Alcohol-associated intestinal dysbiosis impairs pulmonary host defense against Klebsiella pneumoniae

PLoS Pathogens

Derrick R. Samuelson¹  Judd E. Shellito¹  Christopher M. Taylor²  Meng Luo²  Eric D. Tague²  Martin J. J. Ronis²  Vincent J. Maffei²  Patricia E. Molina³  David A. Welsh⁴  Shawn R. Campagna⁵  Eugene E. Blanchard⁵ 

[1] Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America;Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America;Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America;Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America;The Department of Chemistry, The University of Tennessee Knoxville, Knoxville, TN, United States of America

关键词: Gastrointestinal tract;    Alcohol consumption;    Microbiome;    T cells;    Klebsiella pneumoniae;    Klebsiella infections;    Cytotoxic T cells;    Inflammation;   

DOI  :  10.1371/journal.ppat.1006426

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Chronic alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis). To investigate the relationship between alcohol-mediated dysbiosis and pulmonary host defense we developed a fecal adoptive transfer model, which allows us to investigate the impact of alcohol-induced gut dysbiosis on host immune response to an infectious challenge at a distal organ, independent of prevailing alcohol use. Male C57BL/6 mice were treated with a cocktail of antibiotics (ampicillin, gentamicin, neomycin, vancomycin, and metronidazole) via daily gavage for two weeks. A separate group of animals was fed a chronic alcohol (or isocaloric dextrose pair-fed controls) liquid diet for 10 days. Microbiota-depleted mice were recolonized with intestinal microbiota from alcohol-fed or pair-fed (control) animals. Following recolonization groups of mice were sacrificed prior to and 48 hrs. post respiratory infection with Klebsiella pneumoniae. Klebsiella lung burden, lung immunology and inflammation, as well as intestinal immunology, inflammation, and barrier damage were examined. Results showed that alcohol-associated susceptibility to K. pneumoniae is, in part, mediated by gut dysbiosis, as alcohol-naïve animals recolonized with a microbiota isolated from alcohol-fed mice had an increased respiratory burden of K. pneumoniae compared to mice recolonized with a control microbiota. The increased susceptibility in alcohol-dysbiosis recolonized animals was associated with an increase in pulmonary inflammatory cytokines, and a decrease in the number of CD4+ and CD8+ T-cells in the lung following Klebsiella infection but an increase in T-cell counts in the intestinal tract following Klebsiella infection, suggesting intestinal T-cell sequestration as a factor in impaired lung host defense. Mice recolonized with an alcohol-dysbiotic microbiota also had increased intestinal damage as measured by increased levels of serum intestinal fatty acid binding protein. Collectively, these results suggest that alterations in the intestinal immune response as a consequence of alcohol-induced dysbiosis contribute to increased host susceptibility to Klebsiella pneumonia.

【 授权许可】

CC BY