{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:28:27Z","timestamp":1789720107827,"version":"4.0.1"},"reference-count":77,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&amp;D Program of China","award":["2023YFC2308300"],"award-info":[{"award-number":["2023YFC2308300"]}]},{"name":"National Key R&amp;D Program of China","award":["2023YFC2306800"],"award-info":[{"award-number":["2023YFC2306800"]}]},{"name":"National Key R&amp;D Program of China","award":["82272317"],"award-info":[{"award-number":["82272317"]}]},{"name":"National Natural Science Foundation of China","award":["2023YFC2308300"],"award-info":[{"award-number":["2023YFC2308300"]}]},{"name":"National Natural Science Foundation of China","award":["2023YFC2306800"],"award-info":[{"award-number":["2023YFC2306800"]}]},{"name":"National Natural Science Foundation of China","award":["82272317"],"award-info":[{"award-number":["82272317"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Disruption of the gut microenvironment is a hallmark of HIV infection, where regulatory T cells (Tregs) play a critical role in maintaining gut homeostasis. However, the mechanisms by which gut Tregs contribute to immune reconstitution failure in HIV-infected individuals remain poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to analyze gut Treg populations across three cohorts: eight immunological responders (IRs), three immunological non-responders (INRs), and four HIV-negative controls (NCs). Our findings revealed that INRs exhibit an increased proportion of gut Tregs but with significant functional impairments, including reduced suppressive capacity and heightened apoptotic activity. Notably, these Tregs underwent metabolic reprogramming in INRs, marked by an upregulation of glycolysis-related genes and a downregulation of the oxidative phosphorylation (OXPHOS) pathway. Additionally, both the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA concentrations were reduced in INRs. In vitro SCFA supplementation restored Treg function by enhancing suppressive capacity, reducing early apoptosis, and rebalancing cellular energy metabolism from glycolysis to OXPHOS. These findings provide a comprehensive characterization of gut Treg dysfunction in INRs and underscore the therapeutic potential of targeting gut Tregs through microbiota and metabolite supplementation to improve immune reconstitution in HIV-infected individuals.<\/jats:p>","DOI":"10.3390\/cells14151164","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T12:39:29Z","timestamp":1753792769000},"page":"1164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Dysfunction and Metabolic Reprogramming of Gut Regulatory T Cells in HIV-Infected Immunological Non-Responders"],"prefix":"10.3390","volume":"14","author":[{"given":"Minrui","family":"Yu","sequence":"first","affiliation":[{"name":"Medical School of Chinese PLA, Beijing 100853, China"},{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6158-9443","authenticated-orcid":false,"given":"Mengmeng","family":"Qu","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zerui","family":"Wang","sequence":"additional","affiliation":[{"name":"Senior Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhen","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baopeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihuang","family":"Huang","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8126-8145","authenticated-orcid":false,"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8582-8012","authenticated-orcid":false,"given":"Jinwen","family":"Song","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0809-9207","authenticated-orcid":false,"given":"Xing","family":"Fan","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Xu","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Mei","family":"Jiao","sequence":"additional","affiliation":[{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical School of Chinese PLA, Beijing 100853, China"},{"name":"Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Foka, F.E.T., and Mufhandu, H.T. 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