The relationship between gut microbiota and COVID-19 progression: new insights into immunopathogenesis and treatment

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a global health crisis. Increasing evidence underlines the key role of competent immune responses in resisting SARS-CoV-2 infection and manifests the disastrous consequence of host immune dysregulation. Elucidating the mechanisms responsible for deregulated host immunity in COVID-19 may provide a theoretical basis for further research on new treatment modalities. Gut microbiota comprises trillions of microorganisms colonizing the human gastrointestinal tract and has a vital role in immune homeostasis and the gut-lung crosstalk. Particularly, SARS-CoV-2 infection can lead to the disruption of gut microbiota equilibrium, a condition called gut dysbiosis. Due to its regulatory effect on host immunity, gut microbiota has recently received considerable attention in the field of SARS-CoV-2 immunopathology. Imbalanced gut microbiota can fuel COVID-19 progression through production of bioactive metabolites, intestinal metabolism, enhancement of the cytokine storm, exaggeration of inflammation, regulation of adaptive immunity and other aspects. In this review, we provide an overview of the alterations in gut microbiota in COVID-19 patients, and their effects on individuals' susceptibility to viral infection and COVID-19 progression. Moreover, we summarize currently available data on the critical role of the bidirectional regulation between intestinal microbes and host immunity in SARS-CoV-2-induced pathology, and highlight the immunomodulatory mechanisms of gut microbiota contributing to COVID-19 pathogenesis. In addition, we discuss the therapeutic benefits and future perspectives of microbiota-targeted interventions including faecal microbiota transplantation (FMT), bacteriotherapy and traditional Chinese medicine (TCM) in COVID-19 treatment.

Keywords: COVID-19; adaptive immunity; cytokine storm; gut microbiota; inflammation; microbiota-targeted interventions.

Figure 1

Roles of gut microbiota in resisting SARS-CoV-2 infection and pathogenesis. Bacteroidetes can block SARS-CoV-2-induced cytokine storm by targeting the TLR4 signaling pathway. Gut microbiota inhibits SARS-CoV-2 adhesion to target cells by regulating heparin sulfate. Gut microbiota-derived metabolite butyrate reduces the expression of membrane ACE2 and suppresses the activation of viral spike protein. Moreover, butyrate represses SARS-CoV-2-induced cell death by downregulating HMGB1. In addition, butyrate initiates antiviral immune responses by motivating the TLR7 signaling cascade. The metabolite ursodeoxycholate also exerts anti-SARS-CoV-2 effects. It prevents SARS-CoV-2 infection by blocking viral attachment to ACE2. Ursodeoxycholate has the ability to restrict the expression of pro-inflammatory cytokines, thereby ameliorating SARS-CoV-2-induced pathology. Species belonging to the Bacteroidetes phylum, such as Bacteroides dorei, Bacteroides massiliensis, Bacteroides ovatus and Bacteroides thetaiotaomicron, are found to restrain ACE2-mediated viral entry. TLR4, toll-like receptor 4; MyD88, myeloid differentiation factor 88; TRAF6, tumor necrosis factor receptor-associated factor 6; IRAKs, interleukin-1 receptor-associated kinases; IKKα, inhibitor of κB kinase α; IKKβ, inhibitor of κB kinase β; NF-κB, nuclear factor-κB; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin-converting enzyme 2; HMGB1, high mobility group protein 1; dsRNA, double-stranded RNA; TLR7, toll-like receptor 7; IRF7, interferon regulatory factor 7; IFN, interferon.

Figure 2

The involvement of dysbiotic gut microbiota in COVID-19 physiopathology. Gut microbiota affects the susceptibility of host cells to SARS-CoV-2 infection. SARS-CoV-2-induced gut microbiota perturbation contributes to COVID-19 deterioration. Thus, the gut microbiota signature is closely associated with clinical outcomes in COVID-19 patients. In terms of mechanism, gut microbiota exacerbates SARS-CoV-2-induced cytokine storm and leads to hyperinflammation. Moreover, gut microbiota is capable of abrogating host adaptive immune responses by inhibiting CD4⁺ T and CD8⁺ T cell expansion. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin-converting enzyme 2; IFN-γ, interferon-γ; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-18, interleukin-18; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; MIP-1β, macrophage inflammatory protein-1β; TNF-α, tumor necrosis factor-α.

Figure 3

Therapeutic potential of microbiota-directed treatments in COVID-19. Microbiota-targeted therapies, including FMT, probiotics and traditional Chinese medicine, may reverse gut microbiota dysbiosis and play a protective role in antagonizing SARS-CoV-2 infection and pathogenesis. FMT, faecal microbiota transplantation; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin-converting enzyme 2.