Peer-review started: October 12, 2022
First decision: November 3, 2022
Revised: November 8, 2022
Accepted: January 16, 2023
Article in press: January 16, 2023
Published online: March 25, 2023
The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells, forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens. Despite being a lung-centered disease, severe coronavirus disease 2019 (COVID-19) affects multiple systems, including the gastrointestinal tract and the pertinent gut barrier function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage. Alternatively, SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins. In addition, SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels (dysbiosis) that are accompanied by disruption of local immune responses. The ensuing dysregulation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection. The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury, which simultaneously triggers the activation of the innate immune and coagulation systems, a condition referred to as “immunothrombosis” that drives severe thrombotic complications. Finally, increased intestinal permeability allows an aberrant dissemination of bacteria, fungi, and endotoxin into the systemic circulation and contributes, to a certain degree, to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19. In this review, we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.
Core Tip: Severe coronavirus disease 2019 (COVID-19) is associated with a multi-layered disruption of gut barrier integrity. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inflicts direct cytopathic or indirect immune-mediated injury to intestinal epithelial and endothelial cells and enhances paracellular permeability by downregulating tight junction proteins. SARS-CoV-2 induces profound gut microbiome alterations accompanied by dysregulation of mucosal immune responses. Gut dysbiosis attenuates, through the gut-lung axis, the ability of the respiratory immune system to elicit vigorous responses to contain SARS-CoV-2. Additionally, intestinal barrier dysfunction promotes endothelial activation and predisposes to detrimental COVID-19-related thrombotic complications. Finally, bacterial translocation and endotoxemia contribute to over-exuberant immune responses and hyper-inflammation in severe COVID-19.