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

Abstract

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.

Lactose after Roux-en-Y gastric bypass for morbid obesity, is it a problem?

“…However, glucose kinetics are known to be altered after RYGB. Patients after surgery have similar times to postprandial peak glucose concentrations but peak concentrations are often far higher and also subsequently decline faster than in patients before surgery [20][21][22]. This is in line with the glucose curves in this study.…”

Autocrine negative feedback regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT

“…Primary murine adipocytes were purified from epididymal fat pads from lean C57BL6 mice. Samples of human adipocytes were obtained during bariatric surgery of patients participating in the BARIA study [ 29 ]. The study was performed in accordance with the Declaration of Helsinki and was approved by the Academic Medical Center Ethics Committee of the Amsterdam UMC.…”

Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction

“…We hypothesized that increased flagellin reaches the circulation following a meal, which was previously shown to drive translocation of endotoxins (Ghoshal et al, 2009). We therefore measured postprandial plasma flagellin, C-peptide and plasma glucose in 80 matched participants of our bariatric surgery cohort (Van Olden et al, 2021) comprising obese normoglycemic and obese T2D people during a mixed-meal test (MMT) (Figure 7A, Table S4). C-peptide was chosen as it reflects insulin secretion rates and is not affected by potential differences in clearance by the liver, as is the case for plasma insulin concentrations.…”

“…Participants with T2D were matched with normoglycemic controls according to age, sex and BMI. In addition, 80 participants were selected from our bariatric surgery cohort(Van Olden et al, 2021). (B) Fecal flagellin genes are increased in T2D, as inferred from 16S rRNA gene profiles (HELIUS).…”