Abstract
Microbiota derived metabolites act as chemical messengers that elicit a profound impact on host physiology. Vitamin D receptor (VDR) is a key genetic factor for shaping the host microbiome. However, it remains unclear how microbial metabolites are altered in the absence of VDR. We investigated metabolites from mice with tissue-specific deletion of VDR in intestinal epithelial cells or myeloid cells. Conditional VDR deletion severely changed metabolites specifically produced from carbohydrate, protein, lipid, and bile acid metabolism. Eighty-four out of 765 biochemicals were significantly altered due to the Vdr status, and 530 significant changes were due to the high-fat diet intervention. The impact of diet was more prominent due to loss of VDR as indicated by the differences in metabolites generated from energy expenditure, tri-carboxylic acid cycle, tocopherol, polyamine metabolism, and bile acids. The effect of HFD was more pronounced in female mice after VDR deletion. Interestingly, the expression levels of farnesoid X receptor in liver and intestine were significantly increased after intestinal epithelial VDR deletion and were further increased by the high-fat diet. Our study highlights the gender differences, tissue specificity, and potential gut-liver-microbiome axis mediated by VDR that might trigger downstream metabolic disorders.
Highlights
Microbiota derived metabolites act as chemical messengers that elicit a profound impact on host physiology
We have demonstrated that targeted deletion of Vitamin D receptor (VDR) in intestinal or myeloid cells distinctively transformed metabolite profiles and the gut microbiome, leading to an increased risk of obesity
VDRΔIEC mice challenged with high-fat diet (HFD) diet had the most dramatic changes in metabolites generated from energy expenditure, TCA cycle, tocopherol, and polyamine metabolism
Summary
Microbiota derived metabolites act as chemical messengers that elicit a profound impact on host physiology. Vitamin D receptor (VDR) is a key genetic factor for shaping the host microbiome. It remains unclear how microbial metabolites are altered in the absence of VDR. Intestinal specific deletion of VDR (VDRΔIEC) leads to microbial dysbiosis due to a decrease in the butyrate-producing bacteria[7,8]. It is unclear how the loss of VDR impacts microbial metabolites. We hypothesize that host factors (e.g., VDR status in specific tissues) modulate microbial metabolites and the microbiome, contributing to the high risk of metabolic diseases. We correlated the altered metabolite profiles to specific mechanisms that lead to the observed changes in the host and microbiome
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