A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass

Abstract

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement.

Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota.

Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m², HbA_1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA_1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients.

Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature.

Keywords: bariatric surgery; incretin; microbiota; severe obesity; type 2 diabetes remission.

Figure 1

Insulin, glucose, and C-peptide response to MTT at baseline and 1 year post-surgery. These figures show mean and standard deviation of insulin, glucose and C-peptid (expressed in mmol/L) at each time point after meal tolerance test (MTT). Baseline represented in blue and follow-up in red.

Figure 2

GLP-1 and GLP-2 response to MTT at baseline and 1 year post-surgery. These figures show mean and standard deviation of GLP-1 (expressed in pM) and GLP-2 (expressed in ng/ml) at each time point after meal tolerance test (MTT). Baseline represented in blue and follow-up in red.

Figure 3

Changes and associations between species and metabolic characteristics 1 year post-surgery. Log2 fold-change (FC) expresses the significant increase or decrease (≥+2/-2, P adjusted <0.001) of microbiota species 1 year after surgery compared to baseline levels. It is based on the fitZig model. The yellow color denotes increase, and purple denotes decrease. The correlations of the species and metabolic variables are showed in a heatmap, where red denotes a positive correlation and blue a negative correlation. The intensity of the color is related to the strength of the correlation. Statistically significant associations (P adjusted <0.05) are marked with *. GLP1, glucagon-like peptide 1; GLP2, glucagon-like peptide 2; AUC, area under curve; MTT, Meal tolerance test; LT, lipid test. BMI, body mass index.