biostudies-literatureLee YUNIDDK NIH HHSNIA NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)NIH HHSU.S. Department of Health & Human Services | National Institutes of HealthNIGMS NIH HHS1584-1600https://www.ebi.ac.uk/biostudies/studies/S-EPMC11670331biostudies-literatureUnknown6(8)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.Nature metabolismHost-microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency.PMC11670331DK115690R35 GM131877R56 DK068429R37AG047182GM131877R37 AG047182R01 DK068429P40 OD010440F30 AG077833R01 DK115690F30AG077833DK068429Fox BWKim SNanda SHaynes CMSchroeder FCBaumann VYilmaz LSGuo RYu JCurtis BJLee YUWalhout AJMfalseHost-microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency.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.2024-01-01T00:00:00Z2024 Aug2026-04-12T19:29:26.188Z2026-04-07T13:20:59.026ZS-EPMC116703313911795910.1038/s42255-024-01098-5