Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential

Abstract

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. This review summarizes the changes in the gut immunological barrier during SARS-CoV-2 infection and their prognostic potential.

Alterations in microbiota of patients with COVID‐19: implications for therapeutic interventions

“…The intestinal barrier can be maintained and self‐repaired to a certain extent by intestinal flora and metabolites. However, excessive activation of the immune response and immune microenvironment can cause further epithelial damage 106 . A recent Mendelian randomization study on gut microbiota and COVID‐19 susceptibility and severity further suggested a correlation between gut microbiota dysbiosis and COVID‐19 symptoms, with some dysregulated flora, such as Subdoligranulum and Lactobacillale have been found to be associated with the severity of the disease ( p < 0.05).…”

“…However, excessive activation of the immune response and immune microenvironment can cause further epithelial damage. 106 A recent Mendelian randomization study on gut microbiota and COVID‐19 susceptibility and severity further suggested a correlation between gut microbiota dysbiosis and COVID‐19 symptoms, with some dysregulated flora, such as Subdoligranulum and Lactobacillale have been found to be associated with the severity of the disease ( p < 0.05). These findings suggest that the gut microbiota may have a causal relationship with the severity of COVID‐19, thus providing new evidence and ideas for the study of the pathogenesis of SARS‐CoV‐2 mediated by gut microbiota.…”

Attenuated replication and damaging effects of SARS-CoV-2 Omicron variants in an intestinal epithelial barrier model

“…In addition to respiratory complications, up to 30% of COVID-19 patients experience gastrointestinal symptoms, including diarrhea, abdominal discomfort, loss of appetite and vomiting (Al-Momani et al, n.d.; Hayashi et al, 2021; Zhong et al, 2020). Some COVID-19 patients even develop severe duodenitis associated with gastrointestinal bleeding requiring red blood cell transfusion (Cappell and Friedel, 2023; Eleftheriotis et al, 2023). Impaired intestinal barrier function in SARS-CoV-2 infection allows microbial and endotoxin translocation, which triggers inflammation and may lead to sepsis or contribute to chronic inflammation (Assimakopoulos et al, 2022; Eleftheriotis et al, 2023; Yamada et al, 2022).…”

“…Some COVID-19 patients even develop severe duodenitis associated with gastrointestinal bleeding requiring red blood cell transfusion (Cappell and Friedel, 2023; Eleftheriotis et al, 2023). Impaired intestinal barrier function in SARS-CoV-2 infection allows microbial and endotoxin translocation, which triggers inflammation and may lead to sepsis or contribute to chronic inflammation (Assimakopoulos et al, 2022; Eleftheriotis et al, 2023; Yamada et al, 2022). Altogether, accumulating evidence suggests that SARS-CoV-2 infection of the gastrointestinal tract plays a relevant role in COVID-19 (Jin et al, 2021; Scaldaferri et al, 2020; Zhang et al, 2021).…”

“…Immunohistochemical analysis of gut biopsies from COVID-19 patients stained positive for the SARS-CoV-2 Spike protein and in situ hybridization analysis further support active viral replication (Neuberger et al, 2022). Previous studies suggest that SARS-CoV-2 affects various aspects of gut immune and barrier function and show that the integrity of the intestinal barrier is significantly impaired in a notable portion of COVID-19 patients (Eleftheriotis et al, 2023; Farsi et al, 2022; Tsounis et al, 2023; Yamada et al, 2022; Zuo et al, 2020). Despite its importance in the pathogenesis of COVID-19, the impact of SARS-CoV-2 infection on intestinal barrier function is poorly explored.…”