Gentamicin Induced Microbiome Adaptations Associate With Increased BCAA Levels and Enhance Severity of Influenza Infection

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.

Gentamicin promoted the production of CD4+CD25+ Tregs via the STAT5 signaling pathway in mice sepsis

“…Furthermore, GNT activated Tregs to reduce the mortality of LPS-induced mice, and decreased the concentrations of pro-inflammatory cytokines and increased the concentrations of anti-inflammatory cytokines, contributing to the recovery of neonatal sepsis. Additionally, Sun et al showed that the pre-treatment of mice with GNT regulates the microbiota into guts and could impair the immune response to influenza virus infection [ 33 ]. However, whether the beneficial effects of GNT in sepsis were related to the reduction of bacterial translocation from guts and/or sepsis-related infection need further investigation.…”

“…The role of Tregs in sepsis remains controversial. Hotchkiss et al reported that Tregs impair immunity and contribute to contribute to nosocomial infections and mortality [33]. However, several studies have shown that activated Tregs prevent polymicrobial sepsis mortality [32,34], and regulate the activation status and antigen-presenting cell function and produce anti-inflammatory cytokines, which are beneficial to sepsis [35][36][37].…”

Gut Microbiota Dysbiosis Aggravates Mycoplasma gallisepticum Colonization in the Chicken Lung

“…Gut microbiota metabolites are considered important mediators of gut-lung interactions. For example, gentamicin induced disorder of gut microbiota results in increased branched-chain amino acids levels that suppress immune cells development which could contribute to enhanced severity of the influenza infection ( 28 ). In addition, gut microbiota dysbiosis aggravated lung histopathologic injury, up-regulated pro-inflammatory cytokine production and air-blood permeability, and increased bacterial load caused by avian pathogenic Escherichia coli , which partially due to reduced gut microbiota-derived acetate levels ( 8 ).…”

Gut Microbiota as the Link between Elevated BCAA Serum Levels and Insulin Resistance

“…Sun et al described the effect of the gentamicin intervention in mice infected with the Influenza virus. Besides the reduced survival of the mice, gentamicin treatment also resulted in an increased abundance of Bacteroidetes, decreased abundance of Proteobacteria, and elevated serum BCAA concentration [79].…”

“…The functional capacity of the gut microbiota was derived from its composition using PICRUSt [74,77], predicted by pathway analysis based on metabolome composition [48] or using both approaches [75,78]. Currently, there is only one available human study describing the effect of symbiotic (SG) administration (Bifidobacterium lactis UBBLa-70 + fructooligosaccharide) in combination with low-energy intervention in obese women [79]. Both interventions led to a comparable weight loss but the serum BCAA concentration decreased only in the SG-supplemented group.…”