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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.

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 University of California, Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats before the onset of diabetes (prediabetic PD; n = 15), 2 wk recently diabetic (RD; n = 10), 3 mo (D3M; n = 11), and 6 mo (D6M; n = 8) postonset 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 gas chromatography-quadrupole time-off-flight-mass spectrometry. Metagenomic analysis showed a shift from Firmicutes species in early stages of diabetes (PD + RD) toward 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 cecal 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.

SUBMITTER: Piccolo BD

PROVIDER: S-EPMC6293161 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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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.

Piccolo Brian D BD Graham James L JL Stanhope Kimber L KL Nookaew Intawat I Mercer Kelly E KE Chintapalli Sree V SV Wankhade Umesh D UD Shankar Kartik K Havel Peter J PJ Adams Sean H SH

American journal of physiology. Endocrinology and metabolism 20180717 5

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 University of California, Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats before the onset of diabetes (prediabetic PD; n = 15), 2 wk recently diabetic (RD; n = 10), 3 mo (D3M; n = 11), and 6 mo (D6M; n = 8) poston ...[more]

PMID: 30016149

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Project description:The gut microbiome has the potential to create or modify xenometabolites (i.e., nonhost-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 remains 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 190 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 University of California, 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, suggesting that at least some of the variation is associated with host genetics. Furthermore, modeling approaches revealed that several xenometabolites discriminated UCD-T2DM rats at early stages of diabetes versus those at 3 mo postdiabetes 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 considered to be prediabetic or recently diagnosed diabetic, in contrast to gluconic acid and trimethylamine, which 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 gastrointestinal microbial ecology.NEW & NOTEWORTHY We debut a liquid chromatography-mass spectrometry (LC/MS) platform called the XenoScan, which is a metabolomics platform for xenometabolites (nonself-originating metabolites). This assay has 190 in-house standards with the majority enriched for microbe-derived metabolites. As a proof-of-principle, we used the XenoScan to discriminate genetic differences from cecal samples associated with different rat lineages, in addition to characterizing diabetes progression in rat model of type 2 diabetes. Complementing microbial sequencing data with xenometabolites uncovered novel microbial metabolism in targeted organisms.

Project description:We recently reported sex differences in mesenteric arterial function of the UC Davis type-2 diabetes mellitus (UCD-T2DM) rats as early as the prediabetic state. We reported that mesenteric arteries (MA) from prediabetic male rats exhibited a greater impairment compared to that in prediabetic females. However, when females became diabetic, they exhibited a greater vascular dysfunction than males. Thus, the aim of this study was to investigate whether the female sex hormone, estrogen preserves mesenteric arterial vasorelaxation in UCD-T2DM female rats at an early prediabetic state. Age-matched female Sprague Dawley and prediabetic (PD) UCD-T2DM rats were ovariectomized (OVX) and subcutaneously implanted with either placebo or 17β-estradiol (E2, 1.5 mg) pellets for 45 days. We assessed the contribution of endothelium-derived relaxing factors (EDRF) to acetylcholine (ACh)-induced vasorelaxation, using pharmacological inhibitors. Responses to sodium nitroprusside (SNP) and phenylephrine (PE) were also measured. Additionally, metabolic parameters and expression of some targets associated with vascular and insulin signaling were determined. We demonstrated that the responses to ACh and SNP were severely impaired in the prediabetic state (PD OVX) rats, while E2 treatment restored vasorelaxation in the PD OVX + E2. Moreover, the responses to PE was significantly enhanced in MA of PD OVX groups, regardless of placebo or E2 treatment. Overall, our data suggest that 1) the impairment of ACh responses in PD OVX rats may, in part, result from the elevated contractile responses to PE, loss of contribution of endothelium-dependent hyperpolarization (EDH) to vasorelaxation, and a decreased sensitivity of MA to nitric oxide (NO), and 2) the basis for the protective effects of E2 may be partly attributed to the elevation of the NO contribution to vasorelaxation and its interaction with MA as well as potential improvement of insulin signaling. Here, we provide the first evidence of the role of E2 in protecting MA from early vascular dysfunction in prediabetic female rats.

Dataset Information

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.

Publications

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.

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