BACKGROUND AND AIMSDietary fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) contribute to gastrointestinal (GI) symptoms in individuals with FODMAP sensitivity and/or irritable bowel syndrome (IBS). Oral enzyme supplementation is a strategy to reduce dietary FODMAP exposure and limit FODMAP-associated GI distress. This clinical trial investigated the safety of dietary supplementation with a food-grade, microbial inulinase known to hydrolyze fructan-type or inulin-type FODMAPs and related fructo-oligosaccharides (FOS) in vitro. METHODSA randomized, double-blind, placebo-controlled, parallel design trial was conducted in 60 healthy adult participants of both sexes. Following a 2-week run-in placebo phase, participants were randomized to consume inulinase or placebo capsules twice daily with meals for 4 weeks. The total daily dose of inulinase was 2,000 inulinase activity units (INU). Safety measures included blood clinical chemistry, hematology, lipid profile, high-sensitivity C-reactive protein (hs-CRP), insulin, lactate, and uric acid. GI symptoms were recorded weekly using the 15-item Gastrointestinal Symptom Rating Scale (GSRS). RESULTSFifty-eight participants completed the study. There were no clinically meaningful between-group differences in blood biomarkers. During the 4-week intervention period, 5 (16.7%) of 30 participants reported 5 adverse events (AEs) in the inulinase group, and 8 (26.7%) of 30 participants reported 13 AEs in the placebo group. No statistically significant between-group differences were observed in the change from baseline to 1, 2, 3, or 4 weeks of supplementation with respect to GSRS overall or domain scores. CONCLUSIONSMicrobial inulinase supplementation demonstrated a favorable safety profile in healthy adults. Further investigation in a dose-ranging study in individuals with dietary FODMAP, fructan, or inulin sensitivity or IBS is warranted. ClinicalTrials.gov: NCT05744700.