{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:28:37Z","timestamp":1791818917535,"version":"4.3.4"},"reference-count":208,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002855","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2506006"],"award-info":[{"award-number":["2023YFC2506006"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Metabolic syndrome (MetS) represents a growing global health burden characterized by obesity, insulin resistance, dyslipidemia, and hypertension. Increasing evidence suggests that gut microbiota-associated mediators may serve as signaling intermediates involved in host metabolic regulation. However, the mechanisms by which these mediators interact with host signaling pathways and influence metabolic responses remain incompletely understood. This review summarizes current advances in gut microbiota-associated mediators, focusing on short-chain fatty acids, bile acids, lipopolysaccharide, trimethylamine N-oxide, and branched-chain amino acids. We discuss their interactions with host metabolic and inflammatory pathways, including pathways implicated in FFAR2\/3-mediated signaling, FXR\/TGR5 signaling, TLR4\/NF-\u03baB-mediated inflammatory signaling, and mTORC1-associated nutrient-sensing. Furthermore, we propose a microbiota\u2013mediator\u2013host signaling network framework as an emerging conceptual model to integrate these molecular interactions and highlight the utility of multi-omics approaches in characterizing complex microbiota\u2013host communication. Despite mechanistic advances, substantial challenges remain, including heterogeneous microbial signatures across populations, limited causal evidence, inter-individual variability in therapeutic responses, and barriers to clinical translation of microbiota-targeted interventions. A better understanding of microbiota-associated signaling networks may provide new insights into metabolic regulation and contribute to the rational development of microbiota-targeted strategies that complement established lifestyle interventions for MetS management.<\/jats:p>","DOI":"10.3390\/microorganisms14091865","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:03:41Z","timestamp":1787558621000},"page":"1865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Microbiota\u2013Mediator\u2013Host Signaling Networks in Metabolic Syndrome: From Mechanistic Insights to Therapeutic Targeting"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9960-9243","authenticated-orcid":false,"given":"Xinyi","family":"Zhuang","sequence":"first","affiliation":[{"name":"School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0479-1430","authenticated-orcid":false,"given":"Zhengle","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiahong","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1161\/CIRCULATIONAHA.109.192644","article-title":"Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity","volume":"120","author":"Alberti","year":"2009","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/S0140-6736(11)60813-1","article-title":"The global obesity pandemic: Shaped by global drivers and local environments","volume":"378","author":"Swinburn","year":"2011","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11906-018-0812-z","article-title":"The Global Epidemic of the Metabolic Syndrome","volume":"20","author":"Saklayen","year":"2018","journal-title":"Curr. 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