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Introduction Insulin like peptide-5 (INSL5) is a gut hormone expressed in the ‘L cells’ of the distal colon and rectum. Our recent publication in Gut 1 highlighted that rectal delivery of bile acids to the colon stimulates INSL5 secretion, and that INSL5 levels are raised in bile acid diarrhoea (BAD) and are associated with diarrhoea severity. INSL5 is also raised in a subset of patients with irritable bowel syndrome with diarrhoea (IBS-D), who show additional symptom benefit with ondansetron.Pre-clinical models have confirmed that INSL5 is pro-motility with its actions blocked by 5-HT3 receptor antagonism. Bile acids and short chain fatty acids (SCFAS) are secretagogues of INSL5 in primary culture cell culture models.In this study we have further characterised INSL5 levels in serum or plasma samples from healthy volunteers, patients with BAD and patients with IBS-D.Methods INSL5 levels were measured in prospectively collected samples and retrospectively collected samples from previously published studies. INSL5 was measured via immunoassay using Eli Lilly provided antibodies with a sensitivity of 50 pg/mL.100pg/mL was deemed as a significant symptom cut off for ‘high or low’ INSL5 level as per previously published study.1Results A cohort of patients investigated for BAD, in patients with confirmed BAD (retention <15%, n=60), INSL5 is above 100 pg/ml is ~50% of participants, and ~33% of participants with IBS-D (n=125) who have had an investigation to assess for BAD. INSL5 is also raised in a small case series of patients with diarrhoea with beta thyroid hormone resistance (n=4), who have had SeHCAT confirmed BAD.In healthy volunteers with a validated normal bowel habit (n=25), INSL5 is below 100 pg/mL in ~90% of participants.Of those samples with a connected bowel habit chart (n=100), there is a significant positive association of INSL5 level with Bristol stool form consistency – higher INSL5 is associated with looser stool type.In samples from patients with IBS-D and a connected stool sample, stool volatome analysis identified acetate as being raised in participants with raised INSL5 (>100 pg/ml).Further sample collection and analysis is ongoing.Discussion These results further explore and validate INSL5 as having an association with symptoms in patients with BAD and a subset of patients with IBS-D. We postulate that INSL5 is a biomarker of luminal colonic irritants including bile acids and SCFAs and further work is planned to validate INSL5 as a biomarker for predicting treatment response with ondansetron.Reference Bannon, et al. Gut. doi: 10.1136/gutjnl-2025-335393Abstract P405 Figure 1