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These outcomes are driven by persistent immune activation, systemic inflammation, and metabolic dysfunction despite effective viral suppression with antiretroviral therapy (ART). To investigate mechanisms underlying SNAE pathogenesis, we performed a cross-site multi-omic analysis integrating plasma proteins, plasma metabolites, and mucosal microbiomes (ileum and rectum) in 82 ART-treated people with HIV (PWH) and 10 people without HIV (PWoH) from the United States and Mexico. Geography was the dominant source of variation, particularly across lipid classes. However, individuals at high risk for SNAEs, defined by low CD4 T cell counts and low CD4\/CD8 ratios, shared a consistent signature of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis including elevated plasma IL-6, \u03c9-oxidation products (adipic and suberic acids), and depletion of short-chain fatty acid\u2013producing commensals in the gut mucosa, including\n                  <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                  ,\n                  <jats:italic>Bacteroides uniformis<\/jats:italic>\n                  , and\n                  <jats:italic>Ruminococcus<\/jats:italic>\n                  . Notably,\n                  <jats:italic>A. muciniphila<\/jats:italic>\n                  abundance correlated with lower IL-6 levels, fewer HIV RNA-producing cells in lymph nodes, and higher CD4\/CD8 ratios. Together, these findings identify a shared inflammatory and metabolic phenotype in PWH and implicate\n                  <jats:italic>A. muciniphila<\/jats:italic>\n                  as a potential microbiome-based target to mitigate immune activation and SNAE risk in treated HIV.\n                <\/jats:p>","DOI":"10.64898\/2026.04.09.717347","type":"posted-content","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T18:00:22Z","timestamp":1776103222000},"source":"Crossref","is-referenced-by-count":2,"title":["Multi-omics links microbial dysbiosis, systemic inflammation and metabolomic disruptions to SNAE risk in treated HIV"],"prefix":"10.64898","author":[{"given":"Christopher M.","family":"Basting","sequence":"first","affiliation":[{"name":"Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodi","family":"Anderson","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Escand\u00f3n","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garritt","family":"Wieking","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candace","family":"Guerrero","sequence":"additional","affiliation":[{"name":"Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrett","family":"Reichel","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Cromarty","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Swanson","sequence":"additional","affiliation":[{"name":"Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ty","family":"Schroeder","sequence":"additional","affiliation":[{"name":"Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaina","family":"Creagan","sequence":"additional","affiliation":[{"name":"Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Barrett","sequence":"additional","affiliation":[{"name":"Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Funderburg","sequence":"additional","affiliation":[{"name":"School of Health and Rehabilitation Sciences, Ohio State University, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hunt","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, University of California San Francisco. 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