By Gilang Cahya 
A groundbreaking study led by scientists at the University of Cambridge has identified high levels of a specific gut hormone as a potential underlying cause for a significant proportion of chronic diarrhea cases, including up to 40% of patients diagnosed with irritable bowel syndrome with diarrhea (IBS-D). This discovery, published in the esteemed journal Gut, holds substantial promise for the development of a novel blood test for diagnosis and points towards new therapeutic avenues for a condition that profoundly impacts the quality of life for many.
Unraveling the Mystery of Bile Acid Diarrhea
The research delves into the complex mechanisms of digestion, specifically focusing on bile acids. These essential compounds, produced by the liver, are released into the upper small intestine to aid in the breakdown and absorption of dietary fats. Following their function, bile acids are typically reabsorbed in the lower part of the small intestine and returned to the liver for reuse. However, a condition known as bile acid diarrhea (BAD), or bile acid malabsorption, affects approximately 1 in 100 individuals. In these cases, the bile acids are not efficiently reabsorbed and consequently proceed into the large intestine (colon). This presence of unabsorbed bile acids in the colon acts as a potent irritant, triggering urgent, watery diarrhea and, in severe instances, leading to episodes of incontinence.
The diagnostic challenge for BAD has been significant, as there are currently no routine clinical blood tests available. This diagnostic void often leads to individuals experiencing chronic digestive distress being misdiagnosed or broadly categorized under the umbrella term of Irritable Bowel Syndrome (IBS). It is estimated that as many as one in 20 people suffer from IBS, a diverse group of gastrointestinal disorders. Within this population, a substantial proportion – an estimated one in three patients whose primary symptom is diarrhea – may be suffering from undiagnosed bile acid diarrhea. This means a considerable number of individuals are receiving management strategies for IBS that may not address the root cause of their symptoms.
The Role of Insulin-Like Peptide 5 (INSL5)
Previous research, primarily conducted in animal models, had hinted at a role for the gut hormone Insulin-Like Peptide 5 (INSL5) in the pathogenesis of chronic diarrhea. INSL5 is produced by specialized cells located at the distal end of the colon and in the rectum. Studies in mice indicated that these cells release INSL5 when irritated by the presence of bile acid. Building upon this foundational knowledge, researchers at the Institute of Metabolic Science at the University of Cambridge embarked on an investigation to ascertain whether this hormonal link extended to human cases of chronic diarrhea.
The critical enabler for this human study was the development of a highly sensitive antibody test by the pharmaceutical company Eli Lilly, with whom the Cambridge team collaborated. This advanced testing methodology allowed researchers to accurately quantify minuscule amounts of INSL5 circulating in biological samples, thereby unlocking the potential to explore its role in human gut disorders.
Chronology of Discovery and Key Findings
The journey to understanding INSL5’s role in chronic diarrhea unfolded through a series of meticulous investigations:
- Early Mouse Studies: Established a preliminary link between INSL5 release and gut irritation, particularly in the context of bile acid presence.
- University of Adelaide Study Analysis: A pivotal moment arrived when the Cambridge team analyzed samples from a previously conducted study at the University of Adelaide. This study aimed to investigate the release of the gut hormone GLP-1 (a hormone central to the mechanism of modern weight-loss drugs) by administering bile acid enemas to healthy volunteers. While the enema successfully triggered GLP-1 release, it also inadvertently caused diarrhea. The Cambridge researchers observed a striking correlation: the bile acid enema caused a temporary surge in INSL5 levels. Crucially, the magnitude of this INSL5 increase directly correlated with the urgency and speed with which the volunteers needed to defecate. This finding provided compelling evidence that INSL5 plays a significant role in the physiological response to bile acid exposure and, by extension, in the development of diarrhea.
- Imperial College London Patient Samples: The investigation then progressed to analyzing samples from patients with diagnosed bile acid diarrhea, obtained from Professor Julian Walters at Imperial College London. The results were stark and illuminating. While INSL5 levels were found to be virtually undetectable in healthy volunteers, they were significantly elevated in patients suffering from bile acid diarrhea. Furthermore, a direct correlation was observed between the elevated INSL5 levels and the fluidity of the stool samples, with higher INSL5 concentrations corresponding to more watery stools. This provided robust human evidence linking high INSL5 levels to the characteristic symptoms of bile acid diarrhea.
- Professor Robin Spiller’s IBS Patient Samples: Further exploration focused on patients diagnosed with IBS, a condition that often masks underlying BAD. Samples were obtained from Professor Robin Spiller at the University of Nottingham, who had been investigating the anti-sickness medication ondansetron in patients with IBS. Ondansetron is known to inhibit the action of INSL5 in mice. The Cambridge team’s analysis revealed that approximately 40% of these IBS patients exhibited elevated INSL5 levels, even though bile acid malabsorption had been ruled out through standard investigations. Significantly, these patients with elevated INSL5 levels showed the most pronounced improvement in symptoms when treated with ondansetron. This suggests that a subset of IBS-D patients may indeed have BAD driven by INSL5, even when traditional diagnostic pathways for BAD do not identify it.
Implications for Diagnosis and Treatment
The implications of this research are profound and multifaceted, offering a beacon of hope for individuals struggling with chronic digestive issues.
Development of a Diagnostic 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 considerable excitement 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." The development of a simple, routine blood test for INSL5 could revolutionize the diagnosis of BAD, enabling clinicians to identify the condition far more readily and accurately than current methods allow. This would bypass the current diagnostic odyssey many patients endure, leading to faster access to appropriate treatment and relief from debilitating symptoms.
A New Therapeutic Target
Beyond diagnostics, the research identifies INSL5 as a promising target for novel therapeutic interventions. The observed efficacy of ondansetron, a drug known to block INSL5, in a subset of IBS-D patients with elevated INSL5 levels, points towards a potential repurposing of existing medications or the development of entirely new drugs specifically designed to modulate INSL5 activity. While the precise mechanism by which ondansetron exerts its beneficial effects in these patients is still under investigation, its known side effect of constipation might offer a clue. The Cambridge team plans to conduct further research to elucidate these mechanisms, aiming to either optimize the use of ondansetron or develop more targeted and effective treatments.
Currently, the primary treatment for bile acid diarrhea involves bile acid sequestrants. While these medications are effective for approximately two-thirds of patients, a significant minority do not respond adequately. The identification of INSL5 as a contributing factor could open up new treatment avenues for these non-responders, potentially offering them relief where previous therapies have failed.
Understanding INSL5’s Biological Role
Dr. Bannon offered an insightful perspective on the biological function of INSL5, particularly in the context of causing 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 a crucial biological adaptation: the body’s innate mechanism to expel harmful substances. In BAD, this protective reflex is chronically activated by the misdirected presence of bile acids, leading to persistent and distressing diarrhea.
Broader Impact and Future Directions
The implications of this research extend beyond the immediate realm of bile acid diarrhea. Dr. Bannon’s observation that "gut hormones have been neglected" in research, despite their evident importance in gut health and weight management, underscores a broader paradigm shift in gastroenterological research. For years, the focus has been predominantly on the gut microbiome and inflammatory pathways. This study firmly places gut hormones back into the spotlight, suggesting that a deeper understanding of their intricate roles could unlock solutions for a wide array of digestive disorders.
The study was supported by significant funding from the Medical Research Council and Wellcome, with additional contributions from the National Institute for Health and Care Research Cambridge Biomedical Research Centre. This collaborative effort highlights the importance of sustained investment in fundamental scientific research to address complex health challenges.
The future research trajectory will likely involve further clinical trials to validate the diagnostic potential of INSL5 blood tests and to assess the efficacy and safety of INSL5-targeting therapies, including ondansetron and potentially novel drug candidates. Understanding the precise interplay between bile acids, INSL5, and the colonic environment is paramount. Moreover, exploring whether INSL5 plays a role in other forms of chronic diarrhea, beyond those explicitly linked to bile acid malabsorption, could broaden the impact of this discovery even further.
This discovery represents a significant leap forward in our understanding of chronic diarrhea and IBS-D, moving beyond symptom management to addressing a potential root cause. The prospect of a new diagnostic tool and novel treatment options offers renewed hope for millions worldwide who suffer from these often debilitating conditions.
