The gut microbiota role in SARS-CoV-2 infection

Author(s)

Patrícia Brito Rodrigues

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2023-08-11

Examining board members

Marco Aurélio Ramirez Vinolo; Carmen Veríssima Ferreira; Renata Sesti Costa; Juliana Terzi Maricato; Jaqueline Goes de Jesus

• Advisor: Marco Aurélio Ramirez Vinolo

Abstract

Patients infected with SARS-CoV-2 show significant changes in the composition and functionality of the microbiota, a condition called COVID-19 associated dysbiosis. These alterations have been associated with lower concentrations of short-chain fatty acids (SCFAs), metabolites that work as communications molecules between the microbiota and host cells, including components of the host's immune system. However, the relevance of the intestinal microbiota and its immunomodulatory compounds against SARS-CoV-2 infection is not yet well established. Thus, the aim of this work was to investigate the effect of treatment with SCFAs and the impact of reducing the intestinal microbial load during SARS-CoV-2 infection. For this, we used an in vitro model with intestinal biopsies and human intestinal epithelial cell lineage to evaluate the effect of SCFAs on SARS-CoV-2 infection. We then analyzed in vivo, with K18-hACE2 mice, the impact of microbiota depletion after antimicrobial treatment on clinical and immunological responses to SARS-CoV-2 infection. Furthermore, we compared the effects of gamma variant infection (P.1) versus ancestral SARS CoV-2 infection (B.1) on gut microbiota composition. Our results indicated that SCFAs, when added in vitro, despite reducing the expression of important proteins for virus entry and recognition in the host cell, such as TMPRSS2 and DDX58, respectively, did not impact the viral load in epithelial cells or intestinal biopsies. In the animal model of SARS-CoV-2 infection, we demonstrated that depletion of the intestinal microbiota by acute treatment with oral broad-spectrum antimicrobials does not alter post-infection survival and has only punctual effects on the immune response to SARS-CoV-2 indicating that under these conditions the alteration of the microbiota by antimicrobials does not interfere with the development of the disease. Finally, we observed that infection by the gamma variant in K18-hACE 2 induced changes in components of the intestinal barrier and in the composition of the microbiota that are more evident than in the case of infection by the ancestral strain. We hypothesized that these changes are related to the severity and virus infection of the nervous system. Briefly, in this work we show that, under the conditions tested, acute changes in the intestinal microbiota or in vitro supplementation with microbial metabolites, SCFAs, did not alter the response to SARS-CoV-2 infection. We also show data that indicate that different strains of SARS-CoV-2 have a different impact on the gut microbiota and aspects related to the gut barrier function, which may be relevant to the clinical differences between them (AU)

• FAPESP's process: 19/14342-7 - Comparison of gamma variant tropism and pathogenicity versus original SARS CoV-2 in humanized K18-ACE2 mice: role of gut microbiota
• Grantee: Patrícia Brito Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate