Oxidative ornithine metabolism supports non-inflammatory C. difficile colonization.
Oxidative ornithine metabolism supports non-inflammatory C. difficile colonization.
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DOI：
10.1038/s42255-021-00506-4
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发表时间：
2022-01
影响因子：
20.8
通讯作者：
Sonnenburg JL
中科院分区：
文献类型：
--
作者：
Pruss KM;Enam F;Battaglioli E;DeFeo M;Diaz OR;Higginbottom SK;Fischer CR;Hryckowian AJ;Van Treuren W;Dodd D;Kashyap P;Sonnenburg JL
肠道病原体艰难梭菌（Cd）是一种毒素介导的感染，在美国每年导致超过20万例住院和13，000例死亡。然而，镉可以在没有疾病症状的情况下定殖肠道。在健康人群中，无症状定植由致突变镉的患病率很高，无症状携带者感染的风险增加相比，noncolonized个人，可能是一个水库镉感染的传播。阐明镉在没有疾病的情况下持续存在的分子机制对于理解发病机制和制定精细的治疗策略是必要的。在这里，我们用肠道微生物组元转录组学分析表明，对镉感染和炎症耐受的小鼠表现出精氨酸和鸟氨酸代谢途径的全群落表达增加。查询镉代谢具体，我们利用RNA测序在gnotobiotic小鼠感染两个野生型菌株（630和R20291）和同基因毒素缺陷突变体的这些菌株区分炎症依赖与独立的转录状态。编码氧化性鸟氨酸降解的单个操纵子在非转基因Cd菌株中一致上调。结合非靶向和有针对性的代谢组学与细菌和宿主遗传学，我们表明，饮食和宿主来源的鸟氨酸提供了竞争优势，镉，镉持久性的非炎症，健康的肠道内的机制。使用代谢组学和细菌及宿主遗传学的组合，Pruss等人表明，艰难梭菌中上调的氧化鸟氨酸代谢促进其在非炎症条件下在胃肠道内的持久性。
The enteric pathogen Clostridioides difficile (Cd) is responsible for a toxin-mediated infection that causes more than 200,000 recorded hospitalizations and 13,000 deaths in the United States every year. However, Cd can colonize the gut in the absence of disease symptoms. Prevalence of asymptomatic colonization by toxigenic Cd in healthy populations is high; asymptomatic carriers are at increased risk of infection compared to noncolonized individuals and may be a reservoir for transmission of Cd infection. Elucidating the molecular mechanisms by which Cd persists in the absence of disease is necessary for understanding pathogenesis and developing refined therapeutic strategies. Here, we show with gut microbiome metatranscriptomic analysis that mice recalcitrant to Cd infection and inflammation exhibit increased community-wide expression of arginine and ornithine metabolic pathways. To query Cd metabolism specifically, we leverage RNA sequencing in gnotobiotic mice infected with two wild-type strains (630 and R20291) and isogenic toxin-deficient mutants of these strains to differentiate inflammation-dependent versus -independent transcriptional states. A single operon encoding oxidative ornithine degradation is consistently upregulated across non-toxigenic Cd strains. Combining untargeted and targeted metabolomics with bacterial and host genetics, we demonstrate that both diet- and host-derived sources of ornithine provide a competitive advantage to Cd, suggesting a mechanism for Cd persistence within a non-inflammatory, healthy gut. Using a combination of metabolomics and bacterial and host genetics, Pruss et al. show that upregulated oxidative ornithine metabolism in Clostridioides difficile promotes its persistence within the gastrointestinal tract under non-inflammatory conditions.
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作者：
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通讯作者：
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影响因子：
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