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, could significantly advance diagnostic capabilities, potentially leading to a new blood test, and points towards a novel therapeutic target for a condition that affects millions worldwide.
Unraveling the Mystery of Chronic Diarrhea
For individuals experiencing persistent and debilitating diarrhea, the diagnostic journey can often be arduous and frustrating. Many suffer for years without a clear explanation, their symptoms frequently misattributed to Irritable Bowel Syndrome (IBS) or other less specific gastrointestinal issues. This new study sheds crucial light on a potential biological driver for a substantial proportion of these cases, particularly those characterized by diarrhea as the predominant symptom, known clinically as IBS-D.
The research focuses on a gut hormone called Insulin-Like Peptide 5 (INSL5). While previously suggested in animal models to play a role in chronic diarrhea, this is the first comprehensive human study to establish a strong correlation between elevated INSL5 levels and specific types of chronic diarrhea, most notably bile acid diarrhea (BAD).
The Mechanism of Bile Acid Diarrhea
To understand the significance of this discovery, it is essential to grasp the normal physiological process of bile acid digestion and absorption. When we consume food, particularly fats, the liver synthesizes and releases bile acids into the upper part of the small intestine. These bile acids act as crucial emulsifiers, breaking down fats to facilitate their absorption into the bloodstream. In a healthy digestive system, approximately 95% of these bile acids are efficiently reabsorbed in the lower section of the small intestine, returning to the liver to be reused.
However, in a condition known as bile acid malabsorption (BAM), this reabsorption process is impaired. When bile acids fail to be adequately reabsorbed, they continue their journey into the large intestine (colon). Here, they act as irritants, triggering a cascade of inflammatory responses and disrupting the delicate balance of water and electrolyte transport. The consequence for patients is often the hallmark symptoms of bile acid diarrhea: urgent, watery stools, and in severe cases, a significant risk of fecal incontinence.
The Diagnostic Challenge and the IBS Overlap
Bile acid diarrhea presents a significant diagnostic challenge. Currently, there is no routine, non-invasive blood test that can definitively identify the condition. This diagnostic void often leads to individuals presenting with chronic diarrhea being empirically diagnosed with IBS. It is estimated that as many as one in 20 people worldwide have IBS, a broad umbrella term encompassing various gastrointestinal disorders. Within the IBS population, particularly those with diarrhea as their primary complaint, it is now understood that a significant proportion—estimated to be up to one-third—may actually be suffering from undiagnosed bile acid diarrhea. This represents a substantial number of individuals whose underlying cause of distress is being missed, hindering appropriate treatment.
INSL5: A Hormone in Focus
The current study builds upon prior research that hinted at the involvement of INSL5. Studies conducted in mice had previously indicated that INSL5, a hormone produced by specialized cells located in the distal colon and rectum, might be implicated in chronic diarrhea. These studies suggested that INSL5 is released by these cells when they are irritated by the presence of bile acids. The University of Cambridge researchers, in collaboration with pharmaceutical company Eli Lilly, leveraged a newly developed antibody test capable of detecting minute quantities of INSL5, enabling them to investigate this hormone’s role in human subjects.
Chronology of Discovery and Key Findings
The path to understanding INSL5’s role involved a multi-pronged approach, piecing together evidence from different research contexts.
Early Investigations and Mouse Models: Pre-existing research in mouse models provided the initial hypothesis, suggesting that INSL5, a hormone found in the gut, could be linked to chronic diarrhea. These models indicated that bile acid irritation stimulated INSL5 release.
The University of Adelaide Study and the GLP-1 Connection: A pivotal moment in the human investigation stemmed from an analysis of samples from a study conducted at the University of Adelaide. This earlier research was focused on understanding the release of Glucagon-Like Peptide-1 (GLP-1), a hormone that underpins the efficacy of modern weight-loss medications. In that study, healthy volunteers were administered a bile acid enema, a procedure designed to simulate the effects of excess bile acids in the colon. While the enema successfully triggered GLP-1 release, it also inadvertently induced temporary diarrhea.
Cambridge Team’s Analysis of Adelaide Samples: When the Cambridge team examined samples from this Adelaide study, they made a crucial observation. The administration of the bile acid enema led to a significant and temporary surge in INSL5 levels. Furthermore, 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 that INSL5 is indeed involved in the acute diarrheal response to bile acids in humans.
Professor Julian Walters’ Patient Samples: The research team then obtained samples from Professor Julian Walters at Imperial College London, which included individuals diagnosed with bile acid diarrhea. Their analysis revealed a stark contrast between healthy individuals and those with BAD. In healthy volunteers, INSL5 levels were virtually undetectable. However, in patients with bile acid diarrhea, INSL5 levels were markedly elevated. Crucially, the more severe the watery nature of the stool samples, the higher the INSL5 concentrations. This solidified the link between elevated INSL5 and the pathophysiology of bile acid diarrhea.
Expert Commentary and the Diagnostic Promise
Dr. Chris Bannon, the study’s first author and a clinical fellow at the University of Cambridge’s Institute of Metabolic Science, expressed considerable enthusiasm about 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, highlighting the limitations of existing investigations. "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."
The development of a reliable blood test for INSL5 could revolutionize the diagnosis of bile acid diarrhea, enabling clinicians to identify patients who might currently be misdiagnosed with IBS-D. This would allow for targeted treatment and potentially alleviate years of suffering for many.
Therapeutic Implications: A New Target Emerges
Beyond its diagnostic potential, the discovery of INSL5’s role opens up exciting avenues for therapeutic intervention. The hormone’s direct involvement in mediating diarrheal symptoms suggests it could be a prime target for new treatments.
Ondansetron and IBS Patients: The research team collaborated with Professor Robin Spiller at the University of Nottingham, who had previously administered the anti-sickness medication ondansetron to patients with IBS. Ondansetron is known to block the action of INSL5 in mice. Upon analyzing samples from Professor Spiller’s patients, the Cambridge team found that approximately 40% of these individuals exhibited elevated INSL5 levels, even though their bile acid malabsorption had been ruled out through standard diagnostic procedures. Significantly, these patients with elevated INSL5 showed the most robust response to ondansetron treatment.
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. This observation suggests that by dampening INSL5 activity, the drug may be counteracting the diarrheal signal. The researchers are hopeful that this insight could lead to the repurposing of ondansetron for specific diarrheal conditions or the development of entirely new, more targeted therapies.
Current Treatment Limitations: Current treatments for bile acid diarrhea primarily involve bile acid sequestrants. While effective for many, these medications only provide relief for approximately two-thirds of patients, leaving a significant unmet need for alternative or supplementary therapies. The potential of targeting INSL5 offers a promising new direction for the remaining one-third who do not respond adequately to existing treatments.
The "Poison Sensor" Hypothesis
Dr. Bannon offered a compelling evolutionary perspective on the function of INSL5. "I often get asked why we would have a hormone that gives you diarrhea," he remarked. "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 paints INSL5 as a protective mechanism, evolved to expel harmful substances from the gut. However, in the context of bile acid malabsorption, this protective reflex becomes chronically activated, leading to the debilitating symptoms experienced by patients.
Broader Impact and Future Directions
The implications of this research extend beyond the immediate improvement of diagnostic and therapeutic options for bile acid diarrhea. It underscores the critical, yet often overlooked, role of gut hormones in maintaining gastrointestinal health. As Dr. Bannon highlighted, research has historically focused heavily on the gut microbiome, but the intricate signaling networks mediated by gut hormones are increasingly being recognized as equally vital.
The University of Cambridge team, including Dr. Bannon and the research group led by Professors Fiona Gribble and Frank Reimann at the Institute of Metabolic Science, plans to further investigate the precise mechanisms of INSL5 action and the efficacy of ondansetron. Their work could pave the way for a new era of precision medicine in gastroenterology, where treatments are tailored to specific underlying molecular mechanisms rather than broad symptom categories.
This groundbreaking study, supported by substantial funding from the Medical Research Council and Wellcome, with additional support from the National Institute for Health and Care Research Cambridge Biomedical Centre, represents a significant leap forward in understanding and addressing a common yet poorly understood cause of chronic diarrhea. The promise of a simple blood test and novel treatment strategies offers a beacon of hope for millions suffering from the often-debilitating effects of this condition. The scientific community will be closely watching as this research unfolds, anticipating its transformative impact on patient care.
