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, not only illuminates a previously underappreciated mechanism contributing to these debilitating conditions but also paves the way for the development of a crucial diagnostic blood test and points towards a promising new therapeutic avenue.
Unraveling the Mystery of Bile Acid Diarrhea
The digestive process is a finely tuned symphony, with various organs and substances working in concert to break down food and absorb nutrients. A key player in this process is bile acid, a fluid produced by the liver that aids in the digestion and absorption of fats. Bile acid is released into the upper sections of the small intestine. Following its digestive duties, the vast majority of bile acid is efficiently reabsorbed back into the body in the lower part of the small intestine, a process crucial for maintaining digestive equilibrium.
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 these cases, unabsorbed bile acid, which is naturally irritating to the intestinal lining, continues its journey into the large intestine (colon). The presence of this excess, irritating bile acid in the colon triggers a cascade of symptoms, most notably urgent, watery diarrhea. The severity of these episodes can be profound, with patients sometimes experiencing unpredictable and distressing episodes of incontinence, significantly impacting their quality of life.
The diagnostic challenge posed by BAD is substantial. Currently, there are no routine clinical blood tests that can definitively identify the condition. This diagnostic void often leads to individuals experiencing chronic diarrhea being misdiagnosed or managed under the broader umbrella of Irritable Bowel Syndrome (IBS). IBS itself is a complex gastrointestinal disorder characterized by a range of symptoms, including abdominal pain, bloating, and changes in bowel habits. It is estimated that as many as one in 20 people worldwide suffer from IBS. Within this large patient population, a significant proportion – an estimated one in three patients whose primary symptom is diarrhea – may in fact be suffering from undiagnosed bile acid diarrhea. This highlights a critical gap in clinical practice, where a treatable underlying cause is often overlooked.
The Emergence of Insulin-Like Peptide 5 (INSL5)
For years, the scientific community has sought to understand the intricate hormonal signals that govern gut function. 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 movements and its potential role in chronic diarrhea. INSL5 is primarily produced by specialized enteroendocrine cells located in the distal colon and rectum – the furthest reaches of the large intestine. Studies in mice suggested that these cells release INSL5 when they are irritated, and bile acid was identified as a potent irritant. This initial evidence provided a tantalizing clue, suggesting a potential link between bile acid malabsorption and the release of this specific hormone.
The research team at the Institute of Metabolic Science, University of Cambridge, led by Professors Fiona Gribble and Frank Reimann, embarked on a mission to rigorously investigate whether this mouse-based observation held true for human physiology and, crucially, if INSL5 could be implicated in chronic diarrhea experienced by human patients. The advancement of their research was significantly propelled by the development of a novel antibody test by the pharmaceutical company Eli Lilly, with whom the Cambridge team collaborates. This sophisticated assay enabled researchers to accurately measure even minute quantities of INSL5 in biological samples, a technological leap that was essential for quantifying its presence and fluctuations.
Landmark Study Provides Definitive Human Evidence
The Cambridge researchers were able to leverage existing research data to build a compelling case for INSL5’s role in human diarrhea. They analyzed samples from a study conducted at the University of Adelaide, which had investigated the effects of stimulating the release of another important gut hormone, GLP-1 (Glucagon-Like Peptide-1). GLP-1 is a hormone well-known for its role in regulating blood sugar and appetite, and it forms the basis of several popular weight-loss medications. In the Adelaide study, healthy volunteers were administered a bile acid enema, a procedure designed to introduce bile acid directly into the lower bowel. While this intervention successfully triggered GLP-1 release, it also had the unintended consequence of inducing diarrhea in the participants.
Upon analyzing these samples, the Cambridge team made a pivotal discovery: the bile acid enema caused a significant and temporary surge in INSL5 levels. More importantly, they observed a direct correlation: the higher the INSL5 levels rose, the more rapidly the volunteers experienced the urge to defecate. This finding provided the first robust human evidence directly linking bile acid exposure to increased INSL5 production and subsequent diarrheal symptoms, strongly suggesting that INSL5 is a key mediator of acute diarrheal responses to bile acid in the colon.
Building upon this foundational discovery, the Cambridge researchers then turned their attention to human patients. They obtained valuable samples from Professor Julian Walters at Imperial College London, which included biological material from individuals diagnosed with bile acid diarrhea. The results were striking and confirmatory. In stark contrast to healthy volunteers, where INSL5 levels were almost undetectable, patients with bile acid diarrhea exhibited significantly elevated levels of the hormone. Furthermore, the severity of their diarrhea appeared to be directly proportional to their INSL5 levels; the higher the INSL5 concentration, the more watery the stool samples were.
Dr. Chris Bannon, a clinical fellow at the Institute of Metabolic Science and the study’s first author, articulated the profound implications of these 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 sentiment underscores a shift in understanding the complex physiology of the gut, moving beyond solely focusing on microbial balance to recognizing the critical role of hormonal signaling.
INSL5: A Potential Target for Novel Treatments
Beyond its diagnostic potential, the identification of INSL5 as a key player in bile acid diarrhea opens up exciting possibilities for therapeutic intervention. The research team explored whether targeting INSL5 could offer relief to patients. They obtained further samples from Professor Robin Spiller at the University of Nottingham, who had previously conducted a study administering the anti-sickness medication ondansetron to patients with IBS. Ondansetron is known to act by blocking the action of INSL5, at least in mice.
Analysis of these samples by the Cambridge team revealed a significant finding: approximately 40% of the patients treated with ondansetron exhibited elevated INSL5 levels, even though their bile acid malabsorption had been ruled out through conventional means. Crucially, these patients with raised INSL5 levels demonstrated the most favorable response to ondansetron. This suggests that a subset of patients diagnosed with IBS, who may not have classic bile acid diarrhea, could still have INSL5-driven diarrhea and benefit from treatments that target this hormone.
While the precise mechanism by which ondansetron exerts its therapeutic effect in this context is still under investigation, a known side effect of the drug is constipation. This observation, coupled with the diarrheal symptoms mediated by INSL5, suggests a complex interplay that the researchers are keen to unravel. The team intends to pursue further investigations into this area, with the ultimate goal of either repurposing ondansetron for this specific indication or developing entirely new, more targeted treatments. This research offers a glimmer of hope for the significant proportion of patients for whom current therapies for bile acid diarrhea are not fully effective. Bile acid sequestrants, the current mainstay of treatment for BAD, are only successful in about two-thirds of patients, leaving a considerable number without adequate relief.
Dr. Bannon offered a compelling analogy to explain 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," he explained. "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 perspective frames INSL5 not as a malfuntional hormone, but rather as a protective mechanism that becomes problematic when chronically activated by an irritant like excess bile acid.
The research was a collaborative effort, supported by significant funding from the Medical Research Council and Wellcome, with additional crucial support provided by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre. This multidisciplinary backing underscores the importance and potential impact of this groundbreaking work.
Broader Implications and Future Directions
The implications of this study extend far beyond the immediate development of diagnostic tools and treatments for bile acid diarrhea. It represents a paradigm shift in understanding the complex pathophysiology of chronic diarrhea and IBS. For decades, research into IBS has largely focused on factors such as altered gut motility, visceral hypersensitivity, and the gut microbiome. While these remain important areas of investigation, the Cambridge study firmly places gut hormones, particularly INSL5, on the map as critical regulators of bowel function and potential culprits in unexplained chronic diarrhea.
The potential for a simple blood test to diagnose bile acid diarrhea could revolutionize patient care. Currently, diagnosis often involves invasive procedures or lengthy symptom tracking without a clear answer. A blood test measuring INSL5 levels could provide a rapid, non-invasive, and accurate method for identifying patients who would benefit from specific treatments. This would not only improve patient outcomes but also reduce the burden on healthcare systems by streamlining the diagnostic process and preventing unnecessary investigations.
Furthermore, the identification of INSL5 as a therapeutic target offers a much-needed new avenue for drug development. The success of ondansetron in a subset of patients with elevated INSL5, even those without classic BAD, suggests that targeting this hormone could have broader applications in managing various forms of chronic diarrhea. The ongoing research into the exact mechanisms of action and the potential for drug repurposing or novel drug design holds immense promise for millions of individuals worldwide who suffer from the debilitating effects of chronic diarrhea.
The study’s findings also highlight the importance of interdisciplinary collaboration and the power of leveraging existing research data. The use of samples from previous studies, combined with the development of new diagnostic tools, accelerated the pace of discovery and provided robust human evidence. As Dr. Bannon noted, the field of gut hormones has been historically under-researched compared to other areas like the microbiome. This study serves as a strong impetus for increased focus and investment in understanding the intricate roles of gut hormones in health and disease.
In conclusion, the University of Cambridge study represents a significant leap forward in our understanding of chronic diarrhea and its links to conditions like IBS. By identifying the gut hormone INSL5 as a key mediator, researchers have not only shed light on the underlying mechanisms of bile acid diarrhea but have also laid the groundwork for improved diagnostics and novel therapeutic strategies. This research offers renewed hope for patients who have long struggled with these often-misunderstood and challenging gastrointestinal disorders, promising a future where accurate diagnosis and effective treatment are more readily available.
