Abstract
Environmental and genetic factors represent key components in the establishment/maintenance of the intestinal microbiota. The aryl hydrocarbon receptor (AHR) is emerging as a pleiotropic factor, modulating pathways beyond its established role as a xenobiotic sensor. The AHR is known to regulate immune surveillance within the intestine through retention of intraepithelial lymphocytes, functional redistribution of Th17/Treg balance. Consequently, environmental/genetic manipulation of AHR activity likely influences host-microbe homeostasis. Utilizing C57BL6/J Ahr−/+ and Ahr−/− co-housed littermates followed by 18 days of genotypic segregation, we examined the influence of AHR expression upon intestinal microbe composition/functionality and host physiology. 16S sequencing/quantitative PCR (qPCR) revealed significant changes in phyla abundance, particularly Verrucomicrobia together with segmented filamentous bacteria, and an increase in species diversity in Ahr−/− mice following genotypic segregation. Metagenomics/metabolomics indicate microbial composition is associated with functional shifts in bacterial metabolism. Analysis identified Ahr−/−-dependent increases in ileal gene expression, indicating increased inflammatory tone. Transfer of Ahr−/− microbiota to wild-type germ-free mice recapitulated the increase Verrucomicrobia and inflammatory tone, indicating Ahr−/−-microbial dependence. These data suggest a role for the AHR in influencing the community structure of the intestinal microbiota.
Highlights
Environmental and genetic factors represent key components in the establishment/maintenance of the intestinal microbiota
To examine the contribution of mouse aryl hydrocarbon receptor (AHR) expression with regard to maintenance of the community structure of the intestinal microbiota, littermates (Ahr−/+ and Ahr−/−) from congenic female C57BL6/J (Ahr−/−) and male C57BL6.129-Ahrtm/Bra/J (Ahr−/+) matings were co-housed for 6 months prior to separation based upon genotype, as illustrated in the experimental overview (Supplemental Figure 1)
Phyla level abundance analysis obtained from 16S rDNA gene sequencing between each Ahr genotype revealed significant differences in the percentage abundance of 16S reads associated with Tenericutes (10-fold), TM7 (3-fold), Verrucomicrobia (3-fold), Proteobacteria (1.5-fold) and Actinobacteria (1.3-fold)
Summary
Environmental and genetic factors represent key components in the establishment/maintenance of the intestinal microbiota. Transfer of Ahr−/− microbiota to wild-type germ-free mice recapitulated the increase Verrucomicrobia and inflammatory tone, indicating Ahr−/−microbial dependence These data suggest a role for the AHR in influencing the community structure of the intestinal microbiota. Of particular importance is the role of AHR and its activation by dietary or microbial-derived tryptophan derivatives such as indole-3 carbinol in facilitating gene expression associated with intestinal retention and function of group 3 innate lymphoid cells and intraepithelial lymphocytes[15,16]. Microbial stimulation of such cells, in combination with AHR transcriptional activity, drives the expression of IL22, which in turn stimulates epithelial cells to release anti-microbial factors including RegIII and defensins, contributing to epithelial barrier integrity and microbial homeostasis. We demonstrate that divergence of the microbiota between Ahr genotypes results in changes in metabolite abundance and host gene expression, which likely impacts overall host physiology
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