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We examined whether altered lipid metabolism is an early driving factor in the development of cardiomyopathy using the Th3\/+ mouse model of thalassemia. At age 20\u2009weeks, male and female Th3\/+ mice manifested anemia and iron overload; however, only males displayed metabolic defects and altered cardiac function. Untargeted lipidomics indicated that the circulating levels of 35 lipid species were significantly altered in Th3\/+ mice compared to wild\u2010type controls: triglycerides (TGs) with saturated fatty acids (FAs; TG42:0 and TG44:0) were elevated, while TGs with unsaturated FAs (TG(18:2_20:5_18:2 and TG54:8)) were reduced. Similarly, phosphatidylcholines (PCs) with long chain FAs (palmitic (16:0) or oleic (18:1)) were increased, while PCs with polyunsaturated FAs decreased. Circulating PC(16:0_14:0), GlcCer(d18:1\/24:0) correlated significantly with iron overload and cardiac hypertrophy. 16S rRNA gene profiling revealed alterations in the intestinal microbiota of Th3\/+ mice. Differentially abundant bacterial genera correlated with PC(39:6), PC(18:1_22:6), GlcCer(d18:1\/24:1) and CE(14:0). These results provide new knowledge on perturbations in lipid metabolism and the gut microbiota of Th3\/+ mice and identify specific factors which may represent early biomarkers or therapeutic targets to prevent development of cardiomyopathy in \u03b2\u2010thalassemia.<\/jats:p>","DOI":"10.1096\/fj.202301043r","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T10:34:48Z","timestamp":1698662088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Perturbations in lipid metabolism and gut microbiota composition precede cardiac dysfunction in a mouse model of thalassemia"],"prefix":"10.1096","volume":"37","author":[{"given":"Ying","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Biology York University  Toronto Ontario 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