Abstract
OBJECTIVE: To test whether interventions with putative lipopolysaccharide (LPS)-lowering effects including sevelamer and a synbiotic (Bifidobacterium longum+oligofructose) improve insulin sensitivity in subjects with obesity. METHODS: We randomized 22 lean and 28 human subjects with obesity to receive sevelamer, synbiotic, or placebo orally for 4 weeks. Peripheral insulin sensitivity was measured with an insulin clamp. Plasma cholesterol, endotoxemia markers, intestinal permeability, stool bacterial taxonomic content and plasma metabolites also were assessed. RESULTS: At baseline, subjects with obesity had lower insulin sensitivity and elevated plasma LDL-C concentrations. Sevelamer improved insulin sensitivity and lowered LDL-C in these subjects. Intestinal enrichment of Bifidobacterium longum had no effect on insulin sensitivity or lipids in either group. Markers of endotoxemia and intestinal permeability did not change with any intervention. Plasma metabolomics revealed that sevelamer increases several metabolites, many of them previously linked with positive changes in glucose and lipid metabolism, including biliary acids, amino acids (citrulline, betaine), NAD+ precursors (trigonelline) and xenobiotics (genistein, umbelliferone). CONCLUSION: Sevelamer improves insulin sensitivity and LDL-C in subjects with obesity, but these effects are independent of changes in circulating LPS. Sevelamer increases the levels of multiple metabolites that collectively may mediate improvements in glucose homeostasis and lipids caused by this drug.