House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection - PubMed (original) (raw)

House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection

Kei E Fujimura et al. Proc Natl Acad Sci U S A. 2014.

Abstract

Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c(+)/CD11b(+) and CD11c(+)/CD8(+) cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults.

Keywords: Lactobacilliaceae; airway adaptive immunity; gastrointestinal bacterial community; house environment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Exposure of animals to dust from homes with dogs attenuates the development of allergen-induced airways disease and serum IgE. (A) Whole-lung mRNA analysis by Q-PCR demonstrates a significant decrease in IL-4 and IL-13 in D dust-supplemented, but not in NP-supplemented animals compared with controls. (B) Accompanying the Th2 cytokine reduction was significantly reduced expression of the mucus-associated gene, gob5. (C) Reduced airway mucus secretion and goblet cell metaplasia is observed in the D dust-supplemented animals, as depicted by PAS staining in lung histology. (D) A reduction in draining lymph node numbers in D dust-supplemented animals was also observed. (E) Serum IgE levels reflected the reduction in the development of the Th2 environment in the D dust-supplemented animals. Data represent the mean ± SE from five mice per group; *P < 0.05.

Fig. 2.

Fig. 2.

(A) Exposure to house dust alters cecal microbiome composition. UniFrac-based cluster analysis of cecal microbiota of control, D dust- and NP dust-supplemented animals reveals distinct microbiota compositions in each treatment group. (B) Phylogenetic tree displaying all taxa that exhibited significant (P < 0.05; q < 0.15) relative enrichment (red bars) or depletion (green bars) in airway-protected mice supplemented with D-associated house dust compared with unprotected control animals. Phyla are indicted by color: Acidobacteria (light blue), Actinobacteria (teal), Bacteriodetes (purple), Firmicutes (green), Proteobacteria (red), and other (orange). Family designation of highly enriched or depleted taxa are indicated.

Fig. 3.

Fig. 3.

Supplementation of mice with L. johnsonii attenuates the development of allergic airways disease. (A) Examination of allergen-induced airway hyperactivity (AHR) following methacholine (250 μg/kg, i.v.) exposure demonstrated reduced responses in _L. johnsonii_-supplemented animals. (B) Th2 cytokine mRNA in the lungs (black bars) and protein expression in allergen-restimulated lymph node cells (gray bars) indicated a significant attenuation in _L. johnsonii_-supplemented mice. (C) Upon CRA exposure (black bars), significant increases in total leukocytes, granulocytes (neutrophils and eosinophils), and (D) in total and inflammatory (Ly6c+) DC populations were only observed in the control but not the _L. johnsonii_-supplemented animals (CRA-unexposed controls represented by white bars). (E) Histologic staining with PAS stain revealed a distinct reduction in the inflammatory and mucogenic responses in _L. johnsonii_-supplemented animals. Data represent mean ± SE from five mice per group. *P < 0.05, **P < 0.01.

Fig. 4.

Fig. 4.

Viable L. johnsonii is necessary to attenuate RSV-induced airway responses. (A) Viable (vLj) but not heat-killed (hkLj) L. johnsonii supplementation protects animals from RSV-induced airway hyperreactivity (AHR) assessed at 8 d postinfection. (B) Histologic examination of lungs from RSV-infected animals demonstrates reduced inflammation and PAS-stained airway mucus only in the treatment group who received viable organisms. (C) RSV-restimulated lymph node cell-induced cytokine responses are significantly lower in animals who received viable L. johnsonii supplements. (D) Significant reductions in the number of various leukocyte subsets in the lungs are only observed in animals who received viable L. johnsonii. Data represent mean ± SE from five mice per group. *P < 0.05.

Fig. 5.

Fig. 5.

(A) _L. johnsonii_-supplemented animals that exhibit airway protection exhibit altered cecal microbiome composition. Nonmetric dimensional scaling based on a UniFrac distance matrix reveals that microbial communities of mice supplemented with L. johnsonii are compositionally and phylogenetically distinct from unsupplemented animals. Ellipses constructed around each treatment group indicate the 95% confidence intervals. (B) Compared with unsupplemented control animals, communities supplemented with L. johnsonii or L. johnsonii followed by CRA exposure exhibit the greatest phylogenetic distance (*P < 0.0005, **P < 0.0001, respectively).

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