Obesity- and sex-specific alterations in gut microbiota during the early phase of influenza A virus infection

Abstract

Influenza A virus (IAV) infection leads to gut dysbiosis and increases the risk of secondary gut bacterial infections. Conversely, gut microbiota and their products regulate the severity and outcomes of IAV infection. Obesity markedly alters gut microbiota and is associated with increased IAV severity. Gut microbiota also differs between males and females, and studies have suggested that females with or without obesity suffer from more severe disease than their male counterparts following IAV infection. In this study, our objective was to determine how obesity and biological sex influence baseline gut microbiota and alterations in gut microbiota at the early phase of disease following IAV infection. Male and female C57BL/6J mice were fed either a high-fat or low-fat diet to obtain mice with or without obesity and then infected intranasally with high (10^3 TCID50) or low doses (10^1.5 TCID50) of mouse-adapted A/California/04/2009 H1N1 IAV. Fecal pellets were collected before and after infection, and gut microbiome composition, diversity, and predicted functional pathways were assessed at baseline and during the acute phase of infection using 16S rRNA gene sequencing and functional pathway prediction. High-fat diet (HFD) feeding induced marked alterations in gut microbiome composition and functional pathways in both sexes. Yet, sex-specific differences existed. Following high-dose IAV (HDI) infection, depletion of beneficial bacteria such as Bifidobacterium, Lactobacillus, Dubosiella, and Faecalibaculum was observed in mice with or without obesity. Low-dose IAV (LDI) infection, however, had pronounced effects only in mice with obesity, where they had reduced abundances of beneficial bacteria such as Bifidobacterium, Dubosiella, Faecalibaculum, Lactobacilus, and Oscillibacter. At 3 dpi, obesity-driven gut microbiota differences were mostly preserved and not further perturbed following both HDI and LDI infections. However, sex difference analysis indicated a shift in the relative abundance of beneficial bacteria such as Dubosiella, Roseburia, and Lactobacillus towards a lower proportion than at the baseline, in females with obesity following LDI infection, which might contribute towards the greater influenza disease severity in females with obesity. Our study suggests the interaction of obesity and biological sex in gut dysbiosis following IAV infection in a mouse model, which may drive differential outcomes of influenza disease severity or predispose them differentially to secondary gut bacterial infections.