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Xenometabolite signatures in the UC Davis Type 2 Diabetes Mellitus Rat model revealed using a metabolomics platform enriched with microbe-derived metabolites.

The gut microbiome has the potential to create or modify xenometabolites (i.e., non-host derived metabolites) through de novo synthesis or modification of exogenous and endogenous compounds. While there are isolated examples of xenometabolites influencing host health and disease, wide-scale characterization of these metabolites remain limited. We developed a metabolomics platform ("XenoScan") using liquid chromatography-mass spectrometry to characterize a range of known and suspected xenometabolites and their derivatives. This assay currently applies authentic standards for 189 molecules, enriched for metabolites of microbial origin. As a proof-of-principle, we characterized the cecal content xenometabolomics profile in adult male lean Sprague Dawley (LSD) and UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rats at different stages of diabetes. These results were correlated to specific bacterial species generated via shotgun metagenomic sequencing. UCD-T2DM rats had a unique xenometabolite profile compared with LSD rats, regardless of diabetes status. Furthermore, modeling approaches revealed that several xenometabolites discriminated UCD-T2DM rats with early-onset of diabetes vs. those at 3 months post-diabetes onset. Several xenometabolite hubs correlated with specific bacterial species in both LSD and UCD-T2DM rats. For example, indole-3-propionic acid negatively correlated with species within the Oscillibacter genus in UCD-T2DM rats with early onset of diabetes, in contrast to gluconic acid and trimethylamine that were positively correlated with Oscillibacter species. The application of a xenometabolite-enriched metabolomics assay in relevant milieus will enable rapid identification of a wide variety of gut-derived metabolites, their derivatives, and their potential biochemical origins of xenometabolites in relationship to host GI microbial ecology.