By Gilang Cahya 
A groundbreaking study led by scientists at the University of Cambridge has identified high levels of a specific hormone in the gut as a potential underlying cause for a significant proportion of chronic diarrhea cases. This discovery could shed light on up to 40% of patients diagnosed with Irritable Bowel Syndrome with Diarrhea (IBS-D), offering hope for improved diagnostics and novel therapeutic strategies. The research, published in the esteemed journal Gut, marks a pivotal moment in understanding a complex and often debilitating group of gastrointestinal disorders.
Unraveling the Mystery of Bile Acid Diarrhea
The digestive system is a marvel of biological engineering, with intricate processes ensuring efficient nutrient absorption. When we consume food, the liver plays a crucial role by releasing bile acids into the initial segment of the small intestine. These bile acids are essential for emulsifying fats, breaking them down into smaller components that can then be readily absorbed into the bloodstream. Following their digestive duties, the vast majority of these bile acids are efficiently reabsorbed by the intestinal lining in the lower part of the small intestine, a process that conserves these vital compounds.
However, for approximately one in every 100 individuals, this finely tuned reabsorption mechanism falters. This leads to a condition known as bile acid diarrhea, also referred to as bile acid malabsorption (BAM). In BAM, incompletely reabsorbed bile acids continue their journey into the large intestine, or colon. Here, they exert an irritant effect on the colon’s delicate lining, triggering a cascade of symptoms that can include urgent, watery diarrhea, abdominal discomfort, and in severe cases, a distressing risk of incontinence.
The diagnostic challenge posed by bile acid diarrhea is substantial. Currently, there is a notable absence of routine clinical blood tests that can definitively identify the condition. This diagnostic void often leads to a misattribution of symptoms. Many patients experiencing chronic diarrhea, including those with BAM, are frequently diagnosed with Irritable Bowel Syndrome (IBS), a broad category encompassing various functional gastrointestinal disorders. It is estimated that as many as one in 20 people worldwide suffers from IBS. Within this large population, a significant subgroup—estimated at one in three patients whose primary symptom is diarrhea—may be unknowingly living with undiagnosed bile acid diarrhea. This highlights a critical unmet need in gastrointestinal diagnostics and patient care.
The Central Role of 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 regulation of bowel function and its potential link to chronic diarrhea. INSL5 is produced and stored in specialized cells located at the distal end of the colon and in the rectum. Studies in mice suggested that these cells release INSL5 when they are irritated, a phenomenon observed when exposed to bile acid. This provided an early, albeit indirect, clue to a possible connection between bile acid exposure and hormonal signaling in the gut.
The Cambridge-based research team, operating from the Institute of Metabolic Science, embarked on a mission to rigorously investigate whether INSL5 plays a comparable role in human chronic diarrhea. A significant advancement enabling this research was the development of a novel antibody test by the pharmaceutical company Eli Lilly. This highly sensitive test allows researchers to accurately measure minute quantities of INSL5 in biological samples, a capability that was previously lacking and thus hindered direct human studies. The collaboration with Eli Lilly proved instrumental in facilitating this new line of inquiry.
Chronology of Discovery and Key Findings
The path to understanding INSL5’s role involved a multi-stage investigation, building upon prior research and leveraging new diagnostic tools.
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Early Observations (Pre-Cambridge Study): Studies conducted at the University of Adelaide explored methods to stimulate the release of another crucial gut hormone, Glucagon-Like Peptide-1 (GLP-1). GLP-1 is of significant interest due to its established role in weight management and its basis for popular weight-loss medications. During these experiments, researchers administered a bile acid enema to healthy volunteers. While this procedure successfully triggered GLP-1 release, it had an unexpected consequence: inducing diarrhea in the participants.
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The Cambridge Team’s Initial Analysis (Circa 2023-2024): When the Cambridge team analyzed samples from these Adelaide-based studies, a crucial observation emerged. They discovered that the administration of the bile acid enema led to a temporary but dramatic surge in INSL5 levels. Critically, they found a direct correlation: the higher the INSL5 levels, the more rapidly the volunteers experienced the urge to defecate. This finding provided compelling evidence, albeit in a controlled experimental setting, that INSL5 is indeed implicated in the physiological response to bile acid in the gut and is likely to play a role in the development of diarrheal symptoms.
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Human Patient Studies (Circa 2024): The research then progressed to analyzing samples from human patients. Collaborating with Professor Julian Walters at Imperial College London, the Cambridge team obtained samples from individuals diagnosed with bile acid diarrhea. The results were striking. While INSL5 levels were found to be almost undetectable in healthy volunteers, they were significantly elevated in patients suffering from bile acid diarrhea. Furthermore, the severity of their diarrhea, as measured by the water content of their stool samples, directly correlated with the magnitude of their INSL5 levels. This confirmed that the link observed in experimental settings was also present in a clinical population.
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Potential for Diagnostics and Treatment (Ongoing): The implications of these findings are profound. Dr. Chris Bannon, the study’s first author and a clinical fellow at the Institute of Metabolic Science, expressed considerable excitement. "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," Dr. Bannon stated. "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." This opens the door to a much-needed diagnostic tool that could accurately identify BAM and differentiate it from other forms of chronic diarrhea.
The Broader Context: Gut Hormones and Chronic Diarrhea
The diagnostic journey for individuals suffering from chronic diarrhea is often lengthy and frustrating. As Dr. Bannon pointed out, "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." While these are essential steps, the focus on gut hormones has historically been less pronounced compared to other areas of gastrointestinal research, such as the microbiome. "There has been significant research interest in the microbiome, but gut hormones have been neglected," he added. "But it’s becoming increasingly clear that gut hormones play an important role in things like gut health and weight management." This study underscores the critical, and previously underappreciated, role of gut hormones in a wide array of digestive functions.
Therapeutic Implications: Targeting INSL5
Beyond its diagnostic potential, the discovery of INSL5’s role also presents a promising new target for therapeutic intervention. The research team further investigated this possibility by obtaining samples from patients who had participated in a study led by Professor Robin Spiller at the University of Nottingham. In this prior study, patients with IBS had been treated with ondansetron, an anti-sickness medication known to block the action of INSL5 in mice.
Analysis of these samples by the Cambridge team revealed that approximately 40% of these IBS patients exhibited elevated INSL5 levels, even though their bile acid malabsorption had been ruled out through standard tests. Crucially, these patients with elevated INSL5 responded particularly well to ondansetron treatment. This suggests that a subset of IBS-D patients, potentially those with undiagnosed or low-grade BAM, might be experiencing symptoms driven by INSL5 overactivity, and could benefit from therapies that target this hormone.
The precise mechanism by which ondansetron alleviates diarrhea in these patients is still under investigation. However, a known side effect of ondansetron is constipation, which aligns with the idea of dampening excessive gut motility. The Cambridge team plans to conduct further research to elucidate this mechanism, with the ultimate goal of either repurposing ondansetron for this specific indication or developing even more targeted and effective treatments.
Current treatments for bile acid diarrhea primarily involve bile acid sequestrants. While these medications are effective for a majority of patients, they only succeed in about two-thirds of cases, leaving a significant portion of individuals without adequate relief. The identification of INSL5 as a potential therapeutic target offers a new avenue for those who do not respond to existing treatments.
A Natural "Poison Sensor"
Dr. Bannon offered an insightful perspective on the biological purpose of a hormone that can induce 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 evolutionary perspective suggests that INSL5’s primary role is protective, helping the body to expel harmful substances. However, in conditions like BAM, this protective mechanism can become overactive, leading to chronic and debilitating symptoms.
The research was supported by significant funding bodies, including the Medical Research Council and Wellcome, underscoring the importance and potential impact of this work. Additional support was provided by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, further bolstering the collaborative and translational nature of the study.
This comprehensive investigation into INSL5 represents a significant leap forward in our understanding of chronic diarrhea and IBS-D. The potential for a new diagnostic blood test and the promise of targeted therapies offer a beacon of hope for millions of individuals worldwide grappling with these challenging gastrointestinal conditions. The study’s findings not only advance scientific knowledge but also pave the way for tangible improvements in patient care and quality of life.