Gut microbiota in COVID-19: key microbial changes, potential mechanisms and clinical applications

Abstract

The gastrointestinal tract is involved in coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The gut microbiota has important roles in viral entry receptor angiotensin-converting enzyme 2 (ACE2) expression, immune homeostasis, and crosstalk between the gut and lungs, the 'gut-lung axis'. Emerging preclinical and clinical studies indicate that the gut microbiota might contribute to COVID-19 pathogenesis and disease outcomes; SARS-CoV-2 infection was associated with altered intestinal microbiota and correlated with inflammatory and immune responses. Here, we discuss the cutting-edge evidence on the interactions between SARS-CoV-2 infection and the gut microbiota, key microbial changes in relation to COVID-19 severity and host immune dysregulations with the possible underlying mechanisms, and the conceivable consequences of the pandemic on the human microbiome and post-pandemic health. Finally, potential modulatory strategies of the gut microbiota are discussed. These insights could shed light on the development of microbiota-based interventions for COVID-19.

Fig. 1. Possible roles of the gut microbiota in dysfunctional immune responses and COVID-19 severity.

We propose potential mechanisms by which the gut microbiota can contribute to dysfunctional immune responses and coronavirus disease 2019 (COVID-19) severity. The first part hypothesizes that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could lead to gut dysbiosis by several possible mechanisms: (1) invasion of SARS-CoV-2 can activate pattern-recognition receptors (Toll-like receptors (TLRs), RLRs, NLRs), which are recognized by innate immune cells, resulting in the release of various pro-inflammatory cytokines. These activated immune responses could impair gut permeability, disrupt gut microbiota equilibrium and result in an increased abundance of opportunistic pathogens (for example, Enterobacteriaceae and Enterococcus) and decreased abundance of commensal symbionts (for example, Faecalibacterium, Eubacterium and Roseburia). (2) SARS-CoV-2 infection was found to downregulate the expression of angiotensin-converting enzyme 2 (ACE2) and B0AT1 (a molecular ACE2 chaperone) on the luminal surfaces of intestinal epithelial cells, which may facilitate the growth of the pathogens^,,. (3) An in vitro study found that SARS-CoV-2 might directly infect bacteria. In the second part, we propose that specific intrinsic ‘microbiome signatures’ at the point of SARS-CoV-2 infection could influence the severity of infection and host immune response by several putative mechanisms: (i) increased opportunistic pathogens might be further recognized by innate lymphocytes and intensify gut pro-inflammatory responses. (ii) Opportunistic pathogens and toxins could translocate into the circulatory system, causing bacteraemia and exacerbating systematic inflammation and disease severity^,. (iii) Depleted commensal symbionts could negatively influence the recruitment of immune cells, such as activated mucosal-associated invariant T (MAIT) cells, to affect susceptibility and severity of respiratory tract infections^–. CXCL10, C-X-C motif ligand 10.

Fig. 2. Proposed model of gut microbiome changes pre-pandemic, during pandemic, and post-pandemic and how COVID-19 measures influence microbiota diversity during an individual’s lifetime.

a, Prior to the coronavirus disease 2019 (COVID-19) pandemic, the gut microbiota in a healthy individual was characterized by ‘eubiosis’, a balanced gut ecosystem with rich microbial diversity, whilst certain individuals, including older age groups and those with chronic diseases such as inflammatory bowel disease (IBD), diabetes mellitus, cardiovascular disease and obesity, had an altered gut ecosystem with reduced microbial diversity and altered gut microbial composition^,. ‘Dysbiosis’ could contribute to increased susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, increased COVID-19 severity, worsened clinical outcomes and/or decreased COVID-19 vaccine response. b, During the pandemic, acute COVID-19 infection was associated with consistent gut microbiota composition changes and impaired short-chain fatty acid (SCFA) biosynthesis^,, and disrupted tryptophan metabolism^–. Dysbiosis seen in the initial infection was also associated with post-acute COVID-19 syndrome, including chronic respiratory symptoms (for example, coughing or shortness of breath), cardiovascular symptoms (for example, chest pain or palpitation), gastrointestinal symptoms (for example, loss of appetite or diarrhoea), neuropsychiatric symptoms (for example, anxiety or insomnia), musculoskeletal symptoms (for example, joint pain or muscle weakness), and dermatological symptoms (for example, skin rash or hair loss)^–. In the post-acute COVID-19 phase, the gut microbiota remained persistently disrupted, characterized by persistent depletion of SCFA-producing bacteria Faecalibacterium, Eubacterium and Roseburia^,. Alterations of gut microbiota composition in the post-acute stage were also associated with multi-organ post-acute COVID-19 syndrome. c, Beyond the pandemic, existing pandemic control practices with strict implementation of social distancing, extensive hygiene measures, regular vaccination and restricted travel could negatively affect microbiome diversity in infants and have substantial effects on early-life bacterial colonization in the gut, with unknown consequences for disease risk. The key microbial changes consistently reported in multiple human studies are presented.

Fig. 3. Microbiota-based interventions in COVID-19.

Multiple studies have suggested the role of diet, probiotics, and microbiota-derived metabolites and faecal microbiota transplantation in enhancing antiviral capacity and improving clinical outcomes of coronavirus disease 2019 (COVID-19), such as severity and symptoms, potentially through the modulation of gut microbiota. Nevertheless, many of these preliminary conclusions were drawn based on association and retrospective analyses. Further animal and clinical studies are warranted to elucidate the mechanistic links underlying the therapeutic effects of these microbiota-based interventions. BIP, 2,5-bis(3-indolylmethyl)pyrazine; IPA, N6-(Δ2-isopentenyl)adenosine; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SCFA, short-chain fatty acid.