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 the complex mechanisms 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 Bile Acid Diarrhea
The digestive system is a marvel of biological engineering, with intricate processes designed to extract vital nutrients from the food we consume. A critical component of this process involves bile acids, produced by the liver to aid in the digestion and absorption of fats. Upon ingestion, bile acids are released into the upper regions of the small intestine. They then traverse the digestive tract, with the majority being efficiently reabsorbed back into the body in the lower sections of the small intestine. This carefully orchestrated cycle ensures that bile acids are available for ongoing fat digestion without overwhelming the downstream segments of the gut.
However, for approximately one in every 100 individuals, this crucial reabsorption process falters, leading to a condition known as bile acid diarrhea, or bile acid malabsorption (BAM). In BAM, a significant portion of bile acids bypasses their intended reabsorption pathway and continues into the large intestine, or colon. Here, these potent digestive agents act as irritants, triggering a cascade of inflammatory and secretory responses. The consequence is often the hallmark symptoms of BAM: urgent, watery diarrhea, and in severe cases, a distressing risk of incontinence.
The diagnostic landscape for BAM has historically been challenging. The absence of routine, accessible clinical blood tests means that many individuals experiencing these persistent and debilitating symptoms are often misdiagnosed or categorized under the broad umbrella of Irritable Bowel Syndrome (IBS). IBS itself is a complex gastrointestinal disorder affecting an estimated one in 20 people worldwide, characterized by a range of symptoms including abdominal pain, bloating, and altered bowel habits. Within the IBS population, a significant subgroup – estimated at one in three patients whose primary complaint is diarrhea – may actually be suffering from undiagnosed bile acid diarrhea. This diagnostic gap has left countless individuals without appropriate treatment, impacting their quality of life significantly.
The Role of Insulin-Like Peptide 5 (INSL5)
The current study builds upon earlier investigations that hinted at the involvement of a specific gut hormone, Insulin-Like Peptide 5 (INSL5), in the pathology of chronic diarrhea. Research conducted in animal models, specifically mice, had suggested that INSL5, predominantly found in specialized cells at the terminal end of the colon and rectum, might play a role in regulating gut function. These studies indicated that INSL5 is released by these cells when they are exposed to an irritant, such as bile acid.
The Cambridge-based research team, affiliated with the Institute of Metabolic Science at the University of Cambridge, set out to explore whether this potential link between INSL5 and chronic diarrhea extended to human physiology. A crucial enabler of their investigation was the development of a highly sensitive antibody test by pharmaceutical company Eli Lilly, with whom the researchers collaborated. This advanced assay allowed for the precise measurement of even minute quantities of INSL5 in biological samples, opening up new avenues for research that were previously inaccessible.
A Chronology of Discovery
The journey to identifying INSL5’s role was a multi-stage process, involving the analysis of data from several key studies:
Early Observations (Pre-Study): Previous research, notably a study at the University of Adelaide focusing on the gut hormone GLP-1 (the target of popular weight-loss medications), observed that administering a bile acid enema to healthy volunteers not only stimulated GLP-1 release but also, unexpectedly, induced diarrhea.
Cambridge Team’s Initial Analysis (Study Phase 1): Upon re-examining samples from the Adelaide study, the Cambridge researchers made a pivotal discovery. They found that the bile acid enema administration led to a temporary but significant surge in INSL5 levels. Crucially, they observed 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 acute diarrheal response triggered by bile acids.
Clinical Validation in Patients (Study Phase 2): To ascertain the relevance of these findings in human disease, the Cambridge team analyzed samples obtained from Professor Julian Walters at Imperial College London. These samples included individuals diagnosed with bile acid diarrhea. The results were striking. While INSL5 levels were virtually undetectable in healthy control subjects, they were markedly elevated in patients suffering from bile acid diarrhea. Furthermore, a direct relationship was identified between the magnitude of INSL5 elevation and the consistency of the stool samples, with higher INSL5 correlating with more watery stools. This phase provided robust clinical validation for INSL5’s involvement in the chronic diarrheal symptoms associated with BAM.
Investigating Therapeutic Potential (Study Phase 3): The potential of INSL5 as a therapeutic target emerged from an analysis of samples collected by Professor Robin Spiller at the University of Nottingham. Professor Spiller had been investigating the anti-sickness medication ondansetron in patients with IBS. Ondansetron is known to block the action of INSL5 in animal models. The Cambridge team’s analysis revealed that approximately 40% of these IBS patients, even those who had undergone testing and had bile acid malabsorption ruled out, exhibited elevated INSL5 levels. Significantly, these patients with elevated INSL5 showed the most favorable response to ondansetron treatment. This suggests that a subset of IBS patients, previously undiagnosed, may be suffering from a form of bile acid-induced diarrhea mediated by INSL5.
Supporting Data and Scientific Rationale
The scientific rationale behind INSL5’s role is rooted in its function as a "poison sensor." Bile acids, while essential for fat digestion, are potent irritants and can be toxic to the colonic epithelium and the delicate gut microbiome when present in excessive amounts. The presence of INSL5 in the distal colon and rectum suggests a role in detecting such noxious stimuli. When bile acids inappropriately reach these regions, they trigger the release of INSL5. This hormone, in turn, appears to orchestrate a physiological response aimed at expelling the irritant.
Dr. Chris Bannon, the study’s first author and a clinical fellow at the Institute of Metabolic Science, University of Cambridge, articulated this concept: "I often get asked why we would have a hormone that gives you diarrhea. 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."
The data supporting this hypothesis is compelling. The dose-dependent relationship between bile acid exposure, INSL5 elevation, and the speed of transit in volunteers, coupled with the significantly higher INSL5 levels in patients with bile acid diarrhea and their correlation with stool water content, provides a strong mechanistic link. The observation that a subset of IBS patients with elevated INSL5 responded well to ondansetron further solidifies INSL5’s role as a mediator of diarrheal symptoms in these individuals.
Implications for Diagnosis and Treatment
The findings of this study carry profound implications for both the diagnosis and treatment of chronic diarrhea.
A New Diagnostic Frontier: The INSL5 Blood Test
The identification of elevated INSL5 levels in patients with bile acid diarrhea, and its near-absence in healthy individuals, presents a significant opportunity for diagnostic advancement. "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," stated Dr. Bannon. "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."
Currently, diagnosing bile acid diarrhea often involves invasive procedures like the SeHCAT scan, which measures bile acid retention in the body over several days, or empirical trials of medication. A simple, accessible blood test measuring INSL5 could revolutionize diagnostic pathways. It could enable clinicians to rapidly identify patients with BAM, differentiating them from those with other forms of IBS or functional bowel disorders. This would not only lead to more accurate diagnoses but also expedite the initiation of appropriate treatment, alleviating patient suffering sooner.
Repurposing and Developing Novel Therapies
The study also highlights INSL5 as a promising therapeutic target. The observed efficacy of ondansetron in patients with elevated INSL5, even those without a formal BAM diagnosis, suggests that this anti-emetic drug could be repurposed to manage a specific subset of chronic diarrhea cases. While the exact mechanism by which ondansetron alleviates diarrhea in this context is still under investigation, a known side effect of the drug is constipation, which could counteract the diarrheal effects of INSL5.
"The team will now be investigating this further, hopeful that it will allow us either to repurpose the drug or to develop even better treatments," Dr. Bannon added. The development of novel therapies specifically designed to modulate INSL5 activity or block its downstream effects could offer more targeted and effective solutions for patients who do not respond to existing treatments. Current treatments for bile acid diarrhea, primarily bile acid sequestrants, are only effective in about two-thirds of patients, indicating a clear need for alternative or adjunctive therapies.
Broader Context and Future Directions
The research underscores a broader shift in our understanding of gastrointestinal health, emphasizing the often-overlooked importance of gut hormones. "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," Dr. Bannon remarked.
The findings are supported by substantial funding from leading research bodies, including the Medical Research Council and Wellcome, with additional support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre. This backing signifies the scientific community’s recognition of the potential impact of this research.
Looking ahead, further research will be crucial to fully elucidate the complex interplay between bile acids, INSL5, and the gut microbiome. Understanding the precise mechanisms by which INSL5 exerts its diarrheal effects, and how ondansetron intervenes, will be key to optimizing treatment strategies. The potential for a new diagnostic tool and novel therapeutic interventions offers a beacon of hope for the millions worldwide who suffer from the debilitating effects of chronic diarrhea, particularly those with undiagnosed bile acid diarrhea and IBS-D. The work by the Cambridge team marks a significant step forward in unraveling the mysteries of the gut and improving patient outcomes.