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Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin.

  • Author(s): 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
  • et al.
Abstract

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.

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