Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland.
Department of Biology, University of Oxford, Oxford, United Kingdom.
PLoS Biol. 2023 Aug 31;21(8):e3002253. doi: 10.1371/journal.pbio.3002253. eCollection 2023 Aug.
Salmonella Typhimurium elicits gut inflammation by the costly expression of HilD-controlled virulence factors. This inflammation alleviates colonization resistance (CR) mediated by the microbiota and thereby promotes pathogen blooms. However, the inflamed gut-milieu can also select for hilD mutants, which cannot elicit or maintain inflammation, therefore causing a loss of the pathogen's virulence. This raises the question of which conditions support the maintenance of virulence in S. Typhimurium. Indeed, it remains unclear why the wild-type hilD allele is dominant among natural isolates. Here, we show that microbiota transfer from uninfected or recovered hosts leads to rapid clearance of hilD mutants that feature attenuated virulence, and thereby contributes to the preservation of the virulent S. Typhimurium genotype. Using mouse models featuring a range of microbiota compositions and antibiotic- or inflammation-inflicted microbiota disruptions, we found that irreversible disruption of the microbiota leads to the accumulation of hilD mutants. In contrast, in models with a transient microbiota disruption, selection for hilD mutants was prevented by the regrowing microbiota community dominated by Lachnospirales and Oscillospirales. Strikingly, even after an irreversible microbiota disruption, microbiota transfer from uninfected donors prevented the rise of hilD mutants. Our results establish that robust S. Typhimurium gut colonization hinges on optimizing its manipulation of the host: A transient and tempered microbiota perturbation is favorable for the pathogen to both flourish in the inflamed gut and also minimize loss of virulence. Moreover, besides conferring CR, the microbiota may have the additional consequence of maintaining costly enteropathogen virulence mechanisms.
鼠伤寒沙门氏菌通过昂贵的 HilD 控制的毒力因子表达引发肠道炎症。这种炎症减轻了微生物群介导的定植抗性 (CR)，从而促进了病原体的爆发。然而，发炎的肠道环境也可以选择 hilD 突变体，这些突变体不能引发或维持炎症，因此导致病原体的毒力丧失。这就提出了一个问题，即哪些条件支持鼠伤寒沙门氏菌保持毒力。事实上，野生型 hilD 等位基因在自然分离株中占优势的原因仍不清楚。在这里，我们表明，从未感染或已恢复的宿主转移的微生物群会迅速清除具有减弱毒力的 hilD 突变体，从而有助于保存具有毒力的鼠伤寒沙门氏菌基因型。使用具有一系列微生物群组成和抗生素或炎症引起的微生物群破坏的小鼠模型，我们发现不可逆的微生物群破坏会导致 hilD 突变体的积累。相比之下，在微生物群短暂破坏的模型中，由 Lachnospirales 和 Oscillospirales 主导的再生微生物群群落阻止了 hilD 突变体的选择。引人注目的是，即使在不可逆的微生物群破坏后，来自未感染供体的微生物群转移也可以防止 hilD 突变体的出现。我们的研究结果表明，鼠伤寒沙门氏菌在肠道中的定植取决于其对宿主的操纵：短暂和适度的微生物群扰动有利于病原体在发炎的肠道中繁荣，并最大限度地减少毒力丧失。此外，微生物群除了赋予 CR 之外，还可能具有维持昂贵的肠道病原体毒力机制的额外后果。
