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A growing body of evidence suggests that the human gut microbiota plays a role in the development of obesity and related metabolic diseases. However, there is little consensus between studies, which could be due to biological as well as technical variation. In addition, little human data are available to investigate whether tissue-specific insulin sensitivity is related to specific microbial patterns. We examined this relation in two independent cohorts of overweight and obese pre-diabetic men, using phylogenetic microarray data and hepatic, peripheral and adipose tissue insulin sensitivity that were determined by a two-step hyperinsulinemic-euglycemic clamp with [6,6-2H2]-glucose tracer infusion. Despite a prominent subject-specific microbiota, we found significant associations of microbial taxa with tissue-specific insulin sensitivity using regression analysis. Using random forests we found moderate associations with other measures of glucose homeostasis in only one of the cohorts (fasting glucose concentrations AUC = 0.66 and HbA1c AUC = 0.65). However, all findings were cohort-specific due to pronounced variation in microbiota between cohorts, suggesting the existence of alternative states for dysbiosis in metabolic syndrome patients. Our findings suggest individual or group related dynamics, instead of universal microbiota signals, related to the host when the overweight or obese state has already developed and argue that care should be taken with extrapolating significant correlations from single cohorts, into generalized biological relevance.

Background--Intestinal microbiota have been found to be linked to cardiovascular disease via conversion of the dietary compounds choline and carnitine to the atherogenic metabolite TMAO (trimethylamine-N-oxide). Specifically, a vegan diet was associated with decreased plasma TMAO levels and nearly absent TMAO production on carnitine challenge. Methods and Results--We performed a double-blind randomized controlled pilot study in which 20 male metabolic syndrome patients were randomized to single lean vegan-donor or autologous fecal microbiota transplantation. At baseline and 2 weeks thereafter, we determined the ability to produce TMAO from d6-choline and d3-carnitine (eg, labeled and unlabeled TMAO in plasma and 24-hour urine after oral ingestion of 250 mg of both isotope-labeled precursor nutrients), and fecal samples were collected for analysis of microbiota composition. 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans of the abdominal aorta, as well as ex vivo peripheral blood mononuclear cell cytokine production assays, were performed. At baseline, fecal microbiota composition differed significantly between vegans and metabolic syndrome patients. With vegan-donor fecal microbiota transplantation, intestinal microbiota composition in metabolic syndrome patients, as monitored by global fecal microbial community structure, changed toward a vegan profile in some of the patients; however, no functional effects from vegan-donor fecal microbiota transplantation were seen on TMAO production, abdominal aortic 18Ffluorodeoxyglucose uptake, or ex vivo cytokine production from peripheral blood mononuclear cells. Conclusions--Single lean vegan-donor fecal microbiota transplantation in metabolic syndrome patients resulted in detectable changes in intestinal microbiota composition but failed to elicit changes in TMAO production capacity or parameters related to vascular inflammation.

The gut microbiota has been implicated in obesity and cardiometabolic diseases, although evidence in humans is scarce. We investigated how gut microbiota manipulation by antibiotics (7-day administration of amoxicillin, vancomycin, or placebo) affects host metabolism in 57 obese, prediabetic men. Vancomycin, but not amoxicillin, decreased bacterial diversity and reduced Firmicutes involved in short-chain fatty acid and bile acid metabolism, concomitant with altered plasma and/or fecal metabolite concentrations. Adipose tissue gene expression of oxidative pathways was upregulated by antibiotics, whereas immune-related pathways were downregulated by vancomycin. Antibiotics did not affect tissue-specific insulin sensitivity, energy/substrate metabolism, postprandial hormones and metabolites, systemic inflammation, gut permeability, and adipocyte size. Importantly, energy harvest, adipocyte size, and whole-body insulin sensitivity were not altered at 8-week follow-up, despite a still considerably altered microbial composition, indicating that interference with adult microbiota by 7-day antibiotic treatment has no clinically relevant impact on metabolic health in obese humans.