Scientists at the University of Cambridge have identified a gut hormone that may be responsible for many cases of chronic diarrhea, including up to 40% of cases in people with irritable bowel syndrome with diarrhea (IBS-D).
The discovery could lead to a simple blood test for diagnosis and even new treatments for this often-misunderstood condition. The research is published in the journal Gut.
When we eat, the liver produces bile acid to break down fats. This bile acid travels into the small intestine and is normally absorbed back into the body before it reaches the large intestine.
In about one in 100 people, this process doesn’t work properly.
This condition, known as bile acid diarrhea or bile acid malabsorption, allows bile acid to pass into the colon, where it can cause urgent and watery diarrhea, and sometimes incontinence.
Bile acid diarrhea is difficult to diagnose, as there are currently no routine clinical blood tests. Many patients are instead diagnosed with IBS, a broad term for various gut problems.
Around one in three IBS patients who have diarrhea as their main symptom may actually have undiagnosed bile acid diarrhea.
Earlier studies in mice suggested that a hormone called Insulin-Like Peptide 5 (INSL5), found in cells at the far end of the colon and rectum, is released when these cells are irritated by bile acids. INSL5 may trigger diarrhea as a way to flush out irritants.
The Cambridge team, working with pharmaceutical company Eli Lilly, used a new antibody test to measure very small amounts of INSL5 in human samples.
They first analyzed samples from a University of Adelaide study in which volunteers were given a bile acid enema. This caused a spike in INSL5 levels, and the higher the spike, the faster participants needed to use the toilet. This strongly suggested that INSL5 plays a role in diarrhea.
Next, the researchers examined samples from patients with confirmed bile acid diarrhea, provided by Imperial College London. They found almost no INSL5 in healthy volunteers, but much higher levels in patients. The higher the INSL5, the more watery their stools were.
Dr Chris Bannon, first author of the study, said the findings open the door to a possible diagnostic blood test. If INSL5 levels are consistently high only in people with bile acid diarrhea, testing for it could help identify patients who would benefit from targeted treatments.
INSL5 might also be a treatment target. The researchers analyzed samples from a University of Nottingham study where patients with IBS were given ondansetron, a medication used for nausea that also blocks INSL5 in mice.
They found that about 40% of these patients had high INSL5 levels, even without bile acid malabsorption, and these patients responded best to the drug. While the reason ondansetron works isn’t fully clear, constipation is a known side effect, suggesting it counteracts diarrhea.
Bile acid diarrhea is usually treated with bile acid sequestrants, but these work for only about two-thirds of patients. The team hopes their findings could lead to more effective options, either by repurposing ondansetron or developing new drugs to target INSL5.
Dr Bannon explained that INSL5 may act like a “poison sensor.” Since bile acids are toxic to the colon and its microbiome, the body may use INSL5 to detect their presence and trigger diarrhea to flush them out. But in bile acid diarrhea, this system is overactivated, causing severe symptoms.
This study highlights an important but overlooked role of gut hormones in chronic diarrhea. The link between INSL5 and bile acid diarrhea offers both a promising diagnostic marker and a potential drug target.
If confirmed in further studies, a simple blood test for INSL5 could transform diagnosis rates, while drugs that block its action could give relief to patients who do not respond to current treatments. This discovery also reinforces the idea that gut health is shaped not only by bacteria and diet but also by hormones that regulate intestinal function.
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The study is published in Gut.
