Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy

Analysis of the expression pattern of glial cell line-derived neurotrophic factor, neurturin, their cognate receptors GFRα-1 and GFRα-2, and a common signal transduction element c-Ret in the human scalp skin

Background: Glial cell line-derived neurotrophic factor (GDNF) and a related family member, neurturin (NTN), as well as their cognate receptors (GDNF receptors, GFRα-1 and GFRα-2, respectively) are involved in nervous system development and murine hair cycle control. To date, their expression in human scalp skin is still unknown. Materials and methods: The expression pattern of these proteins was examined in human scalp skin by immunofluorescence and immunoalkaline phosphatase staining methods as well as RT-PCR (GDNF). A total of 50 normal human scalp skin biopsy specimens were examined (healthy females, 53-57 years). Results: The expression of GDNF protein was strong in the epidermis and sebaceous and sweat glands. In the epidermis, GDNF protein expression was seen in all layers except the stratum corneum. It was strong in the basal layer and decreased gradually towards the granular layer. The results of RT-PCR analysis revealed that GDNF protein is synthesised in the epidermis. The expression of NTN, GFRα-1, and GFRα-2 proteins was strong in the papillary dermis and sebaceous and sweat glands. In the epidermis, NTN protein expression was absent. The expression of GFRα-1 and GFRα-2 proteins was moderate in the epidermis. The expression of c-Ret protein was consistently strong in the epidermis and sebaceous and sweat glands. These proteins were strongly expressed in both epithelial and mesenchymal compartments of human anagen VI scalp hair follicles. Conclusions: Our investigation reports, for the first time, the expression patterns of GDNF, NTN, GFRα-1, GFRα-2, and c-Ret proteins in human scalp skin. The expression of these proteins in the skin suggests their possible roles in skin homeostasis. The clinical ramifications of these observations mandate further investigations. © Blackwell Munksgaard 2006