SARS-CoV-2 infections causes alterations in gut immunological barrier

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Although coronavirus disease 2019 (COVID-19) is primarily associated with mild respiratory symptoms, a subset of patients may develop more complicated disease with systemic complications and multiple organ injury.

The gastrointestinal tract may be directly infected by SARS-CoV-2 or secondarily affected by viremia and the release of inflammatory mediators that cause viral entry from the respiratory epithelium. Impaired intestinal barrier function in SARS-CoV-2 infection is a key factor leading to excessive microbial and endotoxin translocation, which triggers a strong systemic immune response and leads to the development of viral sepsis syndrome with severe sequelae.

Multiple components of the gut immune system are affected, resulting in a diminished or dysfunctional gut immunological barrier. Antiviral peptides, inflammatory mediators, immune cell chemotaxis, and secretory immunoglobulins are important parameters that are negatively affected in SARS-CoV-2 infection.

Mucosal CD4+ and CD8+ T cells, Th17 cells, neutrophils, dendritic cells, and macrophages are activated, and the number of regulatory T cells decreases, promoting an overactivated immune response with increased expression of type I and III interferons and other proinflammatory cytokines.

The changes in the immunologic barrier could be promoted in part by a dysbiotic gut microbiota, through commensal-derived signals and metabolites. On the other hand, the proinflammatory intestinal environment could further compromise the integrity of the intestinal epithelium by promoting enterocyte apoptosis and disruption of tight junctions.

Figure 1 Key features of intestinal immune barrier disruption during SARS-CoV-2 infection. SARS-CoV-2 infection is associated with profound alterations in the intestinal microflora, manifested by decreased species diversity, depletion of symbiotic microorganisms, and prevalence of pathogenic species. Signals and metabolites derived from the intestinal flora, such as short-chain fatty acids (SCFAs), play an important role in controlling mucosal immunity by promoting T regulatory cell (Treg) responses and the activity of tolerogenic dendritic cells (DCs). This immunoregulatory environment, rich in anti-inflammatory mediators (IL-10, TGF-β), is significantly impaired by SARS-CoV-2. As a result, B cell metabolism and maturation are severely impaired, leading to exhaustion of effective plasma cells that produce secretory dimeric immunoglobulin A (sIgA), which is essential for viral containment. The proliferation of SARS-CoV-2 is also facilitated by its ability to evade recognition by the immune system by interfering with type I and type III IFN signaling. SARS-CoV-2 exerts either direct cytopathic effects on intestinal epithelial cells (IECs) expressing ACE2 and TMPRSS2 receptors or indirect immune-mediated injury. During COVID-19, the expression of several antimicrobial peptides, including defensins, is dysregulated, which increases the infectivity of SARS-CoV-2. In addition, recruitment of intraepithelial lymphocytes (IELs) accelerates IEC apoptosis. The release of damage-associated molecular patterns (DAMPs) due to cell injury and the influx of pathogen-associated molecular patterns (PAMPs) as a result of increased gut permeability lead to immune activation. Macrophages/monocytes, neutrophils, and other cells of the innate immune system secrete large amounts of proinflammatory mediators (IL-1β, IL-6, TNF-α, ROS) and chemokines (CCL5, CXCL10) that cause recruitment of additional immune cells and prime effector T cells. In parallel, disruption of the intestinal barrier facilitates bacterial translocation, endotoxemia, and dissemination of other gut-derived stimuli that contribute to systemic hyperinflammatory responses and cytokine release syndrome, leading to severe COVID-19.

The COVID-19 Research findings were published in the peer reviewed journal:
Frontiers In Immunogy.
https://www.frontiersin.org/articles/10.3389/fimmu.2023.1129190/full

SARS-CoV-2-mediated gut microbiome and immunological changes

The constant interaction of immune cells with the gut microbiome maintains the balance between tolerance to beneficial bacteria and eradication of pathogenic species (80). A complex, dynamic, and bilateral interaction between the gut microbiome and COVID-19 has been described (81).

The gut microbiome of patients with SARS-CoV-2 infection exhibits significant alterations, possibly due to a severe systemic inflammatory response. The mechanisms underlying COVID-19-related dysbiosis are still unclear. However, interactions between the ACE2 receptor and SARS-CoV-2 have been associated with alterations in the composition of the gut microbiota by impairing the secretion AMPs.

The function of the amino acid transporter B0AT1, which mediates intestinal uptake of tryptophan, is dependent on the ACE2 pathway (82). Tryptophan modulates the production of AMPs via the mammalian target of rapamycin (mTOR) pathway (83). Therefore, the deficiency of tryptophan caused by ACE-2 blockade may decrease the production of AMPs and disrupt the intraluminal microbial species. Commensal bacteria also play a critical role in mucosal homeostasis by modulating the expression of ACE2 in the gut (84).

Secretion of proinflammatory cytokines, particularly TNF-α, during respiratory tract infections has a dynamic anorexigenic effect via hypothalamic activity. The decrease in fiber and caloric intake disrupts the composition of the gut microbiota and the synthesis of its metabolites, which in turn strongly influence the transcriptional “training” of innate immune cells (85).

A recent meta-analysis detailed the changes in the gut microbiota during SARS-CoV-2 infection (11). At the phylum level, dysbiosis is characterized by a reduction in the ratio of Firmicutes to Bacteroidetes. In particular, COVID-19 is associated with fewer butyrate-producing bacterial species, including Faecalibacterium and Roseburia (11, 15, 86).

The genus Roseburia is closely associated with colon motility and mucosal tissue integrity and has a crucial anti-inflammatory effect by regulating IL-10 synthesis (87). Several other beneficial genera, including Eubacterium, Alistipes, and Bifidobacterium, are also reduced in COVID-19 patients (11). Bifidobacterium strains mediate robust antimicrobial and antiviral activity, which is balanced by promotion of Treg-mediated responses and induction of tolerogenic DC phenotypes (88).

Alterations in the gut microbiome have also been closely associated with clinical severity of COVID-19 in several studies, suggesting a prognostic role in such patients (12–24). Bacterial genera with significant prognostic value included Eubacterium, Ruminococcus, Faecalibacterium, Bacteroides, Lactobacillus, Clostridium, Roseburia, and Bifidobacterium (12–24). An increase in the dominant genus Enterococcus and a decrease in the families Ruminococcaceae and Lachnospiraceae have been reported in severe COVID-19 cases admitted to the intensive care unit (21).

The changes in the gut microbiota in patients with COVID-19 should be considered as a dynamic process (81). Emerging evidence suggests that the regulatory functions of the gut microbiota effectively support recovery from SARS-CoV-2 infection. The main features of intestinal immune barrier disruption during SARS-CoV-2 infection are shown in Figure 1.

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