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. This groundbreaking research, published in the esteemed journal Gut, not only sheds light on a significant cause of gastrointestinal distress but also paves the way for the development of a novel blood test for diagnosis and points towards promising new therapeutic avenues.
Unraveling the Mystery of Chronic Diarrhea
For millions worldwide, chronic diarrhea is a debilitating condition that significantly impacts quality of life. Often, the underlying cause remains elusive, leading to prolonged diagnostic journeys and a lack of targeted treatment. Irritable Bowel Syndrome with Diarrhea (IBS-D), a common functional gastrointestinal disorder, frequently encompasses patients whose symptoms may stem from unaddressed physiological issues rather than solely the complex interplay of gut bacteria and motility typically associated with IBS. This new study suggests that a specific gut hormone, Insulin-Like Peptide 5 (INSL5), may be a key player in a substantial portion of these unexplained cases.
The journey of digestion involves a sophisticated process where the liver releases bile acids into the upper small intestine to aid in the breakdown and absorption of fats. These bile acids are then intended to be efficiently reabsorbed in the lower part of the small intestine, preventing them from reaching the large intestine. However, in approximately 1% of the population, this reabsorption process is impaired, leading to a condition known as bile acid diarrhea (BAD) or bile acid malabsorption. When bile acids spill into the colon, they act as irritants, triggering urgent, watery diarrhea, and in severe cases, can lead to involuntary fecal leakage, a deeply distressing symptom with significant social and psychological ramifications.
Diagnosing BAD has historically been a challenge. The absence of routine clinical blood tests has meant that many individuals suffering from BAD are misdiagnosed with IBS-D. Current estimates suggest that up to one in three individuals diagnosed with IBS-D may actually be experiencing undiagnosed BAD. This diagnostic gap leaves a significant number of patients without access to the most effective treatments, perpetuating their discomfort and health concerns.
The Role of INSL5: A New Suspect Emerges
Previous research in animal models had hinted at the involvement of INSL5, a hormone produced by specialized cells located in the distal colon and rectum. These studies indicated that INSL5 could be released in response to irritation within the gut, and importantly, that bile acids were a potential trigger. Building upon this foundational work, researchers at the Institute of Metabolic Science at the University of Cambridge embarked on a mission to investigate whether INSL5 plays a similar, crucial role in chronic diarrhea experienced by humans.
The advancement of scientific inquiry in this area was significantly bolstered by the development of a new, highly sensitive antibody test by pharmaceutical giant Eli Lilly. This collaboration allowed the Cambridge team to accurately measure minute quantities of INSL5 in biological samples, a crucial step in validating their hypothesis.
Chronology of Discovery: From Mice to Humans
The investigation into INSL5’s role in human diarrhea began with an analysis of samples from a prior study conducted at the University of Adelaide. This earlier research focused on stimulating the release of Glucagon-Like Peptide-1 (GLP-1), a gut hormone that forms the basis of many modern weight-loss medications. In that study, healthy volunteers were administered a bile acid enema, which successfully triggered GLP-1 release but, unexpectedly, also induced diarrhea.
When the Cambridge team revisited these samples, they made a pivotal discovery. They observed that the bile acid enema caused a temporary but significant surge in INSL5 levels. Crucially, they found a direct correlation: the higher the INSL5 levels, the more immediate and urgent the volunteers’ need to defecate. This finding provided compelling evidence that INSL5 is indeed implicated in the physiological response to bile acid overload and likely contributes to acute diarrheal episodes.
The next critical phase involved examining samples from patients with diagnosed bile acid diarrhea. These samples were obtained from Professor Julian Walters at Imperial College London, a leading expert in gastrointestinal disorders. The results were striking. While INSL5 levels were virtually undetectable in healthy control subjects, they were significantly elevated in patients suffering from bile acid diarrhea. Furthermore, the degree of INSL5 elevation directly corresponded to the severity of their symptoms, with higher INSL5 levels correlating with more watery stool samples.
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 about these findings. "This was a very exciting discovery because it revealed that this hormone could be a major contributor to the symptoms of this often misunderstood condition," he stated. "It also opened up the possibility of developing a blood test to help diagnose bile acid diarrhea, provided that INSL5 levels are indeed uniquely elevated in these individuals."
Dr. Bannon further elaborated on the current diagnostic landscape, highlighting the limitations of existing approaches. "When you present to your doctor with chronic diarrhea, the typical investigations involve testing for food intolerances, ruling out infections, or looking for signs of inflammation. While there has been considerable research interest in the gut microbiome, gut hormones have historically been overlooked. However, it is becoming increasingly evident that gut hormones play a vital role in numerous aspects of gut health and metabolic regulation, including weight management."
Implications for Diagnosis and Treatment
The identification of INSL5 as a potential biomarker for bile acid diarrhea has profound implications for diagnostic practices. A readily accessible blood test measuring INSL5 levels could revolutionize the way BAD is identified. This would not only streamline the diagnostic process, saving patients from prolonged periods of uncertainty and misdiagnosis, but also ensure they receive timely and appropriate treatment.
The research also offers a beacon of hope for improved therapeutic strategies. INSL5 itself presents a potential target for novel treatments. In a further exploration of INSL5’s role, Dr. Bannon and his colleagues analyzed samples from patients who had participated in a study led by Professor Robin Spiller at the University of Nottingham. In that study, patients with IBS had been treated with ondansetron, an anti-sickness medication known to inhibit INSL5 activity in mice.
The Cambridge team’s analysis revealed that approximately 40% of these IBS patients exhibited elevated INSL5 levels, even though their BAD had been ruled out through conventional means. Importantly, these patients with high INSL5 levels demonstrated the most significant improvement in their symptoms when treated with ondansetron. This suggests that a subset of IBS-D patients may have an underlying INSL5-driven diarrheal mechanism that can be effectively managed with existing or repurposed medications.
While the precise mechanism by which ondansetron exerts its beneficial effects in this context is still under investigation, a known side effect of the drug is constipation. This paradoxical effect, in a condition characterized by diarrhea, warrants further detailed study. The Cambridge team is now actively pursuing this line of research, with the ultimate goal of either repurposing ondansetron for a broader patient population or developing even more targeted and effective treatments based on their understanding of INSL5’s function.
Current treatments for bile acid diarrhea primarily involve bile acid sequestrants. While effective for many, these medications only provide relief for about two-thirds of patients, leaving a substantial portion of individuals with persistent symptoms. The potential of targeting INSL5 offers a promising alternative or adjunctive therapy for those who do not respond to current treatments.
Dr. Bannon offered an insightful perspective on the evolutionary role of a hormone that can induce diarrhea. "I am often asked why we would have a hormone that causes diarrhea," he explained. "I tend to think of it as a kind of poison sensor. Bile acids are not meant to be present in the colon; they are irritants and can be toxic to the gut microbiome. It makes biological sense to have a mechanism that detects such toxins and helps the body eliminate them. However, a problem arises when this system is constantly triggered by bile acid, leading to persistent and severe symptoms."
Broader Impact and Future Directions
The implications of this research extend beyond the immediate benefits for patients suffering from chronic diarrhea and IBS-D. It underscores the critical, yet often underappreciated, role of gut hormones in maintaining gastrointestinal health and overall well-being. As our understanding of the complex signaling pathways within the gut deepens, new avenues for addressing a wide range of digestive and metabolic disorders are likely to emerge.
The successful identification and validation of INSL5’s role represent a significant advancement in the field of gastroenterology. The collaborative efforts between academic institutions like the University of Cambridge and pharmaceutical companies like Eli Lilly highlight the power of translational research in bringing scientific discoveries from the laboratory bench to the patient’s bedside.
Future research will undoubtedly focus on refining the INSL5 blood test for clinical use, establishing clear diagnostic thresholds, and conducting larger clinical trials to evaluate the efficacy and safety of INSL5-targeted therapies. Understanding the precise molecular mechanisms through which INSL5 influences gut motility and fluid secretion will be crucial for developing next-generation treatments.
This pioneering work, supported by prestigious bodies such as the Medical Research Council, Wellcome, and the National Institute for Health and Care Research Cambridge Biomedical Research Centre, marks a pivotal moment in the ongoing quest to unravel the complexities of chronic gastrointestinal disorders. By illuminating the role of INSL5, scientists are not only offering relief to those suffering from debilitating diarrhea but also charting a new course for the future of digestive health. The potential to transform the lives of millions through improved diagnostics and targeted treatments is now within closer reach, driven by a deeper understanding of the intricate hormonal symphony orchestrated within our gut.
