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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\u2013endocrine axis encompassing gut\u2013brain, gut\u2013adipose, and gut\u2013pancreas 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\u2010chain 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\u2013endocrine 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\u2010organ integration, and limited causal inference. Overcoming these limitations by precise obesity measurement, integrated cross\u2010organ models, and AI\u2010driven causal modeling could advance the pathophysiological insight and management of obesity.<\/jats:p>","DOI":"10.1111\/jgh.70511","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T13:26:29Z","timestamp":1782307589000},"page":"2297-2309","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Gut Microbiome\u2013Endocrine Axis in Obesity: Mechanisms and Therapeutics"],"prefix":"10.1111","volume":"41","author":[{"given":"Hongfeng","family":"Mao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes Shanghai Sixth People's Hospital 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