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Genetic and environmental factors are implicated in MS development, and among the latter, diets and nutrients are emerging as potential critical contributors. However, a comprehensive understanding of their impacts and the underlying mechanisms involved is lacking. Harnessing state\u2010of\u2010the\u2010art nutritional geometry analytical methods, it is first revealed that globally, increased carbohydrate supply is associated with increased MS disease burden, while fat supply has an opposite effect. Furthermore, in a MS mouse model, experimental autoimmune encephalomyelitis (EAE), it is found that an isocaloric diet high in carbohydrate aggravated EAE, while a diet enriched in fat (HF) is fully protective. This is reflected by reduced neuroinflammation and skewing toward anti\u2010inflammatory phenotypes. The protective effects from the HF diet are multifaceted. Metabolically, HF increased lipid storage in immune cells, correlating with their increased anti\u2010inflammatory IL\u201010 production. Transcriptionally and epigenetically, HF feeding preprogrammed na\u00efve T cells toward a less activated but more tolerogenic phenotype. It is showcased that manipulating diets is a potentially efficient and cost\u2010effective approach to prevent and\/or ameliorate EAE. This exhibits translational potentials for prevention\/intervention of MS and possibly other autoimmune diseases.<\/jats:p>","DOI":"10.1002\/advs.202412236","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T11:54:52Z","timestamp":1743335692000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["High Fat Low Carbohydrate Diet Is Linked to CNS Autoimmunity Protection"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3902-2843","authenticated-orcid":false,"given":"Duan","family":"Ni","sequence":"first","affiliation":[{"name":"Charles Perkins Centre The University of Sydney  D17 Charles Perkins Centre Sydney NSW 2006 Australia"},{"name":"School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney NSW 2006 Australia"},{"name":"Sydney Medical School Nepean The University of Sydney  Sydney NSW 2747 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