Discovery of role of gut hormone in chronic diarrhea could aid development of new tests and treatments

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 help in the development of a blood test and points toward a potential new treatment.

When we eat, the liver releases bile acid to break down fats so that they can be absorbed into the body. Bile acid is released into the top end of the small intestine and then absorbed back into the body at the lower end.

However, around one person in every 100 is affected by a condition known as bile acid diarrhea (also known as bile acid malabsorption), whereby the bile acid is not properly re-absorbed and makes its way into the large intestine (colon). It can trigger urgent and watery diarrhea, and patients can risk episodes of incontinence.

Bile acid diarrhea can be difficult to diagnose as there are currently no routine clinical blood tests. Many individuals are given a diagnosis of irritable bowel syndrome (IBS), an umbrella term for a range of conditions. As many as one in 20 people are thought to have IBS, of which an estimated one in three patients with diarrhea as their main symptom have undiagnosed bile acid diarrhea.

Studies in mice have previously suggested that the gut hormone known as insulin-like peptide 5 (INSL5)—present in cells at the far end of the colon and rectum—may play a role in chronic diarrhea. INSL5 is released by these cells when irritated by bile acid.

Researchers at the Institute of Metabolic Science, University of Cambridge, have been exploring whether this hormone might also underlie chronic diarrhea in humans. This has been possible thanks to a new antibody test developed by pharmaceutical company Eli Lilly, with whom the team is collaborating, which allows them to measure tiny amounts of INSL5.

A study at the University of Adelaide looking at ways to trigger the release of the gut hormone GLP-1—the hormone upon which weight-loss drugs are based—previously found that giving a bile acid enema to healthy volunteers triggered the release of GLP-1, but had the unintended consequence of causing diarrhea.

When the Cambridge team analyzed samples from this study, they found that the bile acid enema caused levels of INSL5 to shoot up temporarily—and the higher the INSL5 levels, the faster the volunteers needed to use the toilet. This confirmed that INSL5 is likely to play a role in chronic cases of diarrhea.

When the team analyzed samples obtained from Professor Julian Walters at Imperial College London, which included samples from patients with bile acid diarrhea, they found that while levels of INSL5 were almost undetectable in healthy volunteers, they were much higher in patients with bile acid diarrhea. In addition, the higher the INSL5 level, the more watery their stool samples.

Dr. Chris Bannon from the University of Cambridge, the study’s first author, said, “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. 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.

“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.”

INSL5 also provides a potential target for treatment. Dr. Bannon and colleagues obtained further samples from Professor Robin Spiller at the University of Nottingham, who had given the anti-sickness medication ondansetron—known to block the action of INSL5 in mice—to patients with IBS.

Analysis of these samples by the Cambridge team showed that around 40% of these patients had raised levels of INSL5, even though they had had bile acid malabsorption ruled out, and these patients responded best to ondansetron.

Exactly why ondansetron is effective is currently unclear, though a known side effect of the drug is constipation. The team will now be investigating this further, hopeful that it will allow them either to repurpose the drug or to develop even better treatments. Bile acid diarrhea is usually treated with so-called bile acid sequestrants, but these are only effective in around two-thirds of patients.

Dr. Bannon added, “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.”

Dr. Bannon is a clinical fellow in the group led by Professors Fiona Gribble and Frank Reimann at the Institute of Metabolic Science, University of Cambridge.

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 help in the development of a blood test and points toward a potential new treatment.

When we eat, the liver releases bile acid to break down fats so that they can be absorbed into the body. Bile acid is released into the top end of the small intestine and then absorbed back into the body at the lower end.

However, around one person in every 100 is affected by a condition known as bile acid diarrhea (also known as bile acid malabsorption), whereby the bile acid is not properly re-absorbed and makes its way into the large intestine (colon). It can trigger urgent and watery diarrhea, and patients can risk episodes of incontinence.

Bile acid diarrhea can be difficult to diagnose as there are currently no routine clinical blood tests. Many individuals are given a diagnosis of irritable bowel syndrome (IBS), an umbrella term for a range of conditions. As many as one in 20 people are thought to have IBS, of which an estimated one in three patients with diarrhea as their main symptom have undiagnosed bile acid diarrhea.

Studies in mice have previously suggested that the gut hormone known as insulin-like peptide 5 (INSL5)—present in cells at the far end of the colon and rectum—may play a role in chronic diarrhea. INSL5 is released by these cells when irritated by bile acid.

Researchers at the Institute of Metabolic Science, University of Cambridge, have been exploring whether this hormone might also underlie chronic diarrhea in humans. This has been possible thanks to a new antibody test developed by pharmaceutical company Eli Lilly, with whom the team is collaborating, which allows them to measure tiny amounts of INSL5.

A study at the University of Adelaide looking at ways to trigger the release of the gut hormone GLP-1—the hormone upon which weight-loss drugs are based—previously found that giving a bile acid enema to healthy volunteers triggered the release of GLP-1, but had the unintended consequence of causing diarrhea.

When the Cambridge team analyzed samples from this study, they found that the bile acid enema caused levels of INSL5 to shoot up temporarily—and the higher the INSL5 levels, the faster the volunteers needed to use the toilet. This confirmed that INSL5 is likely to play a role in chronic cases of diarrhea.

When the team analyzed samples obtained from Professor Julian Walters at Imperial College London, which included samples from patients with bile acid diarrhea, they found that while levels of INSL5 were almost undetectable in healthy volunteers, they were much higher in patients with bile acid diarrhea. In addition, the higher the INSL5 level, the more watery their stool samples.

Dr. Chris Bannon from the University of Cambridge, the study’s first author, said, “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. 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.

“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.”

INSL5 also provides a potential target for treatment. Dr. Bannon and colleagues obtained further samples from Professor Robin Spiller at the University of Nottingham, who had given the anti-sickness medication ondansetron—known to block the action of INSL5 in mice—to patients with IBS.

Analysis of these samples by the Cambridge team showed that around 40% of these patients had raised levels of INSL5, even though they had had bile acid malabsorption ruled out, and these patients responded best to ondansetron.

Exactly why ondansetron is effective is currently unclear, though a known side effect of the drug is constipation. The team will now be investigating this further, hopeful that it will allow them either to repurpose the drug or to develop even better treatments. Bile acid diarrhea is usually treated with so-called bile acid sequestrants, but these are only effective in around two-thirds of patients.

Dr. Bannon added, “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.”

Dr. Bannon is a clinical fellow in the group led by Professors Fiona Gribble and Frank Reimann at the Institute of Metabolic Science, University of Cambridge.