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 groundbreaking research, published in the esteemed journal Gut, not only sheds light on the complex mechanisms behind these often debilitating conditions but also signals a significant step forward in the development of a diagnostic blood test and points towards promising new therapeutic avenues.
Unraveling the Mystery of Bile Acid Diarrhea
The digestive system is a marvel of biological engineering, with numerous hormones and compounds working in concert to process the food we consume. A crucial element in this process is bile acid, a substance produced by the liver to aid in the digestion and absorption of fats. After its release into the upper portion of the small intestine, bile acid is meticulously reabsorbed by the body in the lower sections of the intestine. This efficient recycling mechanism is vital for maintaining digestive health.
However, for a significant minority of the population, this intricate system falters. Approximately one in every 100 individuals experiences a condition known as bile acid diarrhea (BAD), also referred to as bile acid malabsorption. In these cases, the bile acid is not adequately reabsorbed and consequently travels into the large intestine, or colon. This unwelcome presence triggers a cascade of symptoms, most notably urgent and watery diarrhea. The impact on patients can be profound, extending to the risk of episodes of incontinence, severely affecting their quality of life and daily functioning.
The diagnostic challenge posed by BAD has been a persistent hurdle for clinicians. Currently, there are no routine clinical blood tests that can reliably identify the condition. This diagnostic void often leads to a misdiagnosis, with many individuals being labeled as having irritable bowel syndrome (IBS). IBS is a broad, umbrella term encompassing a spectrum of gastrointestinal disorders, affecting an estimated one in 20 people worldwide. Within the IBS population, a substantial proportion – an estimated one in three patients whose primary symptom is diarrhea – may be suffering from undiagnosed bile acid diarrhea, highlighting the critical need for more precise diagnostic tools.
The Emerging Role of INSL5
For years, researchers have sought to identify the underlying causes of chronic digestive issues that elude conventional explanations. Studies conducted in animal models, particularly in mice, had previously hinted at the involvement of a gut hormone called Insulin-Like Peptide 5 (INSL5). This hormone is produced by specialized cells located at the far end of the colon and rectum. Evidence suggested that INSL5 is released in response to irritation, with bile acid emerging as a potential trigger.
The Cambridge-based research team, working at the Institute of Metabolic Science, set out to investigate whether this intriguing hormone played a similar role in chronic diarrhea in humans. Their investigation was significantly bolstered by the development of a novel antibody test by the pharmaceutical company Eli Lilly, with whom the Cambridge team is collaborating. This advanced test possesses the sensitivity to measure even minute quantities of INSL5, a crucial development that opened the door to human studies.
A Chronology of Discovery and Validation
The initial spark for this groundbreaking research came from an unexpected source: a study at the University of Adelaide that was exploring methods to stimulate the release of another important gut hormone, GLP-1. GLP-1 is of particular interest as it forms the basis of several widely used weight-loss drugs. In the Adelaide study, healthy volunteers were administered a bile acid enema, a procedure designed to introduce bile acid into the lower digestive tract. While this indeed triggered the release of GLP-1, it had an unintended consequence: it caused diarrhea in the participants.
When the Cambridge team had the opportunity to analyze blood samples collected during this Adelaide study, they made a pivotal discovery. They observed that the bile acid enema had caused INSL5 levels to surge temporarily in the volunteers. More importantly, they found a direct correlation: the higher the INSL5 levels, the more urgently the volunteers felt the need to defecate. This compelling finding provided strong evidence that INSL5 plays a significant role in the acute episodes of diarrhea triggered by bile acid, suggesting its potential involvement in chronic cases as well.
Building on this promising lead, the Cambridge researchers then examined samples obtained from Professor Julian Walters at Imperial College London. These samples included individuals diagnosed with bile acid diarrhea. The analysis yielded striking results: while INSL5 levels were virtually undetectable in healthy volunteers, they were markedly elevated in patients suffering from bile acid diarrhea. Furthermore, a direct relationship was established between the magnitude of INSL5 elevation and the severity of diarrhea, with higher INSL5 levels correlating with more watery stool samples. This provided robust human data validating the hypothesis that INSL5 is a key player in the pathophysiology of bile acid diarrhea.
Implications for Diagnosis and Treatment
The implications of these findings are far-reaching. Dr. Chris Bannon, the study’s first author and a clinical fellow at the 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," 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."
Currently, when a patient presents with chronic diarrhea, the diagnostic pathway often involves ruling out food intolerances, infections, or inflammatory conditions. While the role of the gut microbiome has garnered significant research attention, the importance of gut hormones in regulating digestive health and metabolic processes has, until now, been relatively under-explored. Dr. Bannon emphasized this point, noting, "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."
Beyond diagnostics, INSL5 also presents itself as a potential target for novel therapeutic interventions. Dr. Bannon and his colleagues further investigated this possibility by analyzing samples from patients treated by Professor Robin Spiller at the University of Nottingham. Professor Spiller had previously administered ondansetron, an anti-sickness medication known to block the action of INSL5 in mice, to patients with IBS. The Cambridge team’s analysis of these samples revealed that approximately 40% of these patients exhibited elevated INSL5 levels, even though their bile acid malabsorption had been ruled out through other means. Crucially, these patients with elevated INSL5 responded most effectively to ondansetron treatment.
A New Frontier in Gut Health Management
The precise mechanism by which ondansetron exerts its therapeutic effect in these individuals is still under investigation. However, it is known that a common side effect of ondansetron is constipation. The research team plans to delve deeper into this aspect, hoping it will lead to either the repurposing of existing medications or the development of entirely new and more effective treatments.
Current management strategies for bile acid diarrhea primarily rely on bile acid sequestrants. While these medications are effective for approximately two-thirds of patients, a significant proportion remain unresponsive, underscoring the unmet need for alternative therapies. The identification of INSL5 as a key mediator opens up a new avenue for drug development, potentially offering relief to those who do not benefit from current treatments.
Dr. Bannon offered a compelling perspective on the functional role of INSL5, addressing a common question about a hormone seemingly designed to induce diarrhea. "I often get asked why we would have a hormone that gives you diarrhea," he mused. "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 analogy provides an intuitive understanding of how an adaptive biological response can become problematic when chronically activated.
The research was spearheaded by Dr. Bannon, a clinical fellow within the esteemed group led by Professors Fiona Gribble and Frank Reimann at the Institute of Metabolic Science, University of Cambridge. This significant scientific endeavor received vital support from the Medical Research Council and Wellcome, with additional contributions from the National Institute for Health and Care Research Cambridge Biomedical Research Centre, underscoring the collaborative and well-funded nature of this important investigation. The findings are expected to stimulate further research into the intricate roles of gut hormones in a wide array of digestive and metabolic disorders.