Tirzepatide and the gut microbiota-obesity axis: metabolic mechanisms and therapeutic perspectives.

Obesity is a chronic multifactorial metabolic disorder characterized by adipose tissue dysfunction, insulin resistance, low-grade inflammation, and altered energy homeostasis. Evidence indicates that the gut microbiota contributes to obesity-related metabolic dysfunction through microbial metabolite production, intestinal barrier regulation, immune activation, bile acid signaling, and gut-brain communication. This narrative review, supported by a structured literature search, synthesizes current evidence on the gut microbiota-obesity axis and the potential role of tirzepatide in modulating microbiota-related metabolic pathways. Microbiota-derived metabolites, including short-chain fatty acids, bile acids, tryptophan derivatives, trimethylamine N-oxide, and fatty acid-derived compounds, may exert beneficial, detrimental, or context-dependent effects depending on microbial composition, diet, host metabolic status, and tissue-specific signaling pathways. Lifestyle, dietary patterns, host genetics, and medication exposure can further modulate gut microbiota composition and function, influencing metabolic outcomes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist, improves glycemic control and promotes weight loss. Evidence suggests that tirzepatide may also be associated with changes in gut microbiota composition, microbial metabolites, intestinal barrier integrity, and inflammatory signaling. However, whether these microbial changes represent direct pharmacological effects or secondary consequences of weight loss, reduced caloric intake, delayed gastric emptying, improved glucose control, or dietary modification remains unclear. This review summarizes current evidence on the gut microbiota-obesity axis and the potential relevance of tirzepatide-associated microbiota modulation.