The Gut Microbiota–Epigenome Axis in Bariatric Surgery: Mechanistic Insights and Therapeutic Perspectives

The global prevalence of obesity has reached an alarming level, placing a significant burden on public health systems and individual well-being. Bariatric surgeries (BSs) result in greater and more sustained weight reduction than emerging medications such as glucagon-like peptide-1 (GLP-1). Despite the proven effectiveness of BS, considerable inter-individual variability in postoperative outcomes persists, with differences in weight loss and remission of obesity-related comorbidities among patients. Gut microbiota gene richness has been shown to change following BS. Importantly, the influence of the gut microbiota extends beyond conventional metabolic pathways to include interactions with the host epigenome. Although growing evidence suggests that microbiota-derived metabolites can influence epigenetic processes, whether inter-individual differences in gut microbiota composition contribute to variability in postoperative weight loss and metabolic outcomes following BS remains largely unknown. The gut microbiota–epigenome axis represents a potential molecular interface between postoperative gastrointestinal remodeling and metabolic adaptation. Surgical remodeling of the gastrointestinal tract reshapes the gut microbiota and its metabolites, including short-chain fatty acids and B vitamins, which may regulate host gene expression through histone deacetylase inhibition, DNA methylation, and modulation of systemic inflammation. Current evidence suggests that postoperative probiotic supplementation may improve glucose homeostasis, lipid profiles, and vitamin B12 and D status while having little or no additional effect on postoperative weight loss. Future research should address the limitations of existing studies by conducting adequately powered, high-quality randomized controlled trials integrating multi-omics technologies and precision medicine approaches to identify microbiome-based therapeutic targets, including postbiotic interventions. Further elucidation of this axis may support the development of precision bariatric strategies, although the clinical utility of microbiome- and epigenome-targeted interventions remains to be established.