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Metabolic syndrome refers to the combination of obesity, hypertension, dyslipidemia and insulin resistance. Metabolic syndrome increases the chance on cardiovascular disease and type 2 diabetes. Strategies to prevent and treat these metabolic derangements are therefore urgently needed. For this purpose better insight in the regulation of inter- and intra-organ metabolic pathways is of key relevance. Bile acids are produced by the liver, are stored in the gallbladder and are released into the intestine upon a meal. Bile acids are essential detergents required for the intestinal absorption of lipids. Recently it was shown that bile acids can also bind to several receptors. Hereby they can influence bile acid, lipid and glucose metabolism. In this thesis we investigated the receptor Lrh1. We show that this receptor is involved in the regulation of bile acid and lipid metabolism. Development of drugs targeted to this receptor could in the future potentially influence bile acid and lipid metabolism and aid to combat dyslipidemia and associated diseases. An increasing level of evidence reveals that gut microbiota are also associated with metabolic diseases. In mice and men we investigated to role of gut microbiota in bile acid and glucose metabolism. We found that gut microbiota influence the absorption of bile acids in the intestine. Moreover, a decrease in certain bacterial species after antibiotic treatment coincided with worsened glucose control in obese subjects. These findings emphasize the importance of a balanced gut flora and offer applicable ways to prevent or counteract metabolic diseases in the future.

BACKGROUND & AIMS: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism.METHODS: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured.RESULTS: Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters.CONCLUSIONS: Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566).