The paper also states that *"the functional-organic dichotomy between some enteric neuropathies, DGBIs and IBD is possibly archaic."

The Pasricha et al."Names Matter" commentary (2025) and the January 2026 NEJM review by the Pasricha and Talley make the same argument in clinical language: the nomenclature of functional disorder is epistemically and therapeutically harmful because it forecloses investigation and communicates false certainty to patients.

Investigation adequate for refractory DGBI from a neurogastroenterological perspective would require at minimum:

1. Full-thickness biopsy of the intestine (surgically or via FTRD endoscopic device) with myenteric plexus immunohistochemistry for ICC (c-Kit/CD117), macrophage phenotyping (CD206, CD163), lymphocyte quantification, and neuronal density assessment
2. Serological screening for autoantibodies against enteric neuronal antigens, anti-vinculin, and anti-CdtB
3. Assessment of muscularis macrophage phenotype in biopsy specimens

None of these investigations is recommended, available in routine clinical practice, or mentioned in Rome V. The FTRD technique for endoscopic full-thickness biopsy has been available since approximately 2014-2016 and has been demonstrated feasible and safe in colonic and gastric tissue. The technical barrier is substantially lower than the institutional barrier.

The Rome V recommendations for DGBIs (positive symptom-based diagnosis, minimal workup, standard endoscopy for selected cases) are structurally incompatible with the neurogastroenterological evidence base as summarised by Holland et al. (2021) and contextualised by Pasricha, Talley, Boeckxstaens, Törnblom, and others across two decades of research. The incompatibility is a matter of institutional inertia, diagnostic convenience, and the structural resistance of a field to evidence that would require it to reconstruct its foundational categories.

The consequence for patients, particularly those with refractory symptoms, is that they are diagnosed with a positive disorder using instruments that cannot evaluate the most plausible mechanisms of their condition, and are then told that the absence of findings constitutes evidence of absence. The neurogastroenterological literature says otherwise.

So I've had IBS-D for about 6 years now. The usual story: went through the whole diagnostic gauntlet, colonoscopy came back clean, got the IBS label, was handed a pamphlet about fiber and sent on my way. Cool.

My triggers are honestly kind of embarrassing in how predictable they are at this point. Stress at work? Flare. Coffee? Flare. Eating literally anything with onion or garlic? Might as well cancel my afternoon. I had a work lunch last Thursday at a Thai place and spent the next 18 hours in and out of the bathroom. My coworkers probably think i have a drinking problem or something lol.

I've done low FODMAP (helped somewhat but it's miserable to maintain long term), tried rifaximin, various probiotics, l-glutamine, the whole deal. Some things take the edge off but nothing has really gotten me to a place where i feel like a normal person.

ANYWAY, I keep seeing BPC-157 come up in IBS discussions and peptide communities. I searched this sub and found a couple older threads but the responses were pretty mixed. Some people saying it's pure broscience, others saying it genuinely helped. The research I've seen is mostly animal studies which... okay, noted, but some of the gut healing mechanisms at least seem plausible?

Here's where I'm at though, even if i wanted to try it, the sourcing question is a nightmare. I'm not about to start injecting myself with research peptides from some random vendor. I've seen a few oral/tablet options pop up, like Infiniwell and Mend. But it's not cheap at all.

I guess my questions are:

1. Has anyone here actually used BPC-157 specifically for IBS (not just tendon healing or whatever) and noticed real improvement?
2. If you did oral vs injectable, did it matter?
3. Does anyone have thoughts on which brands are actually trustworthy? I saw someone in an older thread mention quality control being a huge issue with peptides in general.
4. The cancer concern (VEGF stuff), how worried should I actually be about this? I saw it mentioned here before and it kinda freaked me out.

I'm not looking for miracle cure stories necessarily, just trying to figure out if this is worth exploring or if I should save my money. At this point I've spent so much on supplements that haven't done anything that I'm getting a little jaded, but also... I'm running out of things to try so here I am.

Would really appreciate hearing from anyone who's gone down this road, good or bad results.

Highlights

•

PD microbiome shows specific taxonomic and functional changes, not large-scale differences when compared to controls.

•

IBS-C and PD share similar functional microbiome profiles, suggesting metabolic outputs may drive overlapping GI symptoms.

•

Constipation in PD may be linked to localized immune activation rather than broad immune shifts.

https://www.cghjournal.org/article/S1542-3565(26)00225-9/fulltext

Pop version: https://news.ki.se/large-rise-in-microscopic-colitis-seen-in-sweden

ABSTRACT

Background

There are few population-based studies on the incidence and prevalence of microscopic colitis (MC).

Objective

To assess incidence and prevalence of MC in Sweden.

Design

Nationwide population-based cohort study including all incident cases of biopsy-confirmed MC and all biopsied cases with normal mucosa from 1995 to 2021. Incidence rates (IRs) were age-standardized to the 2021 Swedish population. Age-specific IRs were plotted by sex. Poisson regression estimated trends and female-to-male incidence rate ratios (IRRs). A combined model of MC and normal mucosa evaluated whether changes in MC incidence exceeded background biopsy trends. Point prevalence on 31 December 2021 was derived by dividing MC cases with population denominators. Lifetime risk was computed using a competing-risk cumulative incidence estimator.

Results

We identified 22,519 incident MC cases (71% women) from 1995 to 2021. The mean age-standardized IR across the study period was 8.8 (95% confidence interval(CI)=7.1-10.5) cases per 100,000 person-years and rose steeply from 1995 until 2007 (+17% per year, 95% CI=1.15–1.19), then increased more modestly (+3%, 1.02–1.04). The incidence of MC increased faster than that of normal mucosa, the mean difference was 4.33% per year (95% CI 3.19–5.48). The prevalence of MC was 170 per 100,000 inhabitants in 2021. Lifetime risk was 1 in 54 for women and 1 in 133 for men.

Conclusion

In Sweden, incidence and prevalence of MC continued to rise through 2021. The steeper slope of MC incidence in relation to normal mucosa indicates either a true rise in disease occurrence or an ongoing diagnosis of prevalent cases related to an increased awareness of MC.

Hello everyone, I’m not sure if this has been asked before but as with anything relating symptoms, many of us are unique is some ways. I just hope someone who has had similar experiences to me can help.

I’m a 33 year old male.

So, after doing keto for 1 month in January in order to try and lower my blood sugar, I started having symptoms of tenesmus and loose stools. I brushed it off for 2 weeks then decided to go to a gastroenterologist.

They did CT scan with contrast, stool test, and blood test. CT came back normal, stool test showed no occult blood or inflammation. Blood test did showed inflammatory markers though. My doctor told me my issue was anxiety that I should speak to a psychologist. He did not officially diagnosed me with IBS but that’s the universal diagnosis I suppose. My symptoms did not improved and I got discouraged from visiting the doctor again because I went 4 times and never came out with a solution.

I ordered a GI map test in March and the results showed no detectable Akkermansia and 3 opportunistic bacteria were high. I figured ok this is probably my solution, I ordered Pendulum Akkermansia, took it for 2 weeks but my tenesmus got worse, I stopped taking it but now I’m dealing with horrible burning in the sigimoid and rectum and last night the burning sensation went up my entire GI tract, and then on random parts of my skin.

Has anyone taken that supplement and had similar experiences?

Highlights

• IBS associated with immune-mediated peripheral neuropathies
• Risk increase observed across GBS-related outcomes
• No association found with classic GBS
• Supports gut–immune–neural interaction

Abstract

Background

Irritable bowel syndrome (IBS) is recognized as a systemic disorder involving gut–brain–immune axis dysregulation, but its long-term association with immune-mediated peripheral neuropathies, including Guillain–Barré syndrome (GBS), is unclear.

Methods

We conducted a nationwide retrospective cohort study using the Korean National Health Insurance database, including approximately 2 million adults from 2012 to 2023. Incident IBS cases were identified after a 3-year washout period and matched 1:2 with controls by age, sex, and health examination year. Primary outcomes were GBS immune-mediated peripheral neuropathies and GBS and related immune-mediated peripheral neuropathies defined by ICD-10 codes; classic GBS was a secondary outcome. Cox proportional hazards models were applied.

Results

Among 141,781 patients with IBS and matched controls, IBS was associated with increased risk of the primary outcomes (incidence rate ratio, 1.57; 95% CI, 1.48–1.66). In fully adjusted models, IBS remained associated with GBS immune-mediated peripheral neuropathies (adjusted HR, 1.58; 95% CI, 1.44–1.73) and GBS and related immune-mediated peripheral neuropathies (adjusted HR, 1.50; 95% CI, 1.37–1.65), but not with classic GBS (adjusted HR, 1.25; 95% CI, 0.55–2.87).

Conclusions

IBS was associated with increased long-term risk of GBS spectrum immune-mediated peripheral neuropathies, suggesting a potential association with systemic immune-related condition.

Anyone on it? It calms the inflammation and intestines.

Dr. Falk Pharma and Renexxion announce positive results on naronapride in gastroparesis from the global phase 2b MOVE-IT trial

• MOVE-IT met the primary endpoint with statistically significant improvement in gastroparesis symptoms in 20 mg and 40 mg TID doses vs placebo
• Improvements observed across key symptoms, including nausea, early satiety, post-prandial fullness and upper abdominal pain
• Favorable safety and tolerability profiles
• Late-breaking oral presentation delivered at Digestive Disease Week (DDW) 2026 in Chicago, IL.

Freiburg, Germany and Roscrea, Ireland – May 4, 2026 - Dr. Falk Pharma GmbH (“Dr. Falk Pharma”), a research-based pharmaceutical company specializing in digestive and metabolic medicine, and Renexxion Ireland Limited (“Renexxion”), a clinical-stage biopharmaceutical company, today announced positive results from MOVE-IT (NCT05621811), a global Phase 2b, randomized placebo-controlled trial evaluating the efficacy, safety, and tolerability of naronapride in adults with gastroparesis.

The double-blind, multicenter, 12-week study enrolled 328 adults with moderate-to-severe idiopathic or diabetic gastroparesis symptoms and objective evidence of delayed gastric emptying. Eligible patients received either 10 mg, 20 mg, 40 mg naronapride, or placebo, administered orally three times a day (TID) for 12 weeks. 

MOVE-IT met the primary endpoint, demonstrating statistically significant improvement versus placebo in the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary (ANMS GCSI-DD) Core Symptom Score in the 20 mg TID (p=0.0046) and 40 mg TID (p=0.0156) groups. The ANMS GCSI-DD is a content-validated, patient-reported outcome instrument that assesses the five cardinal gastroparesis symptoms: nausea, vomiting, early satiety, postprandial fullness and upper abdominal pain.

Abstract

The comorbidity of overactive bladder (OAB) and irritable bowel syndrome (IBS) presents a major clinical challenge, with the underlying neural and microbial mechanisms of the gut–bladder axis poorly understood. Here we aimed to delineate the complete causal pathway from a specific gut microorganism to bladder dysfunction and validate it as a therapeutic target. We combined analysis of human OAB–IBS cohorts with a postinflammatory mouse model, integrating retrograde neuronal tracing, multiomics (16S rDNA and metabolomics), fecal microbiota transplantation, urodynamics, dorsal root ganglion (DRG) electrophysiology and pharmacological and/or surgical interventions. We first confirmed a direct anatomical link, identifying dichotomized DRG neurons co-innervating the colon and bladder. Patients with OAB–IBS and mice exhibited a shared gut dysbiosis characterized by Akkermansia muciniphila enrichment. This comorbidity occurred in the absence of local bladder inflammation or urinary colonization with A. muciniphila, confirming a functional, noninfectious mechanism. Fecal microbiota transplantation of A. muciniphila or patient microbiota causally exacerbated visceral hypersensitivity, the OAB phenotype and DRG hyperexcitability. Mechanistically, A. muciniphila enrichment shunted host tryptophan metabolism toward the serotonin (5-HT) pathway. The resulting excess 5-HT acted on specifically upregulated colonic 5-HT3a receptors to drive neuronal sensitization. Crucially, pharmacological blockade of the colonic 5-HT3a receptor or surgical severing of the mesenteric nerves reversed the bladder dysfunction and visceral hypersensitivity. Our findings delineate a novel pathway wherein A. muciniphila drives functional gut–bladder comorbidity by promoting a gut-derived serotonergic signal that sensitizes shared afferent neurons, establishing the gut-specific 5-HT3a receptor as a key, druggable therapeutic target.