Improved Metabolic Health Alters Host Metabolism in Parallel with Changes in Systemic Xeno-Metabolites of Gut Origin

et al. (2014) Improved Metabolic Health Alters Host Metabolism in Parallel with Changes in Systemic Xeno-Metabolites of Gut Origin. PLoS ONE 9(1): e84260. doi:10.1371/journal.pone.0084260 Improved Metabolic Health Alters Host Metabolism in Parallel with Changes in Systemic Xeno-Metabolites of Gut Origin Caitlin Campbell 0 Dmitry Grapov 0 Oliver Fiehn 0 Carol J. Chandler 0 Dustin J. Burnett 0 Elaine C. Souza 0 Gretchen A. Casazza 0 Mary B. Gustafson 0 Nancy L. Keim 0 John W. Newman 0 Gary R. Hunter 0 Jose R. Fernandez 0 W. Timothy Garvey 0 Mary-Ellen Harper 0 Charles L. Hoppel 0 John K. Meissen 0 Kohei Take 0 Sean H. Adams 0 Marc Claret, Institut d'Investigacions Biome`diques August Pi i Sunyer, Spain 0 1 USDA-ARS Western Human Nutrition Research Center, Davis, California, United States of America, 2 West Coast Metabolomics Center, University of California Davis, Davis, California, United States of America, 3 Genome Center, University of California Davis, Davis, California, United States of America, 4 Sports Medicine Program, University of California, Davis School of Medicine, Sacramento, California, United States of America, 5 Department of Nutrition, University of California Davis, Davis, California, United States of America, 6 Department of Nutrition Sciences, University of Alabama , Birmingham , Alabama, United States of America, 7 Human Studies Department, University of Alabama , Birmingham , Alabama, United States of America, 8 Department of Biochemistry , Microbiology and Immunology , University of Ottawa , Ottawa, Ontario , Canada , 9 Pharmacology Department, Case Western Reserve University , Cleveland, Ohio , United States of America Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14-17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women. To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm. Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites (''non-self'' metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower c-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT a-ketoglutaric acid (a-KG), fasting a-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose. The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites. This highlights that interpretations regarding the origins of peripheral blood or urinary ''signatures'' of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host's metabolome. - Funding: This work was supported by USDA-ARS intramural Projects 5306-51530-016-00D and 5306-51530-019-00 (JWN, NLK, SHA), NIH-NIDDK R01DK078328 (OF, NLK, JWN, GH, JF, WTG, CLH, MEH, SHA), NIH 1 U24 DK097154 for the West Coast Metabolomics Center (OF, JWN), and NIH P20 HL113452 (OF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Pre-diabetes and type 2 diabetes mellitus (T2DM) are defined by elevated blood glucose following an overnight fast or at 2 hr following an oral glucose tolerance test (OGTT) [1]; however, a clinically-significant increase in blood sugar is a late event in disease progression and is not an optimal prognostic. Identifying more sensitive T2DM risk markers or those that track deteriorating insulin sensitivity would have potential value as clinical diagnostics and would help elucidate the underlying pathophysiology. Advancements in metabolomics technologies to interrogate hundreds of metabolites in human blood or urine hold promise in this regard. Recent metabolomics studies have highlighted that human insulin resistance, T2DM, and T2DM risk involve significant perturbations in lipid and amino acid metabolism in addition to glucose, as reflected in altered phosphatidylcholine derivatives, positive associations with blood branched-chain amino acids (BCAAs), 2-hydroxybutyrate (2-HB), long- and mediumchain acylcarnitines, and negative associations with blood glycine and linoleoyl-glycerophosphocholine (L-GPC)[216]. Measurement of blood metabolites in the overnight-fasted state, while valuable, may not unmask subtle phenotypes associated with insulin resistance or pre-diabetes that manifest when the bodys metabolic machinery is challenged. Since insulin resistance involves impairment of normal glucose and insulin homeostasis, metabolomics analyses following an OGTT are an attractive means to identify biochemical pathways associated with individual variability in insulin action and blood sugar control. To our knowledge, only five studies have reported post-OGTT blood metabolite profiling in humans [1721]. These reports highlighted that in healthy individuals a glucose challenge with attendant increases in blood insulin and glucose is accompanied by expected reductions in plasma indices of lipolysis (e.g., glycerol, long-chain fatty acids [LCFA]) and LCFA b-oxidation (e.g., chain-shortened fatty acylcarnitines, b-hydroxybutyrate), and increases in markers of tissue amino acid utilization (e.g., reductions in blood amino acids) and glycolysis (e.g. lactate). Interestingly, the OGTT significantly increased blood bile acid and lysophosphotidylcholine metabolites, although the etiology of this was not identified [17,19]. Post-OGTT metabolite patterns have also been compared between normal glucose tolerant (NGT) and impaired glucose tolerant (IGT) subjects: IGT persons showed blunted postOGTT changes in lactate, glycerol and glycerol-3-phosphate, and leucine/isoleucine [17,20]. We are not aware of any reports examining OGTT-associated metabolomics to determine longitudinal changes in circulating metabolite patterns, to test the hypothesis that improvements in insulin sensitivity or metabolic fitness alter comprehensive metabolite responses. For instance, one would expect that plasma markers that positively correlate with insulin resistance or T2DM in cross-sectional studies (see above) would be reduced by interventions that increase insulin sensitivity. We examined this issue in obese sedentary women with modest hyperinsulinemia, tested before and after a 1417 week (...truncated)