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Commensal microbiota modulate gene expression in the skin

ABSTRACT: Background: The skin harbors complex communities of resident microorganisms, yet little is known of their physiological roles and the molecular mechanisms that mediate cutaneous host-microbe interactions. Here, we profiled skin transcriptomes of mice reared in the presence and absence of microbiota to elucidate the range of pathways and functions modulated in the skin by the microbiota. Results: A total of 2820 genes were differentially regulated in response to microbial colonization and were enriched in gene ontology (GO) terms related to the host-immune response and epidermal differentiation. Innate immune response genes and genes involved in cytokine activity were generally upregulated in response to microbiota and included genes encoding toll-like receptors, antimicrobial peptides, the complement cascade, and genes involved in IL-1 family cytokine signaling and homing of T cells. Our results also reveal a role for the microbiota in modulating epidermal differentiation and development, with differential expression of genes in the epidermal differentiation complex (EDC). Genes with correlated co-expression patterns were enriched in binding sites for the transcription factors Klf4, AP-1, and SP-1, all implicated as regulators of epidermal differentiation. Finally, we identified transcriptional signatures of microbial regulation common to both the skin and the gastrointestinal tract. Conclusions: With this foundational approach, we establish a critical resource for understanding the genome-wide implications of microbially mediated gene expression in the skin and emphasize prospective ways in which the microbiome contributes to skin health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE98877 | GEO | 2018/01/24

REPOSITORIES: GEO

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Project description:Exposure to xenobiotics has repeatedly been associated with adverse health effects. While the majority of reported cases still relates to direct substance effects, there is increasing evidence that microbiome-dependent metabolism of xenobiotic substances likewise has direct adverse effects on the host. This can be due to microbial biotransformation of compounds, interaction between the microbiota and the host’s endogenous detoxification enzymes or altered xenobiotic bioavailability. Polycyclic aromatic hydrocarbons (PAH) such as Benzo[a]pyrene (B[a]P) are among the most abundant environmental pollutants and contaminants. Yet, effects of the skin microbiota on B[a]P absorption, metabolism and distribution in humans remain unclear. Here, we demonstrate that skin microbiota do metabolize B[a]P on and in human skin in situ, using a recently developed commensalic skin model. In this model microbial metabolism leads to high concentrations, of known microbial B[a]P metabolites on the surface as well as in the epidermal layers. In contrast to what was observed for uncolonized skin, metabolite as well as B[a]P concentrations were subject to altered rates of skin penetration and diffusion, resulting in up to 58 % reduction of metabolites recovered from basal culture medium. The results indicate the reason for this altered behavior to be a microbial induced change of the epidermal barrier function. Compared to uncolonized models, commensal colonization led to strengthening of tight junctions (TJ) as well as increased epidermal differentiation in the form of increased expression of E-cadherin, K10, FLG and IVN. Concomitantly colonized models showed decreased formation and penetration of the ultimate carcinogen Benzo[a]pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), leading, in consequence, to fewer BPDE-DNA adducts formed. Befittingly, transcript and expression levels of key proteins for repairing environmentally induced DNA-damage such as XPC were also found to be reduced in the commensalic models, as was expression of B[a]P-associated cytochrome P450-dependent monooxygenases (CYPs) such as CYP1A1. The results show that the microbiome can have significant effects on the toxicology of external chemical impacts. The respective effects rely on a complex interplay between microbial as well as host metabolism and microbe-host interactions all of which cannot be adequately assessed using single-system studies. Given the high species-specificity of such interactions adequate toxicological assessments should thus increasingly rely on complex human models wherever possible.

Project description:The mammalian gut harbors a diverse microbial community (gut microbiota) that mainly consists of bacteria. Their combined genomes (the microbiome) provide biochemical and metabolic functions that complement host physiology. Maintaining symbiosis seems to be a key requirement for health as dysbiosis is associated with the development of common diseases. Previous studies indicated that the microbiota and the hostM-bM-^@M-^Ys epithelium signal bidirectional inducing transcriptional responses to fine-tune and maintain symbiosis. However, little is known about the hostM-bM-^@M-^Ys responses to the microbiota along the length of the gut as earlier studies of gut microbial ecology mostly used either colonic or fecal samples. This is of importance as not only function and architecture of the gut varies along its length but also microbial distribution and diversity. Few recent studies have begun to investigate microbiota-induced host responses along the length of the gut. However, these reports used whole tissue samples and therefore do not allow drawing conclusions about specificity of the observed responses. Which cells in the intestinal tissue are responsible for the microbially induced response: epithelial, mesenchymal or immune cells? Where are the responding cells located? We used using extensive microarray analysis of laser capture microdissection (LCM) harvested ileal and colonic tip and crypt fractions from germ-free and conventionally-raised mice to investigate the microbiota-induced transcriptional responses in specific and well-defined cell populations of the hostM-bM-^@M-^Ys epithelium. Ileum and colon segments were dissected from germ-free and conventionally-raised 10-12 weeks old female C57Bl/6 mice, washed and frozen as OCT blocks. Cryosections were prepared from these OCT blocks and tip/crypt fractions isolated using laser capture microdissection. To investigate the microbiota-induced transcriptional responses specific for specific subpopulations of intestinal epithelial cells, tip and crypt fractions of ileal and colonic epithelium of germ-free and conventionally-raised 10-12 weeks old female C57Bl/6 mice were harvested using laser capture microdissection and probed in an extensive microarray analysis.

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Commensal microbiota modulate gene expression in the skin

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