The Gut Microbiome-Endocrine Axis in Obesity: Mechanisms and Therapeutics.

Obesity, a major global health challenge and a key risk factor for metabolic diseases, represents a state of dysregulated energy homeostasis. The gut microbiome has emerged as a critical mediator of obesity pathogenesis, yet the precise endocrine mechanisms linking microbial signals to metabolic dysfunction remain incompletely understood. Therefore, at the perspectives of gut microbiome-endocrine axis encompassing gut-brain, gut-adipose, and gut-pancreas axes, this review elucidates how gut microbiota and their metabolites influence systemic endocrine homeostasis through energy intake, fat storage, and hormonal secretion. Mechanistic studies highlight the roles of short-chain fatty acids, bile acids, and microbial peptides in modulating obesity control and related metabolic health. We further summarize the current therapeutics targeting gut microbiome in the gut-endocrine axis, including prebiotics, probiotics, synbiotics, postbiotics, fecal microbiota transplantation, and lifestyle approaches and highlight their mechanistic and translational relevance. The major challenges of gut microbiome studies are discussed, including obscure phenotyping, insufficient cross-organ integration, and limited causal inference. Overcoming these limitations by precise obesity measurement, integrated cross-organ models, and AI-driven causal modeling could advance the pathophysiological insight and management of obesity.