Highlights

• • Among all innervated organs, the stomach is most heavily innervated by the vagus nerve.
• • Vagal efferent control uses molecularly distinct pathways mediating excitation and inhibition of stomach functions.
• • Vagal sensory neurons have distinct molecular fingerprints and unique morphologies and functions.
• • Further research on the organization of the peripheral and central interfaces is needed to understand the coding logic.

Abstract

The stomach is one of the major targets of the vagus nerve. Vagal cholinergic parasympathetic (efferent) neurons are located in the dorsal motor nucleus of the vagus (DMV) in the caudal brainstem. They do not directly innervate gastric effector cells, but instead a large portion of enteric neurons located in the myenteric plexus, which act as muscle motor neurons and function-specific pattern generators that can regulate specific motility and secretion programs in coordination with physiological needs and environmental conditions. Vagal sensory (afferent) neurons located in the nodose ganglia (NG) innervate all layers of the stomach wall, where they pick up mechanical and chemical signals to inform the brain and effectuate vago-vagal reflexes. The most abundant terminal structures, intraganglionic laminar endings (IGLEs), are in intimate contact with myenteric plexus neurons. Besides sensing gastric tension, they are likely also chemosensors and provide a link between the enteric nervous system and the brain. Transcriptomic analyses of vagal efferent and afferent neurons allowed making great progress on deciphering their respective coding logic, with a predominantly labeled line organization emerging as the general principle. Because of their distinct molecular fingerprints, separate populations of vagal efferents and afferents with unique morphologies and functions have become experimentally and therapeutically accessible. However, the full coding logic also depends on the organization of the peripheral interface with the enteric nervous system, as well as the central interface represented by 2nd and higher order sensory neurons and pre-autonomic neurons upstream of the DMV, which are only starting to be understood.

Abstract

Methods

We sensitized mice to different foods (dairy and gluten) after intestinal inflammation (chemically- and hapten-induced models), then mice were re-exposed to the sensitizing foods through diet enrichment. To study whether inflamed microbiota facilitates adverse food reactions, we employed gnotobiotic models and bacterial supplementation experiments. We assessed markers of intestinal inflammation and sensitization, clinical responses, RNA transcripts, and microbiota composition and function. In a translational approach, we recruited IBD patients in remission and healthy controls, recorded self-reported food intolerances and clinical responses to triggering foods, and collected feces for gut microbiota analyses.

Results

Intestinal inflammation facilitates food sensitization by disrupting microbial antigen metabolism, recruiting mast cells to the colon, and favoring IgE production. In gnotobiotic models, inflammation-driven depletion of colonic bacteria involved in food digestion contributed to food sensitization. Upon re-exposure to triggering foods, sensitized mice experienced visceral pain and low-grade inflammation through mast-cell mediated mechanisms, which also worsened experimental colitis. Supplementation with depleted bacteria or treatment with mast cell stabilizers attenuated food-driven responses. In IBD patients, self-reported food intolerances were common and associated with microbial disruption and depletion of food-metabolizing bacteria.

Conclusion

Microbial metabolism of foods is disrupted after intestinal inflammation. This facilitates food sensitization, through colonic mast cell-mediated immune responses, which may explain the high number of adverse food reactions reported by IBD patients.

Full paper: https://www.nature.com/articles/s41572-026-00741-7.epdf?sharing_token=uDMKTmvmeZmrmUKwtcfNbNRgN0jAjWel9jnR3ZoTv0NOueCKVhgknnNmNF6-Lw7-ps37W84ZHIaDcXePiND5_txcdwi0wst907LGtMLDLC8h5ckNMjemicCl6HJdI4mZQou0WM4Lb3pGe7oZxkRAKTI9vWcGV4uZ5gklswV-RJ8%3D

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent disorders of gut–brain interaction, characterized by recurrent abdominal pain or abdominal discomfort associated with altered bowel habits in the absence of identifiable structural disease. IBS affects ~4–11% of the global population and is associated with substantial healthcare utilization, impaired quality of life and considerable socioeconomic burden. IBS is increasingly recognized as a heterogeneous condition caused by dysregulated bidirectional communication within the gut–brain axis. Altered gastrointestinal motility, visceral hypersensitivity, epithelial barrier dysfunction, neuroimmune activation, gut microbiome and metabolome changes, central pain amplification, stress and autonomic dysregulation, and sex-related biological influences underlie pathophysiological mechanisms. IBS can develop after a gastrointestinal infection and can frequently co-occur with other disorders of gut–brain interaction, chronic pain conditions, psychological disorders and organic gastrointestinal disorders such as inflammatory bowel disease and coeliac disease. Diagnosis relies on a positive symptom-based approach using the Rome V criteria, supported by clinical assessment and limited testing to exclude differential diagnoses. Management focuses on improving symptoms and quality of life through an individualized, stepwise approach that involves patient education, dietary interventions, pharmacological therapies and gut–brain behaviour therapies. Emerging biomarkers, multi-omics approaches, digital health tools and precision medicine strategies may enable mechanism-based diagnosis and targeted treatment in the future.

Abstract

For decades, we have known that women, especially younger women, are disproportionately affected by pain disorders, including irritable bowel syndrome, endometriosis, menstrual migraines, fibromyalgia, osteoarthritis, and neuropathic pain, all of which degrade quality of life. The adoption of sex as a biological variable in 2016 has begun to transform the field, revealing distinct sex-specific pathways that initiate, amplify, and resolve pain. In this Review, we synthesize recent advances across visceral and somatic pain, highlighting the impact of sex hormones, immune-neural cross-talk, the gut microbiome, and endogenous analgesic circuits. Rather than clinging to the historical standard that simply described the female bias in pain symptoms, these studies begin to explain why females experience heightened pain, paving the path for mechanism-based precision therapeutics.

[Not full text, yet]

We thank Drs Barboi and Macefield for their insightful views regarding renaming the autonomic nervous system. We agree there is only one nervous system. Further, we'd like to add to this by discussing what is being alluded to but not explicitly stated. Our case for returning 'autonomic' is compelling: automaticity is not peculiar to visceral motor pathways, somatic and visceral circuits are both sensorimotor, and integration is distributed across ganglia, spinal cord and brain (Barboi & Macefield, 2025; Macefield & Barboi, 2026). Yet replacing sympathetic and 'visceral cranial' and 'visceral spinal' nerves leaves one nineteenth-century assumption untouched – the idea that the brain and spinal cord are intrinsically central, while the neural apparatus of organs, like the gut is peripheral.

'Central' can mean at least three different properties: location on the bodily axis, topological position in a causal network, or phylogenetic and physiological primacy. The brain and spinal cord are central by the first definition because anatomy made it so. That does not establish either of the others.

The skull is a container, not evidence of causal sovereignty. We therefore propose a deliberately physiological coordinate system: the enteric nervous system (ENS) is the most peripheral, whereas the brain and the spinal cord constitute the neural-nervous system – an extra-enteric apparatus for distant sensing, movement, prediction, memory and action (Fig. 1). This does not deny cortical cognition; it asks what those capacities ultimately serve. Here, 'core' identifies a chosen coordinate origin at the alimentary interface, not a sole homeostatic controller. Hypothalamic, brainstem and spinal circuits remain indispensable for thermoregulation, cardiorespiratory coordination and oxygen delivery, acid–base balance, systemic fluid–electrolyte homeostasis and coordinated elimination.

The phylogenetic evidence is supplied by Dr Kramarik's defence of traditional terminology (Kramarik, 2026). Primordial organisms (like Hydra), he observes, have no brain. Yet they possess sensory, smooth-muscle elements; interstitial plexuses can function on their own but can be modulated by extrinsic signals. The cnidarian Hydra first emerged 600 million years ago. It is not a proxy for a vertebrate ancestor. But its organisation is instructive. Its ectodermal and endodermal neurons form spatially distributed, synaptically interacting networks without a cephalised brain or ganglion; predating the evolution of the brain and spinal cord by around 50 million years. Whole-body imaging in Hydra reveals functional modules associated with feeding, elongation, contracting, stretching and somersaulting, while transcriptomic analysis and modelling suggest an additional dense, distributed neuropeptide-GPCR communication network. Feeding is therefore not the network's only task. Learning-like responses have also been reported (De La Cruz Roetzenhuber et al., 2026; Hanson, 2023; Yuste, 2024). Hydra can survive experimentally after loss of neurons, although coordinated movement is impaired. While the CNS provides separate cardiovascular and respiratory systems, it demonstrates distributed neural coordination, not the sufficiency of a gut-like network for vertebrate homeostasis.

Furness and Stebbing's comparative analysis across animal groups, including animals without a CNS, inferred that an ENS-like neurovisceral system arose before and independently of the CNS – the first brain (Furness & Stebbing, 2018). Therefore, evolutionary age alone does not privilege the CNS. The 'first brain' is a functional metaphor, not a claim of direct homology. Chemical coordination and adaptive behaviour predate cephalised nervous systems and even neurons, as illustrated by learning-like adaptation in single-celled organisms and by synaptic proteins with pre-animal origins (Colgren & Burkhardt, 2022; Dussutour, 2021). Vertebrate enteric neurons are predominantly neural-crest derived, whereas cnidarian neurons develop in a different embryological context; the progressive restriction of neural-crest fates does not imply continuity from a Hydra-like ancestor (Soldatov et al., 2019). But pre-existence joined to conserved architecture, transmitters and trophic dependencies shows the organism's principal nutrient-matter interface is more than an age. From this perspective, cephalisation added devices for finding, acquiring and protecting what the gut must transform: sensation locates resources, locomotion reaches them, reward values them and memory predicts them. This is a functional and comparative coordinate system, not a claim of embryological priority in vertebrates.

The ENS approaches the criteria for a true ANS most closely in the small intestine and much of the colon, but its autonomy is conditional. Enteric circuits comprise intrinsic sensory neurons, interneurons, and excitatory and inhibitory motor neurons; it is embedded in glial, epithelial, endocrine, immune and microbial networks that coordinate digestion and defence (Sharkey & Mawe, 2023). Isolated bowel can generate complex neurogenic motor patterns without neural input (Spencer & Hu, 2020). The regional syntheses by Furness and colleagues provide the clearest corrective to any categorical autonomy claim: CNS control is essential in the oesophagus and internal anal sphincter; modest in the stomach and distal colon than in the small intestine; coordinated rectal evacuation also depends on lumbosacral and pelvic pathways (Furness et al., 2014; Furness, Murdland et al., 2026). Prof. Langley eventually conceded that 'autonomic' implied too much independence – yet perhaps for the neural apparatus within the alimentary wall, Drs Barboi and Macefield retain ENS as a useful term. Perhaps their exception could become the centre of the model: extrinsic nerves are not the source of autonomy, they tune a network already capable of sensing, integrating and acting.

[Automatic translation from Norwegian to English via Deepseek]

"Over half a million Norwegians have the condition irritable bowel syndrome (IBS).

For many, it involves major stomach and intestinal problems, reduced quality of life, and can affect both physical and mental health.

There is no effective cure. But for many years, IBS patients have hoped that research on fecal transplantation (FMT) would produce results.

The treatment involves introducing stool from a healthy donor into the patient’s intestine.

Previous studies have shown very good results.

But the largest study ever now concludes that stool from healthy donors does not provide symptom relief in patients with IBS.

The findings are being presented in the renowned journal The Lancet on Friday.

Equally large effect in the placebo group

– This is surprising. Initially, we expected to have findings from previous studies confirmed, says doctor and associate professor Peter Holger Johnsen.

He works at the University Hospital of North Norway (UNN) in Harstad and UiT The Arctic University of Norway.

– The study unfortunately shows that this treatment has no effect compared with placebo. We do not recommend fecal transplantation as a treatment for IBS. Previous studies have been small and inconsistent, while this is a large and thoroughly conducted study that provides a far more reliable answer as to whether the treatment works. 450 patients participated in the study. Two-thirds received stool from a healthy donor. One-third received only their own stool, i.e., placebo.

Almost as many in the two groups experienced improvement in symptoms, such as abdominal pain, diarrhea, and constipation.

40 percent of those who received donor stool experienced symptom relief after three months.

38 percent in the placebo group experienced exactly the same improvement. That so many in both groups experienced improvement, Johnsen explains as follows:

– We believe the placebo effect in IBS may be particularly strong because the disease is closely linked to the interaction between the gut and the brain. There is extensive cross-connection between the nervous system, the gut, and the gut flora, and the influence probably goes both ways. This is a complicated interaction that we still do not fully understand.

The bacteria from the donors actually changed the patients' gut flora. Nevertheless, this change did not lead to these patients feeling healthier than the others.

The Gastrointestinal Association is disappointed with the result

The Gastrointestinal Association has contributed to the study with user involvement and recruitment of participants.

– I think those who have followed the study are desperate now. Many with IBS do not receive satisfactory treatment and follow-up today, says Secretary General Mads Johansson.

– But the study is very important nonetheless, and provides good knowledge. Finding good treatment for IBS is like putting together a puzzle. Now we have gotten several pieces in place, and can chart the course ahead. I still believe the future's treatment may lie in the gut flora, and it is important that research continues.

There is also another large multicenter study on fecal transplantation (FMT) ongoing in Norway.

It includes 478 patients with irritable bowel, and uses a different method to administer the stool.

Magdy El-Salhy, who is a chief physician and professor emeritus in gastroenterology, believes the choice of method is crucial.

– The Refit2 study is an important and well-conducted study. It shows that FMT with enemas via the rectum does not work. In our study, patients receive the stool via a tube that goes down into the small intestine. We have clear findings that FMT with this method has promising results in IBS.

Advises against treatment at private clinics

Research communities in Harstad, Oslo, Bergen, Ålesund, and Kristiansand have contributed to the Refit2 study. And the patients come from all over the country.

Many patients have probably had high hopes for this treatment and the study, says Eline Randulff Hillestad. She is a clinical nutritionist and local project manager at Haukeland University Hospital in Bergen.

Even though the findings are negative, they contribute to increasing our knowledge. We need to research more on what the gut flora actually means for our body. Fecal transplantation against IBS is so-called experimental treatment, and in the public health service it is only given in connection with studies.

Nevertheless, there are private clinics in Norway and other countries that offer the treatment. Neither the researchers nor the Gastrointestinal Association have an overview of the extent, but they advise IBS patients against using private offers. It can become a very expensive medicine and you have no guarantee of the effect, says Hillestad.

The conclusions in this study are also an important clarification because the treatment is an offer at certain private clinics. Fecal transplantation has been and is being tested against a range of diseases.

The treatment form and gut flora in general receive much attention. It can be anything from age-related diseases like parkinsonism to diseases that cause inflammation in the gut and blood diseases, says doctor Peter Holger Johnsen at UNN in Harstad.

So far, intestinal infection with Clostridioides difficile is still the only condition where fecal transplantation has an established place. Here, however, the treatment is very effective and can in some cases be life-saving, according to Johnsen.

"Guy Boeckxstaens of KU Leuven explains how mast cells may alter pain signalling through IgE dependent responses to food antigens and activation of the MRGPRX2 receptor. 

Why can eating a familiar food cause abdominal pain in someone with irritable bowel syndrome (IBS)? At IBS Days, Guy Boeckxstaens of KU Leuven explains how mast cells may alter pain signalling through IgE dependent responses to food antigens and activation of the MRGPRX2 receptor. 

His team’s research suggests that intestinal infection or bacterial toxins can disrupt tolerance to food antigens. In experimental models, later exposure to those foods activates mast cells and heightens visceral pain; studies in patients with IBS have also observed local mast cell responses to food antigens. These findings point to mast cells and the substances they release as potential treatment targets, although their clinical role still needs to be established"

Abstract

Background

Bile acid diarrhoea (BAD) is an increasingly recognized cause of chronic diarrhoea. The 75-selenium homocholic acid taurine (SeHCAT) test remains the gold standard for diagnosis. The primary pharmacological treatment involves bile acid–binding agents, most commonly colestyramine. This study aimed to review the management of BAD at our centre and to identify factors associated with response to colestyramine.

Materials and methods

This single-centre retrospective study included all patients with an abnormal SeHCAT test (retention <15%) from 1 January 2020 to 31 December 2023 associated with chronic diarrhoea. Patients receiving empiric bile acid chelators without prior SeHCAT testing and those under 18 years of age were excluded. The primary endpoint was treatment success with colestyramine, defined as complete or partial clinical response without treatment discontinuation due to intolerance. Univariable comparisons and multivariable logistic regression were performed to identify factors independently associated with treatment success.

Results

Ninety-seven patients were included; 72.2% were women, with a mean age of 54.4 ± 15.1 years. Severe BAD was observed in 60.8% of cases. Overall, 77.3% of patients responded to colestyramine (43.2% complete, 34.0% partial). In multivariable analysis, baseline higher number of bowel movements per day was independently associated with a lower probability of treatment success (odds ratio 0.79, 95% confidence interval 0.68–0.92; P = 0.003). Colestyramine failure was generally due to intolerance-related discontinuation (17.5% of the cohort) followed by lack of efficacy (5.1%). No severe adverse events were documented.

Conclusion

Colestyramine appears to be an effective first-line therapy for BAD in routine clinical practice. However, treatment success in this study reflects both clinical response and tolerability, as treatment failure was more frequently related to intolerance than lack of efficacy.

Significance

Early-life enteric infections are a major health concern that have the potential to impact gut, immune, and brain development. Here we show that such infections reprogram innate immune signaling through pattern recognition receptors on intestinal epithelial cells, disrupting the microbiota–gut–brain axis into adulthood. These findings identify early-life enteric infection as a driver of long-lasting neuroimmune imbalance. Furthermore, we demonstrate that probiotic-derived muropeptides can attenuate inflammation and restore neuroimmune communication. Our work suggests that restoring gut-brain signaling may prevent long-term complications of childhood enteric disease.

Abstract

Early-life enteric infection disrupts the developing microbiota–gut–brain (MGB) axis. Using a neonatal Enteropathogenic Escherichia coli (EPEC) model, we show that intestinal epithelial cell (IEC) nucleotide oligomerization domain (NOD)1 signaling coordinates neuroimmune outcomes throughout early development and into adulthood. Neonatal mice infected at postnatal day (P)7 exhibited ileal inflammation, with increased pro-inflammatory cytokines and monocyte/macrophage infiltration, and loss of myenteric neurons in wild-type mice but not in NOD1 conditional knockout (Nod1^(ΔIEC)) mice. These deficits persisted into adulthood (P56), with increased intestinal permeability, sustained inflammatory/repair signatures, neuroinflammation, altered neurogenesis, and impaired recognition memory, which were absent in Nod1^(ΔIEC) mice, establishing a crucial role for IEC NOD1 in long-term MGB remodeling. Last, bioactive peptidoglycan fragments (muropeptides) were isolated from probiotic Lactobacillus strains and tested as possible therapeutics. Excitingly, supplementation of muropeptides attenuated neonatal EPEC-induced mucosal inflammation and enteric neuron loss without altering bacterial burden, potentially via IEC NOD2. Together, these findings identify IEC NOD-dependent signaling linking early-life enteric infection to enduring gut-brain dysfunction and reveal probiotic-derived muropeptides as candidate therapeutics.

Transcript

"Bobbi Pritt, M.D. (07:43):

Welcome to the deep dive. We're going beyond the headlines today with Dr. Leslie Donato, a clinical chemist at Mayo Clinic, to discuss a unique panel she and her colleagues in Gastroenterology developed for bile acid malabsorption. Thank you for joining me, Dr. Donato.

Leslie Donato, Ph.D. (07:59):

Thank you for having me. It's a pleasure.

Bobbi Pritt, M.D. (08:01):

Yeah, it's a pleasure to have you here. So, I have a few questions for you. For listeners who aren't familiar with this syndrome, maybe we could start with what bile acid malabsorption is, including some of the common symptoms and underlying causes.

Leslie Donato, Ph.D. (08:17):

Sure. So, let's start from the beginning and the background of what bile acids are. They are synthesized in the liver and released into the small intestine where they function to solubilize dietary fats and then facilitate the absorption of those lipids in the small intestine. The ones that are initially made in the liver are called primary bile acids, mainly chenodeoxycholic acid and cholic acid. These primary bile acids are then metabolized and converted into what we call secondary bile acids by microbes in the GI tract. And this is mainly, lithocholic acid and deoxycholic acid, which are excreted in the stool. Interestingly, most of our bile acids are reabsorbed by an active transport mechanism in the terminal ileum. The remainder, and it's really only about 5% of our total synthesized bile acids, are actually excreted in a stool, so a very small portion. This process of reabsorption is really important for actually inhibiting the synthesis of more bile acids in our body.

It's essentially a negative feedback regulatory loop that we have. So in the condition of bile acid malabsorption, or sometimes called bile acid diarrhea, it's a condition where there's essentially too much bile acids that are excreted, and the increased bile acids in the colon actually cause an influx of water that leads to chronic diarrhea for these individuals. And it can be really debilitating. Bile acid diarrhea can be caused from a variety of different clinical conditions, such as ileal disease or resection, primary or idiopathic overproduction of bile acids or others. It's important to know that, however, that if a patient presents to their physician with chronic diarrhea, there actually are a lot of conditions that do lead to this condition and a lot of clinical diseases or conditions that are on the differential diagnosis. So, chronic diarrhea can be found in cases of infections, malignancy, food sensitivities, autoimmune or inflammatory conditions, et cetera.

So, bile acid malabsorption or bile acid diarrhea is only one of the many possible reasons for chronic diarrhea. Lastly, for patients with bile acid diarrhea, it's really important to identify the cause of it because there actually are quite effective treatments for these patients called bile acid sequestrants. They essentially bind up all the excess bile acids in the colon and prevent that influx of water, thus significantly restoring normal bowel consistency in those patients.

Bobbi Pritt, M.D. (10:55):

Well, it's really interesting, Dr. Donato, and I have to admit, this isn't something I've thought about before, although I've learned a little bit more about the power of microbes in the intestinal tract, and as a microbiologist, of course, that's of interest to me. It's very interesting to think of all these different causes of diarrhea, and of course our clinicians are trying to figure this out. So, let's talk about the tests that you have helped develop for diagnosis of malabsorption of the bile acids. I understand Mayo Clinic's bile acid malabsorption panel is a unique tool. Can you explain what it is and what makes it unique?

Leslie Donato, Ph.D. (11:31):

Yes, I can. It's actually important, I think, to know the history of the development of this panel test, so we'll go through a couple of iterations first until we get there. So historically, the gold standard to diagnose bile acid diarrhea, or bile acid malabsorption, has been a noninvasive test called the CCAT method that monitors an orally administered gamma-emitting molecule through the GI tract. Now, this method exposes patients to radiation, but is actually not even available in the United States. So, we have worked here at Mayo Clinic to fill this diagnostic gap. The first test that we brought up several years ago now is a stool-based, an only stool-based, test called a 48-hour fecal bile acid test. This test measures five different bile acids found in the stool. There's two primary bile acids and three secondary bile acids. We basically call this test the gold standard in the U.S. because it is the best approximation of true disease in the U.S.

For this test, the patient is placed on a high-fat diet for a total of five days. They are instructed to collect their stool excreted over a 48-hour period during that high-fat diet, and then send the entire volume of stool to the laboratory. We then extract the bile acids present in the stool and measure them by mass spectrometry. We're looking for two things that indicate bile acid malabsorption. The first thing we look for, is it increased in the total concentration of bile acids in the stool? The second thing we're looking for is actually an increased percent of primary bile acids in the stool. It turns out that increased primary bile acids is also a hallmark of bile acid malabsorption. So, these are the two things that we measure in that, what we now consider the gold standard test within the U.S., is this 48-hour stool collection.

As you can imagine, it might be unpalatable for patients to actually go on this very long, strict, high-fat diet, and then actually have to collect their stool for two full days and have to store it themselves and send the whole sample in. So, a little bit cumbersome for patients. So the second test we brought up is actually an indirect screening test that actually is a serum marker that we can test. It's an indirect way to identify bile acid malabsorption, looking at a metabolic precursor in the biosynthetic pathway for bile acids. The compound is called 7-alpha-hydroxy-4-cholesten-3-one, or we call it 7AlphaC4 for short. So again, it's found in the serum, not in a stool sample, so the patient doesn't have to collect a stool sample, and it's elevated when that negative feedback loop is disrupted, that I told you about before.

This test is less sensitive for identifying patients with bile acid malabsorption, but the sample collection process is more palatable. It does have to be collected in the fasting state though, so the patient does have to fast overnight and then come in for that serum collection in the morning. So that's the second test we brought up. So now we'll talk about the third test, which is actually the panel test that you're asking me about. It's actually maybe the best of both worlds here. It's kind of a combination of the two. It's a panel test that requires actually both the fasting serum collection and a stool collection. However, the nice thing about this panel test is that the stool is a random collection now. So, the patient doesn't have to go through that high-fat diet, collect their stool at home for two full days, and you know, store it in their own refrigerator at home and do that.

It's a random stool. So, one-time collection. Collect a sample, send it in. The test uses both the results from the 7AlphaC4 and the serum. And from the stool, the information we're collecting out of that is actually just the percent of primary bile acids from the stool sample. And from those two pieces of data now, we can identify patients with bile acid malabsorption. The test is nearly as good as that best-case scenario that we have in the U.S., that 48-hour collection. But it's really a nice option for patients and physicians because the ease of collecting a fasting serum, and most importantly, a random stool collection, is much more palatable for patients. So, allowing for a random stool collection in this panel is really a game-changer. For physicians, this means that during an encounter with a patient with chronic diarrhea, the patient could be asked to collect the random stool on the same day, even within the clinic, you know, even at the clinic during the visit itself, without having to go through somewhat cumbersome collection of that 48-hour collection.

The patient will still need to get that fasting serum sample drawn to complete the sample collection, of course, with the panel. And the collection really needs to be ideally within the same day, but we allow within three days just so we know that the patient condition hasn't changed between the two collections. But it really is a nice option for patients to have this panel test for a really good and accurate identification of patients with bile acid malabsorption. And this test actually is exclusively offered at Mayo Clinic at this point.

Bobbi Pritt, M.D. (16:47):

Well, that's wonderful, Dr. Donato. Sounds like an excellent option for patients. So, you've launched this test now, this third iteration. Can you share what you've learned about bile acid malabsorption? Anything that you've learned, especially from real-world use of this test?

Leslie Donato, Ph.D. (17:03):

Yeah, great question. Initially, this test was developed to identify a cause of chronic diarrhea in patients with a condition called irritable bowel syndrome, or IBS-D or IBS with diarrhea. Most of the initial clinical studies, many of which were performed here at Mayo Clinic with our GI physician, Dr. Michael Camilleri, were performed in this patient population. So, a lot of the initial studies and implementation was in IBS-D patients. But surprisingly, we've actually learned that the prevalence of bile acid diarrhea is really quite high in our total population. It's actually 1% of our entire population, which is actually pretty similar to that of celiac disease, which a lot of people know about, but we don't talk about this chronic diarrhea and bile acid malabsorption. Interestingly, within the IBS-D population, the prevalence of bile acid malabsorption is actually around 35 to 40%, so it really is quite substantial in that population.

And furthermore, we've actually expanded the testing of this in other diseases. So, we've actually identified and shown that bile acid malabsorption can be found in a variety of different clinical conditions, not only IBS. So it's been shown to be present in ulcerative colitis, Crohn's disease, microscopic colitis, and most recently, in patients with neuroendocrine tumors who can suffer from chronic diarrhea. So this means that if bile acid malabsorption is identified in these patients, there could be a therapy that, again, might alleviate their chronic diarrhea symptoms, which is really helpful in a broader clinical scenario.

Bobbi Pritt, M.D. (18:42):

Well, that's very interesting. Well, let's think about looking ahead. You've done so much great work in this area. What do you see as further opportunities for advancing diagnostic tools for conditions like bile acid malabsorption?

Leslie Donato, Ph.D. (18:55):

Yeah. Well, focusing on bile acid malabsorption, I'm really excited about future discoveries of clinical utility of our testing in various GI and non-GI conditions, because of course, we know chronic diarrhea and diarrheal symptoms can really be present in a variety of different clinical conditions. I'm confident that we'll actually find more patient groups that will benefit from testing, again, because testing really leads to a clinical use of a therapeutic that can really be beneficial for those patients. So, I'm really excited about that. And additionally, new studies are looking at different therapeutic approaches to treating patients with bile acid diarrhea or malabsorption, other than using those bile acid sequestrants, which can have some negative side effects, of course. Actually, a recent, small, randomized control trial, again, led by our internal GI physician, Dr. Camilleri, looked at probiotic supplementation, and it did show that this decreased the percentage of primary bile acids in the stool.

So, I'm hopeful that more investigation in this type of area, using our methodologies to kind of monitor treatment and then lowering of bile acid malabsorption, the bile acid malabsorption collaboratory phenotype that we see, can identify novel therapeutic options to alleviate the diarrhea symptoms in patients with bile acid malabsorption.

Bobbi Pritt, M.D. (20:17):

Very interesting. Well, Dr. Donato, I learned a lot from listening to you today. Thank you again for joining us and sharing your knowledge with our listeners. It was a pleasure having you.

Leslie Donato, Ph.D. (20:27):

Well, thank you so much for having me.

Bobbi Pritt, M.D. (20:34):

Let's wrap up with the top takeaways and how to learn even more on the topics we discussed. Dr. Morice joined me to discuss findings from a recent survey exploring the strategies laboratories are using to drive growth. We've included a link to the full report in the show notes. We also reminded listeners that now is the time to start preparing for seasonal virus vaccinations, and we've provided a link to Mayo Clinic guidance in the show notes as well. Then Dr. Donato joined me to discuss testing for bile acid malabsorption. And if you'd like to learn more about this topic, we've included several additional resources. The show notes include links to a free webinar featuring Dr. Donato and her GI colleague, Dr. Michael Camilleri. And there's a story about the development of the test discussed today, also a resource outlining the bile acid malabsorption tests and clinical case examples.

Thank you for joining us today. If you haven't already, make sure to subscribe so you never miss an episode. And then next time, Dr. Binnicker will be joining me to discuss seasonal viruses. I hope you can join us."

Interpretation

The trial did not show a clinical benefit of faecal microbiota transplantation in patients with IBS. These findings suggest that microbiota modulation alone might be insufficient for symptom improvement in IBS.

Summary

Background

Gut microbiota composition might have a role in the pathogenesis of irritable bowel syndrome (IBS), and faecal microbiota transplantation has been proposed as a means of restoring healthy gut microbiota for individuals with this condition. We aimed to investigate the efficacy and safety of faecal microbiota transplantation in patients with IBS.

Methods

In this parallel-group, randomised, double-blind, placebo-controlled, phase 3 trial, conducted at five hospitals in Norway, we enrolled men and women aged 18–65 years with moderate-to-severe IBS. IBS diagnosis was defined by the Rome IV criteria and an IBS-Severity Scoring System (IBS-SSS) score of 175 points or higher. A colonoscopy within 5 years before study enrolment was required for all participants aged 50 years or older to rule out colorectal cancer, and participants with IBS with predominantly diarrhoea required negative biopsies to exclude microscopic colitis. Participants were randomly assigned 2:1 to faecal microbiota transplantation with faeces samples from either healthy donors (intervention) or the participants themselves (placebo group). All investigators, participants, and study personnel involved in treatment administration, patient care, and outcome assessment were masked to treatment allocation throughout the study. Treatments were delivered as a once-only rectal enema. The primary endpoint was the proportion of participants with a reduction of 75 points or more in IBS-SSS score at 90 days after treatment compared with baseline, assessed in all patients who received their allocated treatment. All participants were advised to report any adverse event during follow-up to their study contact, preferably by telephone. A patient representative was involved in the planning of the trial. The trial was registered at ClinicalTrials.gov (NCT04691544).

Findings

Between May 5, 2021, and July 14, 2022, we assessed 2304 individuals for eligibility, and 450 participants were enrolled and randomly assigned to the intervention group (299) or placebo group (151); two randomly assigned participants were excluded from analyses because their allocated treatments were switched. 293 (65%) of 448 participants were women, 155 (35%) were men, and the median age was 36 years (IQR 29–44). 119 (40%) participants in the donor faecal microbiota transplantation group and 57 (38%) in the placebo group showed an improvement of at least 75 points on the IBS-SSS at 90 days after treatment. The absolute difference was 1·9 percentage points (95% CI –8·1 to 12·0; p=0·76). The proportion of participants with adverse events was similar in the two study groups.

This milestone marks the first IND submission from XtalPi's proprietary pipeline, recently unveiled in its interim results, validating the company's AI and robotics-driven drug discovery platform and its transition to a clinical-stage organization.

Preclinical data demonstrate sub-nanomolar potency (< 1 nM) alongside a gut-to-blood exposure ratio exceeding 1,000:1, confining pharmacological activity to the gastrointestinal tract to limit systemic exposure.

The candidate is the industry's first gut-restricted pan-TRK inhibitor developed for IBS and IBD, targeting a critical therapeutic gap in the long-term management of chronic pain without the neurological liabilities of systemic inhibitors.

BOSTON and SHENZHEN, CHINA, Sept. 24, 2026 /PRNewswire/ -- XtalPi (HKEX: 2228), an AI- and robotics-driven drug and materials discovery company, today announced the submission of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for KQTD-126. Developed internally, the candidate is a potential first-in-class gut-restricted pan-tropomyosin receptor kinase (pan-TRK) inhibitor designed to treat chronic intestinal pain associated with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).

IBS affects approximately 10%–15% of the global population, while more than 10 million people live with IBD. Chronic abdominal pain is a major burden for patients with IBS and can persist in some patients with IBD even when standard therapies control their underlying inflammation. Despite available treatments, additional options that provide sustained pain relief and are suitable for long-term use remain an unmet clinical need. According to BCC Research, the global IBS and IBD therapeutics market is projected to reach US$52.6 billion by 2030.

KQTD-126 targets the TRK family of receptors (TRKA, TRKB, and TRKC), which directly regulate nerve activity and pain-signal amplification in the gut. While inhibiting these pathways can effectively manages this pain, TRK receptors also operate throughout the central nervous system. Consequently, traditional systemic TRK inhibitors carry a high risk of neurological side effects. A viable chronic pain treatment must therefore confine its activity strictly to the gastrointestinal tract.

Achieving this precise biological profile required navigating a vast chemical space to balance target affinity and kinase selectivity with properties governing tissue distribution. To resolve these competing design objectives, XtalPi leveraged its generative and predictive AI models integrated with its fleet of automated chemistry robots. This closed-loop process of computational design, automated synthesis, empirical screening, and molecular refinement allowed the company to iterate across structural variants and achieve robust gut restriction while preserving strong target activity and selectivity.

In preclinical studies, KQTD-126 achieved pan-TRK inhibition at sub-nanomolar concentrations (IC₅₀ < 1 nM) and maintained high selectivity over other kinases. The candidate also demonstrated a gut tissue-to-blood exposure ratio exceeding 1,000:1. Together, these findings support KQTD-126's development as a locally acting treatment intended to deliver sustained pain relief with a wider therapeutic window.

KQTD-126 is the first program in XtalPi's proprietary pipeline to reach an IND submission since the portfolio was unveiled in the company's recent interim results. As a global scientific utility platform, XtalPi draws on a shared foundation of quantum physics, AI, and robotics to deliver discovery capabilities spanning small molecules, antibodies, peptides, siRNA therapeutics, and molecular glues. This comprehensive infrastructure empowers the company and its partners to pursue high-value targets using the modality best suited to the underlying biology. By advancing internal assets alongside established collaborations, XtalPi maximizes the impact of its technology to resolve complex drug design challenges and deliver transformative therapies for patients worldwide.

About XtalPi

XtalPi Holdings Limited (XtalPi, 2228.HK) was founded in 2015 by three physicists from the Massachusetts Institute of Technology (MIT). It is an innovative R&D platform powered by quantum physics, artificial intelligence, and robotics. By integrating first-principles calculations, AI algorithms, high-performance cloud computing, and standardized automation systems, XtalPi provides digital and intelligent R&D solutions for companies in the pharmaceutical, materials science, agricultural technology, energy, new chemicals, and cosmetics industries.

SOURCE XtalPi Inc.

Summary

Background

Fibromyalgia is a chronic disorder characterised by widespread pain, fatigue, sleep disturbances, and cognitive dysfunction. Evidence suggests pathogenic IgG autoantibodies might contribute to severe symptoms. Rozanolixizumab reduces IgG concentration by targeting the neonatal Fc receptor. This study evaluated its efficacy and safety in patients with severe fibromyalgia.

Methods

This phase 2A, multicentre, randomised, double-blind, placebo-controlled study, included adults (aged 18–70 years) at seven sites in north west England with severe fibromyalgia (Brief Pain Inventory-Short Form [BPI-SF] interference score of ≥6; 10-day mean daily Pain Numeric Rating Scale score of ≥6 to <10). The study consisted of a screening period; a 2-week single-blind placebo run-in period; two subsequent 12-week, double-blind treatment periods; a 2-week single-blind placebo run-out period; and a 5-week safety follow-up. Participants were randomly assigned 1:1:1 to once a week rozanolixizumab 560 mg for 24 weeks (rozanolixizumab–rozanolixizumab); placebo for 12 weeks then rozanolixizumab for 12 weeks (placebo–rozanolixizumab); or placebo for 24 weeks (placebo–placebo); all administered by subcutaneous infusion. The primary endpoint was BPI-SF interference score mean change from baseline after 12 weeks. Treatment-emergent adverse events were assessed. People with lived experience of fibromyalgia consulted on the study and reviewed study materials. This trial is registered with ClinicalTrials.gov, NCT05643794.

Findings

Between Dec 21, 2022, and July 9, 2024, 165 participants were screened, of whom 63 (eight [13%] male and 55 [87%] female, median age 47 years [IQR 38–55], 60 [95%] White) were randomly assigned: 22 to rozanolixizumab–rozanolixizumab, 20 to placebo–rozanolixizumab, and 21 to placebo–placebo. 55 (87%) of 63 participants completed all phases of the study. The primary endpoint met the pre-specified one-sided 10% α level, with greater improvement from baseline observed for rozanolixizumab versus placebo (least squares mean difference –0·5, 80% CI –1·0 to –0·1; p=0·065), but without significance at a two-sided 5% α level (95% CI −1·2 to 0·2; p=0·13). During treatment, no serious treatment-emergent adverse events were reported by study participants receiving rozanolixizumab. The most common treatment-emergent adverse event across the study was headache, reported by nine (41%) of 22 and 11 (30%) of 37 participants receiving rozanolixizumab versus 17 (41%) of 41 and three (15%) of 20 participants receiving placebo, in the first 12 weeks and second 12 weeks of double-blind treatment, respectively.

Interpretation

Rozanolixizumab did not demonstrate broad efficacy in this severe fibromyalgia population. While there was an improvement in BPI-SF, this was not meaningful at a group level. Inability to select for patients with pathogenic autoantibodies might have contributed to between-patient heterogeneity. Response-predictors are required to determine whether IgG reduction benefits subsets of patients with severe fibromyalgia.

Full video: https://www.youtube.com/watch?v=67fizcq7xmg

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"Research on the microbiota-gut-brain axis has gone from the demonstration that intestinal microorganisms can influence brain biochemistry and behavior to the identification of the mechanisms by which microbial signals can reach the central nervous system.

In this interview, Stephen Michael Collins, a professor at McMaster University and one of the pioneers of this research strand, traces some of the main experimental evidences that have linked the gut microbiota to behavioral modifications, anxiety, depression and irritable bowel syndrome, and then focus on an emerging communication mechanism: the vesicles of the bacterial outer membrane. Produced in particular by Gram-negative bacteria, these nanometric structures can protect and transport proteins, DNA fragments, and other bacterial molecules through biological barriers, potentially reaching the brain, and modulating neuroinflammation and neuronal function.

Their effects can vary substantially depending on the origin microorganism, moving from pro-inflammatory signals to a possible favorable modulation of neuroinflammation. According to Collins, these vesicles could therefore represent not only a new element of the microbiota-gut-brain axis, but also a promising platform for the future development of targeted drug, vaccine and immunotherapie conveying systems." Source: https://microbioma.it/video/vescicole-della-membrana-batterica-un-nuovo-protagonista-dellasse-microbiota-intestino-cervello/ Automatic translated from the italian.

Figure from here: https://www.gutmicrobiotaforhealth.com/ibs-days-2026-from-pathophysiology-to-microbiome-modulation/ \"Gram-negative outer membrane vesicles are an important component of the microbiome-gut-brain axis and offer novel therapeutic approaches for managing altered brain function in IBS and behavioral disorders. Source: Stephen Collins’ talk at IBS Days 2026.\"

"The roots of high psychiatric comorbidity in IBS are poorly understood but likely involve multiple pathways. Recent insights point to the role of outer membrane vesicles (OMVs) produced by Gram-negative gut bacteria in brain and behavior. These vesicles are critical for the survival of commensal bacteria, but they can also signal to the host in two ways. Preclinical studies have revealed that oral administration of OMVs increases blood-brain barrier permeability, allowing the release of the vesicle interior, consisting of a variety of cytoplasmic molecules and DNA fragments, into the brain. This results in alterations in brain chemistry and function. The second mechanism involves activation of the vagus nerve via toll-like receptors. Limitations of current knowledge include the cytokine storm induced by lipopolysaccharide from Gram-negative bacteria, contamination, dose-relevance, and the translational gap between rodent studies and human disease." Source: https://www.gutmicrobiotaforhealth.com/ibs-days-2026-from-pathophysiology-to-microbiome-modulation/

"A single bout of food poisoning can trigger a condition called post-infection IBS—and scientists are looking for answers in both the gut microbiome and the brain.

For most people, food poisoning ends when the digestive disruption stops. But for some, those first miserable days are only the beginning. Long after the pathogen has cleared, recurrent abdominal pain, diarrhea, and sometimes constipation can continue for months—or even years.

Doctors call this condition post-infection irritable bowel syndrome. By conservative estimates, it affects at least one in 10 people after an intestinal infection. The risk has gained new relevance amid a string of foodborne outbreaks linked to lettuce, frozen blueberries, sprouts, eggs, and jalapeños. A Cyclospora outbreak traced to iceberg lettuce alone sickened nearly 13,000 people.

Scientists have been trying to uncover its causes—and its solutions—for decades. Their research increasingly points not to a single culprit, but to lasting changes across several interconnected systems.

Post-infection IBS can follow digestive infections caused by a variety of germs, but it’s more likely to follow parasitic and bacterial illnesses than viral ones. The parasite Giardia and the bacteria Campylobacter are among the best-documented culprits, along with Salmonella, E. coli, and Shigella. Cyclospora, notably, is rarely linked to the condition.

One review estimated that the condition accounts for around 9 percent of all IBS cases, although some experts suspect it causes many more. “If I had one day of diarrhea after coming back from Mexico 10 years ago, do I remember that?” says Mark Pimentel, a gastroenterologist and researcher at Cedars-Sinai Medical Center in Los Angeles. He suspects food poisoning causes closer to 60 percent of IBS.

IBS isn’t the only digestive condition that can emerge after an infection. Chang says patients can also develop post-infection functional dyspepsia. This often-overlooked condition causes upper abdominal pain, early fullness, or uncomfortable fullness after eating—although researchers don’t yet know whether it arises through the same mechanisms as post-infection IBS.

Scientists still don’t know why one person recovers completely while another develops lasting symptoms. One set of theories focuses on changes to the gut’s microbiome. An infection blows through the gut’s resident bacterial community like a storm; normally, within days or weeks, that community rebuilds itself. In some people, it doesn’t. “It’s like it undergoes a state of shock,” says Madhusudan Grover, a gastroenterologist at the Mayo Clinic who has spent 15 years studying the aftermath of Campylobacter infections. In a small group of patients followed for a year after infection, some of the microbial residents lost during the illness never returned.

Changes to the microbial community could have a range of downstream effects. For example, Grover’s research in mice suggests that depleting the gut’s microbiome can increase the activity of proteases, protein-degrading enzymes normally kept in check by certain gut bacteria.

Other ideas center around a dysregulated defense system in the recently infected gut. Close examination of patients’ bowels shows evidence of simmering inflammation and an out-of-whack immune system: Some infection-fighting cells are overabundant, some are too scarce, and signaling molecules that govern the body’s often fiery inflammatory responses are miscalibrated. In animal studies, scientists have found evidence of an allergic response that seems localized to the gut.

Yet another set of hypotheses concerns the nerves that govern both contractions and pain sensation in the gut. In mice, gut infections can damage or kill neurons embedded in the intestinal wall, producing lasting changes in how the gut moves. Whether people experience the same neuronal losses remains unclear.

But Benjamin Levy, a gastroenterologist at the University of Chicago, sees evidence that the gut’s sensory system can become hypersensitive in his patients. Normal peristalsis, the gut’s routine muscle contractions, isn’t something most people even notice. “Patients with post-infectious IBS perceive peristalsis as pain,” he says.

Pimentel’s working theory unifies several of these ideas. He suspects that during the initial foodborne infection, the immune system creates swarms of antibodies in response to a toxin made by certain bacteria. Those antibodies may also attack the body’s own tissue—specifically, cells that coordinate the small intestine’s housekeeping functions—leading to an overgrowth of bacteria. The resulting gases and other bacterial byproducts could heighten sensitivity and make the gut lining more permeable, allowing its contents to irritate and inflame the intestine and contribute to persistent diarrhea and pain.

None of these theories fully explains post-infection IBS on its own, and scientists don’t agree on how the pieces fit together.

One notable area of disagreement relates to the brain’s involvement in post-infection IBS. Lin Chang, a gastroenterologist at UCLA who studies how the gut and brain communicate, points to evidence that people who are anxious or depressed at the time they fall ill are more likely to develop lasting gut symptoms afterward. That doesn’t mean the illness is imagined.

Rather, the brain actively processes signals from the gut and may amplify symptoms. Experiments have suggested stress measurably weakens the integrity of the gut’s lining, and stress hormones can make gut pathogens more dangerous, says Grover, who notes pathogens like Campylobacter become more virulent in the presence of the fight-or-flight hormone epinephrine.

Meanwhile, Pimentel believes that the brain is mostly an innocent bystander in post-infection IBS. He points to a study of U.S. troops deployed to Iraq and Afghanistan. In that analysis, combat exposures—including shooting a weapon, being injured, or killing someone—didn’t predict IBS, but experiencing infectious gastroenteritis while deployed did. “The problem is the gut, and it is affecting the brain, and yes, there are brain manifestations,” he says, “but I don't think the fault is the brain.”

(Why women are more likely to have IBS.)

The two views are not necessarily incompatible: An infection may trigger the condition in the gut while the brain influences how symptoms develop or persist. Determining each’s relative contribution is especially challenging because post-infection IBS is diagnosed through a characteristic pattern of symptoms rather than a single physical finding or biomarker. The syndrome likely lumps together subsets of patients with different disease mechanisms, says Grover. That makes it especially important to individualize treatment to each patient depending on the symptoms and concerns they describe.

Although treatments for post-infection IBS generally mirror those for IBS more broadly, several research groups are seeking new therapies targeting the subgroup. Grover is running a trial testing whether a fecal transplant from carefully matched donors can help patients with high gut protease activity, a signature he’s linked to Campylobacter-triggered disease.

In a randomized trial of patients with weakened gut linings, the amino acid glutamine eased symptoms and appeared to strengthen the intestinal barrier, making it less permeable. Chang points to gut-directed hypnosis, which reduces patients’ pain symptoms. Pimentel often prescribes rifaximin, an antibiotic approved for IBS with diarrhea that may alter bacterial activity in the gut. In a small retrospective study, his research group also found that declines in certain self-directed antibodies correlated with symptom improvement. However, the finding does not establish that the antibodies caused those symptoms.

Perhaps most reassuringly, time itself often helps. An eight-year study of a Canadian town sickened by contaminated water found that about half of residents with post-infection IBS no longer met the diagnostic criteria at follow-up, though others remained ill."

A review of his career as a researcher, focused primarily on certain clinical entities and the objectification of their diagnosis and treatment. In the last part, he identifies IBS-PAIN as a major unmeet and suggests targeting the dorsal root ganglion as a more attractive target. He even discusses proof-of-concept work with rimegepant. Full video: https://www.vumedi.com/video/clinical-neurogastroenterology-over-four-decades/

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Full paper: 10.1177/10870547261469626

"Summary:

Researchers analyzing data from more than 1.9 million people found that ADHD is associated with substantially higher rates of digestive problems. People with ADHD had nearly double the odds of constipation, 58% higher odds of irritable bowel syndrome, and more than four times the odds of encopresis."

"Researchers at the University of Warwick have found a striking association between ADHD and digestive health after analyzing data from more than 1.9 million people across 23 studies.

Overall, people with ADHD were almost 50% more likely to experience gastrointestinal symptoms than people without ADHD. Some individual conditions showed even stronger associations. People with ADHD had nearly twice the odds of constipation, a 58% increase in irritable bowel syndrome, and more than four times the odds of encopresis (loss of bowel control).

Growing Evidence for an ADHD Gut Connection

ADHD is estimated to affect about 5% of children and 3-4% of adults worldwide, while reported diagnosis rates have increased sharply over the past four decades.

Digestive problems have already been well documented among people with autism spectrum disorder. At the same time, scientists have gathered increasing evidence for a 'gut-brain axis' that connects digestive health with neurodevelopmental conditions more broadly. Until now, however, researchers have had a less complete picture of how frequently gastrointestinal symptoms occur in people with ADHD.

The new study, published in the Journal of Attention Disorders, is the first systematic review devoted specifically to gastrointestinal symptoms in ADHD. Researchers brought together evidence from studies conducted in countries including the USA, Sweden, Germany and South Korea. Participants ranged in age from 2 to 65.

Co-lead Author Sarah Blake, a Medical Student at Warwick Medical School, said: "Almost every gut symptom we looked at: constipation, IBS, even indigestion, appeared to be associated with ADHD. These symptoms can have a real impact on daily life, but they could easily be overlooked if the focus is on ADHD itself."

What Could Explain the Link?

Researchers do not yet know exactly why ADHD and digestive problems appear to be connected, but several possibilities could contribute.

ADHD-related traits such as impulsivity and irregular eating patterns may influence digestive health. Medications used to treat ADHD can also produce gastrointestinal side effects, including constipation.

Another possible factor involves the gut microbiome. Previous evidence has linked ADHD with differences in gut bacteria, which may influence communication between the digestive system and the brain through the vagus nerve, one of the body's major pathways connecting the gut and brain.

Doctors May Need to Look Beyond ADHD Symptoms

The researchers say clinicians caring for people with ADHD should be aware that gastrointestinal symptoms may also be present and consider asking patients about digestive problems during appointments.

People experiencing more complicated gastrointestinal symptoms could also benefit from support from a dietitian or gastroenterologist.

Importantly, the findings identify an association rather than proving that ADHD itself causes digestive problems. More research will be needed to determine how much of the connection may involve underlying biological factors and how much could be related to medications or other influences.

Dr. Saran Shantikumar, Associate Clinical Professor, Warwick Medical School, said: "We can't yet say ADHD causes these gut problems, or exactly what is driving the link, but the pattern is striking enough to warrant attention. Clinicians caring for people with ADHD may want to consider asking about gastrointestinal symptoms, particularly if they may be affecting quality of life.""

The Auckland Classification defines body surface gastric mapping phenotypes and sets priorities for clinical validation

When standard tests look normal but symptoms continue, body surface gastric mapping may offer additional clues by measuring the stomach’s electrical activity alongside symptoms and gut-brain health. Developed by 47 experts from 13 countries, the Auckland Classification provides standardized criteria for interpreting and reporting these findings.

Greg O’Grady, Co-founder and CEO of Alimetry, and lead author of the consensus classification, discusses its potential relevance to gastric neuromuscular disease, its limitations, and the validation required before routine clinical adoption.

What clinical challenge led to the development of the Auckland Classification, and how does it improve the interpretation of body surface gastric mapping?

Around 1 in 10 people are affected by chronic gastroduodenal disorders worldwide, yet they remain difficult to diagnose and manage. Standard diagnostic approaches are often based on symptoms or nonspecific measures of gastrointestinal transit, such as gastric emptying time. These methods cannot always identify the underlying mechanism or help clinicians select the most appropriate therapy. This diagnostic gap prompted us to develop a more mechanistic approach to patient profiling.

Body surface gastric mapping (BSGM) measures the stomach’s electrical slow waves, which help initiate and coordinate peristalsis. The findings can be assessed alongside real-time symptoms and measures of gut-brain well-being, allowing researchers to examine possible mechanisms of dysfunction rather than only their downstream effects.

The Auckland Classification provides a structured, consensus-based research framework for interpreting BSGM findings. It defines patient phenotypes and establishes a common language for reporting and comparing results. Before its development, there was no standardized approach to determining the potential clinical meaning of these findings.

How does body surface gastric mapping add to existing diagnostic tools when assessing patients with gastroduodenal disorders?

BSGM is intended to complement existing tests rather than replace them. Endoscopy remains essential for identifying or excluding structural pathology, while gastric emptying studies assess transit time. BSGM provides information about the electrical activity coordinating gastric function, particularly in patients whose standard investigations are normal despite persistent symptoms.

Gastric emptying studies measure how quickly the stomach clears a meal, but they do not directly assess the electrical activity involved in that process or the sensory aspects of a patient’s condition. Evaluating electrophysiological findings alongside symptom and psychological assessments may provide a broader view of gastric function.

As a surgeon, I understand how difficult it can be to evaluate patients when existing tests do not identify a specific cause. Symptoms may be associated with neuromuscular dysfunction, visceral hypersensitivity, or altered gut-brain signaling, but standard investigations cannot always distinguish between these mechanisms. This challenge contributed to the development of the Auckland Classification.

How could a standardized classification improve diagnostic reporting and help clinicians make more consistent decisions?

Before the Auckland Classification, individual centers developed their own methods for classifying and reporting BSGM findings. These heterogeneous approaches made it difficult to compare results, conduct multicenter studies, or build the evidence required for clinical adoption.

A standardized classification gives clinicians and researchers shared terminology, phenotype labels, criteria, and an interpretation framework. This consistency supports comparisons between centers and the design of prospective trials. It may eventually help researchers determine whether specific phenotypes are associated with particular treatment responses.

Other areas of medicine have undergone a similar process. The Chicago Classification established a standardized approach to interpreting high-resolution manometry in esophageal motility disorders. The Auckland Classification may provide a comparable research foundation for gastric mapping.

What could this new framework mean for patients?

For patients, the main potential benefit is reducing prolonged diagnostic uncertainty. Many people with chronic gastroduodenal disorders consult several specialists and try multiple medications without receiving a clear explanation for their symptoms. In some cases, standard tests may not be sensitive to the underlying mechanisms.

The Auckland Classification provides a framework for interpreting objective, mechanism-based findings from BGSM. These findings can give clinicians a clearer starting point than transit measurements alone. For example, the test may identify patterns associated with altered gastric electrical or neuromuscular activity, sensory dysfunction, or gut-brain signaling.

The treatment implications remain research oriented, and additional data are needed before specific phenotypes can be used to guide therapy routinely. However, for patients who have spent years without an explanation for their symptoms, an objective characterization of their condition may be a useful step toward more focused clinical assessment.

What further validation is needed before the Auckland Classification can be adopted into routine clinical practice?

The framework was designated version 1.0 because further revisions are expected as the evidence develops.

An immediate priority is the prospective validation of relationships between phenotypes and treatment responses. Early data suggest that patients with the Low Meal Response phenotype may experience a better symptomatic response to prokinetic therapy. The Dysrhythmic phenotype may be associated with lower response rates to initial interventions and a greater need for escalation of care. These observations require confirmation in larger, prospective, multicenter cohorts before they can inform clinical guidelines.

A classification for adolescent patients is also in development. Another research priority is to clarify relationships between BSGM phenotypes and histopathological changes. One example is the possible association between depletion of interstitial cells of Cajal, a feature of gastric neuromuscular disorders, and gastric electrical dysrhythmia.

Version 1.0 should therefore be regarded as the starting point for a framework that can be refined as new evidence becomes available.

What are the main challenges to introducing body surface gastric mapping into everyday diagnostic pathways, including point-of-care settings?

Several practical challenges remain. The current standard protocol is a 4.5-hour supervised test conducted in a clinic or hospital, similar to gastric emptying testing. Alternative protocols are being investigated, and the testing process may change as further evidence becomes available.

Clinical utility, cost-effectiveness, and the effect on subsequent investigations and treatment decisions must be demonstrated prospectively. Reimbursement pathways and access will also influence adoption.

Training and interpretation require investment. Clinicians must understand what BSGM findings mean and how to incorporate them into existing diagnostic pathways. The Auckland Classification addresses part of this challenge by providing a standardized interpretation framework, but further education and implementation support are needed.

Looking ahead, how do you see this classification evolving, and what role could it play in the future of diagnosing and managing gastroduodenal disorders?

The classification applies lessons from cardiac electrophysiology and esophageal motility testing to gastric medicine. Its purpose is to support a shift from broad symptom-based labels toward a more objective, mechanism-based understanding of gastroduodenal disorders.

The framework will be revised as prospective validation studies are completed, evidence for individual phenotypes develops, and new findings emerge. Potential phenotypes that did not meet the evidence threshold for version 1.0 remain under investigation.

Artificial intelligence-assisted analysis may eventually make BSGM interpretation more consistent and scalable. As the evidence develops, the classification could also support therapeutic trial design by helping researchers examine relationships between phenotypes, disease mechanisms, and treatment responses.

The longer-term objective is to support more precise management of gastroduodenal disorders and assess whether similar classification approaches could be applied to colonic conditions.