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Recent evidence highlights intricate interactions between the gut microbiota, metabolites, and host inflammatory responses; however, the causal relationships and underlying mechanisms remain poorly understood. We integrated Mendelian randomization (MR) with multi-omics approaches (including transcriptomics, untargeted metabolomics, and single-cell transcriptomics) to elucidate the causal relationships and underlying mechanisms between gut microbiota and their associated metabolites in the inflammatory response of sepsis. Building on this analysis, we employed machine learning algorithms to identify sepsis-specific diagnostic biomarkers derived from Prevotella 9, fatty acids, and PANoptosis-related genes. These key diagnostic genes were experimentally validated using a pulmonary sepsis organoid model. Seven gut microbiota taxa were identified as causally associated with sepsis, with Prevotella 9 demonstrating significant protective effects (odds ratio\u2009=\u20090.89, P\u2009=\u20090.01). The protective role of Prevotella 9 appears to be mediated through its regulation of fatty acid metabolism. Machine learning algorithms pinpointed three key diagnostic genes for sepsis: ABCC1, CYP1B1, and PPARG. Validation in an independent cohort (area under the receiver operating characteristic curve\u2009=\u20090.93) and the lung-derived organoid model confirmed their relevance. Functional analyses revealed that these genes are involved in immunometabolic pathways, including neutrophil regulation, oxidative stress, and macrophage polarization, and are predominantly expressed in monocytes. This study integrates MR and multi-omics analyses to reveal that Prevotella 9 may regulate sepsis through lipid metabolism. Additionally, three key genes (ABCC1, CYP1B1, and PPARG) were identified based on Prevotella 9, fatty acids, and PANoptosis, contributing to sepsis progression via the regulation of neutrophils, oxidative stress, and macrophage polarization. Monocytes may serve as potential cellular targets for sepsis.<\/jats:p>","DOI":"10.1063\/5.0296018","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T13:48:58Z","timestamp":1767707338000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Integrating Mendelian randomization and multi-omics analysis unravels gut microbiota-driven metabolic mechanisms in sepsis and identifies diagnostic biomarkers through experimental validation"],"prefix":"10.1063","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7342-7644","authenticated-orcid":false,"given":"Guangyao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine 1 , Nanning 530023, Guangxi,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Center of Preventive Disease Treatment, The First Affiliated Hospital of Guangxi University of Chinese Medicine 2 , Nanning 530023, Guangxi,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjing","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Administration, The First Affiliated Hospital of Guangxi University of Chinese Medicine 3 , Nanning 530023, Guangxi,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi University of Chinese Medicine 4 , Nanning 530023, Guangxi,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi University of Chinese Medicine 4 , Nanning 530023, Guangxi,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine 5 , Nanning 530023,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5294-7445","authenticated-orcid":false,"given":"Xiaohua","family":"Hong","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation and College of Pharmacy, Guangxi Medical University 6 , Nanning 530021,","place":["China"]},{"name":"Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education and Center for Translational Medicine, Guangxi Medical University 7 , Nanning 530021,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2072-4889","authenticated-orcid":false,"given":"Sheng","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Center of Preventive Disease Treatment, The First Affiliated Hospital of Guangxi University of Chinese Medicine 2 , Nanning 530023, Guangxi,","place":["China"]},{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi University of Chinese Medicine 4 , Nanning 530023, Guangxi,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"issue":"10219","key":"2026010608485126600_c1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","year":"2020","journal-title":"Lancet"},{"issue":"10141","key":"2026010608485126600_c2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0140-6736(18)30696-2","article-title":"Sepsis and septic shock","volume":"392","year":"2018","journal-title":"Lancet"},{"issue":"8","key":"2026010608485126600_c3","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1007\/s00134-020-06151-x","article-title":"Incidence and mortality of hospital- and ICU-treated sepsis: Results from an updated and expanded systematic review and meta-analysis","volume":"46","year":"2020","journal-title":"Intensive Care Med."},{"issue":"4","key":"2026010608485126600_c4","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1016\/j.ymthe.2023.01.018","article-title":"Gut microbial metabolite hyodeoxycholic acid targets the TLR4\/MD2 complex to attenuate inflammation and protect against sepsis","volume":"31","year":"2023","journal-title":"Mol. 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