Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions

Abstract

The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn's disease, and certain viral infections. In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.

Fig. 1

COVID-19-associated respiratory and gastrointestinal symptoms. Various respiratory and gastrointestinal manifestations occur in patients with COVID-19 including shortness of breath, cough or sore throat, nasal congestion or runny nose, pneumonia, acute respiratory distress syndrome (ARDS), nausea or vomiting, diarrhea, and abdominal pain

Fig. 2

Primary habitats of human microbiota: respiratory and gastrointestinal tracts as SARS-CoV-2 infection targets. SARS-CoV-2 receptors ACE2 and TMPRSS2 are expressed mainly in respiratory and gastrointestinal tracts which provide many suitable habitats for microorganisms. The right side of the figure lists representative bacterial populations in different parts of the respiratory and gastrointestinal tracts

Fig. 3

Potential mechanisms of cytokine storm and secondary pathogen infections resulting from lung microbiota dysbiosis in patients with COVID-19. SARS-CoV-2 infection disrupts lung microbiota eubiosis. Increased abundance of opportunistic pathogens may intensify lung cytokine storm and cause secondary pathogen infections in patients with COVID-19. Pathogen-associated molecular patterns (PAMPs) released from invading opportunistic pathogens may be recognized by host innate lymphocytes such as macrophages and dendritic cells (DCs) via pattern recognition receptors (PRR) including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and NOD-like receptors (NLRs). These induce expression of proinflammatory factors via NF-κB signaling, interferons via IRF3 signaling, and numerous interferon-stimulated genes (ISGs) via JAK/STAT signaling. Excess cytokines may exacerbate COVID-19 symptoms

Fig. 4

Potential mechanisms of cytokine storm and secondary pathogen infections resulting from gut microbiota dysbiosis in patients with COVID-19. Gut microbiota are also disrupted by SARS-CoV-2 infection which potentially triggers cytokine storm and secondary pathogen infections. B⁰AT1 mediates neutral amino acid uptake by luminal surfaces of intestinal epithelial cells. It is also a molecular ACE2 chaperone. B⁰AT1 substrates such as tryptophan and glutamine activate antimicrobial peptide release, promote tight junction (TJ) formation, downregulate lymphoid proinflammatory cytokines, and modulate mucosal cell autophagy via mTOR signaling. As ACE2 is a molecular B⁰AT1 chaperone, ACE2-associated B⁰AT1 may be internalized during SARS-CoV-2 infection, decrease B⁰AT1 on cell membranes, promote gut opportunistic pathogen invasion, facilitate cytokine storms, and exacerbate COVID-19

Fig. 5

Gut commensal-derived metabolites or components potentially promote lung antiviral immune responses via gut–lung axis during the early stages of SARS-CoV-2 infection. Gut microbiota such as Bifidobacterium animalis, Bacteroides thetaiotaomicron, Lactobacillus casei, and Enterobacter cloacae generate riboflavin derivatives that activate mucosal-associated T cells (MAIT) via restrictive major histocompatibility complex (MHC)-related protein-1 (MR1)-mediated recognition. Activated gut MAIT cells may participate in lung antiviral immune responses via gut–lung axis during early stages of SARS-CoV-2 infection. Deaminotyrosine (DAT) generated by gut bacterium Clostridium orbiscindens may protect host from viral infection by initiating amplification loop of type I interferon (IFN) signaling. Microbiota-derived components are required to program DCs during steady state so they can rapidly initiate immune responses to pathogens. Gut microbiota-derived metabolites and components may play vital roles in inhibiting early SARS-CoV-2 infection

Fig. 6

Anti-inflammatory immunomodulation by gut microbiota-derived metabolites and components. Left to right: polysaccharide A (PSA) capsular component of gut commensal Bacteroides fragilis can be transported to gut lamina propria via autophagy-related protein 16-like 1 (ATG16L1) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-dependent autophagy. PSA signals promote FOXP3 + regulatory T-cell (Treg) proliferation and IL-10 production and induce an anti-inflammatory state. Vitamin A or retinoic acid (RA) derived from gut commensal Bifidobacterium infantis upregulates Aldh1a2 encoding retinal dehydrogenase 2 in DCs. Aldh1a2-expressing DCs produce high levels of RA which collaborates with transforming growth factor-β (TGF-β) to promote naive T cell differentiation into FOXP3 + Treg cells and inhibit inflammation caused by SARS-CoV-2 infection. Gut microbiota may produce short-chain fatty acids (SCFAs) acetate, propionate, and butyrate to inhibit inflammation caused by SARS-CoV-2 infection. Butyrate promotes M2-like macrophage polarization and anti-inflammatory activity by upregulating arginase 1 (ARG1), suppressing tumor necrosis factor (TNF) production, and downregulating Nos2, Il6, and Il12b. Butyrate inhibits histone deacetylases, increases transcription at Foxp3 promoter and related enhancer sites in naive T cells, and promotes naive T cell differentiation into Treg cells. Propionate activates GPR43 on Treg cells, thereby enhancing their proliferation. Acetate promotes anti-SARS-CoV-2 antibody production in B cells, thereby inhibiting SARS-CoV-2 infection. Microbiota members induce CX3CR1 + macrophages that inhibit T helper 1 (TH1) and promote Treg cell responses. Cell-surface β-glucan/galactan (CSGG) polysaccharide produced by Bifidobacterium bifidum may induce Foxp3+ regulatory T-cell generation and inhibit inflammation caused by SARS-CoV-2 infection. Gut commensals such as Helicobacter spp. and Clostridium ramosum induce RORγt expression in Foxp3+ regulatory T cells, thereby suppressing TH1, TH2, and TH17 cell-type inflammatory responses

Fig. 7

Potential microbiota-based COVID-19 therapies include fecal microbiota transplantation (FMT), probiotics and prebiotics, engineered symbiotic bacteria, and microbiota-derived metabolites