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Title: Diabetes-associated alterations in the cecal microbiome and metabolome are independent of diet or environment in the UC Davis type 2-diabetes mellitus rat model

Author
item PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC)
item GRAHAM, JAMES - Uc Davis Medical Center
item STANHOPE, KIMBER - Uc Davis Medical Center
item NOOKAEW, INTAWAT - University Arkansas For Medical Sciences (UAMS)
item MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC)
item CHINTAPALLI, S - Arkansas Children'S Nutrition Research Center (ACNC)
item WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)
item HAVEL, PETER - Uc Davis Medical Center
item Ferruzzi, Mario

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/12/2018
Publication Date: 7/17/2018
Citation: Piccolo, B.D., Graham, J.L., Stanhope, K.L., Nookaew, I., Mercer, K.E., Chintapalli, S.V., Wankhade, U.D., Shankar, K., Havel, P.J., Adams, S.H. 2018. Diabetes-associated alterations in the cecal microbiome and metabolome are independent of diet or environment in the UC Davis type 2-diabetes mellitus rat model. American Journal of Physiology - Endocrinology and Metabolism. https://doi.org/10.1152/ajpendo.00203.2018.
DOI: https://doi.org/10.1152/ajpendo.00203.2018

Interpretive Summary: Many factors contribute to, or can modify, the development of diseases such as obesity and type 2 diabetes, including the naturally occurring bacteria residing in the gut (that make up the "gut microbiome"). Most studies have focused on how diet changes the gut bacteria in a negative way to cause obesity and type 2 diabetes, but little attention has been given to how changes in host health status influences the bacteria. We used a rodent model of diabetes that does not require a change in diet to develop obesity and diabetes, to understand which gut bacteria change and how the gut environment changes during the progression of these diseases. We found very few changes between groups from earlier stages of diabetes, but large changes in specific bacteria and bacterial genes when comparing rats from earlier stages versus rats from groups in later stages of uncontrolled diabetes. Specifically, bacteria species belonging to genera called Prevotella and Bacteroides were increased in later stages of diabetes compared to early stages. Meanwhile, bacterial specific genes related to bacteria cell wall contents, protection from stress, and sugar metabolism were also increased in later stages of diabetes compared to early stages. These changes were related to gut content abundances of several metabolites, including phosphate and dehydroabietic acid. Since animals in this study ate the same diet and other environmental factors that change the gut microbiome were similar across all animals, the results suggest that changes in host metabolic health can change the profile and function of bacteria in the gut. The study highlights that both dietary patterns and the host's own health can contribute to the gut microbiome.

Technical Abstract: The composition of the gut microbiome is altered in obesity and type 2 diabetes; however, it is not known whether these alterations are mediated by dietary factors or related to declines in metabolic health. To address this, cecal contents were collected from age-matched, chow-fed male UCD-T2DM rats before the onset of diabetes (pre-diabetic PD, n=15); 2 wk recently-diabetic (RD, n=10); 3 mo (D3M, n=11); and 6 mo (D6M, n=8) post-onset of diabetes. Bacterial species and functional gene counts were assessed by shotgun metagenomic sequencing of bacterial DNA in cecal contents, while metabolites were identified by GC-QTOF-MS. Metagenomic analysis showed a shift from Firmicutes species in early stages of diabetes (PD+RD) towards an enrichment of Bacteroidetes species in later stages of diabetes (D3M+D6M). In total, 45 bacterial species discriminated early and late stages of diabetes with 25 of these belonging to either Bacteroides or Prevotella genera. Furthermore, 61 bacterial gene clusters discriminated early and later stages of diabetes with elevations of enzymes related to stress response (e.g., glutathione and glutaredoxin), and amino acid, carbohydrate, and bacterial cell wall metabolism. Twenty-five metabolites discriminated early vs late stages of diabetes, with the largest differences observed in abundances of dehydroabietic acid and phosphate. Alterations in the gut microbiota and cecal metabolome track diabetes progression in UCD-T2DM rats when controlling for diet, age, and housing environment. Results suggest that diabetes-specific host signals impact the ecology and end-product metabolites of the gut microbiome when diet is held constant.