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Melatonin (MLT) regulates gut microbiota and promotes the production of short\u2010chain fatty acids (SCFAs). However, whether MLT affects SO through the gut microbiota and SCFAs remains unclear. This study aimed to investigate the effect and mechanism of MLT in SO induced by a high\u2010fat diet (HFD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>First, a case\u2010control study was conducted to explore the potential association between serum MLT levels and SO\u2010related parameters in 31 patients. Next, rats fed with a HFD were orally administered with MLT for 16\u2009weeks, and obesity\u2010related metabolic disorders and muscle atrophy were measured. 16S rRNA gene sequencing and gas chromatography\u2013mass spectrometry were used to detect gut microbiota and SCFAs, respectively. Gut barrier integrity was assessed by the expression of the Muc\u20102 protein and tight junction proteins. Finally, faecal microbiota transplantation and SCFAs administration were performed to confirm the causal role of the gut microbiota and SCFAs in the effect of MLT on SO.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The serum levels of MLT decreased in patients with SO (29.87\u2009\u00b1\u20096.71 vs. 24.94\u2009\u00b1\u20095.68, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and were closely associated with appendicular skeletal muscle mass index (<jats:italic>r<\/jats:italic>\u2009=\u20090.3514, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and handgrip strength (<jats:italic>r<\/jats:italic>\u2009=\u20090.2824, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). MLT ameliorated obesity\u2010related metabolic disorders (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), poor muscle mass (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), strength (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and function (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and muscle atrophy (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) in HFD\u2010fed rats. MLT regulated HFD\u2010induced gut dysbiosis, which was mainly characterized by increases in SCFAs\u2010related bacteria and SCFAs (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). MLT recovered HFD\u2010induced impairment of gut barrier integrity by promoting the expression levels of Muc\u20102, claudin\u20101, occludin and zonula occluden\u20101 proteins in the colon (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Correlation analysis showed that SCFAs\u2010related bacteria and SCFAs were negatively associated with SO. Faecal suspension from MLT\u2010treated rats promoted the production of SCFAs in recipient rats (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). In addition, faecal suspension from MLT\u2010treated rats partially mitigated metabolic disorders (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), poor muscle mass and function (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and muscle atrophy (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) in recipient rats. SCFAs treatment alleviated the development of SO in HFD\u2010fed rats by suppressing metabolic disorders (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), reducing muscle oxidative stress and inflammation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and promoting protein synthesis through the AKT\/mTOR\/p70S6k signalling pathway (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MLT mitigated HFD\u2010induced SO by regulating the gut microbiota and promoting the production of SCFAs. MLT might be a novel strategy for delaying the progression of SO.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13869","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T09:32:35Z","timestamp":1749807155000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Melatonin Mitigates Sarcopenic Obesity via Microbiota and Short\u2010Chain Fatty Acids: Evidence From Epidemiologic and In\u00a0Vivo Studies"],"prefix":"10.1002","volume":"16","author":[{"given":"Xiaoxing","family":"Mo","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College Huazhong University of Science and Technology  Wuhan 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linyan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Lab of 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