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 pave the way for a new diagnostic blood test and points towards a potential novel treatment strategy for a condition that significantly impacts quality of life for millions worldwide.
Unraveling the Mystery of Chronic Diarrhea
For many individuals experiencing persistent and often debilitating diarrhea, the underlying cause remains elusive. While infections and inflammatory bowel diseases are common culprits, a significant proportion of patients are diagnosed with Irritable Bowel Syndrome with Diarrhea (IBS-D). However, this new research suggests that a specific, previously underappreciated mechanism – involving the gut hormone Insulin-Like Peptide 5 (INSL5) – may be responsible for a substantial number of these cases, potentially reclassifying them as a distinct entity: bile acid diarrhea (BAD).
Bile acid diarrhea, also known as bile acid malabsorption, affects an estimated one in 100 people. This condition arises when bile acids, essential for fat digestion, are not adequately reabsorbed in the lower part of the small intestine. Instead, they travel into the large intestine (colon), where they act as irritants, triggering urgent, watery stools and, in severe cases, episodes of incontinence. The difficulty in diagnosing BAD stems from the current lack of routine clinical blood tests, often leading to misdiagnosis as IBS-D. It is estimated that up to one in three individuals with diarrhea-predominant IBS may actually have undiagnosed bile acid diarrhea, highlighting a significant gap in current diagnostic capabilities.
The Role of INSL5: A ‘Poison Sensor’ Hypothesis
The investigation into INSL5’s role began with observations in mice, where the hormone, produced by specialized cells in the distal colon and rectum, was found to be released when these cells were irritated by bile acid. This release mechanism suggested a potential role in signaling discomfort or danger within the gut. Dr. Chris Bannon, the study’s first author and a clinical fellow at the University of Cambridge’s Institute of Metabolic Science, described INSL5 as a potential "poison sensor."
“I often get asked why we would have a hormone that gives you diarrhea,” Dr. Bannon explained. “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 hypothesis posits that in individuals with BAD, the constant presence of unabsorbed bile acids in the colon triggers a persistent release of INSL5, leading to the chronic diarrheal symptoms.
A Breakthrough in Measurement: Enabling Human Studies
The crucial step in validating this hypothesis in humans was the development of a highly sensitive antibody test by pharmaceutical company Eli Lilly. This innovative test allowed researchers to accurately measure minute quantities of INSL5 in biological samples. Collaborating with Eli Lilly, the Cambridge team was able to leverage this technological advancement to explore INSL5 levels in human subjects.
Chronology of Discovery: From Mouse Models to Human Validation
The research journey leading to this discovery can be traced through several key phases:
- Pre-2020s: Previous studies in rodent models had identified INSL5 in the gut and suggested its potential involvement in diarrheal responses, particularly when stimulated by bile acids. However, a direct link to human chronic diarrhea remained unconfirmed due to limitations in measurement techniques.
- Early 2020s (Inferred): The development of a novel, highly sensitive antibody test for INSL5 by Eli Lilly marked a significant technological breakthrough, enabling precise quantification of the hormone in human samples.
- Circa 2022-2023 (Inferred): The Cambridge team initiated collaborations to analyze existing study samples, such as those from the University of Adelaide study, to retrospectively investigate INSL5 levels in response to bile acid stimulation.
- Mid-2023 (Inferred): Analysis of samples from patients with diagnosed bile acid diarrhea, obtained from Professor Julian Walters at Imperial College London, provided compelling evidence of elevated INSL5 levels in this patient group.
- Late 2023 – Early 2024 (Inferred): Further investigation involved analyzing samples from patients with IBS who received ondansetron, a medication known to block INSL5 action in mice, obtained from Professor Robin Spiller at the University of Nottingham. This phase revealed a significant subset of IBS-D patients with elevated INSL5 who responded positively to ondansetron.
- Publication of Findings: The culmination of this research was published in the journal Gut, presenting the comprehensive findings linking INSL5 to chronic diarrhea and BAD.
Supporting Data: Empirical Evidence from Human Studies
The Cambridge researchers meticulously analyzed samples from various sources to build a robust case for INSL5’s role.
1. Re-analysis of the University of Adelaide Study:
This study, originally focused on the gut hormone GLP-1, involved administering a bile acid enema to healthy volunteers. While the enema successfully triggered GLP-1 release, it also induced temporary diarrhea. When the Cambridge team analyzed samples from this study, they observed a direct correlation: the higher the INSL5 levels post-enema, the faster the volunteers experienced the urge to defecate. This initial finding strongly suggested that INSL5 is implicated in the acute diarrheal response to bile acid exposure.
2. Analysis of Patients with Bile Acid Diarrhea:
Samples from Professor Julian Walters’ cohort, comprising patients with confirmed bile acid diarrhea, provided even more striking results. In stark contrast to healthy volunteers, where INSL5 levels were found to be "almost undetectable," patients with BAD exhibited significantly elevated INSL5 concentrations. Furthermore, a direct relationship was observed between the magnitude of INSL5 elevation and the watery consistency of their stool samples. This correlation provides strong clinical evidence for INSL5’s role in the pathogenesis of chronic diarrhea in BAD.
3. Investigating Irritable Bowel Syndrome with Diarrhea (IBS-D):
A significant aspect of the study focused on patients diagnosed with IBS-D, a condition often difficult to differentiate from BAD. Samples were obtained from Professor Robin Spiller’s work, where patients with IBS had been treated with ondansetron, an anti-sickness medication known to inhibit INSL5 activity in preclinical models. The Cambridge team’s analysis revealed that approximately 40% of these IBS-D patients had elevated INSL5 levels, even though bile acid malabsorption had been ruled out by standard diagnostic procedures. Crucially, these patients with elevated INSL5 showed the most favorable response to ondansetron treatment. This finding is particularly significant as it suggests that a substantial proportion of patients diagnosed with IBS-D may, in fact, have an underlying INSL5-mediated diarrheal mechanism, potentially a milder or atypical form of BAD, or a related condition.
Implications for Diagnosis: The Promise of a Blood Test
The consistent elevation of INSL5 in patients with bile acid diarrhea and a subset of IBS-D patients presents a transformative opportunity for diagnostics. Dr. Bannon highlighted the potential: "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."
Currently, the diagnosis of bile acid diarrhea typically involves specialized tests like the SeHCAT scan, which measures bile acid retention in the body, or breath tests. These methods can be time-consuming, expensive, and not universally available. A simple, routine blood test measuring INSL5 levels could revolutionize the diagnostic pathway, enabling faster and more accurate identification of BAD. This could alleviate diagnostic delays, reduce misdiagnoses as IBS-D, and ensure patients receive appropriate treatment sooner.
Therapeutic Potential: Repurposing Drugs and Developing New Treatments
Beyond diagnostics, the findings illuminate a promising avenue for therapeutic intervention. The observation that ondansetron, a medication primarily used to prevent nausea and vomiting, was effective in approximately 40% of INSL5-positive IBS-D patients is a significant development. While the exact mechanism by which ondansetron exerts its effect on diarrhea is not fully understood, its known side effect of constipation suggests it may indeed be by blocking the action of INSL5.
The research team plans to further investigate this connection, with the ultimate goal of either repurposing ondansetron for this specific patient group or developing entirely new treatments that target the INSL5 pathway. Current treatments for bile acid diarrhea, such as bile acid sequestrants, are only effective in about two-thirds of patients, leaving a notable proportion without relief. A targeted approach based on INSL5 levels could offer a more personalized and effective treatment strategy.
Broader Context: The Neglected Role of Gut Hormones
Dr. Bannon also underscored the broader significance of this research within the field of gastroenterology. "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," he stated. "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 study contributes to a growing body of evidence that highlights the multifaceted roles of gut hormones, which are crucial regulators of digestion, metabolism, and gut motility. By bringing INSL5 into the spotlight, the research encourages a more holistic approach to understanding and treating gastrointestinal disorders, moving beyond solely focusing on the microbiome or inflammatory processes.
Funding and Future Directions
This pivotal research was generously supported by the Medical Research Council and Wellcome, with additional crucial funding provided by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre. These grants underscore the importance and potential impact of this line of scientific inquiry.
The research team, led by Professors Fiona Gribble and Frank Reimann at the Institute of Metabolic Science, University of Cambridge, is poised to continue its work. Future research will likely focus on:
- Clinical Trials: Conducting larger, prospective clinical trials to validate the diagnostic utility of INSL5 blood tests and assess the efficacy of ondansetron or other INSL5-targeting therapies in diverse patient populations.
- Mechanism Elucidation: Further investigating the precise molecular mechanisms by which INSL5 induces diarrhea and how ondansetron or other agents counteract this effect.
- Identifying Subtypes of Diarrhea: Differentiating between various causes of chronic diarrhea and precisely identifying those that would benefit from INSL5-targeted interventions.
- Exploring other Gut Hormones: Building on this success to investigate the roles of other under-researched gut hormones in gastrointestinal health and disease.
The identification of INSL5 as a key player in chronic diarrhea and a significant contributor to a substantial portion of IBS-D cases marks a significant advancement in gastroenterology. The potential for a new diagnostic tool and targeted therapies offers renewed hope for millions of individuals struggling with these often debilitating conditions, promising a future of more precise and effective patient care.