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 pave the way for a new blood test and points towards a potential novel treatment strategy for a significant patient population currently struggling with debilitating digestive issues.
Unraveling the Mystery of Chronic Diarrhea
The digestive system is a complex and finely tuned ecosystem responsible for processing food, absorbing nutrients, and eliminating waste. A crucial component of this process involves bile acids, produced by the liver to aid in the digestion of fats. These bile acids are secreted into the upper regions of the small intestine and are designed to be efficiently reabsorbed in the lower parts of the small intestine. However, a condition known as bile acid diarrhea (BAD), also referred to as bile acid malabsorption, affects approximately 1% of the global population. In individuals with BAD, this reabsorption process is impaired, leading to an excess of bile acids entering the large intestine (colon). This influx acts as a potent irritant, triggering urgent, watery diarrhea and, in severe cases, can lead to episodes of incontinence, significantly impacting a patient’s quality of life.
The diagnostic challenge for BAD has been considerable. Currently, there are no routine clinical blood tests available to definitively identify the condition. This diagnostic vacuum often leads to individuals experiencing chronic diarrhea being misdiagnosed or categorized under the broad umbrella term of Irritable Bowel Syndrome (IBS). IBS itself is a common functional gastrointestinal disorder, estimated to affect as many as one in 20 people worldwide. Within the IBS spectrum, a significant subgroup experiences diarrhea as their primary symptom. It is within this group that the Cambridge study suggests a substantial portion, potentially up to one in three of those with diarrhea-predominant IBS, may actually be suffering from undiagnosed bile acid diarrhea.
The Emerging Role of Insulin-Like Peptide 5 (INSL5)
Previous research, primarily conducted in animal models, had begun to implicate a gut hormone called Insulin-Like Peptide 5 (INSL5) in the regulation of bowel function. INSL5 is produced by specialized cells located at the distal end of the colon and in the rectum. These cells have been observed to release INSL5 in response to irritation. A key hypothesis emerging from these preclinical studies was that INSL5 might be released when these cells are exposed to bile acids, suggesting a direct link between bile acid malabsorption and the hormone’s activity.
The University of Cambridge’s Institute of Metabolic Science team, collaborating with pharmaceutical company Eli Lilly, embarked on a mission to investigate whether this preclinical observation held true for human patients. The breakthrough in their research was the availability of a novel antibody test developed by Eli Lilly, which possesses the sensitivity to detect and quantify even minute quantities of INSL5. This technological advancement provided the crucial tool needed to explore the hormone’s role in human gastrointestinal disorders.
A Chronological Unveiling of Evidence
The study’s investigative journey began with an analysis of samples from a prior study conducted at the University of Adelaide. This earlier research aimed to understand the release mechanisms of another important gut hormone, Glucagon-Like Peptide-1 (GLP-1), which is the basis for several widely used weight-loss medications. In that study, healthy volunteers were administered a bile acid enema. While the enema successfully stimulated GLP-1 release, it also unexpectedly induced diarrhea.
When the Cambridge researchers examined the blood samples collected during this Adelaide study, they discovered a striking correlation. The administration of the bile acid enema led to a temporary but significant surge in INSL5 levels. Crucially, the magnitude of this INSL5 increase directly correlated with the speed at which the volunteers experienced the urge to defecate. This observation provided compelling initial evidence that INSL5 plays a role in the physiological response to bile acid in the colon, and likely contributes to the diarrhea experienced in such situations.
Building upon this foundational finding, the Cambridge team then procured samples from patients diagnosed with bile acid diarrhea, kindly provided by Professor Julian Walters at Imperial College London. The results from this patient cohort were even more illuminating. While INSL5 levels were found to be virtually undetectable in healthy volunteers, they were markedly elevated in individuals suffering from bile acid diarrhea. Furthermore, the analysis revealed a direct relationship between the level of INSL5 and the severity of diarrhea, with higher INSL5 concentrations correlating with more watery stool samples. This established a clear link between elevated INSL5 and the pathological state of bile acid diarrhea in humans.
Implications for Diagnosis and Treatment
The implications of these findings are far-reaching, particularly in the realm of clinical diagnostics. Dr. Chris Bannon, the study’s first author and a clinical fellow at the Institute of Metabolic Science, University of Cambridge, expressed his enthusiasm for the discovery. "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."
The current diagnostic pathway for chronic diarrhea typically involves ruling out more common culprits such as food intolerances, infections, or inflammatory bowel diseases. While there has been immense scientific focus on the gut microbiome, the role of gut hormones in gastrointestinal health has historically received less attention. However, Dr. Bannon emphasized the growing recognition of their importance: "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 identification of INSL5 as a key player in bile acid diarrhea also opens up exciting avenues for therapeutic intervention. The research team explored this possibility by analyzing samples from patients participating in a study led by Professor Robin Spiller at the University of Nottingham. In this earlier study, patients with IBS had been treated with ondansetron, an anti-sickness medication known to block the action of INSL5 in mice. The Cambridge team’s analysis of these samples revealed that approximately 40% of these patients exhibited elevated INSL5 levels, even though they had previously undergone testing that ruled out bile acid malabsorption. More significantly, these patients with raised INSL5 levels demonstrated the most substantial improvement in their symptoms when treated with ondansetron.
A New Therapeutic Horizon
While the precise mechanism by which ondansetron exerts its beneficial effects in these patients is still under investigation, a known side effect of the drug is constipation. This observation suggests a potential mechanism through which INSL5 blockade could alleviate diarrhea. The Cambridge team plans to further investigate this aspect, with the hope of either repurposing ondansetron for the treatment of specific subtypes of chronic diarrhea or developing entirely new therapeutic agents that target INSL5 more specifically.
Current treatments for bile acid diarrhea primarily involve the use of bile acid sequestrants, medications designed to bind to excess bile acids in the gut. However, these treatments are only effective in about two-thirds of patients, leaving a considerable proportion without adequate relief. The prospect of a treatment that targets the underlying hormonal mechanism, as suggested by the INSL5 findings, offers a promising alternative for those who do not respond to existing therapies.
Understanding the "Poison Sensor"
Dr. Bannon offered an insightful perspective on the biological purpose of a hormone that, at elevated levels, appears to induce diarrhea. "I often get asked why we would have a hormone that gives you diarrhea," he explained. "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 "poison sensor" analogy highlights how INSL5 might represent an evolutionary adaptation to expel harmful substances from the gut, which can become dysregulated in conditions like bile acid diarrhea.
Supporting Data and Future Directions
The study’s findings are bolstered by several key pieces of supporting data:
- Prevalence of Undiagnosed BAD: The estimate that up to one in three patients with diarrhea-predominant IBS may have undiagnosed BAD suggests a substantial unmet medical need, potentially affecting millions of individuals worldwide.
- Correlation Strength: The direct correlation between higher INSL5 levels and the severity of diarrhea (more watery stools) in patients with BAD provides robust quantitative evidence of the hormone’s role.
- Treatment Efficacy: The observation that approximately 40% of IBS patients with elevated INSL5 responded well to ondansetron, a drug that blocks INSL5 action, strongly supports the hormone as a therapeutic target.
The research was supported by significant funding bodies, including the Medical Research Council and Wellcome, with additional contributions from the National Institute for Health and Care Research Cambridge Biomedical Research Centre. This multidisciplinary and well-funded approach underscores the importance and potential impact of this line of research.
Broader Impact and Future Research
The implications of this study extend beyond the immediate diagnosis and treatment of bile acid diarrhea. It signifies a paradigm shift in understanding the complex interplay between gut hormones, bile acid metabolism, and the manifestation of chronic digestive disorders.
Diagnostic Advancement: The development of a blood test for INSL5 could revolutionize the diagnosis of chronic diarrhea. Currently, a lengthy and often frustrating diagnostic journey is common for patients. A simple blood test could expedite diagnosis, reduce misdiagnosis of IBS, and allow for earlier and more targeted treatment. This could alleviate significant patient suffering and reduce healthcare costs associated with prolonged diagnostic workups.
Therapeutic Innovation: The identification of INSL5 as a therapeutic target opens doors for the development of novel drugs. Beyond repurposing ondansetron, future research could focus on developing highly specific INSL5 antagonists or modulators that offer improved efficacy and fewer side effects than existing treatments. This could lead to personalized treatment strategies based on an individual’s hormonal profile.
Understanding IBS Subtypes: The study suggests that INSL5 may be a biomarker for a specific subtype of IBS with diarrhea, potentially helping to stratify patients and tailor treatments more effectively. This aligns with the broader scientific push towards a more personalized and precision-based approach to medicine.
Interdisciplinary Collaboration: The success of this research highlights the critical importance of interdisciplinary collaboration between academic institutions, pharmaceutical companies, and clinical researchers. The development of novel assays and the sharing of patient data were instrumental in achieving these groundbreaking results.
Looking ahead, Dr. Bannon and his colleagues at the Institute of Metabolic Science, under the leadership of Professors Fiona Gribble and Frank Reimann, are poised to continue their investigations. Their ongoing work will likely focus on refining the diagnostic capabilities, exploring the detailed mechanisms of INSL5 action in the colon, and rigorously evaluating the therapeutic potential of targeting this newly identified gut hormone. This research promises to bring much-needed clarity and effective solutions to the millions who suffer from chronic diarrhea and related gastrointestinal conditions.
