Targeting Gut Microbiota by DPP-4 Inhibitors in Obesity: Mechanistic Insights and Therapeutic Implications.

purpose of reviewObesity is a complex metabolic disorder driven by factors such as chronic inflammation, insulin resistance, and significant alterations in the gut microbiota. Dipeptidyl peptidase-4 (DPP-4), an enzyme primarily known for inactivating incretin hormones like glucagon-like peptide-1 (GLP-1), is now recognized as a critical link between metabolic dysfunction and gut microbiome dysbiosis. This review aims to examine the mechanistic role of DPP-4 and its inhibitors in obesity, specifically focusing on how they modulate the gut microbiome to influence host energy balance and metabolic health. RECENT

findingsRecent experimental and clinical evidence indicates that DPP-4 activity contributes to obesity by influencing microbial composition, diversity, and function. Studies demonstrate that DPP-4 inhibitors can reshape the gut microbiota by reducing dysbiosis, decreasing the Firmicutes-to-Bacteroidetes ratio, and enhancing the production of short-chain fatty acids (SCFAs). Furthermore, these inhibitors improve gut barrier integrity and regulate bile acid metabolism, which helps attenuate systemic inflammation and restore insulin sensitivity. While DPP-4 inhibitors are often weight-neutral in clinical settings, they appear to assist in maintaining metabolic stability by enhancing central satiety signaling and reducing neuroinflammation. The gut microbiome acts as a key intermediary in the metabolic regulation managed by DPP-4. By restoring microbial balance and promoting beneficial metabolites, DPP-4 inhibitors offer therapeutic advantages that extend beyond traditional glycemic control to include improved energy equilibrium and reduced adiposity. Targeting the interactions between DPP-4 and the microbiota represents a promising future therapeutic strategy for managing obesity and its associated metabolic complications.