Keskey Robert C, Xiao Jason, Hyoju Sanjiv, Lam Adam, Kim Daniel, Sidebottom Ashley M, Zaborin Alexander, Dijkstra Anne, Meltzer Rebecca, Thakur Abhimanyu, Zhang Kui, Chen Huanhuan Joyce, Beloborodova Natalia V, Pautova Alisa K, Wolfe Krysta, Patel Bhakti, Thewissen Renee, Zaborina Olga, Alverdy John C
Section of General Surgery, Department of Surgery, University of Chicago, Chicago, IL, USA.
Committee on Immunology, Biological Sciences Division, University of Chicago, Chicago, IL, USA.
Nat Microbiol. 2025 Feb;10(2):388-404. doi: 10.1038/s41564-024-01882-9. Epub 2025 Jan 8.
Sepsis is a major cause of morbidity and mortality, but our understanding of the mechanisms underlying survival or susceptibility is limited. Here, as pathogens often subvert host defence mechanisms, we hypothesized that this might influence the outcome of sepsis. We used microbiota analysis, faecal microbiota transplantation, antibiotic treatment and caecal metabolite analysis to show that gut-microbiota-derived tryptophan metabolites including indoles increased host survival in a mouse model of Serratia marcescens sepsis. Infection in macrophage-specific aryl hydrocarbon receptor (AhR) knockout mice revealed that AhR activation induced transcriptional reprogramming in macrophages and increased bacterial clearance and host survival. However, culture supernatants from multiple bacterial pathogens inhibited AhR activation in vitro. We showed that the secreted siderophore, enterobactin, inhibited AhR activation in vitro and increased sepsis mortality in vivo. By contrast, oral or systemic tryptophan supplementation increased survival. These findings show that sepsis survival depends upon the interplay between pathogen inhibition and the activation of AhR by a microbiota-derived metabolite.
脓毒症是发病和死亡的主要原因，但我们对生存或易感性潜在机制的理解有限。由于病原体常常破坏宿主防御机制，我们推测这可能会影响脓毒症的结局。我们通过微生物群分析、粪便微生物群移植、抗生素治疗和盲肠代谢物分析表明，肠道微生物群衍生的色氨酸代谢物（包括吲哚）可提高粘质沙雷氏菌脓毒症小鼠模型中的宿主存活率。巨噬细胞特异性芳烃受体（AhR）基因敲除小鼠的感染显示，AhR激活可诱导巨噬细胞中的转录重编程，并增加细菌清除率和宿主存活率。然而，多种细菌病原体的培养上清液在体外抑制AhR激活。我们表明，分泌的铁载体肠杆菌素在体外抑制AhR激活，并增加体内脓毒症死亡率。相比之下，口服或全身补充色氨酸可提高存活率。这些发现表明，脓毒症的存活取决于病原体抑制与微生物群衍生代谢物对AhR的激活之间的相互作用。
