Researchers have identified a key gut hormone, Insulin-Like Peptide 5 (INSL5), that appears to play a major role in up to 40% of cases of chronic diarrhea, including a poorly understood condition known as bile acid diarrhea. This discovery, published in the journal Gut, could pave the way for a simple blood test for diagnosis and, crucially, new therapeutic approaches to a condition often misdiagnosed as irritable bowel syndrome (IBS).
The Biology of Bile Acid Diarrhea
The digestive process involves the release of bile acids by the liver to break down fats. Normally, these acids are reabsorbed in the small intestine. However, in roughly 1% of the population, this reabsorption fails, causing bile acids to reach the large intestine (colon), triggering urgent, watery diarrhea and sometimes incontinence. Diagnosing this condition is currently challenging due to the lack of routine clinical tests; many sufferers are incorrectly labeled with IBS.
The Role of INSL5
Studies in mice suggested that the gut hormone INSL5 is released when bile acids irritate cells in the colon and rectum. Researchers at the University of Cambridge, in collaboration with Eli Lilly, developed a new antibody test to measure this hormone in humans. Experiments involving bile acid enemas in healthy volunteers confirmed that higher INSL5 levels correlate with increased urgency to defecate.
Analysis of patient samples from Imperial College London revealed that individuals with confirmed bile acid diarrhea had significantly elevated INSL5 levels compared to healthy controls. The higher the INSL5 level, the more watery their stool. This confirms that INSL5 is not just correlated with chronic diarrhea, but likely causes it.
Implications for IBS and Existing Treatments
The study also examined patients diagnosed with IBS who did not respond to standard treatments. Results showed that roughly 40% of these patients had elevated INSL5 levels, even after ruling out bile acid malabsorption. Interestingly, these patients responded favorably to ondansetron, an anti-sickness medication known to block INSL5 activity in mice.
While the exact mechanism is unclear, the team believes that INSL5 acts as a “poison sensor,” triggering the body to rid itself of irritating bile acids. Current treatments for bile acid diarrhea (bile acid sequestrants) only work about two-thirds of the time. The discovery of INSL5 opens up the possibility of repurposing existing drugs like ondansetron or developing new, more effective therapies.
The Cambridge team plans further investigation to clarify the exact role of ondansetron and optimize treatment strategies. This research marks a significant step toward understanding and managing chronic diarrhea, potentially improving the lives of millions affected by this often-misunderstood condition.
