The role of the intestine in human glucose and lipid metabolism:Source for novel targets in the prevention of cardiometabolic disease

Dit proefschrift richt zich op de invloed van de darmen op het humaan metabolisme, waarbij de darmflora en fecale cholesterolexcretie centraal staan. In deel 1 van het proefschrift wordt beschreven hoe het antibioticum vancomycine de darmflora significant doet veranderen. Dit heeft echter slechts een mild effect op insulinegevoeligheid, één van de belangrijkste uitkomstmaten van dit gedeelte. De eveneens waargenomen toename van primaire- en afname van secundaire galzuren lijkt hiermee weinig effect te sorteren op het metabolisme van glucose en lipiden. Dunne donor darmbacterietransplantaties naar obese mannen met het metabool syndroom leiden daarentegen tot een tijdelijke verbetering van de insulinegevoeligheid, gekoppeld aan meer specifieke veranderingen in de darmflora. Dit effect is variabel en bovendien afhankelijk van de baseline darmflora, waarmee in de toekomst het behandeleffect a priori zou kunnen worden voorspeld. Met deze studies is het bestaan van de relatie darmflora – metabolisme in mensen bevestigd, wat ruimte geeft voor specifiekere darmbacteriegerichte therapieën om metabolisme ten positieve te beïnvloeden. In deel 2 van het proefschrift wordt het bestaan van transintestinale cholesterolexcretie (TICE) in mensen aangetoond. Hiermee kan, onafhankelijk van de galwegen, cholesterol uitgescheiden worden en dit bleek bovendien te stimuleren met ezetimibe. Tegelijkertijd leidden apolipoproteine A-I (apoA-I) infusies in een kleine pilot studie met mensen met een genetisch verlaagd apoA-I tot regressie van atherosclerose, gekoppeld aan verbeterde cholesterol efflux en een trend naar toegenomen fecale cholesterolexcretie. Deze bevindingen ondersteunen toekomstige interventiestudies gericht op fecale cholesterolexcretie, via apoA-I danwel via TICE, om het cardiovasculaire risico in bepaalde subgroepen mensen terug te doen dringen

The incidence of venous thromboembolism in patients with overt hyperthyroidism A retrospective multicentre cohort study

Clinical epidemiolog

The intestinal microbiome potentially affects thrombin generation in human subjects

Thrombosis and Hemostasi

Obesity, non-alcoholic fatty liver disease, and atherothrombosis: a role for the intestinal microbiota?

Whereas the association between intestinal microorganisms and health has been widely accepted in the area of infectious disease, recent advances have now implied a role for the intestinal microbiota in human energy balance. In fact, numerous studies support an intricate relationship between the intestinal microbiota and obesity, as well as subsequent insulin resistance and non-alcoholic fatty liver disease. Intestinal microorganisms also seem to be involved in haemostatic tone and atherogenesis. However, as most of the findings stem from observational data, intervention studies in humans using interventions selectively aimed at altering the composition and activity of the intestinal microbiota are crucial to prove causality. If substantiated, this could open the arena for modulation of the intestinal microbiota as a future target in obesity-associated disease, both as a diagnostic test for personalized algorithms and for selective therapeutic strategie

Effect of Vegan Fecal Microbiota Transplantation on Carnitine- and Choline-Derived Trimethylamine-N-Oxide Production and Vascular Inflammation in Patients With Metabolic Syndrome

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. (18)F-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 (18)F-fluorodeoxyglucose 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. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR 4338

Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity

BACKGROUND: 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 500mg t.i.d. or 7 days of vancomycin 500mg 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 [6,6-2H2]-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 (