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ABSTRACT
Gastrointestinal (GI) infection is evidenced with involvement in COVID-19 pathogenesis caused by SARS-CoV-2. However, the correlation between GI microbiota and the distinct pathogenicity of SARS-CoV-2 Proto and its emerging variants remains unclear. In this study, we aimed to determine if GI microbiota impacted COVID-19 pathogenesis and if the effect varied between SARS-CoV-2 Proto and its variants. We performed an integrative analysis of histopathology, microbiomics, and transcriptomics on the GI tract fragments from rhesus monkeys infected with SARS-CoV-2 proto or its variants. Based on the degree of pathological damage and microbiota profile in the GI tract, five of SARS-CoV-2 strains were classified into two distinct clusters, namely, the clusters of Alpha, Beta and Delta (ABD), and Proto and Omicron (PO). Notably, the abundance of potentially pathogenic microorganisms increased in ABD but not in the PO-infected rhesus monkeys. Specifically, the high abundance of UCG-002, UCG-005, and Treponema in ABD virus-infected animals positively correlated with interleukin, integrins, and antiviral genes. Overall, this study revealed that infection-induced alteration of GI microbiota and metabolites could increase the systemic burdens of inflammation or pathological injury in infected animals, especially in those infected with ABD viruses. Distinct GI microbiota and metabolite profiles may be responsible for the differential pathological phenotypes of PO and ABD virus-infected animals. These findings improve our understanding the roles of the GI microbiota in SARS-CoV-2 infection and provide important information for the precise prevention, control, and treatment of COVID-19.
List of abbreviations
| ABD | = | Alpha, Beta and Delta |
| PO | = | Proto and Omicron |
| SARS-CoV-2 | = | severe acute respiratory syndrome coronavirus 2 |
| COVID-19 | = | Coronavirus Disease 2019 |
| MERS-CoV | = | Middle East respiratory syndrome coronavirus |
| VOCs | = | variants of concern |
| ACE2 | = | angiotensin converting enzyme 2 |
| GI | = | Gastrointestinal |
| MAIT | = | mucosal-associated invariant T |
| SCFAs | = | Short-chain fatty acids |
| DAMPs | = | danger-associated molecular patterns |
| RLRs | = | RIG-I-like receptors |
| NLRs | = | NOD-like receptors |
| NHP | = | non-human primate |
| ABLS3 | = | Animal Biosafety Level 3 |
| AB-PAS | = | Alcian blue and Periodic acid-Schiff |
| OTUs | = | operational taxonomic units |
| H&E | = | hematoxylin-eosin staining |
| PCoA | = | Principal coordinate analysis |
| PBS | = | phosphate-buffered saline |
| PLS-DA | = | partial least squares discriminant analysis |
| PFU | = | plaque- forming units |
| db-RDA | = | distance-based redundancy analysis |
| PICRUSt2 | = | Phylogenetic Investigation of Communities by Reconstruction of Unobserved States |
| FPKM | = | fragments per kilobase of exon per million mapped reads |
| FDR | = | false discovery rates |
| DEGs | = | differentially expressed genes |
| GO | = | Gene Ontology |
| KEGG | = | Kyoto Encyclopedia of Genes and Genomes |
| WGCNA | = | weighted gene co-expression network analysis |
| GSEA | = | Gene set enrichment analysis |
| G-CSF | = | granulocyte colony-stimulating factor |
| GM-CSF | = | granulocyte-macrophage colony-stimulating factor |
| IFNγ | = | interferon gamma |
| TGF | = | transforming growth factor |
| TNF | = | tumor necrosis factor |
| VEGF | = | vascular epithelial growth factor |
| MCP | = | Monocyte Chemoattractant Protein |
| MIP | = | macrophage inflammatory protein |
| MLN | = | mesenteric lymph node |
| IBD | = | Inflammatory Bowel Disease |
Acknowledgments
We appreciate services of all the staff at the National Kunming High-level Biosafety Primate Research Center. We thank Institute of Laboratory Animal Sciences CAMS&PUMC, Guangdong CDC, Chongqing CDC, and Professor Wenjie Tan in China CDC for kindly providing SARS-CoV-2.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Authors’ contributions
HL, XP, and SL designed the study. HC and HL wrote the manuscript. HC, JW, KD, JX, YY, CT, YZ, WY, HW, QH, BL, DK, DW, ZL, JG, YZ, JL, and SL performed experiments. HC, JW, YY analyzed data. All authors have read, edited, and approved the final manuscript.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2334970