Butyrate and Palmitoylethanolamide: Exploring Their Metabolic Potential in Explaining Clinical Improvement in Irritable Bowel Syndrome Patients

Background: Irritable bowel syndrome (IBS) is a disorder of gut_brain interaction (DGBI) in which gut microbiome plays a major role. Butyrate and palmitoylethanolamide (PEA) exert anti_inflammatory and neuromodulatory effects and may represent promising adjunctive treatments. We evaluated the clinical and microbiome_related effects of a combined formulation of sodium butyrate and PEA (BP 3:1) in patients with IBS.Methods. In a randomised, double-blind, placebo-controlled, 2x2 crossover trial, adults with diarrhoea-predominant or mixed IBS received BP 3:1 or placebo for two 6_week periods separated by washout. Gastrointestinal symptoms, IBS Severity Scoring System (IBS_SSS), intestinal permeability, and safety were assessed. Faecal microbiota composition and predicted functional potential were analysed using 16S rRNA sequencing and PICRUSt2.Results: Forty_four patients completed the study. Alpha and beta diversity and taxonomic composition remained stable. In contrast, functional profiling revealed treatment-specific enrichment of microbial pathways involved in methionine and S-adenosyl-L-methionine biosynthesis, while placebo was associated with pathways related to complex carbohydrate degradation. BP 3:1 significantly improved abdominal bloating (p:0,02), stomach gurgling (p:0,014) and nausea (p:0,03) compared with placebo, while IBS-SSS showed a clinically relevant but non-significant numerical reduction (p:0,07). No effects were observed on intestinal permeability. Among clinically improving patients, BP 3:1 was associated with modulation of polyphenol-degrading, biosynthetic and proteolytic microbial pathways. BP 3:1 was well tolerated, with a safety profile comparable to placeboConclusions. BP 3:1 significantly improves IBS symptoms and modulates microbial metabolic potential without inducing a quantitative and/or qualitative alteration in the taxonomic composition of the microbiota. These findings support a functional microbiome_mediated effect in IBS