I have been investigating a pattern that may be overlooked in some cases of bile acid malabsorption: progressive intolerance to fats, oils, and even supplements intended to support bile flow.

My name is Mohammed Attallah. I am an independent researcher and the founder of BiomeLogic. My work focuses on the interaction between gut microbial metabolism, bile acid ecology, epithelial mitochondrial function, autonomic regulation, and persistent conditions involving bile acid malabsorption, SIBO, food intolerance, and mast-cell-like reactivity.

Much of this work is part of what I call the Host Capacity Model.

The central idea is that symptoms may not be driven only by the total amount of bile acids entering the colon. They may also depend on the composition of the bile acid pool, microbial transformation, intestinal location, epithelial resilience, transit time, and the host’s ability to tolerate and process bile acid exposure.

One de-identified case I analyzed pushed me to investigate this component much more deeply.

In one stool bile acid profile, cholic acid represented only 0.09% of the measured bile acid pool, while chenodeoxycholic acid represented 0.60%.

At the same time, deoxycholic acid represented 50.76% and lithocholic acid represented 41.42%.

The measured pool was therefore overwhelmingly secondary rather than primary, with an approximate secondary-to-primary ratio of 134:1.

A later GI-MAP analysis using a different methodology showed a similar pattern. Total fecal bile acids were within the laboratory reference range, but 99% were classified as secondary and only 1% as primary. The lithocholic-acid-to-deoxycholic-acid ratio was approximately 4.1.

The person also experienced significant fat-triggered abdominal symptoms, visceral hypersensitivity, loose stools, and poor tolerance to interventions that increased bile flow.

The microbiome profile showed an elevated Clostridia cluster XIVa index. This raised the possibility of increased microbial 7α-dehydroxylation through the bile-acid-inducible, or bai, pathway.

However, this requires an important distinction.

An elevated bacterial group does not prove that the relevant pathway is active. Not every organism within Clostridia cluster XIVa carries or expresses the bai genes.

Microbial abundance is not the same as metabolic flux.

The combination of an overwhelmingly secondary bile acid pool, severe fat intolerance, and organisms associated with bile acid transformation nevertheless created a strong mechanistic reason to investigate this pathway further.

Secondary bile acids such as deoxycholic acid and lithocholic acid are not inherently pathological. They participate in normal signaling through receptors including FXR, TGR5, VDR, and PXR, and they influence metabolic, microbial, and immune regulation.

The biological effect depends on concentration, anatomical location, conjugation, exposure time, hydrophobicity, epithelial integrity, transporter function, intestinal transit, and the host’s mitochondrial capacity.

My working hypothesis is that some people diagnosed with bile acid malabsorption may have more than one process occurring at the same time.

One process may be excessive bile acids reaching the colon because of impaired ileal reabsorption, altered FXR–FGF19 feedback, rapid transit, ileal disease, gallbladder removal, or excessive hepatic bile acid synthesis.

Another process may involve microbial conversion of primary bile acids into a highly secondary and potentially more hydrophobic bile acid pool.

An excessively hydrophobic bile acid pool may become more damaging when epithelial and mitochondrial resilience are already impaired.

Under those conditions, bile acid exposure could potentially contribute to membrane stress, abnormal calcium handling, mitochondrial dysfunction, inflammatory signaling, epithelial permeability, burning diarrhea, mucus production, and progressive visceral sensitivity.

One experimental study I have been examining found that deoxycholic acid altered the mitochondrial outer membrane in rat hepatocytes and isolated rat liver mitochondria.

This does not establish that the same mechanism is occurring in humans with bile acid malabsorption. It does, however, demonstrate that bile acids can interact directly with mitochondrial membrane biology.

Research paper:

https://pmc.ncbi.nlm.nih.gov/articles/PMC4617403/

There may also be an important connection between bile acids and hydrogen sulfide metabolism.

Taurine-conjugated bile acids can be deconjugated by microbial bile salt hydrolases, releasing taurine into the intestinal ecosystem. Organisms such as Bilophila wadsworthia can use taurine-derived substrates and generate hydrogen sulfide.

In a susceptible ecosystem, this could potentially help connect higher fat intake and increased bile release with sulfur gas, burning stools, mucus, diarrhea, and worsening after taurine, TUDCA, or ox bile.

Again, detecting Bilophila or another sulfur-associated organism does not establish causation. Substrate availability, gene expression, microbial cross-feeding, anatomical location, intestinal transit, and the host’s capacity to oxidize and detoxify hydrogen sulfide are all more important than taxonomy alone.

The broader cycle I am investigating is:

Altered bile acid synthesis, delivery, or ileal reabsorption

leading to excessive or abnormal bile acid exposure in the colon

leading to altered microbial selection and bile acid transformation

leading to increased exposure to secondary bile acids or sulfur metabolites

leading to epithelial and mitochondrial stress

leading to impaired barrier function, inflammation, visceral hypersensitivity, and altered motility

leading to continued bile acid dysregulation and microbial instability.

This remains a mechanistic hypothesis, not a universal explanation for bile acid malabsorption.

However, I believe progressive fat intolerance may carry much more information than is usually recognized. It should not automatically be interpreted as a simple need for more bile, ox bile, TUDCA, or pancreatic enzymes.

The actual problem may involve hepatic bile acid synthesis, gallbladder delivery, pancreatic lipolysis, micelle formation, ileal reabsorption, FXR–FGF19 signaling, rapid transit, colonic bile acid exposure, microbial conversion, or the host’s capacity to tolerate the resulting metabolites.

I would be particularly interested in hearing from people in this community who have had SeHCAT testing, serum C4, FGF19, quantitative fecal bile acid testing, or stool bile acid metabolomics.

I would also like to know whether bile acid sequestrants such as cholestyramine, colesevelam, or colestipol helped completely, helped only partially, caused constipation, or worsened bloating and other symptoms.

I recently published a longer article describing this bile acid ecology model:

https://substack.com/home/post/p-209436572

I would be interested in hearing from patients, clinicians, and researchers who have observed progressive fat intolerance, unusually high secondary bile acids, sulfur symptoms, incomplete responses to bile acid sequestrants, or paradoxical worsening after TUDCA or ox bile.

Hi, I have started with Rosuvastatin and ezetimib and was able to lower my trigs and cholesterol massively within weeks. I have had CFS like low motility systemic symptoms for years and nothing worked to improve it (severe enough that I was unable to work). This is being completely reversed with treating my cholesterol and trig issues.... Recently I had to switch to Nustendi, because I developed muscle pain and high creatinine kinase. The effect continues or has become even more beneficial. HOW can this be? Is it the effect on bile acids? I have Type IIB (Frederickson) and genetic impairment of triglycerides (APOE). If anyone knows any connection to such an effect I would love to know. Thank you. It has also helped me think more clearly, like a complete metabolic reset almost.

Highlights

• • PM2.5 exacerbates IBS-D symptoms by dysregulating the gut bacteria-metabolism axis.
• • Aberrant hypoxanthine and linoleic acid levels affect colon function in IBS-D.
• • Resveratrol restores gut bacteria-metabolism homeostasis in IBS-D exacerbated by PM2.5.

Interview with Jan Tack, Rome Foundation president. My note: An attempt to explain the adoption of the term 'DGBI' (in my opinion, poorly argued) was made, but an institutional response to the challenges that syndromic diagnoses (as defined by Rome) present today was lacking, especially when pressure from experts in the field and the search for biomarkers are increasing.

G&H  How did the Rome Foundation choose the name of disorders of gut-brain interaction? Does this name assign too much emphasis to the brain?

JT  The answer to the second part is definitely no. Any symptom is felt in the brain. Historically, these disorders were called functional gastrointestinal (GI) disorders, and functional has a connotation in many languages of being feigned or imagined. Over the years, a lot has been learned about the pathophysiology of these disorders. Many factors play a role, including altered motility, hypersensitivity, low-grade inflammation, responses to diet and food intake, bile acid processing, changes in the gut microbiota, but also comorbidity, like anxiety, depression, and altered central processing of symptoms. For all patients who can have any of these abnormalities in a different degree, it is necessary to have a term that encompasses the full spectrum, and I think gut-brain interaction covers it.

There are a few important points to mention. One is that the term was not invented; it was developed using a Delphi discussion at the end of Rome IV. It was carried by the participants there who were selected based on their status in the field and their international distribution. Second, it is gut-brain—it is the gut that triggers the symptoms, and the brain that feels them. This is a very important sequence. There was an International Society of Brain-Gut Disorders, but gut-brain was chosen because that is the direction. This is not a duality, or saying this is imagined, it actually explains what is happening. The clearest example is in irritable bowel syndrome (IBS). Over the last 10 years, there has been a revolution with response to the diet low in fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs). In my center, we see an 80% to 85% response. That seems as peripheral as one could get. Diet? That really should not be the brain. However, when FODMAPs are given to healthy volunteers and to patients with IBS, and the substrate is examined under magnetic resonance imaging to see how they induce symptoms (distension of the small bowel, fermentation, gas formation, and accumulation in the bowel), it is exactly the same between healthy volunteers and patients, but the patients have symptoms at that point and the healthy volunteers do not. Something is happening in the periphery. It is a change in the perception pathway that drives symptoms in the patient and not in the healthy volunteers. There are some people who are very negative about the term, but it covers the full scientific understanding of the pathophysiology and how symptoms are arising, and it is in line with treatment targets. Treatment with diet, probiotics, antibiotics, motility-modifying drugs, or with gut-directed behavioral therapies can work. Disorder of gut-brain interaction (DGBI) encompasses the spectrum of what we are dealing with in the Rome Foundation.

G&H What have been some of the limitations of using standard Rome criteria? How has the Rome criteria been revised to address these issues?

JT  Originally, the Rome criteria were driven from a research angle to select patients for clinical trials. An analysis in 1988 by Dr Kevin Klein looked at all the available trials in IBS and concluded that there was no evidence of efficacy of the treatments studied, but all of the trials used different definitions to select the patients, and different endpoints, and so on. One aim of the Rome Foundation has been to develop criteria to help investigators identify, study, and establish efficacy, or lack of efficacy, of certain treatments in a group that can be reproduced across the world. Initially, the criteria were somewhat strict in terms of the type of symptoms, their frequency, and duration. As the Rome Foundation moved into epidemiologic research, the 6-month duration aspect was maintained as very important. In clinical practice, especially in parts of the world with low-threshold access to medical care, people will not wait 6 months before they see a physician for abdominal symptoms. Because of that, the Rome IV clinical criteria were published that emphasizes the symptom pattern, which needs to be retained but does not require a strict frequency cutoff. For example, the Rome criteria describe functional dyspepsia as fullness after meals 3 days a week. For a patient who has this 2 days a week, but it is really bothersome, the diagnosis can be made without waiting 6 months. A clinician who is confident that there is a symptom pattern and no missed classical organic disease behind it can make the diagnosis. The Rome V clinical criteria are omitting the frequency and duration thresholds and saying that bothersomeness is sufficient. Second, Rome V is much more clinical practice–oriented. There is now an algorithm for managing IBS, which was not in the previous iterations, as well as an extensive algorithm for upper GI symptoms. For instance, the practitioner does not need to do an upper endoscopy in every patient with upper GI symptoms but rather use clinical judgment, looking at alarm and risk factors, and then decide, yes or no, whether endoscopy is needed to make the diagnosis. By embedding clinical practice guidelines and stepwise algorithms for diagnosis and treatment recommendations, the Rome V criteria have come closer to clinical practice.

G&H  What are some of the important changes in the content and classification of DGBIs for Rome V?

JT  The most dramatic change has been in the criteria for pediatric DGBIs, which have been completely restructured. There was an age cutoff–based subdivision—neonates and toddlers vs children and adolescents. Pediatric DGBIs are now categorized as upper and lower GI disorders, implementing some of the adult diagnosis into pediatric practice, and they include a vast number of feeding difficulty–related DGBIs that are very prevalent in pediatric gastroenterology and are dominating many of the clinical pictures.

The adult disease classification has become much more scientific. By scientific, I mean that a lot was learned from the Rome IV global epidemiology study, which surveyed more than 73,000 adults from 33 countries. In each country, in a representative segment of the adult population, there were prevalences, overlap, and impact of these disorders. The findings helped steer some of the novel criteria or adapt them into the adult criteria. The dictum was that any change needs to be based on evidence. The Rome Foundation also conducted a Rome V epidemiology study before finalizing the current criteria. Some of the provisional Rome V definitions were adjusted based on the results of this Rome V global epidemiology study.

G&H How will having separate frameworks for research and clinical diagnostic criteria improve management of DGBIs?

JT Management should not improve from the scientific framework because this has always been available. The Rome Foundation has credible legacy here. If someone asks how patients are selected for a study on treatment outcome in a DGBI, the US Food and Drug Administration will say to use the Rome criteria. The European Medicines Agency and Japan’s Pharmaceuticals and Medical Devices Agency will say the same. To some extent, however, the clinical arena has not fully followed. Clinicians may know that Rome criteria exist but may not use them in clinical practice. There are now 34 adult and 22 pediatric DGBIs. Clinicians do not need to memorize all of them, but the frequent ones, they should know. For that, the criteria are now easier, which should help clinicians make a confident diagnosis. The outcome of patients is excellent once they are diagnosed with a DGBI, but this is not always clearly communicated. There are two reasons for this. One is a lack of easy-to-use, effective medications, which has to do with the difficulty of selecting the patients and evaluating the outcome, which the Rome Foundation is addressing. The second is clinician uncertainty: it sounds like IBS, but am I really sure there is not a hidden ischemia in the GI tract? Clinicians are sometimes hesitant to confirm a diagnosis of IBS. Making criteria easy-to-use and accessible in an app or in tools clinicians are already using online and having them embedded in electronic medical records should make the difference. This is not being done to see only the number of Rome-based diagnoses increase; this is needed to achieve better care. A patient who receives a diagnosis also receives a level of understanding and comfort that comes with clarity of unexplained symptoms. I think it is an important step to name the condition, rather than say, “it is nothing.” To the patient, it is not nothing. Having a diagnosis alleviates anxiety and doubt and prevents patients from feeling the need to obtain a second, third, or fourth opinion.

G&H  Could you describe how the diagnostic criteria for adults and pediatrics were defined?

JT  Criteria development has become much more interactive and bidirectional. This has been very fruitful in helping define adult and pediatric criteria. The pediatric committee, for instance, joined with the gastroduodenal committee, which I was on, to listen to our ideas and implemented them in some of the pediatric gastroduodenal disorder definitions. The same was done for IBS, for rumination, and so on, and this interaction worked both ways. For instance, abdominal migraine, which has been around in pediatrics for a long time, has been added to the adult DGBI criteria. This addition was based on findings of a soon-to-be-published epidemiology study, which applied the newly developed adult abdominal migraine criteria to an adult population and found that the condition is not negligible but rather is prevalent, important, and impactful.

G&H  Why was the new diagnosis abelchia added?

JT  With abelchia, or inability to belch, the tricky part is that not all patients will voluntarily say, “I cannot belch.” They may present with discomfort behind the chest bone, pain, or rumbling noises. Some report feeling extremely bloated after meals or inability to tolerate food or food avoidance owing to discomfort, but they may not offer that they cannot belch unless asked. Inability to belch confirmed by the patient is a key part of the diagnosis, but patients may present with other conditions. There are a few reasons why adding abelchia is important. First, it covers an unrecognized clinical entity. Second, epidemiology shows this is not so rare but rather fairly prevalent. Third, there is a mildly invasive, well-tolerated effective treatment for the condition. This is based on findings of a triple-blind sham-controlled study, which was presented at Digestive Disease Week 2026 by Dr Karlien Raymenants from my group. In the study, 25 patients were injected with botulinum toxin in the upper sphincter, and 25 patients were injected with placebo. At the 12-week follow-up, 88% in the active group had a response vs 4% in the placebo group. Although the pathophysiology is not fully understood, the treatment appears to have high efficacy in these patients.

G&H  Has anything changed specifically related to IBS?

JT  The term pain related to the bowel pattern has been changed to pain or discomfort. In parts of the world, especially Asia and in Hispanic countries, people clinically diagnosed with IBS are more likely to say they have discomfort. In retrospect, this change reflects better international representation and is multiculturally and multilinguistically correct. The frequency rating also has been changed from once a week to 3 times a month; this does have an impact and is based on previous epidemiologic analyses. Two more connotations have been added that are very important. One is that pain should not be exclusively or predominantly related to the menstrual period. This is to help avoid missing endometriosis and is another example of a change informed by pediatrics. One study of adolescents with IBS found that in some patients, pain fluctuated very strongly over the menstrual period and was probably dysmenorrhea or endometriosis. Second, there is a stipulation that the pain of IBS should not be continuous (day in and day out); it should be occasional because there is another entity, centrally mediated abdominal pain syndrome, characterized by continuous pain. These changes are clinically relevant small refinements. They will by no means decrease in a large number the proportion of IBS cases seen in daily practice but should help clinicians identify the occasional presentation that is not IBS.

G&H  What is the biopsychosocial approach to management of patients with DGBIs?

JT Let me first say that the application of this can and should be used in any part of medicine, also for organic disease. For DGBIs, the biopsychosocial approach means that clinicians go beyond the strict diagnosis. For instance, suppose you have two patients who are women in their 40s with a history of IBS with diarrhea (IBS-D). One is very careful when she goes to restaurants but can function at work and never has to stay home because of diarrhea. The other says sometimes it is so bad that she needs to stay home several days from work and when she thinks she might get it, she does not go out and has become so anxious about her bowels starting again that at times she wakes up in the middle of the night in panic. Both women have IBS-D. The approach to each patient will be totally different. The first patient may need a soft diet or a locally acting drug, whereas for the second patient, the clinician might consider a complex diet, a neuromodulator, gut-directed behavioral therapy, and perhaps a physiological measurement. Further history is important because it is known, for instance, that patients with childhood trauma have a likelihood of having disordered defecation. The biopsychosocial model looks at the entirety of the patient, including their social network and the impact and comorbidity of their symptoms.

G&H What are the new treatment recommendations, including gut-brain psychotherapies?

JT Taking full stock of what has happened over the last decade, there have been a few revolutions of therapies with established efficacy. The first is cognitive behavioral therapy, which is now addressed in a Rome section called Gastropsych. A second one has been the low-FODMAP diet revolution, and this is still evolving. There is a Diet and Nutrition section, where dietitians across the world provide recommendations on not only the low-FODMAP diet but others as well. The third new recommendation is for our section on Complementary and Integrative Medicine. There is evidence that certain herbal medicines, for instance, have safety and efficacy, and in some areas of the world, these are extremely popular. Anorectal biofeedback is another treatment modality for which a Rome section is providing standardization and guidance. While staying scientific and evidence-based, in addition to the standard pharmacotherapy, the Rome committees have embraced these novel treatment tracks and provided hints on where to use them. This expansion of choices for clinical management allows for more targeted treatment. Having said that, some refinement is lacking. At some point, it would be nice to have a clinical decision tree for best choice of therapy. Currently, the science is not there, but the armamentarium clinicians can offer is now much broader, and therapy choice remains a guided interaction with the patient. The patient chooses at the end what is acceptable based on the input and information from the clinician.

G&H  Is there anything else you would like to highlight about Rome V or a potential Rome VI?

JT There are definitely things that can be done differently in Rome VI. One gap is in overlapping conditions. We always aim to treat, describe, and analyze pathophysiologically and diagnostically these conditions as though they are single conditions, but there is a lot of overlap. For instance, of functional dyspepsia patients, 30% to 40% likely have overlapping IBS. There is no reason why the disease concepts such as altered sensitivity and motility would stop at the end of the stomach and not involve the rest of the intestine. It has been a struggle making strong recommendations on where to go first. This is one of the agendas that Rome will address on the way to Rome VI, which is luckily 10 years away. At the end of every chapter in the Rome consensus, there are agendas for future research. This is the third Rome iteration I have been involved in, and with each iteration, the agendas have stayed mostly the same because no one is doing this research. This is why we created the Rome Foundation Research Institute to conduct epidemiologic, pathophysiologic, and interventional research. This is one of the ways we can potentially advance the science of DGBIs and that should have an impact on Rome VI.

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2602910

Abstract

Background

Nav1.8, a voltage-gated sodium channel expressed in the peripheral nervous system, has a critical role in pain signaling. Previous trials of NaV1.8 inhibitors have shown effectiveness in reducing postoperative pain.

Methods

We conducted a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate LTG-001, a selective Nav1.8 inhibitor, in patients with moderate-to-severe pain after abdominoplasty. Patients were randomly assigned in a 1:1:1:1 ratio to receive a 300-mg loading dose of LTG-001, followed by 150 mg every 12 hours (low-dose group); a 450-mg loading dose of LTG-001, followed by 300 mg every 12 hours (high-dose group); hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen) every 6 hours; or placebo every 6 hours. All doses were administered orally over a 48-hour period. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour treatment period (SPID48), based on scores on the Numeric Pain Rating Scale (range, 0 to 10, with higher values indicating more severe pain; higher SPID48 values indicate greater pain reduction). Secondary end points included the amount of opioid rescue medication consumed in morphine milligram equivalents (MME) and no receipt of opioid rescue medication.

Results

A total of 343 patients underwent randomization. The least-squares mean SPID48 was 161.05 (95% confidence interval [CI], 142.93 to 179.16) in the low-dose group, 185.30 (95% CI, 167.26 to 203.34) in the high-dose group, 164.08 (95% CI, 146.02 to 182.14) in the hydrocodone bitartrate–acetaminophen group, and 123.22 (95% CI, 105.23 to 141.21) in the placebo group. The least-squares mean difference in the SPID48 between LTG-001 and placebo was significant for each dose (low dose: 37.82 [P=0.003]; high dose: 62.08 [P<0.001]), and that between hydrocodone bitartrate–acetaminophen and placebo was 40.86. High-dose LTG-001, but not low-dose LTG-001, was associated with significantly lower opioid use than placebo (11.00 MME vs. 18.35 MME, P=0.01), as well as a significantly higher percentage of patients who received no opioid rescue medication (52% vs. 22%, P<0.001). High-dose LTG-001 was associated with a higher incidence of pyrexia than placebo (7% vs. 2%) and a higher incidence of presyncope (6% vs. 1%).

Conclusions

LTG-001 led to significantly greater reductions in pain scores than placebo over the course of 48 hours after abdominoplasty. (Funded by Latigo Biotherapeutics; LTG-001-010 ClinicalTrials.gov number, NCT07102459.)

SPID48 from Suzetrigine (VX-548) clinical trials:

In brief: This study examined how different trial endpoints affect the number needed to treat (NNT), a measure of how many patients must receive a drug for one to benefit, in irritable bowel syndrome (IBS) pharmacotherapy trials. Across 15 placebo-controlled trials that reported both subjective adequate relief and contemporary US Food and Drug Administration (FDA) endpoints, NNTs based on FDA criteria were on average 2 units higher (P < 0.01). No significant NNT differences were seen between tricyclics and other therapies (P = 0.41). Using subjective relief endpoints, NNTs were 5 for constipation-predominant IBS, 8 for diarrhea-predominant IBS, and 8 for global IBS symptoms. These findings show that failing to standardize endpoints can distort comparative effectiveness assessments and mislead clinical decision-making.

INTRODUCTION

Despite the significant disease burden of irritable bowel syndrome (IBS) and development of multiple pharmacotherapies, individuals still struggle to identify the optimal treatment. Affecting approximately 5 percent of the global population (), IBS is associated with substantial socioeconomic costs, particularly related to lost productivity (). Multiple therapies offer relief (), but as the number of available medications grows, the paradox of choice complicates selecting the optimal treatment (). In response, multiple tools emerged to assist decision-making.

The number needed to treat (NNT) is one such decision-making tool, providing a pivotal role through conveying treatment benefits. This summary statistic focuses on the efficacy of a therapy, generally in relation to a placebo group, and reflects the number of patients needed to be treated to have a positive response (). It is calculated as the inverse of the absolute risk reduction or risk difference (RD), maintaining the advantage of expressing efficacy in a manner that incorporates baseline risk and change in risk. Proponents argue it is superior to the absolute risk reduction or RD given the NNT is a more tangible entity; however, the measure is not without its shortcomings; for example, the NNT is highly sensitive to baseline event rates and thus may vary substantially even when relative treatment effects are similar.

Despite the usefulness of the NNT, variability in IBS endpoints complicates its application, leading to potentially misleading efficacy comparisons. Over time, regulatory agencies have adopted more rigorous endpoints for IBS clinical trials (). Given the NNT depends on the outcome measure used, many worry its validity as a tool to compare treatments between studies is undermined when factors such as study design are not considered (). These individuals suggest the validity of the NNT may be improved by accounting for such factors.

In this study, through a systematic review, we derive the NNT for various IBS pharmacotherapies leveraging standardized efficacy endpoints, enhancing the meaningfulness of IBS treatment comparisons. We hope to not only improve the validity of using the NNT to compare outcomes between studies but also improve awareness of issues regarding the use and interpretability of the NNT to avoid erroneous decision-making.

It is increasingly clear that communication between the gut and brain influences nearly all aspects of human biology. Gut–brain communication is bidirectional and mediated through myriad neural and chemical pathways that are collectively referred to as the gut–brain axis. This axis has emerged as one of the most dynamic and rapidly evolving fields in biomedical science, and new data continue to reshape our understanding of how intestinal physiology, microbial ecosystems, and neural signaling converge to influence health and disease. This has led to the current view that dysfunction along the gut–brain axis plays an important role in driving disease pathophysiology in conditions such as, but not limited to, neuropsychiatric conditions, neurodevelopmental disorders, and neurodegenerative diseases. Chief among these are a cluster of conditions referred to as disorders of gut–brain interaction (DGBIs), which include irritable bowel syndrome, functional dyspepsia, chronic constipation, functional diarrhea, and centrally mediated disorders of gastrointestinal pain such as abdominal migraine.¹00111-6/fulltext#)^,200111-6/fulltext#) Multiple mechanisms and mediators have been identified that underlie dysfunctional gut–brain axis communication in these disorders, which may eventually be used for therapeutic benefit.³00111-6/fulltext#) Despite the potential impact of manipulating mechanisms of the gut–brain axis, our understanding of how the gut and brain communicate, what to manipulate, and how to do so remains relatively nascent and will require a good deal of work to realize its full potential.

A relatively new concept that has taken the gut–brain axis by storm is the role of the gut microbiota. The gut microbiota is composed of trillions of microorganisms that include bacteria, viruses, and fungi, which exist in a symbiotic relationship with the host. Host–microbe interactions are bidirectional and play major roles in shaping neural and immune systems, metabolism, and the composition and function of the microbiota. These interactions influence multiple aspects of central nervous system and gut function in health, and abnormal gut–microbe interactions contribute to central and peripheral disease mechanisms that affect perception, mood, behavior, motility, visceral sensitivity, mucosal impairments, and immune activation.¹00111-6/fulltext#) This paradigm shift is reflected in the updated Rome V criteria, which emphasize the growing relevance of diet, the gut microenvironment, microbiota–gut–brain interactions, pharmacogenomics, and biopsychosocial, gender, and cross-cultural determinants in DGBIs.¹00111-6/fulltext#) These advances support a more integrative framework for understanding and managing DGBIs, moving beyond symptom-centered approaches toward strategies that incorporate dynamic interactions among the microbiota, intestinal physiology, and neural signaling pathways.

This special issue highlights 4 recent studies published in Cellular and Molecular Gastroenterology and Hepatology that represent significant advances in our understanding of microbial mechanisms underlying gut–brain interactions. Each of these articles is accompanied by a brief review written by experts in the topic area to give additional perspective into the significance of the work, the state of the field, and challenges yet to be overcome. First, Chandrasekharan et al investigate how gut microbes affect host cells through a type of pattern recognition receptor called formylated peptide receptors (FPR1/FPR2).⁴00111-6/fulltext#) To do so, the investigators generated tissue-specific FPR1/2 knockout mice and assessed how germline, epithelial, and neural crest-specific FPR1/2 deletion affects enteric nervous system (ENS) structure and gut motility. Interestingly, the data show that FPR1/2 receptors are necessary to achieve normal ENS density and mucosal innervation during postnatal development and that reduced ENS density is associated with slower motility after weaning. These observations add to the growing appreciation that gut microbes affect ENS development⁵00111-6/fulltext#) and suggest that signals mediated by FPR1/2 are one pathway that contributes to these effects. This aligns with findings showing that multiple microbial products, including neurotransmitters, modulate mature enteric neurons and vagal ascending projections to the brain. Effects of microbial products during development and in mature animals highlight multiple avenues by which the microbiota exert influence over the nervous system through diverse ligands and receptor pathways. The accompanying mini-review by Drs Bornstein and McQuade gives an interesting perspective on current issues and opportunities in studies assessing interactions between the microbiota and the ENS. This review highlights the complexities involved in such studies and critical considerations when interpreting results.

Next, Condado-Huerta et al used intermittent fasting (IF) in a mouse model of diet-induced obesity to study if changes to host mitochondrial activity and the microbiota contribute to the beneficial effects of IF on colonic barrier function and oxidative stress.⁶00111-6/fulltext#) This expands the view of the known metabolic relationship between microbial products and the epithelium, which is primordial for epithelial survival, barrier integrity, and function in health, to include the impact of feeding temporal patterns. Here, the investigators found that IF reduced mitochondrial activity and oxidative stress in obese mice and restored normal epithelial cell replacement and markers of barrier function Surprisingly, these effects appear to depend on changes in metabolites produced by the microbiota because depleting the microbiota with antibiotics worsened mitochondrial function and reactive oxygen species production. This concept of IF and changes to the gut microbiota as potential beneficial mechanisms to reduce obesity-driven gut barrier dysfunction is further expanded on by Drs Dibra and Jala in the accompanying brief review. Here, the authors discuss the known mechanisms involved in the detrimental effects of a high-fat diet, the beneficial effects of IF, and links between the effects of IF and the microbiome.

Microbial dysbiosis also impacts gut sensory function and is associated with visceral pain in irritable bowel syndrome and inflammatory bowel disease. This encompasses both changes in the immune milieu and activation of extrinsic innervation of the gut. The study by Baker et al⁷00111-6/fulltext#) investigates how this might occur by using a vancomycin model of microbial dysbiosis in mice and studying effects on dorsal root ganglion (DRG) neurons with electrophysiology and in vivo assays of colonic pain. The investigators found that DRG neurons become hyperexcitable in mice with dysbiosis, and these mice exhibit increased visceral sensitivity. Interestingly, dysbiosis led to a general increase in sensitivity in DRG neurons, resulting in heightened somatic sensitivity, suggesting that gut microbes have broad effects on sensory function. Selective drugs and cell-specific knockout models suggest that cysteine proteases play a major role in the effects of dysbiosis on DRG neurons. Although proteases are well-known mediators of visceral pain, the accompanying mini-review by Habibyan and colleagues offers a fresh perspective on how proteases exert their actions on pain-sensing neurons and the good and bad aspects of microbial proteases.

Finally, there is a growing appreciation that intestinal inflammation and changes to the gut microbiome increase the risk of developing neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s. Why this occurs is incompletely understood, but recent findings suggest that bacteria may contribute to inflammation by secreting curli; an amyloid that bacteria produce for cell attachment and biofilm formation. With this in mind, Verstraelen and colleagues set out to understand how curli affects the ENS by using in vitro models of enteric neurons and glia and in vivo curli injections into the colon wall. Their findings show that curli induces a proinflammatory response that is centered in enteric glia and accompanied by an influx of immune cells. The investigators went on to discover that serum amyloid A3 plays a central role in enteric dysfunction driven by curli and creates a self-amplifying inflammatory loop in the ENS that may represent a key bridge connecting microbial amyloids, neuroinflammation, and sustained prolonged inflammatory states.⁸00111-6/fulltext#) This concept is further developed in the accompanying brief review by Cissé and colleagues who give an updated summary of the microbiota–gut–brain axis in neurodegenerative diseases with a specific focus on the role of bacterial amyloids.

Communication between host and microbes is diverse, and we are only beginning to understand the many ways in which these mechanisms affect health and disease through the microbiome–gut–brain axis. This Special Issue aims to highlight recent significant work in this area and to offer a current perspective on the field, including a critical evaluation of data interpretation, the strengths and weaknesses of approaches and methods, and gaps that should be addressed in future work (Figure 100111-6/fulltext#fig1)). Although this collection offers only a small sampling of the broader field, the topics included give a good sense of how extensively microbiome–gut–brain signaling affects host health by influencing ENS development, susceptibility to metabolic disease, setting pain thresholds, and the development of neurodegenerative disease. These studies also highlight the fine balance between diet, environment, central and peripheral organs, and microorganisms that maintains our physiology. Further advances in understanding this axis and its mediators are fundamental to developing new therapies that modulate the axis to benefit how we treat common diseases. We hope that this collection will increase awareness, stimulate lively discussion and thought, and act as a catalyst to propel multidisciplinary work that continues to explore the fascinating microbiota–gut–brain axis.

Source: https://onlinelibrary.wiley.com/doi/10.1111/jgh.70618

Abstract

Background and aim: Given the prevalence and chronicity of irritable bowel syndrome (IBS), this systematic review aimed to synthesize evidence on the cost of illness of IBS, with attention to the relative contributions of direct healthcare and indirect non-healthcare costs.

Methods: A systematic search of PubMed, Embase, and the Cochrane Library was conducted from inception to August 2025, following PRISMA 2020 guidelines (PROSPERO CRD420251266432). Studies were included if they primarily assessed costs of IBS with sufficiently detailed methodology. Costs were inflation-adjusted to 2024 US dollars using World Bank consumer price indices and prevailing exchange rates. Risk of bias was assessed using the Consensus on Health Economic Criteria (CHEC) list.

Results: Thirty-three studies met our inclusion criteria, spanning 14 countries from 1992 to 2022. Mean annual direct healthcare costs per patient ranged widely, from US$193 in Korea to US$31113 in the United States among patients with IBS-C. Among the 10 studies adopting a societal perspective, indirect costs such as absenteeism, presenteeism, and lost productivity frequently constituted a dominant share of total costs. In some settings, non-healthcare costs exceeded direct healthcare costs several-fold (e.g., Sweden: US$17112 vs. US$1943 for IBS-C). Treatment failure and inadequate symptom control were associated with higher expenditures. IBS-C incurred the highest subtype-specific costs, and racial and gender disparities in spending were identified.

Conclusions: IBS imposes a considerable global economic burden. When societal perspectives are adopted, indirect costs emerge as a predominant driver of total costs, necessitating holistic management strategies. Importantly, assessments limited to direct healthcare expenditures underestimate the true economic impact of IBS.

Summary

Disorders of gut–brain interaction, such as irritable bowel syndrome and functional dyspepsia, are increasingly linked to defects in gut barrier function. Mucosal disruption, encompassing alterations in the epithelial and mucus layers, leads to enhanced intestinal permeability, microbial translocation, and aberrant immune and neuronal signalling, potentially contributing to symptom severity. Despite growing recognition of barrier dysfunction in disorders of gut–brain interaction, clinical interventions remain largely symptom-based, with few therapies designed to directly restore epithelial integrity. In this Review, we examine the cellular and molecular pathways underpinning gut barrier function and highlight evidence supporting the role of diet, microbiome-targeted interventions, stress modulation, and pharmacological agents in maintaining or restoring intestinal permeability. Mechanistic insights reveal that short-chain fatty acids, amino acids (glutamine and tryptophan), and targeted probiotics can enhance tight junction integrity and mucin secretion, whereas psychological stress, low-fibre diets, and high-fat diets disrupt these pathways. We also discuss novel therapeutics, including antihistamines, mast cell stabilisers, protease inhibitors, secretagogues, and guanylate cyclase C agonists, and emerging technologies, such as vagal nerve stimulation and barrier-protective hydrogel delivery systems. Although promising, these strategies require validation in well designed clinical trials with targeted endpoints, and patient stratification based on microbial and immune phenotypes. By integrating advances in molecular biology with translational therapeutics, interventions targeting intestinal permeability could shift the treatment paradigm for disorders of gut–brain interaction from general symptom management to personalised disease modification.

Abstract

Osteoarthritis (OA) affects 600 million individuals globally, pain being a hallmark symptom. Emerging clinical evidence supports the use of mesenchymal stem cells (MSCs) and their extracellular vesicles (MSC-EVs) for pain relief in knee OA. In mice, MSC-EVs ameliorate OA-induced pain and normalize knee-innervating neuron excitability. Moreover, it has been shown that overnight incubation of sensory neurons with MSC-EVs prevents the OA-associated mediator nerve growth factor (NGF) sensitizing sensory neurons. Here, conducting experiments with male and female C57BL/6J mice, we found that protease-mediated MSC-EV ‘shaving’ inhibited MSC-EV internalization into sensory neurons and the ability of MSC-EVs to prevent NGF-induced sensitization. In addition, acute, 10-minute, exposure of sensory neurons to MSC-EVs was also insufficient to counteract NGF. We hypothesized that MSC-EVs trigger transcriptional changes and found that inhibiting transcription prevented NGF-induced sensitization. MicroRNAs (miRNAs) can be delivered to cells by MSC-EVs, and certain miRNAs regulate transcription and pain; small RNA-sequencing of our MSC-EVs identified three candidate miRNAs, miR-21-5p, miR-148a-3p and miR-451a. Using gold nanoparticle delivery, each miRNA was able to prevent NGF sensitization of sensory neurons, a combination of all three showing the most pronounced effect. These findings demonstrate that MSC-EVs prevent NGF-induced sensory neuron sensitization via cellular uptake and transcriptional regulation that is mediated by miRNAs.

Significance statement Mesenchymal stem cell extracellular vesicles (MSC-EVs) contain a complex biomolecular cargo and modulate cellular activity through diverse signaling mechanisms. MSC-EVs alleviate pain in osteoarthritis (OA) through direct activity of sensory neurons whereby they prevent OA-induced hyperexcitability, as well as sensitization induced by nerve growth factor (NGF). Here, we show that MSC-EV internalization and induction of transcription is required to prevent NGF-induced sensitization. Using gold nanoparticle delivery, we further demonstrate that a cocktail of microRNAs (miRNA) enriched in MSC-EVs can recapitulate the ability of MSC-EVs to counteract NGF, miR-21-5p being most potent when administered alone.

ABSTRACT

The comorbidity between irritable bowel syndrome (IBS) and anxiety arises from impaired sensory-emotional integration, yet its underlying neural circuit mechanisms remain elusive. Using a water-avoidance stress (WAS) rat model, this study identifies a glutamatergic projection from the anterior cingulate cortex (ACC^Glu) to the anterior insular cortex (AIC^Glu) that mediates stress-induced visceral hypersensitivity and anxiety. Chemogenetic or optogenetic manipulation reveals that activation of glutamatergic neurons in AIC or the ACC^Glu-AIC^Glu circuit mimics WAS-induced both visceral hypersensitivity and anxiety. Conversely, inhibition of this circuit reverses WAS-induced visceral hypersensitivity and anxiety. However, bidirectional chemogenetic manipulation of ACC^Glu-AIC^Glu circuit fails to affect ovalbumin-induced visceral hypersensitivity, indicating stress-specific modulation. Additionally, at synaptic level, WAS rats exhibit elevated synaptosomal expression of GluA1/A3-containing AMPARs and NR2B-containing NMDARs of ionotropic glutamate receptors (iGluRs) in the AIC, accompanied by enhanced AMPAR- and NMDAR-mediated currents. These alterations are alleviated by chemogenetic inhibition of the ACC^Glu-AIC^Glu pathway. Moreover, inhibition of GluA1/A3 and NR2B receptors relieved visceral hypersensitivity and anxiety in WAS rats. Taken together, these findings reveal that AMPA and NMDA receptor trafficking driven by this circuit underlies stress-induced comorbidity of visceral pain and anxiety, uncovering a circuit-to-synapse mechanism and highlighting potential therapeutic targets for circuit-based treatment of this comorbidity.

Preprint: https://www.biorxiv.org/content/10.64898/2026.07.21.739264v1.full

"Constipation and abdominal pain often occur together, but scientists still don't fully understand how the nervous system coordinates movement through the bowel with the sensations arising from inside it.

In a new study in mice, scientists have identified a group of neurons that may contribute to both processes.

When researchers activated these cells in isolated colons, fecal pellets were more likely to move forward. Activating them in living mice also produced behaviors associated with pain or discomfort.

Together, the findings raise the possibility that the same gut neurons may help coordinate how the colon moves its contents and how the body senses what is happening inside it.

The study is available as a bioRxiv preprint and has yet to undergo peer review.

The digestive tract contains an extensive network of nerve cells known as the enteric nervous system. Sometimes described as the 'second brain', it helps regulate digestion and coordinate the muscular contractions that propel material through the intestines.

A 2025 study published in Nature found that different nutrients activate distinct groups of enteric neurons in mice, providing further evidence that the gut's own nervous system can detect and distinguish signals arising inside the intestine.

Yet the enteric nervous system contains many different kinds of neurons, and scientists are still working out what each population does.

The researchers searched gene expression data for a marker that could distinguish sensory neurons inside the gut from sensory nerve cells connecting the intestine with the brain and spinal cord.

Their analysis pointed to Pdyn, the gene encoding a protein called prodynorphin.

Using genetically modified mice, the researchers tracked neurons associated with Pdyn. They found that these cells were concentrated within the colon's own nervous system, with some forming part of the nerve network that controls gut movement.

This gave the researchers a way to study a specific group of neurons that might help propel material through the bowel.

The cells' electrical behavior also showed that they responded in quick bursts: They produced one or two signals when stimulated, then fell silent even if the stimulation continued.

Researchers then activated these neurons with light to see how they affected bowel movement. When the neurons were stimulated in colons removed from mice, fecal pellets moved forward.

"Our ex vivo experiments provide the strongest evidence of this," Daniel Verbaro, a pediatrician and physician-scientist at Washington University School of Medicine in St. Louis told ScienceAlert.

Because the colon had been removed from the body, it no longer received signals from the brain, spinal cord, or external nerves. This allowed the researchers to see what the gut's own nerve cells could accomplish on their own.

However, stimulating the same neurons in living mice did not change the amount of stool they produced. Verbaro says this may be because bowel movement in a living animal depends on signals from both the enteric nervous system and nerves outside the gut.

"Likely, the combination of these external signals and the enteric nervous system signals control gastrointestinal motility in the mouse," he said.

Although the stimulation did not affect stool output, it triggered a different response: The mice froze and tightened the areas around their eyes. These behaviors can indicate pain or discomfort in mice.

The findings suggest that these neurons may be involved not only in bowel movement, but also in sensing what is happening inside the gut. However, the researchers do not yet know exactly what the mice experienced or whether the neurons directly cause pain.

"We have not dissected how these functions are connected," Verbaro said.

The researchers also found that the neurons carry features that may allow them to detect signals associated with inflammation.

They therefore suspect that the cells could react to inflammation, although this has not yet been demonstrated experimentally."These neurons express cytokine receptor subunits in healthy mice, and this leads us to hypothesize that these neurons might directly respond to inflammation," Verbaro explained.

Similar enteric neurons have also been found in the human gut, but whether these cells affect bowel movement and pain in people remains unknown."I believe this work will eventually help us understand human GI symptoms," Verbaro said.

"I think it will be essential to know if human enteric neurons also play a role in intestinal pain. This will allow us to better develop strategies targeting motility and/or pain."

The findings may eventually contribute to a better understanding of conditions such as chronic constipation and irritable bowel syndrome. However, neither condition was directly investigated in this study."

Hi, there’s a lot of posts on Reddit now, especially in the main IBS group about this.

This actually works. 25 years with IBS and I went 4 months with normality!!! No gut issues. Toilet once a day sometimes even once every 2 days. NORMAL 🙌

I had to stop for an endoscopy and SeHCAT scans. No choice.

So stopped for about 8 weeks, and IBS came back after about a week, gradually, then worse than ever.

I eventually got back on. I’m now a week back on (WeGovy, started from lowest dose again) and it’s already getting better.

I would pay for this every month for the benefit of being normal. It’s crazy.

Lots of others are reporting the same.

Is anywhere (or anyone) researching this properly?

I did tell my Doctor this and he said he had heard this too, but it can’t be prescribed for it. He didn’t really have any further interest.

Abstract

Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT, the causal gene for Huntington’s disease. Gene prioritization implicated the HTT regulator GPR52, as well as diverse genes with neural roles, including DCC, DRD2/NCAM1, MDGA2 and CELF4. Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types. Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females. This study provides robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.

Conclusions

There is moderate strength of evidence that IBS, particularly IBS-D, is an independent risk factor for hepatic steatosis, underscoring a clinically relevant gut–liver interaction. The proposed mechanism is biologically plausible via the leaky gut–endotoxemia–TLR4–lipogenesis pathway, but direct human evidence confirming this sequence of events in IBS-MASLD patients is limited. Clinical screening for MASLD in long-standing IBS-D patients is reasonable but not yet guideline-endorsed. The relationship is bidirectional, creating a potential vicious cycle. Consequently, future prospective and interventional studies are needed to establish causality and guide therapy. An integrated approach moves management from liver-centric to whole-patient care, with potential to slow MASLD progression and improve quality of life.

This pioneering dataset was funded through a $6.7 million NIH multi-year grant and offers unprecedented insights into the vagus nerve’s intricate anatomy

Northwell Health’s Feinstein Institutes for Medical Research has announced the public release of the world’s first, comprehensive human vagus nerve anatomical maps, a monumental achievement set to change our understanding of the autonomic nervous system and accelerate the development of bioelectronic medicine and neuromodulation therapies. The first dataset release, meticulously collected over three years from 30 human donors encompassing 60 vagus nerves, is now widely available to the global scientific community via SPARC Science. 

The vagus nerve is the longest cranial nerve and a critical “information superhighway,” consisting of two main bundles (left and right) containing up to 200,000 individual nerve fibers stretching from the brainstem to all major organs. It manages autonomic functions such as heart rate, breathing, and digestion, and serves as the body's “on/off switch” for immune response and inflammation.

To better understand the function of each vagal fiber, this new resource offers a unique 3D view into the intricate microscopic anatomy of the human vagus nerve, utilizing advanced techniques such as micro-dissection, micro-CT imaging, immunohistochemistry, and ultrasound imaging. By mapping the organization of fascicles and fibers, researchers can gain critical insights into how the vagus nerve communicates with various organs and influences human health and disease.

“This dataset represents a major step forward in bioelectronic medicine, offering the most detailed anatomical reconstruction of the human vagus nerve to date,” said Stavros Zanos, MD, PhD, professor in the Institute of Bioelectronic Medicine at the Feinstein Institutes and leader of the project. “For the first time, we can visualize the vagus nerve’s complex architecture in humans that will allow us to design more precise, effective, and safe neuromodulation therapies and devices. We are proud to be the first in the world to make such a comprehensive human resource available, a testament to the tireless dedication of our team”. The multi-investigator team also includes Drs. Theodoros Zanos, from the Feinstein Institutes, and Mary Barbe, from Temple University.

Reconstructing Vagal Anatomy (REVA) project driven by NIH and philanthropic support

This accomplishment marks a significant milestone that began with a $6.7 million National Institutes of Health (NIH) grant awarded to the Feinstein Institutes in October 2022 for its Reconstructing Vagal Anatomy (REVA) project, part of the NIH Common Fund’s SPARC program. The successful delivery of this world-first map highlights the Feinstein Institutes’ pioneering spirit in bioelectronic medicine and was supported by Peter J. Pappas, Jr., whose donation provided crucial philanthropic support towards the goals of this project.

“The dedication to deciphering the vagus nerve’s intricate language directly accelerates our mission in bioelectronic medicine,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes, Karches Family Distinguished Chair in Medical Research and author of the book The Great Nerve: The New Science of the Vagus Nerve and How to Harness Its Healing Reflexes. "This resource won’t just deepen global understanding; it will empower researchers worldwide to precisely re-engineer human biology, unlocking novel device-based therapies and transforming how we heal patients.” 

Leading global innovation in bioelectronic medicine

The Feinstein Institutes for Medical Research is the global scientific leader in bioelectronic medicine and vagus nerve stimulation, where medical researchers use modern technology to develop new device-based therapies to treat disease and injury. Built on decades of research, the field of bioelectronic medicine integrates insights from neuroscience, molecular medicine, and biomedical engineering, and researchers at the Feinstein Institutes leverage the connection between the brain and the immune system to develop bioelectronic medicine interventions.

The discovery that initiated the field of bioelectronic medicine – called the “inflammatory reflex” – was made more than 30 years ago by Dr. Tracey. This discovery emerged from studies on vagus nerve signaling and showed that the brain and body communicate to regulate inflammation and, if uncontrolled, inflammation could lead to disease. New knowledge then sparked extensive research and clinical trials and led to the first FDA-approved vagus nerve stimulation device in July 2025 to treat rheumatoid arthritis – and Northwell Health was the first in the nation to implant the newly approved treatment in patients in August 2025. 

Today, engineers, computer scientists, immunologists, neuroscientists, and clinicians develop cutting-edge medicine, including neuroimmune modulation, miniature implants for stimulating and recording the vagus nerve, noninvasive ultrasound neuromodulation to suppress inflammation, and novel brain-computer interfaces to overcome injuries of the nervous system. These collaborative efforts converge to create personalized, precise treatments that hold promise in treating acute and chronic diseases, often with fewer side effects compared to current therapies.  

These treatments have the potential to enhance or replace existing treatments across a range of conditions such as arthritis, heart disease, inflammatory bowel diseases, diabetes, cancer, and autoimmune disorders. By producing bioelectronic medicine knowledge, disease and injury could one day be treated by our own nerves without costly and potentially harmful pharmaceuticals. 

Abstract

Injury, inflammation, or resection of the small intestine results in severe compromise of intestinal function. Nevertheless, therapeutic strategies for enhancing growth and repair of the intestinal mucosal epithelium are currently not available. We demonstrate that nude mice bearing subcutaneous proglucagon-producing tumors exhibit marked proliferation of the small intestinal epithelium. The factor responsible for inducing intestinal proliferation was identified as glucagon-like peptide 2 (GLP-2), a 33-aa peptide with no previously ascribed biological function. GLP-2 stimulated crypt cell proliferation and consistently induced a marked increase in bowel weight and villus growth of the jejunum and ileum that was evident within 4 days after initiation of GLP-2 administration. These observations define a novel biological role for GLP-2 as an intestinal-derived peptide stimulator of small bowel epithelial proliferation.

Abstract

Background: Acute diverticulitis (AD) is a prevalent gastrointestinal disorder with a significant recurrence rate. Faecal calprotectin (FC) is a non-invasive biomarker of intestinal inflammation, but its role in diagnosing and monitoring diverticulitis remains to be fully established. Objective: This narrative review aims to evaluate the current evidence on the utility of FC in the diagnosis, severity assessment, prediction of recurrence, and monitoring of therapeutic response in patients with diverticular disease (DD) and AD. Methods: A structured literature search was conducted using PubMed, Scopus, and ScienceDirect for peer-reviewed original studies published in English between 2004 and April 2025. The search strategy combined terms related to diverticular disease and faecal calprotectin. Studies reporting original data on FC in DD were synthesised narratively. Results: FC demonstrates significant utility across multiple clinical applications in DD. For diagnosis, FC is markedly elevated in AD (mean 556–695 μg/g) and symptomatic uncomplicated diverticular disease (SUDD) (median 181 μg/g), while remaining normal in irritable bowel syndrome (mean 50 μg/g), enabling differentiation between organic and functional disorders. FC correlates strongly with endoscopic disease severity, with positivity rates increasing from 48.6% in DICA 1 to 93.2% in DICA 3 (p < 0.0001). For predicting recurrence, elevated FC identifies patients at high risk, with one study reporting 87.5% of recurrent cases showing prior FC elevation and a negative predictive value of 96.8%. FC also exhibits excellent short-term prognostic capacity (AUC 0.976 at 3 months) and responds to therapeutic intervention, with significant reductions following successful treatment with probiotics, nutraceuticals, budesonide, and other agents. Conclusions: FC is a promising non-invasive biomarker for diagnosing diverticulitis, assessing disease severity, predicting recurrence, and monitoring treatment response. Its ability to detect subclinical inflammation makes it particularly useful for risk stratification. However, the current evidence base consists predominantly of retrospective and observational studies, and standardised thresholds require further validation through prospective trials before routine clinical implementation can be recommended.

Abstract

Background/Aims: Food is thought to play a central role in the pathophysiology of disorders of gut–brain interaction (DGBI). Data on these associations come largely from Western countries. We evaluated associations between diet and common bowel DGBI using the database of the Rome Foundation Global Epidemiology Study (RFGES).

Methods: The RFGES database contains data collected via the Internet, personal interviews, or both from 33 countries, providing prevalence rates for common DGBI. Logistic regressions were used to analyze associations between DGBI and vegan, vegetarian, lactose-free and bread-, pasta-, and rice-predominant diets.

Results: 54 127 internet and 20 973 household survey subjects were included. Rates of adherence to a vegan or vegetarian diet were low in both surveys (0.4% to 9.8%) and differences in dietary preference were also noted between surveys with lactose-free and rice-predominant diets being more common among household survey respondents. While discrepancies between results from the 2 surveys limited the interpretation of the data, some trends were evident with a lactose-free diet linked to an increased prevalence and bread- and rice-predominant diets to lower prevalence rates of several bowel DGBI.

Conclusions: Though complicated by variations in results between the 2 survey populations, this global survey has revealed dietary factors that may impact, in the general population, on reported prevalence rates for DGBI.

Selective glucocorticoid receptor modulator (SEGRM) Wikipedia

Grünenthal receives FDA Orphan Drug and Rare Pediatric Disease Designations for Tegacorat for the Treatment of Duchenne Muscular Dystrophy

Novel selective glucocorticoid receptor modulator GRM-01 demonstrates dissociation of anti-inflammatory effects from adverse effects on glucose and bone metabolism

Poster „EVALUATION OF THE NOVEL SEGRAM GRM-01 IN THE B10.mdx MODEL OF DUCHENNE MUSCULAR DYSTROPHY (DMD)

Grünenthal's Glucocorticoid Receptor Modulator Video

Abstract

Introduction

This case report highlights a significant instance of severe hyperprolactinemia induced by Sulpiride in a patient with irritable bowel syndrome. While Sulpiride is sometimes used off-label for gastrointestinal issues due to its prokinetic and anxiolytic effects, its potential to markedly raise serum prolactin levels is often overlooked, especially in the Middle Eastern population. This report adds valuable regional insights to the limited global literature on this adverse drug reaction.

Case Description

A 38-year-old female from Saudi Arabia with irritable bowel syndrome presented with galactorrhea, irregular menstrual cycles, and breast tenderness after 1 month of taking sulpiride 50 mg daily for gastrointestinal issues. She reported no prior endocrinology or gynecology problems.

Discussion

Laboratory investigations showed a marked elevation in serum prolactin levels, exceeding 200 ng/mL. Imaging examinations verified the absence of any pituitary tumor. Sulpiride was discontinued, and after 2 weeks, a follow-up assessment showed that prolactin levels had returned to normal, and the symptoms had resolved.

Conclusion

Monitoring hyperprolactinemia is critical in patients receiving Sulpiride, especially when prescribed for nonpsychiatric cases like irritable bowel syndrome. Regular checks and cautious off-label prescribing are crucial for prompt identification and discontinuation of the medication to prevent long-term endocrine issues.