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Fecal multi-omics analysis reveals diverse molecular alterations of gut ecosystem in COVID-19 patients.

ABSTRACT: Gut ecosystem has profound effects on host physiology and health. Gastrointestinal (GI) symptoms were frequently observed in patients with COVID-19. Compared with other organs, gut antiviral response can result in more complicated immune responses because of the interactions between the gut microbiota and host immunity. However, there are still large knowledge gaps in the impact of COVID-19 on gut molecular profiles and commensal microbiome, hindering our comprehensive understanding of the pathogenesis of SARS-CoV-2 and the treatment of COVID-19. We performed longitudinal stool multi-omics profiling to systemically investigate the molecular phenomics alterations of gut ecosystem in COVID-19. Gut proteomes of COVID-19 were characterized by disturbed immune, proteolysis and redox homeostasis. The expression and glycosylation of proteins involved in neutrophil degranulation and migration were suppressed, while those of proteases were upregulated. The variable domains of Ig heavy chains were downregulated and the overall glycosylation of IgA heavy chain constant regions, IgGFc-binding protein, and J chain were suppressed with glycan-specific variations. There was a reduction of beneficial gut bacteria and an enrichment of bacteria derived deleterious metabolites potentially associated with multiple types of diseases (such as ethyl glucuronide). The reduction of Ig heave chain variable domains may contribute to the increase of some Bacteroidetes species. Many bacteria ceramide lipids with a C17-sphingoid based were downregulated in COVID-19. In many cases, the gut phenome did not restore two months after symptom onset. Our study indicates widely disturbed gut molecular profiles which may play a role in the development of symptoms in COVID-19. Our findings also emphasis the need for ongoing investigation of the long-term gut molecular and microbial alterations during COVID-19 recovery process. Considering the gut ecosystem as a potential target could offer a valuable approach in managing the disease.

SUBMITTER: He F

PROVIDER: S-EPMC8310733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: Children usually develop less severe symptoms responding to Coronavirus Disease 2019 (COVID-19) than adults. However, little is known about the molecular alterations and pathogenesis of COVID-19 in children. Methods: We conducted plasma proteomic and metabolomic profilings of the blood samples of a cohort containing 18 COVID-19-children with mild symptoms and 12 healthy children, which were enrolled from hospital admissions and outpatients, respectively. Statistical analyses were performed to identify molecules specifically altered in COVID-19-children. We also developed a machine learning-based pipeline named inference of biomolecular combinations with minimal bias (iBM) to prioritize proteins and metabolites strongly altered in COVID-19-children, and experimentally validated the predictions. Results: By comparing to the multi-omic data in adults, we identified 44 proteins and 249 metabolites differentially altered in COVID-19-children against healthy children or COVID-19-adults. Further analyses demonstrated that both deteriorative immune response/inflammation processes and protective antioxidant or anti-inflammatory processes were markedly induced in COVID-19-children. Using iBM, we prioritized two combinations that contained 5 proteins and 5 metabolites, respectively, each exhibiting a total area under curve (AUC) value of 100% to accurately distinguish COVID-19-children from healthy children or COVID-19-adults. Further experiments validated that all the 5 proteins were up-regulated upon coronavirus infection. Interestingly, we found that the prioritized metabolites inhibited the expression of pro-inflammatory factors, and two of them, methylmalonic acid (MMA) and mannitol, also suppressed coronaviral replication, implying a protective role of these metabolites in COVID-19-children. Conclusion: The finding of a strong antagonism of deteriorative and protective effects provided new insights on the mechanism and pathogenesis of COVID-19 in children that mostly underwent mild symptoms. The identified metabolites strongly altered in COVID-19-children could serve as potential therapeutic agents of COVID-19.

Project description:The gut microbiota is the largest and most complex microecosystem in animals. It is influenced by the host's dietary habits and living environment, and its composition and diversity play irreplaceable roles in animal nutrient metabolism, immunity, and adaptation to the environment. Although the gut microbiota of red deer has been studied, the composition and function of the gut microbiota in Gansu red deer (Cervus elaphus kansuensis), an endemic subspecies of red deer in China, has not been reported. In this study, the composition and diversity of the gut microbiome and fecal metabolomics of C. elaphus kansuensis were identified and compared for the first time by using 16S rDNA sequencing, metagenomic sequencing, and LC-MS/MS. There were significant differences in gut microbiota structure and diversity between wild and farmed C. elaphus kansuensis. The 16S rDNA sequencing results showed that the genus UCRD-005 was dominant in both captive red deer (CRD) and wild red deer (WRD). Metagenomic sequencing showed similar results to those of 16S rDNA sequencing for gut microbiota in CRD and WRD at the phylum and genus levels. 16S rDNA and metagenomics sequencing data suggested that Bacteroides and Bacillus might serve as marker genera for CRD and WRD, respectively. Fecal metabolomics results showed that 520 metabolites with significant differences were detected between CRD and WRD and most differential metabolites were involved in lipid metabolism. The results suggested that large differences in gut microbiota composition and fecal metabolites between CRD and WRD, indicating that different dietary habits and living environments over time have led to the development of stable gut microbiome characteristics for CRD and WRD to meet their respective survival and reproduction needs. KEY POINTS: • Environment and food affected the gut microbiota and fecal metabolites in red deer • Genera Bacteroides and Bacillus may play important roles in CRD and WRD, respectively • Flavonoids and ascorbic acid in fecal metabolites may influence health of red deer.

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Fecal multi-omics analysis reveals diverse molecular alterations of gut ecosystem in COVID-19 patients.

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