Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk of long COVID has been associated with the depletion or over-abundance of specific taxa within the gut microbiome. However, the microbial mechanisms mediating these effects are not yet known. We hypothesized that altered microbial production of tryptophan and its downstream derivatives might contribute to inappropriate immune responses to viral infection. In patients hospitalized with COVID-19 (n = 172), serum levels of tryptophan and indole-3-propionate (IPA) negatively correlated with serum levels of many proinflammatory mediators (including C-reactive protein and Serum amyloid A), while C-glycosyltryptophan (C-Trp), indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA) levels were positively correlated with levels of acute phase proteins, proinflammatory cytokines, alarmins and chemokines. A similar pattern was observed in long COVID patients (n = 20) where tryptophan and IPA were negatively associated with a large number of serum cytokines, while C-Trp and IAA were positively associated with circulating cytokine levels. Metagenomic analysis of the fecal microbiota showed the relative abundance of genes encoding the microbial enzymes required for tryptophan production (e.g. anthranilate synthase) and microbial tryptophan metabolism was significantly lower in patients hospitalized with COVID-19 (n = 380) compared to healthy controls (n = 270). Microbial tryptophan metabolites reduced innate cell proinflammatory responses to cytosolic DNA sensor Stimulator of interferon genes (STING), toll-like receptor (TLR)-3 and TLR-4 stimulation in vitro, while IL-10 secretion was enhanced. Microbial tryptophan metabolites also modified ex vivo human lymphocyte responses by limiting the production of TH1 and TH17 associated cytokines, while enhancing secretion of IL-22. These data suggest that lower levels of tryptophan production and tryptophan metabolism by gut microbes may increase the risk of severe and chronic outcomes to SARS-CoV-2 infection due to impaired innate and adaptive responses to infection. Screening patients for lower-level microbiome capacity for tryptophan metabolism may help identify at-risk individuals.

中文翻译：

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微生物色氨酸代谢破裂与 SARS-CoV-2 急性炎症反应和长期 COVID 有关。


对严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2） 感染的保护和长期 COVID 风险与肠道微生物组中特定分类群的耗竭或过度有关。然而，介导这些影响的微生物机制尚不清楚。我们假设色氨酸及其下游衍生物的微生物产生的改变可能导致对病毒感染的不适当免疫反应。在 COVID-19 住院患者 （n = 172） 中，血清色氨酸和 3-丙酸吲哚 （IPA） 水平与许多促炎介质（包括 C 反应蛋白和血清淀粉样蛋白 A）的血清水平呈负相关，而 C-糖基色氨酸 （C-Trp）、吲哚-3-乳酸 （ILA） 和吲哚-3-乙酸 （IAA） 水平与急性期蛋白、促炎细胞因子、警报素和趋化因子水平呈正相关。在长期 COVID 患者 （n = 20） 中观察到类似的模式，其中色氨酸和 IPA 与大量血清细胞因子呈负相关，而 C-Trp 和 IAA 与循环细胞因子水平呈正相关。粪便微生物群的宏基因组分析显示，编码色氨酸产生所需微生物酶（例如 邻氨基苯甲酸合酶）和微生物色氨酸代谢的基因的相对丰度在 COVID-19 住院患者 （n = 380） 中显着降低与健康对照 （n = 270）。微生物色氨酸代谢物在体外降低了对胞质 DNA 传感器干扰素基因刺激剂 （STING）、toll 样受体 （TLR）-3 和 TLR-4 刺激的先天细胞促炎反应，同时 IL-10 分泌增强。 微生物色氨酸代谢物还通过限制 TH1 和 TH17 相关细胞因子的产生，同时增强 IL-22 的分泌来改变离体人淋巴细胞反应。这些数据表明，由于对感染的先天性和适应性反应受损，肠道微生物的色氨酸产生和色氨酸代谢水平较低可能会增加 SARS-CoV-2 感染严重和慢性后果的风险。筛查患者的色氨酸代谢的较低微生物组能力可能有助于识别高危个体。