Commensal C. acnes promote epidermal keratinocyte lipid synthesis via PPAR

We observed in human and mouse skin that exposure to C. acnes resulted in greatly increased epidermal lipids as indicated by bodily staining and hypothesized that this microbe may regulate keratinocyte lipid metabolism. To test this, human keratinocytes (NHEKs) were exposed to sterile C. acnes supernatant and showed a dose dependent increase in Oil Red O staining (p-value <0.001), and increases of ceramides, cholesterol and free fatty acids detected by differential mobility spectrometry-based shotgun lipidomic analysis. Triglycerides increased to the greatest degree; specially those which contain the following fatty acids: (16:0), (16:1), (18:1) and (18:2). Whole mouse epidermis exposed to C. acnes showed a similar response. Transcriptional analysis further defined the pathway for these induced lipids as RNA-seq analysis and subsequent validation by qPCR showed that C. acnes promoted upregulation of genes involved in ceramide, free fatty acid and triglyceride metabolism. This induction was induced in part by short chain fatty acids (SCFAs) made by C. acnes during its growth (propionic acid and isovaleric acid) as exposure to SCFAs also induced keratinocyte lipid accumulation and transcription of the lipid synthesis genes. Activation was mediated by peroxisome proliferator-activated receptors (PPARs) since siRNA silencing of PPARa and g receptors in NHEKs blocked increases in total lipid or induction of lipid synthesis genes (AGPAT4, GPAT3 and DGAT1) when exposed to C. acnes supernatant. This effect did not occur upon silencing of PPARb. Induction of lipids in NHEKs delayed C. acnes growth. Taken together, these results suggest that metabolites from C. acnes trigger upregulation of lipid synthesis in the skin that may decrease its survival while also influencing the epidermal barrier and host defense.