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Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (T\n                    <jats:sub>reg<\/jats:sub>\n                    ) cells to preserve gut\u2013immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired T\n                    <jats:sub>reg<\/jats:sub>\n                    cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs T\n                    <jats:sub>reg<\/jats:sub>\n                    cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 \u0394T mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut\u2013immune homeostasis and dictates outcome in pathobiont infections.\n                  <\/jats:p>","DOI":"10.1038\/s42255-026-01533-9","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T09:01:15Z","timestamp":1779094875000},"page":"1368-1389","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2041-2320","authenticated-orcid":false,"given":"Annamaria","family":"Regina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6607-2291","authenticated-orcid":false,"given":"Francesca","family":"Solagna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malkon Sanchez","family":"Estrada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike M. 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