Atlas of one-carbon metabolism in conventional and germ-free mice reveals folate as a key determinant of biochemical pathways

Folates participate in the one-carbon metabolism (OCM) cycle, supporting many biochemical pathways. Existing methods to profile folate are limited in the diversity of vitamers they measure and the samples they profile. We present a metabolomics workflow for stable extraction, separation, and measurement of folates, along with precursors and products of OCM-associated pathways. We profiled these metabolites in 37 mouse tissues to chart the first ‘OCM atlas’, revealing vast heterogeneity across organs and a novel folate derivative. We discovered that in adult mice, the gut microbiota is a consumer of folate, and folate polyglutamylation in the host is not regulated by folate availability. Germ-free mice show tissue-specific shifts in methyl donor abundances relative to conventionally-raised mice, indicative of altered DNA methylation. Correlation analyses uncovered the central roles played by folates in potentially modulating other biochemical pathways in tissues, thus linking microbial folate consumption directly to its global impacts on host metabolism. (https://chaudharilab.com/folate-atlas/)