https://www.sciencedirect.com/science/article/abs/pii/S2095927326003282?via%3Dihub

Abstract

Intestinal mucosal secretion is central to coordinating the gut microenvironment with mechanical signals. Yet, in situ monitoring of small-molecule in the intestine remains challenges because of the distinctive mechanical deformation and highly biofouling environment. Here, we introduce a sensing interface inspired by the host-guest molecular recognition. A stretchable electrode was constructed by co-electrodepositing 2-hydroxypropyl-β-cyclodextrin (HC) and poly(3,4-ethylenedioxythiophene) (PEDOT, P) onto the conductive gold nanotubes (Au NTs) framework. This approach couples the deformation-tolerant electrochemical performance of Au NTs with HC-enabled selective recognition of serotonin (5-HT), while effectively mitigating biofouling in complex biological environment. The resulting Au@HCP NTs sensor enables dynamic capture of mechanically evoked 5-HT release from enterochromaffin cells (ECs) under biomimetic stimulation, spanning both cellular and tissue-level readouts. Beyond monitoring, we further conceptualize ECs mechanosensory plasticity as an immunomodulatory node. Diverse microbial mimetics elevate ECs-derived 5-HT, and the platform reveals 5-HT signaling as a core mechanism that integrates immune information with mechanosensation in ECs. Collectively, this work establishes a host-guest recognition-based strategy for real-time small-molecule monitoring in complex, mechanically dynamic environments, offering a generalizable route toward in situ sensing under unique mechanical demand.

URL: https://journals.healio.com/doi/10.3928/00485713-20250916-01

DOI: https://doi.org/10.3928/00485713-20250916-01

https://news.ddw.org/news/the-science-of-ibs-and-sibo-emerging-tools-refine-diagnosis-and-personalize-care/

Irritable bowel syndrome (IBS) and related small intestinal bacterial overgrowth (SIBO) carry a burden that is easy to underestimate, according to neurogastroenterologist Sean Spencer, MD, PhD, assistant professor of medicine at Stanford University. “These disorders may not shorten lifespan, but they can profoundly affect patients’ daily lives,” Dr. Spencer said. “The degree to which symptoms disrupt work, sleep, diet, social activities and emotional well-being is a major burden — one that can significantly reduce healthspan.” And, he added that it can be difficult for GI providers as well, because of the complexity involved in pinpointing the source of patients’ symptoms and finding a path to help them.

In his presentation at Digestive Disease Week® (DDW) 2026, he described how advances in our understanding of these conditions’ underlying physiology and the emergence of new diagnostic and therapeutic approaches are helping clinicians and patients grapple with these disorders.

Food, microbiome and immunity

Part of the clinical challenge lies in how the conditions are conceptualized, Dr. Spencer said. While they’re now formally called disorders of brain-gut interaction, “IBS and SIBO are really disorders of the food-microbiome-immune-brain-gut interface.”

This distinction illuminates two pathways by which dietary triggers can produce symptoms, so understanding their interplay is essential to selecting the right intervention, he said. “Some dietary intolerances can be mediated by the immune system as well as by the microbiome. In some cases, the underlying cause for their symptoms can be something that’s fixable outside of food.”

Emerging innovations on the horizon

The low-FODMAP diet remains a cornerstone of IBS intervention with its evidence-supported structured elimination followed by systematic reintroduction. For SIBO, breath testing — or, less commonly, direct small bowel aspirate — is a diagnostic modality, followed by treatment with antibiotics. But these approaches have limits.

“Providers should try the FODMAP diet but should really be thinking holistically when a patient presents with IBS symptoms because their complex physiology can sometimes be driving a food intolerance,” he said.

Two categories of innovation are expanding the toolkit available to clinicians. Confocal laser endomicroscopy (CLE)-based food intolerance testing (C-FIT) is a mucosal testing approach that’s particularly relevant for patients who fail to respond to the low-FODMAP diet, Dr. Spencer said. Early literature suggests C-FIT may identify immune-mediated food sensitivities that conventional approaches miss, helping clinicians distinguish immunologic from microbiome-driven intolerance.

Enzyme-based therapies targeting specific FODMAP components offer another promising avenue. Research on IBS patients without celiac disease showed that they can react to a wheat component called fructan rather than to gluten. “It may not actually be non-celiac gluten intolerance. It may be non-celiac wheat fructan intolerance,” he said. Adding a powder containing a fructan-degrading enzyme to their food may help people with this sensitivity regain their ability to enjoy meals and dine out socially; ongoing studies are testing this.

The field now has the capacity — and the obligation — to move in a more personalized and mechanistically grounded direction, Dr. Spencer concluded. “These newer approaches are going to be really important going forward to help providers move beyond trial-and-error approaches toward identifying the underlying cause driving an individual patient’s symptoms” he said.

10.1053/j.gastro.2026.04.039

Background

Fecal microbiota transplantation (FMT) could improve symptoms of irritable bowel syndrome (IBS) in some previous trials. We updated a prior meta-analysis of randomized controlled trials (RCTs) determining this issue.

Methods

We searched CENTRAL, MEDLINE, and Embase (via Ovid) from inception to February 20^(th), 2026 to identify potential studies. We included RCTs that reported the proportion of patients with IBS symptom improvement assessed between 4 and 24 weeks after FMT. For primary outcome, we estimated risk ratios (RR) of proportion of patients with IBS symptoms not improved. Data were pooled using a random effects model. The certainty of evidence was assessed using GRADE.

Results

Thirteen RCTs involving 693 patients were eligible for this review. For the intention-to-treat analysis, FMT may reduce IBS symptoms at 12 weeks compared with placebo, but the evidence is very uncertain (RR of symptom not improved with FMT compared to placebo = 0.72; 95% CI 0.50–1.03). However, in the per-protocol analysis, FMT was statistically significant at improving symptoms (RR 0.67; 95% CI 0.46–0.97). Overall adverse events were not different in both groups (RR 0.98; 95% CI 0.75–1.29). The subgroup analysis reported IBS symptom improvement using single dose of FMT (RR 0.62; 95% CI 0.41–0.93), and when IBS was diagnosed by Rome IV criteria (RR 0.38; 95% CI 0.17–0.86).

Conclusions

This systematic review suggested there was very low certainty of evidence that FMT improved IBS symptoms. FMT was effective in some subgroup analyses and in the overall per protocol analysis but this needs to be interpreted with caution.

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://news.ddw.org/news/moving-beyond-the-fishing-expedition-in-chronic-diarrhea/

Fortunately for the 179 million people in the U.S. who experience diarrhea in a given year, their distress usually resolves fairly quickly. However, a subset of people struggles with diarrhea lasting four weeks or more, and the condition is then called chronic diarrhea.

While guidelines provide clinicians some guidance for appropriate diagnosis and treatment, one expert contended in a session at Digestive Disease Week® (DDW) 2026 that the guidelines are outdated and provide clinicians with recommendations that lead to imprecise, trial-and-error treatment that delays relief for patients*. DDW News* asked that expert, Michael Camilleri, MD, DSc, of the Clinical Enteric Neuroscience Translational and Epidemiological Research Program at Mayo Clinic, to share more on his perspectives.

DDW: What are the main issues with current approaches to chronic diarrhea?

Dr. Camilleri: If we don’t go through the appropriate diagnostic thinking process and objective testing that is available, we may assume the chronic diarrhea is due to irritable bowel syndrome with diarrhea (IBS-D). Many patients are simply labeled with IBS-D.

And then the guidelines, which are rather out of date, send clinicians off on a sequence of trial-and-error therapies without requiring a definitive diagnosis first that would better personalize treatment. That’s why we need to “get the BS out of IBS-D,” as was suggested in a paper by other experts in the field.

DDW: What alternative approaches to diagnosis do you propose?

Dr. Camilleri: At present, the guidelines send us off on a fishing expedition. I’m saying we can do better. We can get a firm diagnosis and individualize treatment for each patient.

Several treatable etiologies are underrecognized, including bile acid diarrhea, accelerated colonic transit, celiac disease and lactose and sucrose malabsorption. Individually, these may be relatively uncommon, but together they may account for 10% to 20% of patients seen by gastroenterologists in clinical practice.

Diagnosis is now much simpler than in the past. There is now a rapid combined screening blood-and-stool test for bile acid diarrhea. There is also an effective test for rapid colonic transit. However, these tests have either not been widely available or have only recently become available. The scintigraphic colonic transit test is available in only a few medical centers, but investigators in Sweden have validated a test for rapid colonic transit based on radio-opaque markers. Another factor is that there hasn’t been enough emphasis in guidelines or practice updates on these alternative diagnoses or on making clinicians aware of the diagnostic opportunities now available.

DDW: You emphasize that treatment can be better tailored. What does that entail?

Dr. Camilleri: Treatment should align with the underlying mechanism. For rapid transit, we have simple medications like loperamide available over the counter. For bile acid diarrhea, there’s strong evidence for bile acid sequestrants such as cholestyramine, colesevelam and colestipol. An important point about these sequestrants is timing – they should be taken before bedtime, so bile acids are sequestered and don’t damage the colon lining overnight and result in chronic diarrhea.

There’s also an approved medication, alosetron, which is rarely used but highly effective based on clinical trials. On rare occasions, it can cause a form of superficial, not transmural, ischemic colitis. It carries a black box warning, which deters clinicians, although the risk is very low. When you look at the evidence – particularly based on network meta-analyses – alosetron and related 5-HT3 antagonists rank among the most effective treatments.

DDW: What would you emphasize as the key takeaway for clinicians?

Dr. Camilleri: Move away from empiric fishing expeditions and toward precision medicine. When we have the ability to make a specific diagnosis, we should be making it so that we can provide more specific treatment. If you get the right diagnosis, then the treatment approach is often plain and obvious.

https://onlinelibrary.wiley.com/doi/10.1111/jnc.70461

ABSTRACT

Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis, satiety and gastrointestinal (GI) motility through interaction with its receptor (GLP-1R). While central GLP-1 pathways are well studied, the distribution and functional role of GLP-1R within the human enteric nervous system (ENS) remain unclear. We characterised GLP-1R expression across the human GI tract, examining its anatomical localisation among distinct enteric neuronal subtypes. Non-inflamed, full-thickness human GI tissues (antrum, ileum, ascending, descending and sigmoid colon; N = 30, 5 different human samples per region) were obtained from surgical resections and analysed using immunohistochemistry, epifluorescence and confocal microscopy. Mean number of positive pixels of GLP-1R and PGP9.5 was quantified in mucosal varicosities, muscle, submucosal and myenteric plexuses. GLP-1R co-localisation with neuronal markers (PGP9.5, nNOS, ChAT, Substance P, CGRP, Calretinin, HuC/D) was assessed. Quantification used Mander's coefficient, and statistical analysis used one-way ANOVA with Tukey's post hoc test. GLP-1R was expressed abundantly in ENS structures, including mucosal varicosities, muscle, submucosal plexus and myenteric neurons throughout the lower GI tract, with significantly higher expression in the colon compared to the stomach and ileum (p < 0.05). Co-localisation analyses revealed preferential GLP-1R expression in nNOS-expressing inhibitory neurons and CGRP-expressing varicosities, moderate expression in calretinin-expressing neurons, and sparse expression in ChAT-expressing and substance P-immunoreactive excitatory neurons. Whole-mount confocal imaging confirmed GLP-1R localisation to HuC/D-immunoreactive neuronal cell bodies with punctate, membrane-associated staining. GLP-1R is differentially expressed across the human ENS, with increased expression in inhibitory neurons and putative extrinsic sensory afferents, particularly in the distal colon. This suggests that peripherally released GLP-1 acts locally within the ENS to regulate motility and sensory signalling, underpinning both its physiological functions and the gastrointestinal side effects of GLP-1-based therapies.

https://preview.redd.it/wdws55degv1h1.png?width=1985&format=png&auto=webp&s=a4b20a21ec6d11033e85667173163402c11fcc17

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.

https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2982.2008.01099.x

Abstract

Abstract Advances in minimally invasive surgery have made laparoscopy and full-thickness bowel biopsy possible in the investigation of patients with suspected gastrointestinal neuromuscular disorders. The safety and diagnostic yield of this investigation have not been formally reported. A prospective study was undertaken of 124 patients with clinico-physiological diagnoses of chronic intestinal pseudo-obstruction, enteric dysmotility and severe irritable bowel syndrome undergoing LFTB in three European teaching centres with expertise in the management of gastrointestinal neuromuscular disorders. Perioperative data were collected including complications. Diagnostic yield was expressed as proportion with well-established specific neuromuscular abnormalities based on a protocol of routine and immunohistochemical techniques. The majority of patients underwent a laparoscopically assisted procedure with extracorporeal biopsy. Median operating time was 50 min, conversion rate 2% and length of stay 1 day. There was an 8% readmission rate for obstructive symptoms but minimal other morbidity and no mortality. Overall specific diagnostic yield was 81%, being high for jejunal biopsies (89%) but low for a small number of ileal and colonic biopsies. Laparoscopy and full-thickness biopsy of the bowel appears acceptable in terms of safety. It should be performed in a jejunal site to achieve a high diagnostic yield.

https://voices.nejm.org/doi/full/10.1056/VOICESpost2600008

"Let’s begin with three scientific facts:

1. The vast number of microbes that inhabit our body — the bacteria, fungi, viruses — have an enormous influence on sickness and health.

2. This microbiome is a fascinating area of scientific exploration, with new discoveries coming all the time.

3. The for-profit companies offering microbiome testing of your poop are full of s--t.

That’s the only conclusion I can draw from an important study recently published in Communications Biology. It confirms an impression I already had after reviewing the glossy, expensive reports patients occasionally bring to clinic.

Here’s what the investigators did: they sent identical stool samples to seven direct-to-consumer microbiome testing companies. If these tests were reliable, you’d expect similar results.

Instead, here’s what they found:

• Each testing service reported very different microbial profiles. In some cases, they didn’t even agree on which organisms were present.

• The differences between companies were as large as — or larger than — the differences seen between entirely different individuals. In other words, your “gut health snapshot” may say more about the lab than about your gut.

• The interpretations were all over the map. Different companies could label identical samples as both “healthy” and “unhealthy.”

• Recommendations based on the same sample were widely divergent.

If you’re wondering what kind of advice and claims accompany these reports, here are some typical examples, lightly adapted from actual ones I’ve seen:

Probiotic Replacements: A “deficiency” in a genus like Akkermansia or Bifidobacterium is identified — followed immediately by a recommendation to purchase a proprietary blend containing those organisms. Note the use of long, fancy-sounding bacterial names, which adds an aura of scientific credibility.

A Subscription Model: The software often defaults to a recurring monthly shipment. Justification for these ongoing purchases conveniently includes the need for “rebalancing” your microbiome in the setting of alterations that occur due to dietary and other environmental pressures.

The “Precision” or “Personalized” Claim: The marketing leans heavily on words like personalized, bespoke, and customized. This is hard to square with the fact that different companies make different recommendations on the same sample.

Yes indeed — supplement and probiotic purchasing advice frequently tops the list of recommendations; it’s all part of an ongoing (and auto-renewing) “journey” to optimal gut health. To give you an idea of how this works to maximize the chance of further profits, here’s an example of what you’ll receive (again, lightly adapted from those I’ve come across):

• Over 30 detailed health scores

• Hundreds of personalized food and drink recommendations

• A clear look at how your gut microbiome affects your overall health

• Option to buy custom-made supplements and carefully selected pre- and probiotics

Surprise, surprise: the same companies (or their affiliates) that analyze your sample will sell you the products they recommend. Is it any wonder this is the very definition of a burgeoning market, projected to reach $2.26 billion by 2030?

The Untapped Potential

There’s a deep irony in this story, one that my ID colleague Dr. Elizabeth (Libby) Hohmann rants passionately about on a regular basis. The microbiome is one of the most promising frontiers in medicine. Some careful, hypothesis-driven research could meaningfully influence conditions ranging from gastrointestinal disease to cardiovascular, musculoskeletal, and even neuropsychiatric health.

But that kind of science is hard. It requires time, funding, rigor, and a willingness to accept failure. So if you’re a for-profit company, which path would you choose?

• The slow, expensive, evidence-based route with controlled trials, regulatory oversight, and uncertain payoff?

• Or the fast, largely unregulated “wild west” of the wellness market, where you can sell tests, interpretations, and supplements directly to consumers?

Exactly.

So What Should We Tell Our Patients?

When patients bring in these reports — often beautifully formatted, quite expensive, and sometimes colorfully displayed on their phone app — I usually start by agreeing with the premise that the microbiome matters, and we’re learning more about it every year. I throw in some concise dietary advice, courtesy of this Michael Pollan classic: “Eat [real] food. Not too much. Mostly plants.”

Or, to quote my friend Libby: “Spend your money on good food, not supplements or probiotics.”

Then I quickly inform them that we’re not at the point where these tests can provide reliable, actionable information. The same sample can yield different results depending on the company — and there’s no consensus on what “normal” even looks like, or what actions (if any) are appropriate based on these results.

That’s a kinder, gentler way of saying that the results are worth no more to the consumer than the specimen they sent in.

https://www.nature.com/articles/s41467-026-72093-5

Abstract

Antibodies are central mediators of the adaptive immune response, and they are powerful research tools and therapeutics. Antibody discovery requires substantial experimental effort, such as immunization campaigns or in vitro library screening. Predicting antibody-antigen binding a priori remains challenging. However, recent machine learning methods raise the possibility of in silico antibody discovery, bypassing or reducing initial experimental bottlenecks. Here, we report a virtual screen using AlphaFold-Multimer (AF-M) that prospectively identified nanobody binders to MRGPRX2, a G protein-coupled receptor (GPCR) and therapeutic target for the treatment of pseudoallergic inflammation and itch. Using previously reported nanobody-GPCR structures, we identified a set of AF-M outputs that effectively discriminate between interacting and non-interacting nanobody-GPCR pairs. We used these outputs to perform a prospective in silico screen, identified nanobodies that bind MRGPRX2 with high affinity, and confirmed activity in signaling and functional cellular assays. Our results provide a proof of concept for fully computational antibody discovery pipelines that can circumvent laboratory experiments.

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.

https://www.jpain.org/article/S1526-5900(25)00881-8/abstract [Abstract presented at the 2026 USASP Annual Scientific Meeting]

Abdominal pain is the primary comorbidity in patients with irritable bowel syndrome (IBS). Proteases and histamine, originating from intestine mast cells and/or microbiota, are known to increase colonic nociceptors excitability to cause pain. However, the effects of their combined signaling and the mechanisms involved have not been studied. We hypothesize that proteases and histamine present in fecal supernatants (FS) from IBS patients activate protease-activated receptor-2 (PAR2) and histamine receptor-1 (H1R) signaling to synergistically enhance colonic nociceptive signaling to cause abdominal pain. Luminal application of IBS-FS increased colonic afferent nerve mechanosensitivity in mice by 50% (p <0.001), this effect was blocked by either PAR2 (GB83) or H1R (pyrilamine) antagonists. Co-expression of PAR2 and H1R in human and mouse nociceptors was confirmed with RNAScope in-situ hybridization. Trypsin and histamine at subthreshold concentrations alone had no effect. However, their co-application increased afferent mechanosensitivity (46%; p <0.001). Similarly, their co-application increased dorsal root ganglion (DRG) neural excitability in patch clamp recordings by 33% (p <0.05) but have no effect alone. Pre-activation of PAR2 enhanced histamine-induced excitability and was prevented by endocytosis inhibitors, pistop2 and dyngo4a. Likewise, bioluminescence resonance energy transfer (BRET) measurements in HEK cells expressing PAR2 and H1R showed that trypsin amplified histamine-induced mGαq and β-arrestin2 recruitment to the plasma membrane and early endosomes. In contrast, pre-activation of H1R does not enhance trypsin induced hyperexcitability. Our findings revealed a novel pathway where protease-mediated PAR2 endosomal signaling amplifies histamine-induced pain signaling. These findings may inform future studies on therapies and biomarkers for IBS.

In a session at DDW 2026, Professor Nicholas Talley traced a historical evolution of these conditions, stating that some of them remain, in clinical practice, as they were in 1910 (citing the case of functional dyspepsia).

Source: https://x.com/PaulMoayyedi/status/2051332009482498284/photo/1

Changing the terminology used to describe these conditions is fundamental, but can only occur if accompanied by pathophysiological investigation and targeted treatments.

Today, there are new testable models proposed, but Rome V ignores them in its introductory chapter and theoretical definition.

Source: https://x.com/GI_NutritionFdn/status/2051326263369842897

Furthermore, Talley criticized the fundamentalism imposed by diagnostic criteria such as Rome V.

Source: https://x.com/PaulMoayyedi/status/2051329214201078167