By Gilang Cahya 
Cambridge, UK – A groundbreaking study spearheaded by scientists at the University of Cambridge has identified high levels of a specific hormone within gut cells as a potential underlying cause for a significant proportion of chronic diarrhea cases, including up to 40% of patients diagnosed with Irritable Bowel Syndrome with Diarrhea (IBS-D). This discovery, published in the esteemed journal Gut, not only illuminates the complex mechanisms behind these often debilitating conditions but also paves the way for the development of a novel blood test for diagnosis and points towards promising new therapeutic avenues.
The research delves into the intricate digestive process, where the liver plays a crucial role in releasing bile acids to aid in the breakdown and absorption of fats. These bile acids are secreted into the upper small intestine and are typically reabsorbed further down. However, for approximately one in every 100 individuals, this reabsorption process falters, leading to a condition known as bile acid diarrhea (BAD), also referred to as bile acid malabsorption. In such cases, excess bile acids enter the large intestine, triggering urgent, watery diarrhea and potentially leading to episodes of incontinence, profoundly impacting quality of life.
The Diagnostic Challenge and the Role of INSL5
The diagnosis of bile acid diarrhea has historically been a significant hurdle, largely due to the absence of routine clinical blood tests. Consequently, many individuals presenting with these symptoms are often misdiagnosed with Irritable Bowel Syndrome (IBS), a broad classification encompassing various gastrointestinal disorders. It is estimated that as many as one in 20 people worldwide live with IBS, and within this population, an estimated one-third of those whose primary symptom is diarrhea may be suffering from undiagnosed bile acid diarrhea. This diagnostic gap has left countless patients without appropriate treatment and understanding.
Previous investigations, primarily conducted in animal models, had suggested a potential role for the gut hormone Insulin-Like Peptide 5 (INSL5) in chronic diarrhea. INSL5, produced by specialized cells located at the distal end of the colon and rectum, is known to be released in response to irritation, including that caused by bile acids. Building upon these earlier findings, researchers at the Institute of Metabolic Science at the University of Cambridge set out to explore whether INSL5 could similarly be implicated in human chronic diarrhea. The feasibility of this investigation was significantly enhanced by the development of a new, highly sensitive antibody test by pharmaceutical company Eli Lilly, a collaborator on the study, which allowed for the precise measurement of minute quantities of INSL5.
Unraveling the Link: From Mouse Studies to Human Trials
A pivotal moment in the research came from an analysis of samples collected during a study at the University of Adelaide. This earlier research focused on stimulating the release of the gut hormone GLP-1, a hormone that forms the basis of popular weight-loss medications. In that study, healthy volunteers were administered a bile acid enema, which successfully triggered GLP-1 release but, as an unintended consequence, induced diarrhea. When the Cambridge team examined samples from these volunteers, they observed a dramatic and temporary surge in INSL5 levels following the bile acid enema. Crucially, they found a direct correlation: the higher the INSL5 levels, the more immediate and urgent the need for bowel movement. This observation provided compelling evidence that INSL5 is indeed a key player in the physiological response leading to diarrhea.
The research team then proceeded to analyze samples from patients with diagnosed bile acid diarrhea, provided by Professor Julian Walters at Imperial College London. The results were striking. While INSL5 levels were found to be almost undetectable in healthy individuals, they were significantly elevated in patients suffering from bile acid diarrhea. Furthermore, the degree of stool water content directly correlated with the magnitude of INSL5 elevation, reinforcing the hormone’s direct link to the severity of diarrheal symptoms.
Dr. Chris Bannon, the study’s first author and a clinical fellow at the Institute of Metabolic Science, University of Cambridge, expressed his enthusiasm for the findings: "This was a very exciting discovery because it demonstrated that this hormone could be playing a significant role in the symptoms of this often misunderstood condition. It also opened up the possibility of developing a blood test to help diagnose bile acid diarrhea, provided that INSL5 levels are exclusively elevated in these individuals."
He further elaborated on the diagnostic landscape, noting, "When you present to your doctor with chronic diarrhea, the typical approach involves tests for food intolerances, ruling out infections, or searching for signs of inflammation. While there has been considerable research into the gut microbiome, gut hormones have historically been overlooked. However, it is becoming increasingly evident that gut hormones exert a profound influence on crucial bodily functions such as gut health and weight management."
Therapeutic Implications: Targeting INSL5
Beyond its diagnostic potential, the discovery of INSL5’s role in bile acid diarrhea presents a promising new target for therapeutic intervention. Dr. Bannon and his team collaborated with Professor Robin Spiller at the University of Nottingham, who had previously administered ondansetron, an anti-sickness medication known to block INSL5 activity in mice, to patients with IBS.
Upon analyzing samples from this cohort, the Cambridge team found that approximately 40% of these patients exhibited elevated INSL5 levels, even though they had previously been cleared of bile acid malabsorption. These patients also demonstrated the most significant positive response to ondansetron treatment. This suggests that INSL5 may be contributing to diarrheal symptoms in a broader range of IBS patients than previously understood, and that ondansetron, or similar agents, could offer relief to a substantial subset of these individuals.
While the precise mechanism by which ondansetron alleviates diarrhea in these patients is still under investigation, a known side effect of the drug is constipation. The research team is keen to explore this further, with the hope of either repurposing ondansetron for the treatment of chronic diarrhea or developing even more targeted and effective therapies. Current treatments for bile acid diarrhea primarily involve bile acid sequestrants, which are effective in only about two-thirds of patients, highlighting the need for alternative or complementary approaches.
Dr. Bannon offered a fascinating perspective on the evolutionary purpose of INSL5: "I often get asked why we would have a hormone that causes diarrhea. I conceptualize it as a form of poison sensor. Bile acids are not intended to be present in the colon; they act as irritants and are toxic to the gut microbiome. It stands to reason that the body would possess a mechanism to detect toxins and facilitate their expulsion. However, a problem arises when this system is continuously triggered by bile acid, leading to severe and persistent symptoms."
Broader Impact and Future Directions
The implications of this research extend far beyond the immediate scope of bile acid diarrhea and IBS-D. It underscores the critical, and often underestimated, role of gut hormones in maintaining overall gastrointestinal health and influencing systemic well-being. The development of a reliable blood test for INSL5 could revolutionize the diagnostic process for millions of individuals who have suffered for years with unexplained chronic diarrhea, offering them clarity and access to appropriate treatment.
The identification of INSL5 as a therapeutic target also opens exciting avenues for drug development. Pharmaceutical companies and research institutions will likely focus on creating more specific modulators of INSL5 activity, potentially leading to treatments with fewer side effects and greater efficacy than current options. This could significantly improve the quality of life for a substantial patient population.
The research was generously supported by grants from 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. This collaborative effort, involving leading academic institutions and pharmaceutical partners, exemplifies the power of interdisciplinary research in tackling complex health challenges.
Looking ahead, the Cambridge team plans to conduct further investigations to fully elucidate the mechanisms of INSL5 action and its interaction with other gut signaling pathways. The goal is to translate these fundamental discoveries into tangible clinical benefits, offering hope and relief to those burdened by chronic digestive disorders. The journey from understanding a complex hormone to developing a diagnostic tool and effective treatment is a testament to persistent scientific inquiry and its profound impact on human health.
