The human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypass

Gut Microbes. 2022 Jan-Dec;14(1):2050635. doi: 10.1080/19490976.2022.2050635.


Roux-en-Y gastric bypass (RYGB) is efficient at inducing drastic albeit variable weight loss and type-2 diabetes (T2D) improvements in patients with severe obesity and T2D. We hypothesized a causal implication of the gut microbiota (GM) in these metabolic benefits, as RYGB is known to deeply impact its composition. In a cohort of 100 patients with baseline T2D who underwent RYGB and were followed for 5-years, we used a hierarchical clustering approach to stratify subjects based on the severity of their T2D (Severe vs Mild) throughout the follow-up. We identified via nanopore-based GM sequencing that the more severe cases of unresolved T2D were associated with a major increase of the class Bacteroidia, including 12 species comprising Phocaeicola dorei, Bacteroides fragilis, and Bacteroides caecimuris. A key observation is that patients who underwent major metabolic improvements do not harbor this enrichment in Bacteroidia, as those who presented mild cases of T2D at all times. In a separate group of 36 patients with similar baseline clinical characteristics and preoperative GM sequencing, we showed that this increase in Bacteroidia was already present at baseline in the most severe cases of T2D. To explore the causal relationship linking this enrichment in Bacteroidia and metabolic alterations, we selected 13 patients across T2D severity clusters at 5-years and performed fecal matter transplants in mice. Our results show that 14 weeks after the transplantations, mice colonized with the GM of Severe donors have impaired glucose tolerance and insulin sensitivity as compared to Mild-recipients, all in the absence of any difference in body weight and composition. GM sequencing of the recipient animals revealed that the hallmark T2D-severity associated bacterial features were transferred and were associated with the animals' metabolic alterations. Therefore, our results further establish the GM as a key contributor to long-term glucose metabolism improvements (or lack thereof) after RYGB.

Keywords: Microbiota; bacteroides; bariatric surgery; clustering; diabetes remission; fecal matter transplantation; obesity; relapse; roux-en-Y gastric bypass; type-2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteroidetes
  • Body Weight
  • Diabetes Mellitus, Type 2* / microbiology
  • Gastric Bypass* / methods
  • Gastrointestinal Microbiome*
  • Humans
  • Mice
  • Weight Loss

Grant support

This work was supported by the Fondation Leducq [17CVD01]; Fondation pour la Recherche Médicale [FDT201904008276, FDT202106012793]; F-CRIN-FORCE network [FORCE]; Join Program Initiative (JPI) [Microdiet (2017-01996_3)]; Société Francophone de Diabétologie [Allocation de Recherche SFD - Pierre Fabre Médicament Bourse et Allocation Exceptionnelle 2018]; Prix Auguste Loubatiere [2021]; Fondation Bettencourt Shueller [2019]; CAPES-COFECUB [8887.130206/2017-0]; National Agency of Research [ANR-10-IAHU-05]; Institut Benjamin Delessert [PPr 2016 IBD]; European Union’s 7th Framework Program for research, technological development and demonstration [HEALTH-F4-2012-305312 -METACARDIS]; Assistance Publique-Hôpitauxde Paris [HRC02076 and BARICAN cohort]; INSERM [ITMO, IRP INSERM]; Société Française de Nutrition [2020].