Xenometabolite signatures in the UC Davis type 2 diabetes mellitus rat model revealed using a metabolomics platform enriched with microbe-derived metabolites

Authors: MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC); YERUVA, LAXMI - Arkansas Children'S Nutrition Research Center (ACNC); PACK, LINDSAY - Arkansas Children'S Nutrition Research Center (ACNC); GRAHAM, JAMES - University Of California, Davis; STANHOPE, KIMBER - University Of California, Davis; CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC); WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC); SHANKAR, KARTIK - University Of Colorado; HAVEL, PETER - University Of Colorado; Ferruzzi, Mario; PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/4/2020
Publication Date: 7/20/2020
Citation: Mercer, K.E., Yeruva, L., Pack, L., Graham, J.L., Stanhope, K.L., Chintapalli, S.V., Wankhade, U.D., Shankar, K., Havel, P.J., Adams, S.H., Piccolo, B.D. 2020. Xenometabolite signatures in the UC Davis type 2 diabetes mellitus rat model revealed using a metabolomics platform enriched with microbe-derived metabolites. American Journal of Physiology - Gastrointestinal and Liver Physiology. 319(2):G157-G169. https://doi.org/10.1152/ajpgi.00105.2020.
DOI: https://doi.org/10.1152/ajpgi.00105.2020

Interpretive Summary: The naturally-occurring bacteria in our gut produce a large set of small molecules (i.e., metabolites) that interact with each other and the host, and play a role in driving the health effects of diet. These molecules are part of a broader class of molecules that are considered as non-self derived, which are referred to as "xenometabolites". Somebacteria-derived xenometabolites have been shown to alter host health and disease, but very few have been characterized and very few experiments specifically target this class of metabolites. Therefore, we created a technique to measure a broader set of xenometabolites, with a particular focus on bacteria-derived xeno-metabolites. The xenometabolomics platform was used on gut samples from a rat model of type 2 diabetes that does not require diet to develop obesity and diabetes. Compared to a lean and non-diabetic rat, the xenometabolite profile of the diabetic rats were markedly different. We also used statistical modeling techniques to show that the xenometabolite profile changed when diabetic rats progressed to later stages of diabetes, similar to how the bacterial make up changed during diabetes. We also uncovered relationships between xenometabolites and specifc sets of bacteria. These "xenometabolite hubs" provided new information about how the gut microbiome and bacterial ecology track shifts in host health, and provides new information about the potential mechanisms underlying the body's communication to and from the normal bacteria resident in the gut. Future studies will test how changes in nutrition and quality of diet influence the xenometabolome.

Technical Abstract: 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.