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

Obesity 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 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.