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Antibiotic perturbation of the intestinal microbiota in murine models of allergic airways disease

University of British Columbia

Rates of allergic airways disease are steadily rising in developed countries, arguing for an environmental etiology. Epidemiological studies have pointed to a role for the infant gut microbiota in immune system development that could alter allergic disease susceptibility. To investigate whether changes in gut microbiota impact disease severity in murine models of asthma and hypersensitivity pneumonitis (HP), we administered clinical doses of antibiotics to mice during different periods in their development. Classically, allergic asthma is induced by T helper type 2 (Th2) inflammatory responses. In contrast, HP develops via Th1/Th17-mediated mechanisms. Consistent with their polarized immune phenotypes, these two diseases were exacerbated after different antibiotic exposures. Mice receiving perinatal vancomycin developed more severe asthma relative to control animals, as demonstrated by increased Th2-driven airway inflammation, antigen-specific IgE and lung pathology. The data presented here suggest that increased asthma severity in this model of allergic airways disease is mediated by mechanisms involving elevated IgE levels and reduced regulatory T cell populations. This effect was not observed in mice given streptomycin, nor when either antibiotic was administered to adult mice. Conversely, the severity of HP was unaffected by vancomycin, but increased after streptomycin treatment; this was demonstrated by exacerbated airway inflammation of the Th1/Th17-type, as well as increased IFNγ and IL-17A cytokine production and lung pathology. Microbial community analysis reveals that antibiotic treatment has profound effects on the gut microbiota; these effects were highly specific to the type of antibiotic used and the length of administration. Bacteroidetes dominated the intestinal flora after streptomycin treatment, while vancomycin drastically reduced diversity and promoted the overgrowth of a distinct group of Firmicutes. The extensive use of antibiotics in our society warrants a closer look at the effects of different antibiotics on the composition of the microbiota and how this may impact the prevalence of diseases like asthma and HP. The work in this thesis presents an interesting dichotomy, where contrasting shifts in gut flora appear to have opposite consequences depending on the immunological nature of the disease.

Text

2014-04-15

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/46421

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/