COVID-19 患者肠道微生物组中短链脂肪酸和 L-异亮氨酸生物合成的长期损伤。

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids (SCFAs) were depleted in SARS-CoV-2-infected patients. We aimed to characterize a functional profile of the gut microbiome in patients with COVID-19 before and after disease resolution. METHODS: We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (at up to 6 times points) during hospitalization and beyond 1 month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites. RESULTS: Compared with non-COVID-19 controls, patients with COVID-19 with severe/critical illness showed significant alterations in gut microbiome functionality (P < .001), characterized by impaired capacity of gut microbiome for SCFA and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in patients with COVID-19. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in patients with COVID-19 before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT- proB-type natriuretic peptide, and C-reactive protein (all P < .05). CONCLUSIONS: Gut microbiome of patients with COVID-19 displayed impaired capacity for SCFA and L-isoleucine biosynthesis that persisted even after disease resolution. These 2 microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome.

背景和目的：由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）感染引起的 2019 年冠状病毒病（COVID-19）与肠道微生物群落组成的改变有关。参与短链脂肪酸（SCFA）代谢的肠道细菌的系统发育群在 SARS-CoV-2 感染患者中减少。我们旨在描述 COVID-19 患者在疾病缓解前后的肠道微生物组的功能特征。

方法：我们对 66 名未使用抗生素的 COVID-19 患者和 70 名非 COVID-19 对照者的粪便样本进行了鸟枪法宏基因组测序。在住院期间和出院后 1 个月内（最多 6 次）采集粪便样本。我们评估了与疾病严重程度和血液炎症标志物相关的肠道微生物途径。我们还确定了疾病缓解前后粪便样本中微生物功能的变化，并使用粪便代谢物的靶向分析验证了这些功能。

结果：与非 COVID-19 对照组相比，患有严重/危重症 COVID-19 的患者的肠道微生物组功能发生了显著改变（P<0.001），其特征为肠道微生物组合成 SCFA 和 L-异亮氨酸的能力受损，尿素生成能力增强。在 COVID-19 患者康复后 30 天以上，肠道微生物组中 SCFA 和 L-异亮氨酸的生物合成仍然受损。粪便代谢物的靶向分析显示，COVID-19 患者在疾病缓解前后粪便中 SCFA 和 L-异亮氨酸的浓度明显降低。SCFA 和 L-异亮氨酸生物合成的缺乏与疾病严重程度显著相关，并导致 CXCL-10、NT-proB 型脑钠肽和 C 反应蛋白的血浆浓度升高（均 P<0.05）。

结论：COVID-19 患者的肠道微生物组显示出合成 SCFA 和 L-异亮氨酸的能力受损，即使在疾病缓解后仍然存在。这两种微生物功能与宿主免疫反应相关，强调了肠道微生物功能在 SARS-CoV-2 感染发病机制和结果中的重要性。