Abstract
Besides promoting inflammation by mobilizing lipid mediators, group IIA secreted phospholipase A2 (sPLA2-IIA) prevents bacterial infection by degrading bacterial membranes. Here, we show that, despite the restricted intestinal expression of sPLA2-IIA in BALB/c mice, its genetic deletion leads to amelioration of cancer and exacerbation of psoriasis in distal skin. Intestinal expression of sPLA2-IIA is reduced after treatment with antibiotics or under germ-free conditions, suggesting its upregulation by gut microbiota. Metagenome, transcriptome, and metabolome analyses have revealed that sPLA2-IIA deficiency alters the gut microbiota, accompanied by notable changes in the intestinal expression of genes related to immunity and metabolism, as well as in the levels of various blood metabolites and fecal bacterial lipids, suggesting that sPLA2-IIA contributes to shaping of the gut microbiota. The skin phenotypes in Pla2g2a–/– mice are lost (a) when they are cohoused with littermate WT mice, resulting in the mixing of the microbiota between the genotypes, or (b) when they are housed in a more stringent pathogen-free facility, where Pla2g2a expression in WT mice is low and the gut microbial compositions in both genotypes are nearly identical. Thus, our results highlight a potentially new aspect of sPLA2-IIA as a modulator of gut microbiota, perturbation of which affects distal skin responses.
Highlights
The gut microbiota present on the epithelial barriers comprises approximately 3 × 1013 microbial cells, most of which exhibit commensalism with the host
We previously showed that, when a model of skin carcinogenesis induced by 9,10-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to various sPLA2-deficient mice on a BALB/c background (Figure 1A), a lack of sPLA2-IID, which is expressed in lymphatic DCs and M2 macrophages, augments antitumor immunity through reduced mobilization of ω3 fatty acids [31], whereas a lack of sPLA2-IIF, which is expressed in epidermal keratinocytes, attenuates keratinocyte hyperproliferation through reduced mobilization of a specific lysophospholipid [32], thereby preventing skin carcinogenesis
Since reduced skin cancer and increased psoriasis are observed in mice lacking sPLA2-IID, which attenuates Th1/Th17 immunity by mobilizing ω3 fatty acids in lymphatic tissues [31], it is plausible that an altered systemic immunological balance may underlie the skin phenotypes in Pla2g2a–/– mice
Summary
The gut microbiota present on the epithelial barriers comprises approximately 3 × 1013 microbial cells, most of which exhibit commensalism with the host. The microbiota is involved in the initiation, progression, and dissemination of cancer, both at epithelial barriers and in sterile tissues [6, 7]. Various microbial metabolites such as tryptophan derivatives, vitamins, secondary bile acids, and short-chain fatty acids have profound influences on host responses [8,9,10]. Genetic deletion of several host factors involved in epithelial barrier or innate/adaptive immunity causes dysbiosis, resulting in altered susceptibility to various diseases, which can be transferred to WT mice by cohousing or fecal transfer [11, 12]. Transfer of feces from healthy donors to individuals with metabolic syndrome has been shown to alter the gut microbiota of the recipients, leading to improved insulin sensitivity [13]
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