Host-microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency

文献类型： 外文期刊

第一作者： Lee, Yong-Uk

作者： Lee, Yong-Uk;Guo, Rui;Nanda, Shivani;Yilmaz, L. Safak;Walhout, Albertha J. M.;Fox, Bennett W.;Curtis, Brian J.;Yu, Jingfang;Baumann, Victor;Schroeder, Frank C.;Guo, Rui;Kim, Sookyung;Haynes, Cole M.;Nanda, Shivani;Nanda, Shivani

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期刊名称：NATURE METABOLISM （ 影响因子：18.9； 五年影响因子：21.0 ）

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年卷期： 2024 年

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收录情况： SCI

摘要： In humans, defects in leucine catabolism cause a variety of inborn errors in metabolism. Here, we use Caenorhabditis elegans to investigate the impact of mutations in mccc-1, an enzyme that functions in leucine breakdown. Through untargeted metabolomic and transcriptomic analyses we find extensive metabolic rewiring that helps to detoxify leucine breakdown intermediates via conversion into previously undescribed metabolites and to synthesize mevalonate, an essential metabolite. We also find that the leucine breakdown product 3,3-hydroxymethylbutyrate (HMB), commonly used as a human muscle-building supplement, is toxic to C. elegans and that bacteria modulate this toxicity. Unbiased genetic screens revealed interactions between the host and microbe, where components of bacterial pyrimidine biosynthesis mitigate HMB toxicity. Finally, upregulated ketone body metabolism genes in mccc-1 mutants provide an alternative route for biosynthesis of the mevalonate precursor 3-hydroxy-3-methylglutaryl-CoA. Our work demonstrates that a complex host-bacteria interplay rewires metabolism to allow host survival when leucine catabolism is perturbed.

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