A systems biology approach to understand gut microbiota and host metabolism in morbid obesity: design of the BARIA Longitudinal Cohort Study.

INTRODUCTION: Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. METHODS: The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years. RESULTS: Preoperative MMT of 170 patients were analysed and clear differences were observed in glucose homeostasis between individuals. Repeated MMT in 10 patients showed satisfactory intra-individual reproducibility, with differences in plasma glucose, insulin and triglycerides within 20% of the mean difference. CONCLUSION: The BARIA study can add more understanding in how gut-microbiota affect metabolism, especially with regard to obesity, glucose metabolism and NAFLD. Identification of key factors may provide diagnostic and therapeutic leads to control the obesity-associated disease epidemic.

Distinct differences in gut microbial composition and functional potential from lean to morbidly obese subjects.

INTRODUCTION: The gut microbiome may contribute to the development of obesity. So far, the extent of microbiome variation in people with obesity has not been determined in large cohorts and for a wide range of body mass index (BMI). Here, we aimed to investigate whether the faecal microbial metagenome can explain the variance in several clinical phenotypes associated with morbid obesity. METHODS: Caucasian subjects were recruited at our hospital. Blood pressure and anthropometric measurements were taken. Dietary intake was determined using questionnaires. Shotgun metagenomic sequencing was performed on faecal samples from 177 subjects. RESULTS: Subjects without obesity (n = 82, BMI 24.7 ± 2.9 kg m-2 ) and subjects with obesity (n = 95, BMI 38.6 ± 5.1 kg m-2 ) could be clearly distinguished based on microbial composition and microbial metabolic pathways. A total number of 52 bacterial species differed significantly in people with and without obesity. Independent of dietary intake, we found that microbial pathways involved in biosynthesis of amino acids were enriched in subjects with obesity, whereas pathways involved in the degradation of amino acids were depleted. Machine learning models showed that more than half of the variance in body fat composition followed by BMI could be explained by the gut microbiome, composition and microbial metabolic pathways, compared with 6% of variation explained in triglycerides and 9% in HDL. CONCLUSION: Based on the faecal microbiota composition, we were able to separate subjects with and without obesity. In addition, we found strong associations between gut microbial amino acid metabolism and specific microbial species in relation to clinical features of obesity.

The effects of laparoscopic Roux-en-Y gastric bypass and one-anastomosis gastric bypass on glycemic control and remission of type 2 diabetes mellitus: study protocol for a multi-center randomized controlled trial (the DIABAR-trial).

BACKGROUND: Metabolic surgery induces rapid remission of type 2 diabetes mellitus (T2DM). There is a paucity of high level evidence comparing the efficacy of the laparoscopic Roux-en-Y gastric bypass (RYGB) and the laparoscopic one-anastomosis gastric bypass (OAGB) in glycemic control. Also, the mechanisms that drive the conversion of T2DM in severe obese subjects to euglycemia are poorly understood. METHODS: The DIABAR-trial is an open, multi-center, randomized controlled clinical trial with 10 years follow-up which will be performed in 220 severely obese patients, diagnosed with T2DM and treated with glucose-lowering agents. Patients will be randomized in a 1:1 ratio to undergo RYGB or OAGB. The primary outcome is glycemic control at 12 months follow-up. Secondary outcome measures are diverse and include weight loss, surgical complications, psychologic status and quality of life, dietary behavior, gastrointestinal symptoms, repetitive bloodwork to identify changes over time, glucose tolerance and insulin sensitivity as measured by mixed meal tests, remission of T2DM, presence of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in liver biopsy, oral and fecal microbiome, cardiovascular performance, composition of bile acids, and the tendency to develop gallstones. DISCUSSION: The DIABAR-trial is one of the few randomized controlled trials primarily aimed to evaluate the glycemic response after the RYGB and OAGB in severe obese patients diagnosed with T2DM. Secondary aims of the trial are to contribute to a deeper understanding of the mechanisms that drive the remission of T2DM in severe obese patients by identification of microbial, immunological, and metabolic markers for metabolic response and to compare complications and side effects of RYGB and OAGB. TRIAL REGISTRATION: ClinicalTrials.gov NCT03330756 ; date first registered: October 13, 2017.

Effects of 12-week treatment with dapagliflozin and gliclazide on faecal microbiome: Results of a double-blind randomized trial in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Patients with type 2 diabetes (T2D) are usually treated with (combinations of) glucose-lowering medication. The effects of these drugs can be influenced by intestinal microbiota and vice versa, as these drugs can also influence microbiome composition. However, as there is currently little clinical insight into this bug-drug interaction, our study aimed to evaluate the effects of 12-week treatment with the SGLT2 inhibitor dapagliflozin and sulphonylurea gliclazide on gut microbiome composition in T2D patients treated with metformin. METHODS: A total of 44 patients were randomized to either dapagliflozin or gliclazide treatment for 12 weeks. At baseline and after 12 weeks, faecal samples and 24-h urine were collected. During study visits, anthropometric data were measured and blood samples drawn after an overnight fast. Microbiome composition was determined by 16S rRNA gene sequencing. Plasma glucose, insulin, HbA1c and urinary glucose excretion were measured using conventional methods. RESULTS: While dapagliflozin and gliclazide similarly improved glycaemic control, dapagliflozin reduced and gliclazide increased fasting insulin. Dapagliflozin also greatly increased urinary glucose excretion whereas gliclazide did not, while body mass index, fat mass percentage and waist circumference were reduced by dapagliflozin, but increased by gliclazide. However, neither treatment significantly affected either gut microbiome alpha diversity or composition and, after treatment, no associations were found between microbiome composition and other clinical parameters. CONCLUSION: Even though gliclazide and dapagliflozin have different metabolic actions in patients with T2D, neither treatment altered the faecal microbiome, thereby suggesting that the observed metabolic changes are not mediated by their effects on the microbiota.