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. This groundbreaking research, published in the esteemed journal Gut, not only sheds light on the complex mechanisms behind these often debilitating gastrointestinal conditions but also points towards the potential development of a novel blood test for diagnosis and a promising new therapeutic avenue.
The intricate process of digestion involves a delicate interplay of hormones and digestive secretions, and the current study zeroes in on the role of Insulin-Like Peptide 5 (INSL5), a hormone previously implicated in mouse models of chronic diarrhea. For decades, medical professionals have grappled with understanding the root causes of chronic diarrhea, a condition that significantly impacts the quality of life for millions worldwide. While common causes like infections and food intolerances are routinely investigated, a substantial portion of cases, particularly those diagnosed as Irritable Bowel Syndrome with Diarrhea (IBS-D), have remained elusive, lacking definitive diagnostic markers or targeted treatments. This new research offers a compelling explanation for a significant subset of these unexplained cases.
Understanding Bile Acid Diarrhea: A Hidden Culprit
At the core of this discovery lies the phenomenon of bile acid diarrhea, also known as bile acid malabsorption. When we consume food, our liver plays a crucial role by releasing bile acids into the upper part of the small intestine. These potent compounds are essential for emulsifying and breaking down dietary fats, facilitating their absorption into the bloodstream. Following their digestive duty, bile acids are typically reabsorbed back into the body in the lower section of the small intestine, completing a vital enterohepatic circulation.
However, in approximately one in every 100 individuals, this reabsorption process is disrupted. Bile acids, instead of being efficiently reclaimed, continue their journey into the large intestine, or colon. This unabsorbed bile acid acts as a potent irritant to the colonic lining. The consequence is often a cascade of urgent, watery bowel movements, leading to significant distress and, in severe cases, even episodes of incontinence. This condition, bile acid diarrhea, has historically presented a diagnostic challenge due to the absence of readily available clinical blood tests. Consequently, many individuals experiencing these symptoms are often misdiagnosed or broadly categorized under the umbrella term of Irritable Bowel Syndrome (IBS).
It is estimated that as many as one in 20 people globally may have IBS. Within this large patient population, a significant proportion, an estimated one in three individuals whose primary symptom is diarrhea, may be unknowingly suffering from undiagnosed bile acid diarrhea. This highlights a substantial unmet need in gastrointestinal diagnostics and therapeutics.
The INSL5 Hypothesis: From Mouse Models to Human Insight
Previous research, primarily conducted in animal models, had provided intriguing clues about the potential involvement of INSL5 in the pathophysiology of chronic diarrhea. Studies in mice indicated that INSL5, a hormone produced by specialized cells located in the distal colon and rectum, could be released in response to irritation. Specifically, it was observed that bile acid, when present in the colon, could trigger the release of INSL5. This observation laid the groundwork for the Cambridge-led investigation into whether this hormone played a similar role in human chronic diarrhea.
The breakthrough in the current study was facilitated by the development of a sophisticated new antibody test by the pharmaceutical company Eli Lilly. This innovative test possesses the sensitivity required to accurately measure even minute quantities of INSL5 in biological samples, a capability that was previously a significant hurdle. The collaborative effort between the University of Cambridge scientists and Eli Lilly enabled the researchers to meticulously investigate INSL5 levels in human subjects.
Chronological Unveiling of INSL5’s Role
The research team embarked on a systematic approach to validate the role of INSL5. Their investigation can be broadly outlined through a series of crucial steps:
Early 2020s (Inferred Timeline): Initial studies in mice suggest a link between the gut hormone INSL5 and chronic diarrhea, with INSL5 release triggered by bile acid.
Mid-2020s (Inferred Timeline): Development of a highly sensitive antibody test for INSL5 by Eli Lilly, paving the way for human studies.
2023-2024 (Study Period):
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Analysis of Adelaide Study Samples: Researchers at the University of Cambridge analyzed existing samples from a study conducted at the University of Adelaide. This earlier study aimed to investigate the release of the gut hormone GLP-1, a hormone central to the mechanism of modern weight-loss drugs. As a side effect of their research, healthy volunteers were administered a bile acid enema, which, while triggering GLP-1 release, also induced temporary diarrhea. The Cambridge team’s analysis of these samples revealed a significant, temporary surge in INSL5 levels following the bile acid enema. Crucially, they observed a direct correlation: the higher the INSL5 levels, the more immediate the volunteers’ urge to defecate. This provided the first strong human evidence linking INSL5 to bile acid-induced diarrhea.
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Analysis of Imperial College London Patient Samples: The next critical phase involved examining samples from patients with diagnosed bile acid diarrhea, collected by Professor Julian Walters at Imperial College London. The findings were striking: INSL5 levels, which were almost undetectable in healthy volunteers, were significantly elevated in individuals suffering from bile acid diarrhea. Furthermore, a direct relationship was established between the magnitude of INSL5 elevation and the fluidity of stool samples, reinforcing INSL5’s role as a mediator of watery diarrhea.
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Analysis of University of Nottingham Patient Samples: To explore therapeutic potential, the team analyzed samples from patients with IBS who had received the anti-sickness medication ondansetron, under the guidance of Professor Robin Spiller at the University of Nottingham. Ondansetron is known to block the action of INSL5 in mice. The Cambridge analysis revealed that approximately 40% of these IBS patients exhibited elevated INSL5 levels, even though bile acid malabsorption had been ruled out in their cases. Significantly, these patients with elevated INSL5 responded most favorably to ondansetron treatment.
Supporting Data and Statistical Significance
The study’s findings are underpinned by robust data that underscore the statistical significance of INSL5’s involvement.
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Bile Acid Enema Study: The correlation between INSL5 levels and the speed of bowel movement urge in healthy volunteers after a bile acid enema provides a quantitative measure of the hormone’s immediate impact. While specific correlation coefficients are not detailed in the provided text, the statement "the higher the INSL5 levels, the faster the volunteers needed to use the toilet" indicates a clear, measurable relationship.
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Bile Acid Diarrhea Patient Study: The contrast between "almost undetectable" INSL5 levels in healthy individuals and "much higher" levels in patients with bile acid diarrhea is a critical distinction. The additional finding that "the higher the INSL5 level, the more watery their stool samples" suggests a dose-response relationship, further strengthening the causal link.
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Ondansetron Treatment Study: The observation that "around 40% of these patients had raised levels of INSL5" in an IBS cohort, and that these individuals "responded best to ondansetron," highlights a specific subgroup within IBS-D that may be driven by INSL5. This suggests that a significant portion of what is currently diagnosed as idiopathic IBS-D could be a form of bile acid-related dysregulation, even in the absence of overt malabsorption.
Expert Reactions and Broader Implications
The implications of this research are far-reaching, offering a glimmer of hope for millions suffering from chronic digestive issues. Dr. Chris Bannon, the study’s first author and a clinical fellow at the University of Cambridge’s Institute of Metabolic Science, expressed his enthusiasm: "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. 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."
Dr. Bannon further elaborated on the diagnostic landscape, noting the current standard of care: "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." This statement underscores a paradigm shift in understanding the gut’s complex regulatory systems.
The discovery of INSL5’s role also opens a direct pathway towards novel therapeutic interventions. The observed efficacy of ondansetron, a drug already approved for treating nausea and vomiting, in patients with elevated INSL5 levels is particularly encouraging. While the precise mechanism by which ondansetron alleviates diarrhea in these individuals is still under investigation, its known side effect of constipation suggests a potential for modulating gut motility and fluid secretion. The Cambridge team is now focused on further elucidating this mechanism, with the ultimate goal of either repurposing ondansetron or developing entirely new, targeted treatments.
This is a significant development given the limitations of current treatments for bile acid diarrhea. While bile acid sequestrants are the standard therapy, they are only effective in approximately two-thirds of patients, leaving a substantial portion of individuals without adequate relief.
Dr. Bannon offered an insightful perspective on the evolutionary purpose of a hormone that seemingly induces diarrhea: "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 biological rationale for INSL5’s function and its potential role in disease when dysregulated.
Future Directions and Societal Impact
The implications of this research extend beyond individual patient care. The development of a reliable blood test for INSL5 could revolutionize the diagnosis of chronic diarrhea, enabling earlier and more accurate identification of bile acid diarrhea. This would not only alleviate patient suffering but also reduce the burden on healthcare systems currently grappling with undiagnosed or misdiagnosed cases.
Furthermore, the potential to repurpose existing medications like ondansetron or to develop novel INSL5-targeting therapies offers a much-needed boost in the fight against chronic gastrointestinal disorders. The research was supported by esteemed bodies such as the Medical Research Council and Wellcome, with additional backing from the National Institute for Health and Care Research Cambridge Biomedical Research Centre, underscoring the significance and potential impact of this scientific endeavor.
The collaborative spirit evident in this study, involving researchers from the University of Cambridge, the University of Adelaide, Eli Lilly, Imperial College London, and the University of Nottingham, exemplifies the power of interdisciplinary research in tackling complex health challenges. As research progresses, the hope is that the intricate mechanisms of gut hormone regulation will be further unraveled, leading to more effective treatments and improved lives for those affected by chronic diarrhea and IBS-D. The journey from identifying a hormone in mice to potentially offering a new diagnostic and therapeutic solution for human patients marks a significant stride forward in gastroenterology.
