By Gilang Cahya 
A groundbreaking study led by scientists at the University of Cambridge has unveiled a significant connection between elevated levels of a specific gut hormone, Insulin-Like Peptide 5 (INSL5), and a substantial portion of chronic diarrhea cases, potentially explaining up to 40% of diagnoses in patients with Irritable Bowel Syndrome with Diarrhea (IBS-D). This discovery, published in the prestigious journal Gut, not only sheds light on the intricate mechanisms of digestive disorders but also paves the way for the development of novel diagnostic tools and therapeutic interventions.
Unraveling the Mystery of Bile Acid Diarrhea
The digestive process is a complex interplay of enzymes, hormones, and mechanical actions designed to extract nutrients from food. A crucial component of this process involves bile acids, which are synthesized in the liver and released into the upper small intestine to aid in the digestion and absorption of fats. Following their role in fat emulsification, bile acids are meticulously reabsorbed in the lower section of the small intestine and returned to the liver, forming an efficient enterohepatic circulation.
However, for approximately 1% of the population, this carefully orchestrated system falters, leading to a condition known as bile acid diarrhea (BAD), also referred to as bile acid malabsorption. In individuals with BAD, bile acids are not adequately reabsorbed in the small intestine and consequently flow into the large intestine (colon). This influx of bile acids into the colon acts as a potent irritant, triggering a cascade of symptoms characterized by urgent, watery diarrhea, and in severe cases, the risk of fecal incontinence.
Diagnosing BAD has historically been a significant clinical challenge due to the absence of routine, readily accessible blood tests. This diagnostic gap often leads to patients presenting with chronic diarrhea symptoms being misdiagnosed or broadly categorized under the umbrella term of Irritable Bowel Syndrome (IBS). IBS, affecting an estimated one in 20 individuals globally, encompasses a range of functional gastrointestinal disorders. Within the IBS population, it is estimated that up to one in three patients whose primary symptom is diarrhea may be suffering from undiagnosed BAD. This underscores the substantial burden of misdiagnosis and the potential for improved patient outcomes with a more precise understanding of the underlying causes.
The Emerging Role of Insulin-Like Peptide 5 (INSL5)
Previous research conducted in animal models, specifically mice, had hinted at the involvement of the gut hormone INSL5 in the pathogenesis of chronic diarrhea. INSL5 is produced by specialized cells located in the distal regions of the colon and rectum. Studies suggested that these cells release INSL5 when they are irritated, and this irritation was hypothesized to be linked to the presence of bile acids in these areas.
The Cambridge-based research team, affiliated with the Institute of Metabolic Science, sought to investigate whether this proposed mechanism held true for human physiology. Their work was significantly facilitated by the development of a new antibody test by the pharmaceutical company Eli Lilly, a collaborator on the study. This advanced assay possesses the sensitivity required to accurately measure even minute quantities of INSL5 in biological samples, a crucial advancement for investigating its role in gastrointestinal disorders.
Chronology of Discovery and Supporting Evidence
The investigation into INSL5’s role in chronic diarrhea gained momentum through a series of carefully designed analyses.
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Early Clues from Mouse Studies: Pre-clinical research in mice indicated that INSL5, produced in the colon and rectum, was released when these tissues were exposed to irritants, including bile acids. This laid the theoretical groundwork for human investigation.
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Analysis of University of Adelaide Study Data (Circa Late 2010s – Early 2020s): A pivotal moment in the research came with the re-examination of samples from a study conducted at the University of Adelaide. This original study aimed to investigate the release of Glucagon-Like Peptide-1 (GLP-1), a hormone central to weight-loss drug mechanisms, by administering a bile acid enema to healthy volunteers. While the enema successfully triggered GLP-1 release, it also predictably induced temporary diarrhea. Upon analyzing these samples, the Cambridge team observed a significant and temporary surge in INSL5 levels correlating directly with the severity of the induced diarrhea. The faster volunteers felt the urge to defecate, the higher their INSL5 levels. This observation provided compelling evidence for INSL5’s involvement in acute diarrheal responses.
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Analysis of Professor Julian Walters’ Patient Cohort (Early 2020s): Building on these findings, the researchers obtained valuable samples from patients with confirmed bile acid diarrhea, collected by Professor Julian Walters at Imperial College London. The analysis revealed a stark contrast: while INSL5 levels were virtually undetectable in healthy volunteers, they were markedly elevated in individuals suffering from BAD. Furthermore, a direct correlation was established between higher INSL5 concentrations and the water content of stool samples, reinforcing INSL5’s role in driving the watery nature of the diarrhea characteristic of BAD.
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Investigation into Potential Therapeutic Targets (Early 2020s): The discovery of INSL5’s elevated levels in BAD patients naturally led to questions about potential treatments. The team then analyzed samples from patients with IBS who had received ondansetron, an anti-sickness medication known to block INSL5 activity in mice. These samples were provided by Professor Robin Spiller at the University of Nottingham. The analysis revealed that approximately 40% of these IBS patients exhibited elevated INSL5 levels, even though they had undergone testing and had bile acid malabsorption ruled out. Crucially, these individuals with high INSL5 and undiagnosed BAD symptoms showed the most significant improvement when treated with ondansetron.
Expert Perspectives and the Significance of the Findings
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 for the findings. "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."
He further elaborated on the current diagnostic landscape: "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 highlights a potential paradigm shift in how chronic diarrhea is approached, moving beyond the focus on the microbiome and inflammation to include hormonal regulation.
Implications for Diagnosis and Treatment
The identification of INSL5 as a key player in chronic diarrhea has profound implications for both diagnosis and treatment.
Development of a Novel Blood Test
The discovery that INSL5 levels are significantly elevated in patients with BAD, and potentially absent or low in healthy individuals and those with other forms of diarrhea, opens the door for the development of a simple and accessible blood test. Such a test could revolutionize the diagnostic pathway for chronic diarrhea, enabling clinicians to quickly and accurately identify patients with BAD. This would not only expedite treatment but also reduce the incidence of misdiagnosis and the associated patient distress and healthcare costs.
A New Target for Therapeutic Intervention
Beyond diagnostics, INSL5 presents a promising target for novel therapeutic strategies. The observed efficacy of ondansetron, an anti-sickness drug that inhibits INSL5, in a subset of IBS patients with elevated INSL5 levels suggests a potential repurposing of existing medications. While the precise mechanism by which ondansetron alleviates diarrhea is still under investigation, a known side effect of the drug is constipation. Researchers are actively exploring this further, hoping to either leverage ondansetron as a treatment for BAD or to develop more targeted therapies that specifically modulate INSL5 activity.
Current treatments for BAD primarily involve bile acid sequestrants, medications that bind to bile acids in the gut and prevent their absorption. While effective for approximately two-thirds of patients, this leaves a significant proportion with persistent symptoms. The potential for INSL5-targeting therapies could offer a much-needed alternative or adjunct treatment for these individuals.
Understanding the Biological Rationale
Dr. Bannon offered a compelling biological explanation for the existence 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 "poison sensor" analogy vividly illustrates how a protective physiological response can become pathological when chronically activated.
Broader Context and Future Directions
This research, supported by the Medical Research Council, Wellcome, and the National Institute for Health and Care Research Cambridge Biomedical Research Centre, underscores the growing appreciation for the complex hormonal regulation of gastrointestinal function. The intricate communication network within the gut involves numerous hormones that influence motility, secretion, nutrient absorption, and even appetite. The identification of INSL5’s role in BAD adds another crucial piece to this intricate puzzle.
The findings have far-reaching implications for understanding not only BAD but also other functional gastrointestinal disorders where gut hormone dysregulation may play a role. Future research will likely focus on:
- Clinical Validation of the INSL5 Blood Test: Rigorous clinical trials will be necessary to validate the sensitivity and specificity of an INSL5 blood test for diagnosing BAD across diverse patient populations.
- Mechanism of Action of Ondansetron: Further investigation into how ondansetron exerts its anti-diarrheal effects in the context of BAD is crucial for optimizing its use and developing superior therapies.
- Development of Targeted INSL5 Modulators: Pharmaceutical research will likely explore the development of novel drugs that selectively target INSL5 pathways to treat BAD and potentially other related conditions.
- Investigating INSL5 in Other Diarrheal Conditions: The study’s findings may prompt investigations into whether INSL5 plays a role in other forms of chronic diarrhea beyond BAD, broadening the scope of its potential impact.
The University of Cambridge’s work represents a significant advancement in our understanding of chronic diarrhea, offering hope for improved diagnostics and more effective treatments for millions of individuals worldwide suffering from this debilitating condition. The transition from a neglected area of research to a potential therapeutic target signifies a triumph of scientific inquiry and collaboration.
