Levels of insulin-like peptide 5, a hormone secreted by L cells in the distal colon and rectum, were significantly elevated in patients with bile acid diarrhoea and a subset of those with irritable bowel syndrome with diarrhoea, according to a multicenter study.
Insulin-like peptide 5 (INSL5) concentrations correlated with stool consistency and urgency assessed by Bristol Stool Form Score and visual analogue scale measures, suggesting a role in the pathophysiology of chronic diarrhoea.
In healthy volunteers (n=7), a rectal enema containing 3,500 mg taurocholic acid triggered a twofold to threefold increase in INSL5 within 10 minutes, which declined over the next hour. This effect was not observed with placebo. All patients receiving 3,500 mg taurocholic acid defecated within 100 minutes, compared with 5 of 7 receiving 1,500 mg and none receiving placebo. The increase in INSL5 was negatively correlated with time to defecation (r²=0.34) and positively associated with the desire to defecate.
Among patients with bile acid diarrhoea (BAD) (n=19), 17 had fasting INSL5 levels more than 100 pg/mL. In contrast, levels in healthy volunteers (n=10) were typically less than 100 pg/mL, with many below the assay's detection limit of 50 pg/mL. INSL5 concentrations were significantly higher in patients with primary BAD (p_adj=0.008) and secondary BAD (p_adj<0.001) compared with healthy patients. INSL5 levels also correlated with average Bristol Stool Form Score (r²=0.33).
In the TRITON study cohort (n=64), 42% of patients with irritable bowel syndrome with diarrhoea had INSL5 levels more than 100 pg/mL. These patients experienced greater improvement in stool consistency after ondansetron treatment. An ANCOVA model showed a significant interaction between treatment group and INSL5 level, indicating that INSL5 may predict therapeutic response. No similar interaction was observed for peptide YY (PYY).
Fasting INSL5 correlated with PYY (r²=0.33), but not with glucagon-like peptide 1 (r²<0.01). INSL5 levels did not increase postprandially, unlike PYY and glucagon-like peptide 1, supporting the hypothesis that INSL5 secretion is driven by rectal exposure to luminal stimuli such as bile acids rather than food intake.
Validation using liquid chromatography–tandem mass spectrometry confirmed that the immunoassay accurately measured INSL5. These findings suggest that INSL5 may be involved in promoting colonic motility and may help identify patients likely to respond to 5-HT₃ receptor antagonists like ondansetron.
“This is the first study to explore INSL5 levels in patients with chronic diarrhoea,” wrote lead author Christopher A. Bannon of the Institute of Metabolic Science, Cambridge, United Kingdom, and colleagues. “It highlights that delivery of bile acids to the rectum stimulates INSL5 release and is associated with a defecation response.”
Further studies are needed to determine whether INSL5 directly contributes to diarrhoea severity and to evaluate its clinical utility in managing patients with chronic diarrhoea.
Full disclosures can be found in the published study.
Source: Gut