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.

Keywords: bariatric surgery; gut microbiota; insulin resistance; metabolites; obesity.

Fig. 1

A systems biology approach, identifying gut microbial, immunological and metabolic markers in a large and well‐phenotyped bariatric surgery cohort: the BARIA study.

Fig. 2

Glucose, insulin and triglycerides measurements during 2‐hour 7‐sample mixed meal test, stratified by glycaemic classification, as formulated in the American Diabetes Association criteria: normoglycemic (Healthy), impaired fasting glucose (IFG), increased haemoglobin A1c (IHbA1c), combination of IFG and IHbA1c (Comb) and type 2 diabetes mellitus (T2DM). Values are presented as means with 95% confidence intervals. (a) glucose curves; (b) insulin curves; (c) triglycerides curves.

Fig. 3

Area under the curve (AUC) of insulin and glucose during mixed meal test and HOMA2 insulin resistance (IR) and beta cell function (B), stratified by glycaemic classification, as formulated in the American Diabetes Association criteria: normoglycemic (Healthy), impaired fasting glucose (IFG), increased haemoglobin A1c (IHbA1c), combination of IFG and IHbA1c (Comb) and type 2 diabetes mellitus (T2DM). Points are individual values, solid line represents linear regression, banded area is 95% confidence interval. (a) Glucose AUC and HOMA2 IR. (b) Glucose AUC and HOMA2 B (%). (c) Insulin AUC and HOMA2 IR. (d) Insulin AUC and HOMA2 B. Correlation coefficient (R) and P‐values calculated with Spearman’s rank correlation test.

Fig. 4

Reproducibility of mixed meal test (MMT). Bland Altman plots of MMT (repeated within 1 week) for glucose, insulin and triglycerides. Blue line is mean of difference between measurements, red line is ± 1.96*SD of mean difference, and green line is ± 20% of mean difference. (a) Glucose area under the curve (AUC) in mmol L⁻¹*time. (b) Glucose AUC per cent change. (c) Insulin AUC in mmol L⁻¹*time. (d) Insulin AUC per cent change. (e) Triglycerides AUC in mmol L⁻¹*time. (f) Triglycerides AUC per cent change.