By Gilang Cahya 
A groundbreaking study spearheaded by scientists at the University of Cambridge has uncovered a significant link between elevated levels of a specific gut hormone, Insulin-Like Peptide 5 (INSL5), and a substantial portion of chronic diarrhea cases, including up to 40% of patients diagnosed with Irritable Bowel Syndrome with Diarrhea (IBS-D). This discovery, published in the prestigious journal Gut, not only illuminates the underlying mechanisms of these often debilitating conditions but also paves the way for the development of a novel blood test for diagnosis and potentially new therapeutic interventions.
Unraveling the Mystery of Bile Acid Diarrhea
The digestive system is a marvel of biological engineering, with intricate processes designed to extract nutrients and energy from the food we consume. A critical component of this process involves bile acids, produced by the liver, which are essential for the breakdown and absorption of fats in the upper regions of the small intestine. Following their initial role, bile acids are designed to be efficiently reabsorbed back into the bloodstream at the lower end of the small intestine, completing a vital cycle.
However, for approximately one in every 100 individuals, this finely tuned system falters. They experience a condition known as bile acid diarrhea (BAD), also referred to as bile acid malabsorption (BAM). In these cases, the bile acid is not adequately reabsorbed and consequently travels into the large intestine, or colon. This presence of excess bile acid in the colon acts as a potent irritant, triggering a cascade of symptoms that can include urgent, watery diarrhea and, in severe instances, episodes of fecal incontinence.
The diagnostic challenge posed by BAD is substantial. Currently, there is no routine clinical blood test that can reliably identify the condition. This diagnostic void often leads to individuals experiencing prolonged suffering, with many eventually receiving a diagnosis of Irritable Bowel Syndrome (IBS). IBS itself is an umbrella term encompassing a variety of gastrointestinal disorders, affecting an estimated one in 20 people globally. Within the IBS cohort, particularly those whose primary symptom is diarrhea, a significant proportion – estimated to be as high as one in three – may be suffering from undiagnosed bile acid diarrhea. This diagnostic uncertainty means that many patients are treated for a condition they do not have, while the root cause of their distress remains unaddressed.
The Emerging Role of Insulin-Like Peptide 5 (INSL5)
For years, the scientific community has been exploring various factors that contribute to chronic digestive issues. Prior research, primarily conducted in animal models, had hinted at the involvement of a gut hormone called Insulin-Like Peptide 5 (INSL5). This hormone is produced by specialized cells located in the distal colon and rectum. Studies in mice indicated that INSL5 is released by these cells when they are irritated, and preliminary findings suggested a correlation between its release and the occurrence of diarrhea.
The Cambridge-based research team, situated at the Institute of Metabolic Science, set out to rigorously investigate whether INSL5 played a comparable role in human chronic diarrhea. A critical enabler of their investigation was the development of a sophisticated new antibody test by pharmaceutical company Eli Lilly, with whom the Cambridge team is collaborating. This advanced assay possesses the remarkable sensitivity required to accurately measure even minute quantities of INSL5 in biological samples, a crucial step in validating its potential as a diagnostic marker.
Chronology of Discovery: From Mouse Models to Human Validation
The journey from initial hypothesis to validated findings involved several key research phases:
Early Animal Studies: Previous investigations in mice provided the initial clues, suggesting that INSL5, produced in the distal gut, is released in response to irritation and may be linked to diarrheal responses.
University of Adelaide Study Analysis: A significant turning point in the Cambridge study’s validation process involved the re-analysis of samples from a study conducted at the University of Adelaide. This earlier research focused on triggering the release of another gut hormone, GLP-1, which is the basis for widely used weight-loss medications. In that study, healthy volunteers received a bile acid enema. While this intervention successfully stimulated GLP-1 release, it also had the unintended consequence of inducing temporary diarrhea.
The Cambridge team, upon analyzing blood samples from these volunteers, made a crucial observation: the bile acid enema led to a sharp, temporary surge in INSL5 levels. Furthermore, they found a direct correlation: the higher the INSL5 levels, the more immediate and urgent the volunteers’ need to defecate. This finding provided compelling evidence that INSL5 is indeed implicated in acute diarrheal responses, strongly suggesting its involvement in chronic cases.
Collaboration with Imperial College London: Building on these insights, the Cambridge researchers obtained samples from Professor Julian Walters at Imperial College London. These samples included those from patients definitively diagnosed with bile acid diarrhea. The analysis yielded striking results: while INSL5 levels were barely detectable in healthy volunteers, they were significantly elevated in patients suffering from BAD. Moreover, a clear dose-response relationship emerged, with higher INSL5 concentrations correlating directly with the wateriness of the stool samples. This provided the first robust human evidence linking elevated INSL5 to bile acid diarrhea.
Investigating IBS-D and Treatment Potential: Further research extended to samples collected by Professor Robin Spiller at the University of Nottingham. Professor Spiller had administered ondansetron, an anti-sickness medication known to block INSL5 activity in mice, to patients diagnosed with IBS. The Cambridge team’s analysis of these samples revealed that approximately 40% of these IBS patients exhibited elevated INSL5 levels, even though bile acid malabsorption had been previously ruled out in their cases. Crucially, these patients with high INSL5 levels demonstrated the most significant improvement in symptoms when treated with ondansetron. This suggested that a subset of IBS-D patients may have an underlying, undiagnosed INSL5-driven mechanism contributing to their symptoms.
Implications for Diagnosis and Treatment
The ramifications of these findings are profound and multifaceted, impacting both how these conditions are diagnosed and how they can be treated.
A New Diagnostic Horizon: The INSL5 Blood Test
"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," stated Dr. Chris Bannon, the study’s first author and a clinical fellow at the Institute of Metabolic Science. "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 prospect of a simple, non-invasive blood test for bile acid diarrhea represents a paradigm shift in diagnosis. Currently, confirming BAD often involves invasive procedures or specialized diagnostic tests that are not universally available. A reliable blood test would not only expedite diagnosis, reducing patient suffering and healthcare costs associated with misdiagnosis and delayed treatment, but also allow for earlier intervention. This could significantly improve the quality of life for countless individuals who have long struggled with unexplained chronic diarrhea.
The current diagnostic pathway for chronic diarrhea typically involves ruling out common culprits such as food intolerances, infections, or inflammatory bowel diseases like Crohn’s disease or ulcerative colitis. While the gut microbiome has garnered considerable research attention, the role of gut hormones has, until now, been comparatively under-explored. Dr. Bannon emphasized this point, noting, "When you go to the doctor with chronic diarrhea, it’s likely they’ll test for food intolerances, rule out an infection or look for signs of inflammation. 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."
Targeting INSL5: A Potential Therapeutic Avenue
Beyond diagnostics, the discovery of INSL5’s role opens up a promising new avenue for therapeutic intervention. The finding that ondansetron, a drug already approved for nausea and vomiting, appears to alleviate symptoms in patients with high INSL5 levels, suggests a potential for repurposing this medication.
"INSL5 also provides a potential target for treatment," Dr. Bannon explained. While the precise mechanism by which ondansetron alleviates diarrhea in these specific patients is still under investigation, a known side effect of the drug is constipation. The research team plans to delve deeper into this aspect, hoping to either validate ondansetron as a treatment for this subset of patients or to develop even more targeted and effective therapies.
Traditional treatments for bile acid diarrhea primarily involve bile acid sequestrants, medications designed to bind to excess bile acids in the gut. However, these treatments are only effective in approximately two-thirds of patients, leaving a significant portion of individuals without adequate relief. The development of INSL5-targeted therapies could offer a much-needed alternative for these non-responders.
The ‘Poison Sensor’ Hypothesis
Dr. Bannon offered an intriguing evolutionary perspective on the function of INSL5: "I often get asked why we would have a hormone that gives you diarrhea. 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 "poison sensor" analogy provides a compelling explanation for how a hormone that induces diarrhea could serve a protective role. In a healthy state, the transient release of INSL5 might act as an alarm system, prompting the expulsion of harmful substances from the colon. However, in conditions like bile acid diarrhea, this system becomes perpetually activated by the presence of unabsorbed bile acids, leading to chronic and disruptive symptoms. Understanding this dynamic is crucial for developing treatments that can modulate INSL5 activity without compromising its essential protective functions.
Broader Impact and Future Directions
The implications of this research extend beyond the immediate scope of bile acid diarrhea and IBS-D. It underscores the critical, and often overlooked, role of gut hormones in maintaining gastrointestinal health. As the understanding of the complex interplay between hormones, the gut microbiome, and digestive function deepens, new therapeutic strategies for a wide range of gastrointestinal disorders may emerge.
The study was supported by substantial funding from the Medical Research Council and Wellcome, with additional contributions from the National Institute for Health and Care Research Cambridge Biomedical Research Centre. This collaborative effort highlights the importance of interdisciplinary research and pharmaceutical partnerships in driving scientific innovation.
Looking ahead, the Cambridge team’s focus will be on further validating the diagnostic potential of INSL5 blood tests and exploring the precise mechanisms of ondansetron’s efficacy. Their work has the potential to revolutionize the diagnosis and treatment of chronic diarrhea, offering hope and relief to millions of individuals worldwide who suffer from these challenging conditions. This research marks a significant step forward in understanding the intricate physiology of the gut and harnessing that knowledge for improved human health.
Dr. Bannon is a clinical fellow in the esteemed group led by Professors Fiona Gribble and Frank Reimann at the Institute of Metabolic Science, University of Cambridge, a testament to the robust research environment that fostered this breakthrough. The collective expertise and dedication of these researchers have brought us closer to unraveling the complexities of gut health and offering tangible solutions to persistent medical challenges.
