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.

在人类中，亮氨酸分解代谢的缺陷会导致多种先天性代谢错误。在这里，我们使用秀丽隐杆线虫来研究mccc-1 （一种在亮氨酸分解中发挥作用的酶）突变的影响。通过非靶向代谢组学和转录组学分析，我们发现广泛的代谢重新布线，有助于通过转化为以前未描述的代谢物来解毒亮氨酸分解中间体，并合成甲羟戊酸（一种重要的代谢物）。我们还发现，亮氨酸分解产物 3,3-羟甲基丁酸 (HMB)（通常用作人类肌肉增强补充剂）对秀丽隐杆线虫有毒，而细菌会调节这种毒性。无偏见的遗传筛选揭示了宿主和微生物之间的相互作用，其中细菌嘧啶生物合成的成分减轻了 HMB 毒性。最后， mccc-1突变体中酮体代谢基因的上调为甲羟戊酸前体3-羟基-3-甲基戊二酰辅酶A的生物合成提供了替代途径。我们的工作表明，当亮氨酸分解代谢受到干扰时，复杂的宿主-细菌相互作用会重新连接新陈代谢，从而使宿主能够生存。