Abstract
Involvement of gut microbiota in pulmonary disease by the gut-lung axis has been widely observed. However, the cross-talk messengers between respiratory mucosal immunity and gut microbiota are largely unknown. Using selective pharmacologic destruction of gut microenvironment mouse models, we found gut microbiota displayed significantly lower alpha diversity and relative abundance of bacteria in Gentamicin treated mice. Metagenomic studies revealed functional differences in gut bacteria in altering metabolic profiles in mice blood. Branched-chain amino acids (BCAAs) are the essential factors linked between gut and lung. During this process, selective destruction of gut microbiota by Gentamicin induced high levels of BCAAs, and the high levels of BCAAs impacted the lung immunity against influenza virus. In vivo, Gentamicin-treated mice or mice fed with high BCAAs diets displayed reduced survival. At the sites of infection, the number of CD11b+Ly6G+ cells decreased, and CD8+ T cells increased accompanied by exuberant expression of pro-inflammatory cytokines could result in tissue damage. CD11b+Ly6G+ cells transplantation conferred remarkable protection from influenza virus infections. In vitro, BCAAs promoted bone marrow-derived cells differentiation to dendritic cells. Taken together, these findings demonstrate that Gentamicin induced disruption of the gut microbiota leads to increased BCAA levels that suppress CD11b+Ly6c+ cell development in association with overactive CD8+ T responses which may contribute to enhanced severity of the viral infection.
Highlights
The human intestinal tract harbors trillions of microorganisms referred to as the gut microbiota, which fulfils many essential functions, with disruption of the structure of this community leading to dysbiosis [1,2,3]
Branched-chain amino acids (BCAAs) promoted bone marrow-derived cells differentiation to dendritic cells. These findings demonstrate that Gentamicin induced disruption of the gut microbiota leads to increased BCAA levels that suppress CD11b+Ly6c+ cell development in association with overactive CD8+ T responses which may contribute to enhanced severity of the viral infection
To investigate the role of gut microbiota diversity altered by different antibiotics during influenza virus infection, mice were treated with antibiotics (Streptomycin, Vancomycin, Tinidazole, and Gentamicin, all antibiotics cannot be absorbed by intestine) separately, and intranasal challenged with sublethal dose (103.5TCID50) Influenza A virus (A/Puerto Rico/ 8/1934, PR8)
Summary
The human intestinal tract harbors trillions of microorganisms referred to as the gut microbiota, which fulfils many essential functions, with disruption of the structure of this community leading to dysbiosis [1,2,3]. People have reached a greater understanding of gut-lung axis. This axis from the simple fact that gut microbiota can influence lung function and pathogen clearance mediated by metabolites, microbiota produces, or via immune cells and immune factors [10]. Understanding the mechanisms that mediate cross-talk between the gut microbiota and lung defenses and how this interaction facilitates optimal lung health is of growing interest. Mechanistically, this phenomenon remains poorly defined, the existence of the gut-lung axis and its implications in both health and disease could be profoundly important for lung infection
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