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

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.

Dairy fat and risk of cardiovascular disease in 3 cohorts of US adults

“…Values for the amounts of dietary fats and other nutrients in the foods were obtained from the Harvard University Food Composition Database, which is derived from USDA sources (22), and supplemented with information from manufacturers. In a validation study (20), the specific types of fat intake were ascertained reasonably well compared with four 1-wk dietary records collected over 1 y.…”

Obese Mice Fed a Diet Supplemented with Enzyme-Treated Wheat Bran Display Marked Shifts in the Liver Metabolome Concurrent with Altered Gut Bacteria

“…SCFAs serve as fuel or receptor ligands that have been implicated in influencing many processes including the following: gastrointestinal tract growth (76), gut-derived satiety hormones (77), and immune system modulation (78) [also reviewed in (79,80)]. However, SCFAs are not the sole regulators of host physiology: changes in the gut microbiome lead to alterations in many microbe-derived metabolites, often called ''xenobiotics'' but more accurately termed ''xenometabolites'' (81). Indeed, in the current study, there were marked ETWB-related changes in host physiology and liver metabolism that were concurrent with gut microbiome shifts, with no difference in total cecal SCFA abundance, indicating that factors independent of SCFAs were involved.…”

Effects of Different Exercise Modes on the Urinary Metabolic Fingerprint of Men with and without Metabolic Syndrome

“…Metabolomic investigation of the effect of exercise can shed light on the underlying biochemistry, promoting the understanding of the body’s response to the perturbation caused by exercise [21,22,23], which could translate into personalized exercise prescription for individuals with cardiometabolic risk factors. Exercise metabolomic studies so far have investigated isolated aspects of MetS, such as obesity [24,25] and insulin sensitivity [26,27,28], but not MetS as a clinical entity.…”