By Gilang Cahya 
High levels of a hormone found in cells in the gut could underlie many cases of chronic diarrhea and help explain up to 40% of patients with irritable bowel syndrome with diarrhea, according to a new study led by scientists at the University of Cambridge. This groundbreaking research, published in the esteemed journal Gut, not only sheds light on the complex mechanisms of digestive disorders but also paves the way for the development of a novel blood test for diagnosis and points towards promising new therapeutic avenues.
Unveiling the Mystery of Bile Acid Diarrhea
The digestive system is a marvel of intricate processes, with the liver playing a crucial role in nutrient absorption. When we consume food, the liver releases bile acids into the upper part of the small intestine. These essential compounds are vital for breaking down dietary fats, facilitating their absorption into the bloodstream. Subsequently, the majority of these bile acids are efficiently reabsorbed in the lower sections of the small intestine, completing a vital cycle.
However, for a significant minority of the population, this finely tuned system falters. Bile acid diarrhea, also known as bile acid malabsorption (BAM), affects approximately one in every 100 individuals. In these cases, the bile acids are not adequately reabsorbed and instead travel into the large intestine, or colon. This unchecked presence of bile acids in the colon acts as a potent irritant, triggering a cascade of symptoms including urgent, watery diarrhea, and in severe instances, the distressing risk of incontinence.
The diagnostic challenge posed by BAM is substantial. Currently, there are no routine clinical blood tests available to reliably identify the condition. This diagnostic vacuum often leads to individuals experiencing prolonged digestive distress being misdiagnosed or broadly categorized under the umbrella term of Irritable Bowel Syndrome (IBS). IBS, itself a complex condition affecting an estimated one in 20 people, is characterized by a range of gastrointestinal symptoms. Within the IBS population, it is estimated that as many as one in three patients whose primary symptom is diarrhea may be suffering from undiagnosed BAM. This highlights a significant unmet need in gastrointestinal diagnostics and treatment.
The Emerging Role of Insulin-Like Peptide 5 (INSL5)
For years, scientific inquiry has explored various potential culprits behind chronic digestive issues. Previous studies conducted in animal models, specifically mice, had hinted at a potential role for a gut hormone known as Insulin-Like Peptide 5 (INSL5). This hormone is primarily produced by specialized cells located in the distal regions of the colon and rectum. Research suggested that INSL5 is released by these cells when they are irritated by the presence of bile acid.
The recent work by researchers at the Institute of Metabolic Science at the University of Cambridge has sought to validate and expand upon these findings in humans. The critical enabler for this investigation was the development of a highly sensitive antibody test by the pharmaceutical company Eli Lilly, with whom the Cambridge team is collaborating. This innovative test possesses the capability to accurately measure even minute quantities of INSL5, a crucial advancement for understanding its physiological and pathological roles.
Chronological Unraveling of INSL5’s Impact
The research team’s journey to understanding INSL5’s role involved a meticulous analysis of samples from several key studies, piecing together a compelling narrative.
Early Indications from Weight-Loss Drug Research: A pivotal moment in the investigation came from an unexpected source. A study conducted at the University of Adelaide, focused on ways to trigger the release of another gut hormone, GLP-1 (the hormone upon which many modern weight-loss drugs are based), provided crucial early data. In this study, healthy volunteers were administered a bile acid enema. While this was intended to explore GLP-1 release, it had the unintended consequence of inducing diarrhea in the participants.
When the Cambridge team had the opportunity to analyze samples from this Adelaide study, they made a significant observation. The administration of the bile acid enema led to a temporary but dramatic surge in INSL5 levels. Crucially, the researchers found a direct correlation: the higher the INSL5 levels observed, the more urgent and immediate the volunteers’ need to defecate. This finding provided compelling evidence that INSL5 is indeed intimately involved in the physiological response to bile acid in the gut, and likely plays a role in acute episodes of diarrhea.
Confirmation in Bile Acid Diarrhea Patients: Building on this initial insight, the Cambridge researchers obtained samples from patients with diagnosed bile acid diarrhea, generously provided by Professor Julian Walters at Imperial College London. The results were striking. While INSL5 levels were found to be almost undetectable in healthy volunteers, they were significantly elevated in patients suffering from bile acid diarrhea. Furthermore, the analysis revealed a direct relationship between the magnitude of INSL5 elevation and the severity of the diarrhea, with higher INSL5 levels correlating with more watery stool samples. This provided robust clinical evidence supporting INSL5’s involvement in the chronic manifestation of bile acid diarrhea.
A Potential Diagnostic Breakthrough: Dr. Chris Bannon, the study’s first author and a clinical fellow at the Institute of Metabolic Science, expressed the profound significance of these findings. "This was a very exciting finding because it showed us that this hormone could be playing a big part in symptoms of this misunderstood condition," Dr. Bannon stated. "It also meant it might allow us to develop a blood test to help diagnose bile acid diarrhea if INSL5 levels are only high in these individuals."
The implications for diagnosis are substantial. Currently, when patients present with chronic diarrhea, medical professionals typically embark on a diagnostic pathway that includes testing for food intolerances, ruling out infections, and searching for signs of inflammation. While the role of the gut microbiome has garnered significant research attention, gut hormones have historically been a somewhat neglected area of investigation. Dr. Bannon highlighted this disparity, adding, "There has been significant research interest in the microbiome, but gut hormones have been neglected. But it’s becoming increasingly clear that gut hormones play an important role in things like gut health and weight management." The identification of INSL5 as a potential biomarker for BAM could revolutionize diagnostic approaches, offering a more targeted and efficient route to identifying the root cause of chronic diarrhea for many patients.
Therapeutic Horizons: Targeting INSL5
Beyond its diagnostic potential, the discovery of INSL5’s role opens up exciting avenues for therapeutic intervention. The hormone not only signals a problem but also presents a potential target for new treatments.
Investigating Ondansetron as a Potential Treatment: The Cambridge team further explored the therapeutic implications of INSL5 by examining samples from a study conducted by Professor Robin Spiller at the University of Nottingham. In this prior research, Professor Spiller had administered ondansetron, an anti-sickness medication known to block the action of INSL5 in mice, to patients with IBS.
The Cambridge team’s analysis of these samples revealed that approximately 40% of these IBS patients exhibited elevated INSL5 levels, even though they had previously been diagnosed with IBS and had bile acid malabsorption ruled out. Crucially, these patients with elevated INSL5 levels showed the most significant positive response to ondansetron treatment. This suggests that a subset of IBS patients with diarrhea may, in fact, have undiagnosed bile acid malabsorption mediated by INSL5, and that ondansetron could be a viable treatment option for them.
While the precise mechanism by which ondansetron exerts its beneficial effect in these patients is still under investigation, a known side effect of the drug is constipation. The research team plans to delve deeper into this observation, hoping it will lead to either the repurposing of ondansetron for this specific patient group or the development of even more targeted and effective therapies.
Limitations of Current Treatments: The current standard treatment for bile acid diarrhea involves the use of bile acid sequestrants. While effective for many, these medications only provide relief for approximately two-thirds of patients, leaving a significant proportion without adequate symptomatic control. The potential for a new therapeutic approach targeting INSL5 offers hope for those who do not respond to existing treatments.
Understanding INSL5’s Evolutionary Purpose: Dr. Bannon offered an insightful perspective on the evolutionary rationale behind a hormone that appears to induce diarrhea. "I often get asked why we would have a hormone that gives you diarrhea," he mused. "I think of it as a kind of poison sensor. Bile acids aren’t meant to be in the colon – they’re an irritant to the colon and they’re toxic to the microbiome. It makes sense that you would have something that detects toxins and helps the body rid itself of them. But a problem develops if it’s always being triggered by bile acid, causing very dramatic symptoms." This perspective frames INSL5 not as a malady-inducing agent but as a protective mechanism that, in the context of chronic bile acid exposure, becomes dysregulated and leads to debilitating symptoms.
Broader Implications and Future Directions
The implications of this research extend far beyond the immediate diagnostic and therapeutic potential for bile acid diarrhea. It underscores the critical, and often overlooked, role of gut hormones in maintaining overall digestive health and influencing a range of bodily functions. The identification of INSL5 as a key player in chronic diarrhea could prompt a broader re-evaluation of other gut hormones and their potential involvement in various gastrointestinal disorders, including different subtypes of IBS.
The collaboration between academic institutions like the University of Cambridge and pharmaceutical companies such as Eli Lilly exemplifies a modern approach to medical research, where fundamental scientific discovery is rapidly translated into potential clinical applications. The support for this research from esteemed bodies like the Medical Research Council and Wellcome, with additional backing from the National Institute for Health and Care Research Cambridge Biomedical Research Centre, highlights the recognized significance of this line of inquiry.
Moving forward, the research team plans to conduct further investigations to solidify the diagnostic utility of INSL5 and to elucidate the precise mechanisms by which ondansetron and potentially other INSL5-targeting agents exert their therapeutic effects. This work holds the promise of transforming the lives of millions suffering from chronic diarrhea and related gastrointestinal conditions, offering them not only accurate diagnoses but also more effective and personalized treatment options. The journey to fully understanding and managing these complex disorders is ongoing, but the discovery of INSL5’s pivotal role marks a significant leap forward in that endeavor.
