By Gilang Cahya 
A groundbreaking study spearheaded by researchers at the University of Cambridge has unveiled a critical link between elevated levels of the gut hormone Insulin-Like Peptide 5 (INSL5) and a significant proportion of chronic diarrhea cases, including up to 40% of patients diagnosed with irritable bowel syndrome with diarrhea (IBS-D). This pivotal discovery, published in the esteemed journal Gut, not only sheds light on the underlying mechanisms of these often debilitating gastrointestinal conditions but also heralds the potential development of a much-needed blood test for diagnosis and points towards novel therapeutic avenues.
Unraveling the Mystery of Bile Acid Diarrhea
The intricate process of digestion involves the liver releasing bile acids into the upper part of the small intestine to facilitate the breakdown and absorption of fats. Following their role in digestion, these bile acids are typically reabsorbed by the lower sections of the small intestine. 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, excess bile acids inappropriately travel into the large intestine (colon), where they act as irritants, triggering a cascade of symptoms that can include urgent, watery diarrhea and, in severe instances, episodes of incontinence.
The diagnostic challenge for BAD has historically been significant. The absence of routine clinical blood tests has meant that many individuals experiencing these persistent symptoms are often misdiagnosed with irritable bowel syndrome (IBS). IBS, an umbrella term encompassing a spectrum of functional gastrointestinal disorders, affects an estimated one in 20 people globally. Within this broad category, it is believed that a substantial proportion of patients whose primary symptom is diarrhea may be suffering from undiagnosed bile acid diarrhea. Previous estimates suggest that as many as one in three individuals with diarrhea-predominant IBS could have undiagnosed BAD, highlighting the widespread nature of this diagnostic gap.
The Role of INSL5: A Previously Overlooked Player
Prior research, primarily conducted in animal models, had hinted at the involvement of a gut hormone named Insulin-Like Peptide 5 (INSL5) in the regulation of bowel movements. INSL5 is produced by specialized cells located in the terminal portion of the colon and rectum. These cells are known to release INSL5 in response to irritation, and it was hypothesized that bile acids, when present in the colon, could be a potent trigger for this release.
The Cambridge team, based at the Institute of Metabolic Science, set out to rigorously investigate whether this observed link in mice translated to human physiology. Their investigation was significantly advanced by the availability of a novel antibody test, developed in collaboration with pharmaceutical company Eli Lilly. This sophisticated test enabled the researchers to accurately quantify minute quantities of INSL5 in biological samples.
Evidence from Human Studies: From Controlled Experiments to Patient Cohorts
The researchers first analyzed samples from a study conducted at the University of Adelaide. This earlier research aimed to explore ways to stimulate the release of glucagon-like peptide-1 (GLP-1), a hormone that forms the basis of many modern weight-loss medications. In that study, healthy volunteers were administered a bile acid enema. While the enema successfully triggered GLP-1 release, it also had the unintended consequence of inducing diarrhea.
Upon re-examining the samples from these volunteers, the Cambridge team made a crucial observation: the bile acid enema caused a transient but significant surge in INSL5 levels. Critically, they found a direct correlation between the magnitude of the INSL5 increase and the urgency and frequency with which the volunteers needed to defecate. This finding provided compelling initial evidence that INSL5 plays a role in acute diarrheal episodes triggered by bile acids.
Building upon this foundational discovery, the Cambridge researchers then turned their attention to patient cohorts. They obtained valuable samples from Professor Julian Walters at Imperial College London, which included specimens from individuals diagnosed with bile acid diarrhea. The results were striking. While INSL5 levels were found to be virtually undetectable in healthy control subjects, they were markedly elevated in patients with BAD. Furthermore, a direct relationship was observed between higher INSL5 concentrations and the water content of stool samples, indicating a stronger diarrheal effect.
Implications for Diagnosis: Towards a Reliable Blood Test
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. He elaborated on the diagnostic potential, adding, "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."
The current diagnostic pathway for chronic diarrhea typically involves ruling out common causes such as food intolerances, infections, or inflammatory bowel diseases. While the role of the gut microbiome has garnered considerable research attention, the intricate signaling pathways involving gut hormones have historically been less explored. Dr. Bannon emphasized the growing recognition of their importance, 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." The identification of INSL5 as a key mediator in BAD could finally bridge this gap, offering a more targeted and efficient diagnostic approach.
Therapeutic Horizons: Repurposing and Developing New Treatments
Beyond its diagnostic implications, the research into INSL5 opens promising avenues for therapeutic intervention. The study investigated the potential of ondansetron, an anti-sickness medication already in clinical use. Pre-clinical studies in mice had indicated that ondansetron could block the action of INSL5.
To test this hypothesis in humans, the Cambridge team analyzed samples from patients who had participated in a trial led by Professor Robin Spiller at the University of Nottingham. In this trial, patients with IBS had been treated with ondansetron. The Cambridge researchers discovered that approximately 40% of these patients exhibited elevated INSL5 levels, even though their cases had been screened and bile acid malabsorption had been ruled out. Crucially, these patients with high INSL5 levels showed the most significant improvement in their symptoms when treated with ondansetron.
While the precise mechanism by which ondansetron exerts its beneficial effect in this context remains under investigation, a known side effect of the drug is constipation. This observation suggests that by mitigating the stimulatory effect of INSL5, ondansetron might be effectively reducing the diarrhea. The research team is now focused on further elucidating this mechanism, with the ultimate goal of either repurposing ondansetron for the treatment of INSL5-related diarrhea or developing entirely new, more targeted therapies.
Current treatments for bile acid diarrhea primarily involve bile acid sequestrants. While effective for a majority of patients, these medications fail to provide relief for roughly one-third of individuals, underscoring the need for alternative or adjunctive therapies. The identification of INSL5 as a key mediator could lead to treatments that directly target this hormonal pathway, potentially offering relief to a broader patient population.
A Protective Mechanism with a Downside
Dr. Bannon offered an insightful perspective on the evolutionary purpose of a hormone that can induce diarrhea. He posited that INSL5 might function as a "poison sensor." Bile acids are not intended to reside in the colon; their presence there can be toxic to the delicate gut microbiome and act as a significant irritant. "It makes sense that you would have something that detects toxins and helps the body rid itself of them," Dr. Bannon explained. However, he cautioned that when this system is chronically triggered by the persistent presence of bile acids, it can lead to the development of severe and debilitating diarrheal symptoms.
This research was generously supported by grants from the Medical Research Council and Wellcome, with additional funding provided by the National Institute for Health and Care Research Cambridge Biomedical Research Centre. The collaborative efforts of researchers at the University of Cambridge, University of Adelaide, Imperial College London, and the University of Nottingham, alongside the support of Eli Lilly, underscore the multidisciplinary nature of modern scientific inquiry.
The findings represent a significant leap forward in understanding the complex pathophysiology of chronic diarrhea and IBS-D. The potential for a new diagnostic tool and targeted therapies offers a beacon of hope for millions worldwide who suffer from these often-misunderstood conditions, promising improved diagnostic accuracy and more effective treatment strategies in the near future.
