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

• Published in: PloS one 2014-01, Vol.9 (1), p.e84260
• Main Authors: Campbell, Caitlin, Grapov, Dmitry, Fiehn, Oliver, Chandler, Carol J, Burnett, Dustin J, Souza, Elaine C, Casazza, Gretchen A, Gustafson, Mary B, Keim, Nancy L, Newman, John W, Hunter, Gary R, Fernandez, Jose R, Garvey, W. Timothy, Harper, Mary-Ellen, Hoppel, Charles L, Meissen, John K, Take, Kohei, Adams, Sean H, Claret, Marc
• Format: Article
• Language: English
• Subjects: Adult; alpha-ketoglutaric acid; Analysis; Area Under Curve; Biology; blood; Body weight; Body weight loss; Diabetes therapy; Diet; digestive system; Discriminant Analysis; Elongation; exercise; Exercise therapy; fasting; Fasting - blood; Fatty acids; Fatty Acids - blood; Female; Fitness; gamma-tocopherol; Gastrointestinal Tract - metabolism; Glucose; Glucose - metabolism; Glucose tolerance; Glucose Tolerance Test; glucose tolerance tests; Glutamine; Health; Humans; Insulin; Insulin resistance; Intervention; Intestinal microflora; intestinal microorganisms; Ketoglutaric acid; Least-Squares Analysis; long chain fatty acids; Malate; malates; Medicine; Metabolism; Metabolites; Metabolome; Microorganisms; Middle Aged; Mitochondria; Multivariate analysis; Nutrition research; Obesity; Obesity - blood; Obesity - metabolism; Oxidation; Peripheral blood; Phenotype; Physical Fitness; Pyruvic acid; Sedentary Behavior; Sensitivity; Sensitivity analysis; Studies; Tocopherol; Type 2 diabetes; Weight Loss; Weight reduction; women; Xenobiotics - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084260

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 γ-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT α-ketoglutaric acid (α-KG), fasting α-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.