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 cases of patients with irritable bowel syndrome with diarrhea, according to a new study led by scientists at the University of Cambridge. The research, published in the journal Gut, could help in the development of a blood test and points towards a potential new treatment, offering a beacon of hope for millions suffering from debilitating digestive disorders that have long defied straightforward diagnosis and effective management.
Unraveling the Mystery of Bile Acid Diarrhea
The intricate process of digestion involves a complex interplay of organs and biochemicals. When we consume food, particularly fats, the liver plays a crucial role by releasing bile acids into the upper section of the small intestine. These bile acids act as emulsifiers, breaking down fats into smaller droplets that can be more readily absorbed by the intestinal lining. Following their digestive duties, bile acids are efficiently reabsorbed into the bloodstream in the lower part of the small intestine, completing a vital cyclical process that conserves these valuable digestive aids.
However, for approximately one in every 100 individuals, this finely tuned system falters. They are affected by a condition known as bile acid diarrhea, also referred to as bile acid malabsorption. In these cases, the bile acids are not fully or correctly reabsorbed in the small intestine. Consequently, an excess amount of bile acid continues its journey into the large intestine, or colon. This unwelcome presence acts as a powerful irritant, triggering frequent, urgent, and often watery bowel movements. For some patients, the severity of these episodes can be so profound that it leads to a significant risk of incontinence, profoundly impacting their quality of life and social engagement.
The Diagnostic Challenge and the IBS Conundrum
Diagnosing bile acid diarrhea has historically been a significant clinical hurdle. The absence of routine, readily available blood tests for this condition means that many individuals experience prolonged periods of undiagnosed suffering. This diagnostic vacuum often leads to a broader, less specific diagnosis of Irritable Bowel Syndrome (IBS), an umbrella term encompassing a variety of functional gastrointestinal disorders characterized by abdominal pain, bloating, and changes in bowel habits. While IBS affects a substantial portion of the population, with estimates suggesting as many as one in 20 people may have some form of IBS, a significant subgroup of these patients, particularly those whose primary symptom is diarrhea, may be unknowingly suffering from undiagnosed bile acid diarrhea. It is estimated that as many as one in three patients presenting with diarrhea as their main IBS symptom could have this underlying, identifiable condition.
A Novel Lead: Insulin-Like Peptide 5 (INSL5)
Previous research, primarily conducted in animal models, had hinted at the involvement of a gut hormone called Insulin-Like Peptide 5 (INSL5) in the development of chronic diarrhea. INSL5 is produced by specialized cells located in the distal colon and rectum, the furthest reaches of the large intestine. Studies in mice indicated that these cells release INSL5 when irritated by the presence of bile acid. This observation provided a crucial starting point for the University of Cambridge researchers, who sought to determine if this hormonal pathway was also operative in human chronic diarrhea.
The breakthrough in investigating INSL5 in humans became possible through a collaborative effort with the pharmaceutical company Eli Lilly. This partnership facilitated the development of a sophisticated new antibody test capable of detecting and quantifying minuscule amounts of INSL5 in biological samples. This technological advancement was instrumental in enabling the Cambridge team to explore the hormone’s role in human digestive health.
The Adelaide Study: Early Indicators of INSL5’s Role
An earlier study at the University of Adelaide offered compelling preliminary evidence linking INSL5 to diarrhea. This research was focused on understanding how to stimulate the release of Glucagon-Like Peptide-1 (GLP-1), a gut hormone that has gained considerable attention for its role in weight management and is the basis for several popular weight-loss medications. In this study, healthy volunteers were administered a bile acid enema. While the enema successfully triggered the release of GLP-1, it also had an unintended and significant consequence: it induced diarrhea in the participants.
When the Cambridge team analyzed samples from this Adelaide study, they made a pivotal discovery. The administration of the bile acid enema led to a dramatic, temporary surge in INSL5 levels. Crucially, the researchers observed a direct correlation: the higher the INSL5 levels in the volunteers, the more immediate and pressing their need to use the toilet became. This finding provided strong empirical support for the hypothesis that INSL5 plays a direct role in the physiological mechanisms that precipitate diarrheal episodes, particularly in the context of bile acid exposure.
Clinical Validation: INSL5 Elevated in Bile Acid Diarrhea Patients
Building on these initial findings, the Cambridge researchers obtained samples from patients diagnosed with bile acid diarrhea, kindly provided by Professor Julian Walters at Imperial College London. The analysis of these samples yielded striking results. In stark contrast to healthy volunteers, in whom INSL5 levels were found to be almost undetectable, patients with bile acid diarrhea exhibited significantly elevated levels of this gut hormone. Furthermore, the degree of INSL5 elevation correlated directly with the severity of their symptoms, with higher INSL5 levels being associated with more watery stool samples. This clinical validation solidified the link between elevated INSL5 and the pathological processes underlying bile acid diarrhea.
A Potential Diagnostic Revolution
Dr. Chris Bannon, the study’s first author and a clinical fellow at the University of Cambridge’s Institute of Metabolic Science, described the findings as "very exciting." He elaborated on the significance: "This showed us that this hormone could be playing a big part in symptoms of this misunderstood condition. 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 patient care are substantial. Currently, individuals experiencing chronic diarrhea often undergo a battery of tests, including those for food intolerances, infections, and inflammatory conditions. While research into the gut microbiome has garnered significant attention, the role of gut hormones in digestive health and weight management has, until now, been comparatively under-explored. Dr. Bannon highlighted this oversight, stating, "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 could fundamentally change how chronic diarrhea is investigated and diagnosed, offering a more targeted and efficient diagnostic pathway.
Targeting INSL5: A New Avenue for Treatment
Beyond its diagnostic potential, elevated INSL5 also presents a promising target for therapeutic intervention. The Cambridge team further investigated this possibility by examining samples from patients who had participated in a study led by Professor Robin Spiller at the University of Nottingham. In that study, patients with IBS had been treated with ondansetron, an anti-sickness medication known to block the action of INSL5 in mice.
The analysis of these samples revealed that approximately 40% of the patients treated with ondansetron had elevated INSL5 levels, even though bile acid malabsorption had been ruled out in their cases. More importantly, these patients with elevated INSL5 exhibited the most favorable response to ondansetron treatment. This finding suggests that INSL5 may play a role not only in classic bile acid diarrhea but also in a subset of IBS patients who present with diarrheal symptoms and elevated INSL5, even in the absence of overt bile acid malabsorption.
The precise mechanism by which ondansetron exerts its therapeutic effect in these patients is still under investigation. However, a known side effect of ondansetron is constipation, which aligns with the potential to counteract the diarrheal effects mediated by INSL5. The research team is now embarking on further studies to elucidate this mechanism, with the ultimate goal of either repurposing ondansetron for this specific indication or developing entirely new and more targeted treatments. Current treatments for bile acid diarrhea typically involve bile acid sequestrants, which are effective in only about two-thirds of patients, indicating a clear need for alternative or supplementary therapies.
The ‘Poison Sensor’ Hypothesis: Understanding INSL5’s Function
Dr. Bannon offered an insightful perspective on the evolutionary rationale behind a hormone that appears to induce diarrhea. He proposed that INSL5 might function as a "poison sensor" within the gut. Bile acids, he explained, are not intended to be present in the colon, where they can act as irritants and potentially disrupt the delicate balance of the gut microbiome. "It makes sense that you would have something that detects toxins and helps the body rid itself of them," he stated. However, he cautioned that when this system is constantly triggered by the presence of bile acid, as in bile acid diarrhea, it leads to the development of chronic and severe symptoms. This "poison sensor" hypothesis provides a compelling framework for understanding the physiological role of INSL5 and the pathological consequences of its overactivation.
Broader Implications and Future Directions
The findings from the University of Cambridge study represent a significant step forward in understanding and managing chronic diarrhea and IBS with diarrhea. The identification of INSL5 as a key player opens up exciting possibilities for improved diagnostic tools, potentially leading to a simple blood test that can differentiate between various causes of chronic diarrhea. This would not only expedite diagnosis but also reduce the burden of unnecessary and often inconclusive investigations.
Furthermore, the therapeutic implications are equally profound. Targeting INSL5 offers a novel therapeutic strategy for a patient population that has historically faced limited treatment options. The potential to repurpose existing medications like ondansetron or to develop new drugs that specifically modulate INSL5 activity could revolutionize the management of these conditions.
The research was supported by grants from the Medical Research Council and Wellcome, with additional vital support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre. These funding bodies play a critical role in advancing scientific understanding and translating research discoveries into tangible benefits for patients.
The ongoing work by Dr. Bannon and his colleagues, under the leadership of Professors Fiona Gribble and Frank Reimann at the Institute of Metabolic Science, is poised to further illuminate the complex landscape of gut hormone signaling and its impact on digestive health. As research progresses, the hope is that this newfound understanding will translate into improved lives for the millions worldwide affected by chronic diarrhea and IBS. The journey from identifying a hormonal link to developing a definitive diagnostic test and effective treatment is often long and complex, but this latest research marks a significant and promising milestone in that endeavor.
