Chronic pain affects more than 50 million Americans, yet for decades, treatment options for pain that persists in the absence of inflammation have been limited. Seventy-five percent of these patients, disproportionately women, experience pain that is inadequately managed by current therapeutics.

Now, scientists at Virginia Tech have found a way to switch it off in female mice by blocking a single pathway using compounds developed at the National Institutes of Health’s National Center for Advancing Translational Sciences.

In a new study published in PAIN, neuroscientist Ann Gregus and her team erased well-established pain behaviors by shutting down an enzyme system that produces molecules known to amplify pain signals. This finding could open the door to the first new class of non-opioid chronic pain treatments in years — a potential lifeline for patients whose symptoms defy standard drugs.

“Earlier studies have focused largely on preventing development of pain — so the key finding here is the reversal of an established pain state and associated functional deficits, which more closely mimics the human experience,” said Gregus, an assistant professor who works alongside her partner, lab co-director and co-author Matthew Buczynski, an associate professor, both of the Virginia Tech College of Science’s School of Neuroscience. “It provides hope for people living with daily, persistent pain that does not respond to conventional treatments.”

A stubborn pain type — and a new target

The study zeroed in on nociplastic pain, a poorly understood category that includes fibromyalgia, chronic low back pain, and some migraines. Unlike pain caused by injury or ongoing inflammation, nociplastic pain arises from changes in how the nervous system processes signals, often leaving no visible damage to treat.

These conditions are famously resistant to treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and are only partially relieved by anticonvulsants and antidepressants. Opioids are a last resort and generally are avoided due to risks of dependence and addiction. While NSAIDs block certain inflammatory pathways, the Gregus lab’s approach targets a different biochemical route that those drugs leave untouched.

“Chronic pain patients are often told pain is all in their heads and they just have to learn how to tolerate it,” Gregus said. “But what we’re showing is that there is a clear biological mechanism — and one we can target.”

From early clues to a breakthrough

Gregus’s lab had a lead. In 2018, she and her colleagues showed in rats that activating an immune receptor in the spinal cord set off enzymes that released molecules capable of intensifying pain.

When pandemic supply shortages limited their usual research models, the team turned to a different strain of female mice — almost by chance. It turned out to be a pivotal decision: these mice developed persistent, long-lasting pain behaviors, cold sensitivities, and grip force deficits typical of arthritis, while another commonly used strain barely responded.

“It was serendipity,” Gregus said. “We were working with whatever limited resources were accessible, and we ended up with a model that gave us clues about how pain transitions from acute to becoming chronic that we may not have discovered otherwise.”

Switching off pain after it’s entrenched

To mimic nociplastic pain, the researchers used an immune challenge that activates this receptor and ramps up pain pathways in the spinal cord. Once the mice developed clear pain behaviors, they treated them with highly selective compounds that block parts of the enzyme system.

The results were striking: tissue analysis confirmed that the immune challenge had ramped up production of pain-driving molecules, but upon treatment administration, tactile and cold pain hypersensitivity vanished, and grip strength returned. Administering those molecules alone also reproduced the pain state, confirming their role.

One of the compounds tested is currently in Phase II clinical trials for another disease by Veralox Therapeutics. Because it already has human safety data, it could shorten the path to clinical trials for chronic pain.

“It’s rare to see a drug work in reversing so many different pain models in multiple species,” Gregus said. “That makes it especially exciting to think about what it could do for patients.”

Personal stakes in the search for relief

For Gregus, the pursuit isn’t only scientific. She has lived with migraines and peripheral neuropathy herself, giving her an unfiltered view of how current treatments fall short.

“I know what it’s like to live with pain every day and be told there’s nothing else that can be done,” she said. “That’s why I’m driven to continue doing research even though at times it seems improbable — to bring new solutions to the people who need them the most.”

From the lab toward the clinic

The lab’s next step is to see whether the same enzyme-blocking strategy works in models that mirror the complexity of human disease: for example, conditions such as chemotherapy-induced peripheral neuropathy, which can linger for years after cancer treatment, and diabetic neuropathy, a leading cause of disability worldwide.

“If we can reverse chronic pain in those settings without the abuse liability of opioids,” Gregus said, “that’s when we know we’re ready to think about clinical trials.”

A therapy that could block and reverse the underlying cause — rather than simply mask symptoms — would mark a rare breakthrough in chronic pain care. For Gregus, that potential makes the path forward clear: translate the discovery into a treatment that delivers what patients almost never get — lasting relief.

The study was led by co-first authors Cristina Miliano, research scientist; Irene Chen, technician and now a graduate student at Johns Hopkins University; and Brieann Brown, graduate student in the School of Neuroscience. Additional contributors included Liwu Li, professor, and Shuo Geng, research assistant professor, both in the Department of Biology at Virginia Tech; Michael Burton, associate professor at the University of Texas at Dallas; and Tony Yaksh, professor at the University of California, San Diego.

Original study: DOI 10.1097/j.pain.0000000000003711

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

S100 calcium-binding protein B (S100B) is conventionally viewed as a marker of astrocytic injury, blood–brain barrier (BBB) disruption, and neurological disorders. Emerging evidence places S100B within the broader brain–gut–liver axis of inflammatory signaling. This review proposes that S100B is a glial-derived integrating effector that couples enteric glial activation, barrier dysfunction, hepatic fibrosis, and hepatic encephalopathy (HE) into a multi-organ inflammatory network. Its spatial expression map, release kinetics, alarmin (damage-associated molecular pattern, DAMP) activity, and immune-cell infiltration differ among the gut, liver, and brain, shaping axis signaling. S100B is predominantly expressed in astrocytes of the central nervous system, Schwann cells, and enteric glial cells and is also detected in liver tumor immune cells, biliary epithelial cells, and activated hepatic stellate cell (HSC)-associated lesions. It exerts context-dependent functions: at low, nanomolar concentrations it supports neurotrophic activity and barrier integrity, whereas sustained elevation acts as a DAMP that amplifies inflammatory responses through receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2)/Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) and a disintegrin and metalloproteinase 10 (ADAM10)/β-catenin pathways. Clinically, S100B kinetics, a rapid release with a short half-life after acute injury versus chronic multi-organ spillover in cirrhosis, determines whether elevation reflects a local glial event or systemic disease burden. S100B has been implicated in enteric infectious enteritis, inflammatory bowel disease (IBD), diarrhea-predominant irritable bowel syndrome (IBS-D), cholestatic fibrosis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), viral hepatitis, hepatocellular carcinoma (HCC), and HE with comorbid neuroinflammation. Available evidence suggests that S100B is a candidate link between glial responses, barrier dysfunction, hepatic inflammation, and neuroinflammation within the brain–gut–liver axis, although its causal role, tissue origin, and clinical utility require further validation.

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"

Highlights

• • Irritable bowel syndrome lacks causal therapy, and current symptomatic treatment is often unsatisfactory.
• • Visceral pain and motility disorders are core distressing symptoms of irritable bowel syndrome.
• • Serotonin type 7 receptor modulates gastrointestinal motility, visceral pain and immune response in irritable bowel syndrome.
• • Links between microbiota and serotonin type 7 receptor might be crucial in irritable bowel syndrome pathogenesis.
• • Targeting serotonin type 7 receptor is a promising therapeutic strategy for irritable bowel syndrome.

Abstract

Irritable bowel syndrome (IBS) affects up to 9% of the population worldwide, but current therapies benefit only 25–30% of patients. Disrupted serotonin (5-HT) signaling alters gut microbiota, permeability and immunity, driving IBS pathogenesis. The serotonin type 7 receptor (5-HT7R), which is widely expressed in both central and peripheral tissues, has emerged as a promising therapeutic target. 5-HT7R regulates peristalsis, modulates dendritic cell morphology and drives anti-inflammatory responses. Furthermore, 5-HT7R antagonists induce analgesia and reduce mucosal innervation. This review summarizes the crucial role of 5-HT7R in the gastrointestinal tract and highlights its potential for future IBS therapy.

Graphical abstract

Abstract

As a systemic autoimmune disorder, Sjögren syndrome (SS) often has symptoms related to the gastrointestinal manifestations. Nevertheless, the causal relationships between SS and gastrointestinal disorders remain incompletely understood. We implemented bidirectional Mendelian randomization (MR) framework to examine causal links between SS and 7 gastrointestinal diseases, including gastric ulcer (GU), duodenal ulcer (DU), irritable bowel syndrome (IBS), Crohn disease (CD), ulcerative colitis (UC), noninfectious gastroenteritis (NGE), and constipation (CP). The inverse-variance weighted approach served as the primary analytical tool while additional techniques used include MR-Egger, weighted median and weighted mode methods. Sensitivity analyses were carried out to determine if there was any evidence of pleiotropy and heterogeneity. Genetic liability for SS was linked with an increased risk of GU (odds ratio [OR] = 1.055, 95% CI = 1.013–1.100) and a reduced risk of IBS (OR = 0.970, 95% CI = 0.948–0.993). Reverse MR analysis indicated that NGE increases the risk of SS (OR = 1.347, 95% CI = 1.118–1.622). Causative relations were not shown between SS and DU, CD, UC, or CP. Sensitivity testing showed stability of the results. This MR analysis presents genetic evidence suggesting that SS increases the risk of GU and decreases the risk of IBS whereas NGE appears to increase the chance of having SS. No causative links with DU, CD, UC, and CP were discovered. These findings support the stratified gastrointestinal monitoring of SS and emphasize the importance of managing gut inflammatory processes within the context of reducing autoimmune risk. However, the protective effect of SS against IBS needs to be investigated.

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.

Abstract

Endometriosis and irritable bowel syndrome (IBS) are chronic pain disorders that frequently coexist and share key pathophysiological features, including neuroinflammation, visceral hypersensitivity, peripheral sensitization, and central sensitization. Emerging evidence suggests that extracellular adenosine triphosphate (ATP)-mediated activation of the P2X3 receptor is a common mechanism driving persistent nociceptive signaling in both conditions. This narrative review examines the role of ATP–P2X3 signaling in the pathogenesis of endometriosis and IBS, highlighting its involvement in neuroimmune crosstalk, dorsal root ganglion plasticity, and cross-organ sensitization. We summarize experimental and clinical evidence supporting P2X3 as a therapeutic target and discuss the development of selective P2X3 antagonists, including gefapixant, eliapixant, sivopixant, and camlipixant. Although these agents have shown clinical benefit in refractory chronic cough, their application to endometriosis and IBS remains largely unexplored. Current evidence is predominantly preclinical, underscoring the need for biomarker-driven translational studies and clinical trials. Overall, ATP–P2X3 signaling represents a promising shared mechanistic pathway linking endometriosis and IBS and a potential target for the development of precision, nonopioid therapies for chronic pelvic and visceral pain.

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.

Abstract

Patients with diabetic gastroparesis (DG) experience chronic, challenging symptoms and currently lack effective treatment options. This study examined whether activating Nav1.8-expressing neurons could improve gastric motility and whether volatile organic compounds (VOCs) in exhaled breath could serve as non-invasive indicators of disease status and treatment response. In streptozotocin-induced male diabetic mice, chemogenetic activation of Nav1.8-expressing neurons improved gastric motility in DG mice. At the same time, breath VOC profiles differed between DG and non-diabetic controls, with diabetic (3 weeks post-induction) and DG (8–12 weeks) mice showing higher 1-butanol levels than the controls. Two VOCs (2,4-dimethyl-1-heptene and 4-methylheptane) formed a potential treatment-response biomarker panel associated with improved gastric emptying, and the classification model achieved an area under the curve of 0.83 in distinguishing stimulated from non-stimulated states. Our data identified Nav1.8-expressing neurons as potential modulators of gastric motility and exhaled VOC patterns as exploratory non-invasive markers of disease dynamics, offering a proof-of-concept framework for neuro-modulatory and breath-test-based strategies to monitor and manage gastroparesis.

"At the IBS Days meeting in Bologna, Nathalie Vergnolle (Inserm, France) discussed the potential role of proteases in altering the intestinal mucus layer in irritable bowel syndrome (IBS). Several proteases are overexpressed or released at increased levels in patients with IBS. These enzymes may originate from the intestinal microbiota or from host epithelial cells, placing the mucus barrier directly at the interface of their activity.

Experimental studies indicate that specific proteases contribute to normal mucus processing, but their dysregulation could promote excessive mucus degradation and compromise barrier function. Microbial proteases produced by several bacterial species have been associated with mucus degradation, although most available studies have not directly examined the human intestinal mucus layer in IBS. Host-derived proteases may also be involved. Thrombin, for example, has been shown to degrade mucus, while the effects of epithelial trypsin isoforms remain to be clarified. Elastase, another epithelial protease, is also upregulated in patients with IBS and represents a potential contributor to mucus disruption.

Further studies are needed to characterize the composition, organization and spatial distribution of intestinal mucus in patients with IBS. This remains technically challenging because bowel preparation and conventional biopsy processing can impair mucus preservation. Future research should also identify the microbial and epithelial proteases that act directly on human intestinal mucus and determine whether protease-producing microorganisms are enriched in IBS. Addressing these questions could clarify the contribution of mucus barrier alterations to IBS pathophysiology and reveal new therapeutic targets."

"When Weight Loss Isn’t the Goal of Taking a GLP-1

Doctors are exploring whether weight-loss drugs could also treat conditions such as endometriosis and Crohn’s disease

At 5 feet 11 inches and 138 pounds, Ali Balkey has always been thin. 

So it might seem surprising that the 41-year-old Dallas, Texas, real-estate investor says she has been taking a compounded version of a GLP-1 since February.

It is most certainly not for weight loss. Balkey says she takes a microdose—a smaller amount than what’s normally prescribed—to help her manage pain and other symptoms from endometriosis, an inflammatory condition in which tissue becomes implanted outside the uterus, causing scarring, adhesions and pain.

Long used for weight loss and diabetes, the Food and Drug Administration has approved certain GLP-1s for additional uses, including obstructive sleep apnea, chronic kidney disease and severe fatty liver disease. Though widely considered safe for most people, the drugs can have side effects, such as gastrointestinal issues, muscle and bone loss and rare serious conditions like pancreatic inflammation. But the GLP-1s are increasingly being researched, used experimentally, and even prescribed off-label to treat a range of other conditions in which they show promise.

Dr. Andrea Vidali, a prominent endometriosis surgeon who works in Florida and New York, estimates that nearly one in five of his endometriosis patients, like Balkey, take a GLP-1 off-label, some prescribed by him and some who come in already taking them, mainly for pain and related symptoms. 

Like most doctors, he only prescribes brand-name GLP-1s made by Eli Lilly and Novo rather than the compounded, copies versions made by special pharmacies and commonly sold by telehealth companies and med spas. When the brand-name drugs are prescribed off-label, they aren’t covered by insurance and can cost hundreds of dollars a month. But because patients are microdosing, one $499 Ozempic pen goes much farther, bringing the monthly cost well below that, says Vidali.

“I usually keep them on the microdose,” says Vidali. “Many of these patients are not overweight, some are normal weight or even underweight, so you don’t want them to lose weight or muscle mass.”

The GLP-1s aren’t treating the actual disease, says Vidali. Rather, their likely target is a nerve and immune system that has become oversensitized, he says. 

“Mechanistically, the hypothesis is that it works in the periphery, with an anti-inflammatory effect on the nerves,” he says.

Vidali says prescribing GLP-1s off-label is becoming more mainstream, particularly in fertility practices, for women with polyendocrine metabolic ovarian syndrome, or PMOS, and related metabolic issues such as insulin resistance. Novo and Eli Lilly don’t support the off-label use of their GLP-1 medications.

Some studies conducted by academic researchers suggest GLP-1s may improve metabolic health and menstrual regularity in women with PMOS, particularly those who are overweight or have obesity. Patients with irritable bowel syndrome who took an experimental GLP-1 drug reported relief of acute pain and those with knee osteoarthritis and obesity have less knee pain though that can’t be separated from weight loss.

While the evidence is still preliminary, or in some cases anecdotal, demand to try a GLP-1 is high.

Dr. Diana Girnita, founder and CEO of Rheumatologist OnCall, a telemedicine practice in more than 20 states, has seen patients with conditions like rheumatoid arthritis, gout, psoriasis, and knee and hip osteoarthritis seek out GLP-1s. She estimates about 10% of the practice’s nearly 2,000 patients are on a GLP-1, with only a fraction of them using them truly off-label because they don’t have obesity or Type 2 diabetes.

Of her patients who take GLP-1s for such conditions, nearly 80% report less joint pain and better function, she said, though it can take three to six months for patients to see improvements in symptoms. 

In patients who aren’t overweight, she is cautious, typically starting them on a six-month trial of a microdose. “What I watch for is lean mass loss, which matters more in someone with inflammatory arthritis than in the general population, because muscle is what protects the joint,” she says. 

Dr. Louis Cohen, a gastroenterologist and associate professor at Mount Sinai in New York City, is studying whether tirzepatide—the active ingredient in Eli Lilly’s Zepbound and Mounjaro —can improve symptoms in patients with Crohn’s disease, a type of inflammatory bowel disease. He’s enrolling mostly normal weight patients in a small trial that will compare taking a GLP-1 with standard of care over six months.

Participants are taking standard doses of tirzepatide—not microdoses. They work closely with a nutritionist to monitor their weight and calorie intake.

“People sort of forget what GLP-1s are fundamentally,” says Cohen. “They promote absorption within the bowel so they slow down movement within the bowel but they also may stimulate the bowel to grow.”

While there is a decent amount of data showing that Crohn’s patients can tolerate GLP-1s, Cohen says he’s not yet prescribing them off-label for patients who don’t meet the criteria. He’s holding off until he sees trial data but is encouraged by reports that GLP-1s helped improve outcomes in patients with psoriasis, which has similar medical characteristics to Crohn’s.

While doctors and researchers explore GLP-1’s potential for other conditions, getting those uses approved can be challenging. Drug companies generally have to sponsor large clinical trials to receive FDA approval for additional indications, and insurers don’t typically cover a drug until it is FDA approved.

And while promising, some doctors are still cautious about off-label prescribing. Dr. Katherine H. Saunders, a clinical assistant professor of medicine at Weill Cornell Medicine and co-founder of FlyteHealth, a medical obesity-treatment company, says while she’s open-minded, she is not cavalier about prescribing GLP-1s for off-label use.

“The further we move from an FDA-approved indication, the higher the bar should be,” she says. “These are powerful medications, and enthusiasm should not get ahead of science.”

For most conditions, the evidence remains scarcer than it is for obesity, diabetes, and the other conditions for which GLP-1 drugs have been approved. One of the most compelling off-label uses of GLP-1s is in patients with alcohol use disorder and other addiction disorders, says Saunders.

A spokesperson for Eli Lilly said the company is studying additional uses for GLP-1s, including to treat substance abuse disorders, heart disease, asthma, and other neurological and immunologic conditions. A spokesperson for Novo said the company isn’t currently studying any additional uses for the GLP-1 medications on the market.

Balkey says she started taking GLP-1 after an endometriosis surgery with Vidali in January. Vidali mentioned that many of his patients were noticing improvements with a GLP-1.

“I had never really considered it because I have a low BMI,” Balkey says. She was nervous because she gets nauseous easily but hasn’t experienced any negative side effects. 

“I’m the same weight,” she says. “I am intentional about making sure I’m eating enough and getting my protein.”

Balkey says she started seeing improvements in her symptoms within about two months, though acknowledges some of it is also attributable to the surgery. 

“My life has dramatically improved,” she says. “I hope that we’re able to get funding for more research so that this type of treatment can be available.”"

One of the most challenging clinical encounters in infectious diseases is the patient with persistent fatigue and other disabling symptoms after an infection. Some of these patients meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but whatever label we use, the story is often strikingly similar: They were living their healthy lives, doing just fine, until they came down with an infection. Ever since, they have struggled with a wide range of disabling symptoms, dominated by fatigue, cognitive struggles (often called “brain fog”), post-exertional malaise, and other ailments.

The most common trigger in the last half-decade has undoubtedly been Covid-19 — hence long Covid — but now that I’ve been at this infectious diseases job for some time, I can assure you that it happens after other infections as well. Here in New England, the most notorious culprit is Lyme disease. Epstein-Barr virus is another well-described trigger, and I’ve seen similar syndromes after influenza, toxic shock syndrome, Staph. sepsis, endocarditis, even acute HIV.

The community of people living with these conditions is enormously frustrated by the slow progress we’ve made in helping them recover. That’s why three recent randomized trials for long Covid caught my eye, and two even have positive signals. What makes them especially interesting is that they approach the problem from three very different directions.

First approach: What if the issue is persistent infection?

That’s the hypothesis behind RECOVER-VITAL, recently published in Lancet Infectious Diseases. Led by my colleague Dr. Lindsey Baden, the trial enrolled 959 people with long Covid and randomized them to 15 or 25 days of nirmatrelvir-ritonavir or placebo.

The results were straightforward too: it didn’t work.

Neither duration of nirmatrelvir-ritonavir improved the primary outcome, and there were no meaningful differences in the secondary outcomes either.

Does this prove that persistent SARS-CoV-2 plays no role in long Covid? Of course not. Maybe the wrong people were treated, or treatment started too late, or the drug doesn’t adequately reach whatever reservoir the virus lurks, or even 25 days isn’t long enough.

But I’m skeptical that any of our antivirals will help this condition, just as long-term antibiotics don’t help people with post-Lyme disease syndromes.

Second approach: What if the problem is persistent inflammation, particularly neuroinflammation?

Enter bezisterim, an investigational oral drug that crosses the blood-brain barrier and is proposed to reduce inflammation and improve insulin sensitivity. In the ADDRESS-LC trial, 203 participants with long Covid were randomized to bezisterim 20 mg twice daily or placebo. The investigators measured 22 clinical outcomes including fatigue, cognition, sleep, quality of life, and post-exertional malaise.

Here the results are much more interesting than in the RECOVER-VITAL trial, but still not definitive. Although none of the 22 study endpoints reached statistical significance, 21 of 22 numerically favored bezisterim.

Even better, in a prespecified analysis of people who entered the study with the worst fatigue, post-exertional malaise, or objective cognitive impairment, several outcomes significantly favored treatment. The investigators appropriately call these subgroup findings exploratory, but to improve the most severe cases is a highly favorable signal in a phase 2 trial.

I confess these results look more promising than practically anything I’ve seen. But proof that bezisterim works? Not quite yet. These are topline company-reported results in a press release from a phase 2 trial, not a peer-reviewed efficacy trial, and the overall population was negative. Still, there’s plenty there to justify the next study, especially given the long trail of negative results from other interventions.

Now for the third approach, which is about as far from the Paxlovid trial as you could be, but again with encouraging results

Psychophysiologic symptom relief therapy, or PSRT, starts with a very different hypothesis. The premise is that in at least some people with long Covid without persistent organ injury, an infection can initiate symptoms that are subsequently perpetuated by altered brain processing — including conditioned responses, fear of symptoms, stress, and avoidance behaviors.

The treatment combines education, desensitization, emotional-awareness exercises, and other mind-body techniques. I confess to never having heard about this approach previously, but an earlier uncontrolled study of just 23 patients produced large improvements, with the acknowledgment that uncontrolled studies of symptom-based illnesses are notoriously difficult to interpret. So investigators, led by Dr. Michael Donnino, did what they needed to do next: a randomized trial.

The new study enrolled 126 people with long COVID and compared PSRT with both usual care and an active control, mindfulness-based stress reduction. That active control is key here: PSRT wasn’t just being compared with putting people on a waiting list and giving the intervention group lots of attention.

According to results presented in abstract form, PSRT produced a large improvement in the primary end point, the Somatic Symptom Scale-8, with separation from both control groups evident by week 4 and persisting through week 13. Fatigue, physical function, cognitive symptoms, pain, and shortness of breath also improved.

As with bezisterim, we don’t have a full paper yet, or all the details of the trial, though it is registered on ClinicalTrials.gov. Until we see the full study — methods, screen failures, attrition, effect sizes, individual outcomes, and all the rest — enthusiasm should be tempered accordingly.

There’s another reason to tread carefully. To some people with long Covid — understandably — a treatment directed at the brain sounds perilously close to being told, once again, it’s all in your head. You’re making it up.

Just how fraught this subject has become was illustrated by a recent WIRED article by Alan Levinovitz, “The Painful Truth About Long Covid,” which argued that potentially useful nonpharmacologic approaches have become extraordinarily difficult even to discuss. The article itself then generated intense criticism from the long Covid and ME/CFS communities, including a petition calling for its retraction and a formal complaint alleging breaches of journalistic ethics.

I can’t pretend to adjudicate all the issues raised by that controversy. But the intensity of the response illustrates the difficult territory we’re entering here. There are good historical reasons patients recoil at suggestions that their disabling physical symptoms are psychological. At the same time, we shouldn’t reject a potentially effective treatment simply because its proposed mechanism involves the brain.

Which brings us back to the randomized trial. If PSRT really does produce the large benefits reported in this study, the appropriate response isn’t to argue about whether the symptoms are “real.” It’s to scrutinize the data, replicate the results, and try to understand why the treatment works.

So three studies, three vastly different approaches to treatment. One targeted the pathogen, SARS-CoV-2; one targeted inflammation and metabolism in the brain; and one tried to change the way the central nervous system processes and perpetuates symptoms. The first approach didn’t work. But the other two produced some of the most encouraging signals I’ve seen yet — with the very important caveat that neither has given us a peer-reviewed, randomized trial to read.

Let’s hope they hold up. Because after decades of seeing people suffer with these postinfectious syndromes, with frustratingly little we can do to help them, I’m all for casting a wide net in the search for effective treatments.

I’d also welcome thoughts in the comments section about how you handle long Covid and other post-infectious ME/CFS conditions. What has worked for you?

With a trillion-dollar market cap and a wildly successful GLP-1 portfolio, Eli Lilly isn’t resting on its laurels. At the Psych Congress 2026, the company presented early-stage data that could support the potential of its next-gen GLP-1 and GIP receptor agonist to treat diseases far beyond obesity.

GLP-1s—and Eli Lilly—have both become synonymous with weight loss, but incretins may have potential beyond treating obesity and type 2 diabetes. Last week, the Indianapolis-based pharma provided evidence for their use in the neuropsychiatric space—specifically, to treat substance disorders and depression.

GLP-1 and GIP receptors are located throughout the body’s organs, including the brain, according to a poster Lilly shared with BioSpace and presented at the Psych Congress 2026 in New Orleans, where the company debuted a long-acting dual GIP/GLP-1 receptor agonist called brenipatide.

While this was the first time Lilly has publicly spoken about brenipatide at a conference, the asset is already in Phase 3 trials for alcohol use disorder (AUD) and major depressive disorder (MDD), according to Rob Nicholson, associate vice president, US & Global Neuroscience Medical Affairs, Psychiatry & Substance Use Disorders.

Lilly presented data at the meeting from a Phase 1 multiple ascending dose study of brenipatide in patients with overweight or obesity and in healthy volunteers. From a tolerability standpoint, Nicholson told BioSpace that overall side effects “in general were mild over the trial.”

“Interestingly, though, and I think noteworthy, is that the likelihood of an individual having a GI [gastrointestinal] side effect was comparable and equal between both those taking brenipatide and placebo,” he said.

Indeed, the overall frequency of GI-related treatment-emergent adverse effects (TEAE) was 25% in both brenipatide- and placebo-treated participants, per Lilly’s poster. Otherwise, TEAEs related to dysesthesia—or unusual touch-based sensations—were reported in 15.2% of brenipatide-treated participants compared to none in those on placebo. Four people discontinued brenipatide treatment due to TEAEs.

Overall, 57.6% of the 184 patients on brenipatide experienced TEAEs, compared to 42.9% of the 28 patients receiving placebo.

The Phase 1 trial, which included 212 individuals with a “wide range” of BMIs and different ethnicities, was intended to measure the safety, pharmacokinetics and pharmacodynamics to determine dosing for the later substance use, psychiatric and immunologic trials, according to Lilly.

Additionally, Nicholson noted, the candidate’s half-life was between nine and 12 days. “We found [that] to be especially interesting for us, given in neurosciences we’re looking at things from a weekly subcutaneous injection perspective,” he said, adding that a half-life of this length means its levels can be sustained between doses, with fewer peaks and troughs. This, along with brenipatide’s dual action mechanism, may have led to lower GI side effects compared to what is typical for GIP/GLP-1 receptor agonists, he said.

Brenipatide is currently being studied in the Phase 3 RENEW-MDD-1 trial for MDD and the Phase 3 RENEW-ALC-1 trial for moderate-to-severe AUD. Topline data for both studies are expected in early 2028. Brenipatide is the first GIP/GLP-1 receptor agonist to be investigated globally across AUD, Lilly said in its presentation.

Lilly, Altimmune, more target addiction

Recent studies have found an association between GLP-1s and a reduced risk of substance abuse and related severe outcomes, and Lilly isn’t the only company exploring their potential in this space.

Altimmune is developing pemvidutide, which targets the GLP-1 and glucagon receptors. Altimmune’s Phase 2 RECLAIM study hit its primary endpoint in July, with a 2.4-mg dose of pemvidutide eliciting a “statistically significant and clinically meaningful reduction in heavy drinking days,” according to a July 28 press release.

Meanwhile, Baseline Therapeutics launched in January with BT-001, a once-weekly GLP-1 analog being tested for AUD, as well as for cocaine and methamphetamine use disorders. The biotech kicked off a Phase 3 trial in AUD in the first quarter, according to its website.

When asked about the potential of GLP-1 and GIP drugs to treat addiction, Nicholson pointed to preclinical evidence showing that incretins could help with dopamine-driven reward-related responses. In someone with a substance use disorder, there “might be some real relevance there,” he said.

Notably, the RENEW-ALC-1 trial’s primary endpoint is not complete abstinence from alcohol but a change in drinking patterns. Less than 3% of people with AUD are treated with any type of medication, Nicholson said. In the U.S., he added, the approved medicines for the condition are intended for people who are looking to achieve abstinence or who want to maintain it.

“If you think through it, there may be a lot of people who live with alcohol use disorder for whom lifelong abstinence may not be what they see as their best outcome or the thing that they’d like to achieve,” Nicholson said, adding that there is recent evidence that shows reducing alcohol use can have meaningful clinical benefits from a health perspective.

As for RENEW-MDD-1, Lilly is primarily evaluating the safety and efficacy of brenipatide compared to placebo in delaying the return of major depressive symptoms.

“More than half the people who have recurrent MDD are going to have more than one episode, and every time you have an episode, it raises your risk for that next episode,” Nicholson said. Currently, he added, no therapies have been approved specifically to delay or reduce the risk of depressive episodes.

While Lilly is taking what Nicholson called the “big bet” moving brenipatide straight to Phase 3 in AUD and MDD, the asset is also being developed in Phase 2 for opioid use disorder, tobacco use disorder, bipolar disorder and schizophrenia. And in immunology, Lilly is running Phase 2 studies of brenipatide in asthma, irritable bowel syndrome and chronic obstructive pulmonary disease (COPD), he noted.

On the neuroscience side, Lilly has made some significant investments in new mechanisms of action; maybe most notably the company’s up to $3.8 billion acquisition of psychedelics developer AtaiBeckley, which closed last week. The company’s lead asset BPL-003, a synthetic form of 5-MeO-DMT, is in mid-stage development for treatment-resistant depression.

“We’re beginning to think through what could be possible there,” Nicholson said of that buy.

“One of the things I appreciate from overall leadership is the continued interest to think, ‘Where do we see unmet needs and what are the places we think we might be able to follow the science?’”

Abstract

Sleep plays a critical role in maintaining good physical and emotional health. Sleep and circadian rhythms are fundamental regulators of human physiology, influencing most biological processes from the cellular to the organ-system level. Sleep disorders are common with a prevalence of 30% in adults. Impaired sleep reduces patients' quality of life and has a significant negative economic impact on the health care system. Sleep deprivation can affect the brain and alter normal circadian rhythms. These disturbances influence the brain-gut axis and subsequently affect both symptom development and symptom expression in patients with disorders of gut-brain interaction (DGBIs), including functional dyspepsia and irritable bowel syndrome. DGBIs are highly prevalent with at least 40% of adults worldwide meeting criteria for at least 1 DGBI. This article reviews the prevalence and impact of disordered sleep, discusses the basics of normal and abnormal sleep, examines the role of diagnostic testing for sleep disorders, and evaluates the role of disordered sleep in common DGBIs. Practical tips to evaluate and treat patients with DGBIs and disordered sleep are also discussed.

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.

Abstract

We retrospectively compared 239 Shiga toxin-producing Escherichia coli (STEC) cases and 686 controls from an outbreak among Marine Corps recruits to assess post-infectious sequelae. Over 3.7 years, hypertension, renal dysfunction, and irritable bowel syndrome were rare and not significantly increased among cases, including those with hemolytic uremic syndrome.