Background Coronavirus disease 2019 (COVID-19) is an emerging serious global health problem. Gastrointestinal symptoms are common in COVID-19 patients, and severe acute respiratory syndrome coronavirus 2 RNA has been detected in stool specimens. However, the relationship between the gut microbiome and disease remains to be established. Methods We conducted a cross-sectional study of 30 patients with COVID-19, 24 patients with influenza A(H1N1), and 30 matched healthy controls (HCs) to identify differences in the gut microbiota by 16S ribosomal RNA gene V3–V4 region sequencing. Results Compared with HCs, COVID-19 patients had significantly reduced bacterial diversity; a significantly higher relative abundance of opportunistic pathogens, such as Streptococcus, Rothia, Veillonella, and Actinomyces; and a lower relative abundance of beneficial symbionts. Five biomarkers showed high accuracy for distinguishing COVID-19 patients from HCs with an area under the curve (AUC) up to 0.89. Patients with H1N1 displayed lower diversity and different overall microbial composition compared with COVID-19 patients. Seven biomarkers were selected to distinguish the 2 cohorts (AUC = 0.94). Conclusions The gut microbial signature of patients with COVID-19 was different from that of H1N1 patients and HCs. Our study suggests the potential value of the gut microbiota as a diagnostic biomarker and therapeutic target for COVID-19, but further validation is needed.

Coronavirus disease 2019 (COVID-19) is a highly contagious infectious disease. Similar to H7N9 infection, pneumonia and cytokine storm are typical clinical manifestations of COVID-19. Our previous studies found that H7N9 patients had intestinal dysbiosis. However, the relationship between the gut microbiome and COVID-19 has not been determined. This study recruited a cohort of 57 patients with either general ( n = 20), severe ( n = 19), or critical ( n = 18) disease. The objective of this study was to investigate changes in the abundance of ten predominant intestinal bacterial groups in COVID-19 patients using quantitative polymerase chain reaction (q-PCR), and to establish a correlation between these bacterial groups and clinical indicators of pneumonia in these patients. The results indicated that dysbiosis occurred in COVID-19 patients and changes in the gut microbial community were associated with disease severity and hematological parameters. The abundance of butyrate-producing bacteria, such as Faecalibacterium prausnitzii , Clostridium butyricum , Clostridium leptum , and Eubacterium rectale , decreased significantly, and this shift in bacterial community may help discriminate critical patients from general and severe patients. Moreover, the number of common opportunistic pathogens Enterococcus (Ec) and Enterobacteriaceae (E) increased, especially in critically ill patients with poor prognosis. The results suggest that these bacterial groups can serve as diagnostic biomarkers for COVID-19, and that the Ec/E ratio can be used to predict death in critically ill patients.

Figure 1 Changes of faecal microbial communities in different stages (acute, convalescence, postconvalescence) of patients with COVID-19 (n=30), compared with uninfected controls (n=30). (A) α-Diversity, illustrated by microbiota richness (Chao 1 index), was reduced in COVID-19 (p<0.01, Wilcoxon rank-sum test). Boxes represent the 25th-75th percentile of the distribution; the median is shown as a thick line in the middle of the box; whiskers extend to values with 1.5 times the difference between the 25th and 75th percentiles. ***P<0.001. (B) Principal coordinate analysis (PCoA) of Bray-Curtis distance analysis demonstrated that the overall microbial composition of patients with COVID-19 deviated from the uninfected controls (analysis of similarities, R = -0.201, p=0.001). (C) The same PCoA plot as (B), coloured by α-diversity measured by Chao 1 index.

Background Metabolism is critical for sustaining life, immunity and infection, but its role in COVID-19 is not fully understood. Methods Seventy-nine COVID-19 patients, 78 healthy controls (HCs) and 30 COVID-19-like patients were recruited in a prospective cohort study. Samples were collected from COVID-19 patients with mild or severe symptoms on admission, patients who progressed from mild to severe symptoms, and patients who were followed from hospital admission to discharge. The metabolome was assayed using gas chromatography–mass spectrometry. Results Serum butyric acid, 2-hydroxybutyric acid, L-glutamic acid, L -phenylalanine, l -serine, L-lactic acid, and cholesterol were enriched in COVID-19 and COVID-19-like patients versus HCs. Notably, d -fructose and succinic acid were enriched, and citric acid and 2-palmitoyl-glycerol were depleted in COVID-19 patients compared to COVID-19-like patients and HCs, and these four metabolites were not differentially distributed in non-COVID-19 groups. COVID-19 patients had enriched 4-deoxythreonic acid and depleted 1,5-anhydroglucitol compared to HCs and enriched oxalic acid and depleted phosphoric acid compared to COVID-19-like patients. A combination of d -fructose, citric acid and 2-palmitoyl-glycerol distinguished COVID-19 patients from HCs and COVID-19-like patients, with an area under the curve (AUC) > 0.92 after validation. The combination of 2-hydroxy-3-methylbutyric acid, 3-hydroxybutyric acid, cholesterol, succinic acid, L-ornithine, oleic acid and palmitelaidic acid predicted patients who progressed from mild to severe COVID-19, with an AUC of 0.969. After discharge, nearly one-third of metabolites were recovered in COVID-19 patients. Conclusions The serum metabolome of COVID-19 patients is distinctive and has important value in investigating pathogenesis, determining a diagnosis, predicting severe cases, and improving treatment.

The gut microbiota is altered in liver diseases, and several probiotics have been shown to reduce the degree of liver damage. We hypothesized that oral administration of specific Bifidobacterium strains isolated from healthy guts could attenuate liver injury. Five strains were tested in this study. Acute liver injury was induced by D-galactosamine after pretreating Sprague-Dawley rats with the Bifidobacterium strains, and liver function, liver and ileum histology, plasma cytokines, bacterial translocation and the gut microbiome were assessed. Two strains, Bifidobacterium pseudocatenulatum LI09 and Bifidobacterium catenulatum LI10, conferred liver protection, as well as alleviated the increase in plasma M-CSF, MIP-1α and MCP-1 and bacterial translocation. They also ameliorated ileal mucosal injury and gut flora dysbiosis, especially the enrichment of the opportunistic pathogen Parasutterella and the depletion of the SCFA-producing bacteria Anaerostipes, Coprococcus and Clostridium XI. Negative correlations were found between MIP-1α / MCP-1 and Odoribacter (LI09 group) and MIP-1α / M-CSF and Flavonifractor (LI10 group). Our results indicate that the liver protection effects might be mediated through gut microbiota modification, which thus affect the host immune profile. The desirable characteristics of these two strains may enable them to serve as potential probiotics for the prevention or adjuvant treatment of liver injury.