Major microbiota dysbiosis in severe obesity: fate after bariatric surgery

Abstract

Objectives: Decreased gut microbial gene richness (MGR) and compositional changes are associated with adverse metabolism in overweight or moderate obesity, but lack characterisation in severe obesity. Bariatric surgery (BS) improves metabolism and inflammation in severe obesity and is associated with gut microbiota modifications. Here, we characterised severe obesity-associated dysbiosis (ie, MGR, microbiota composition and functional characteristics) and assessed whether BS would rescue these changes.

Design: Sixty-one severely obese subjects, candidates for adjustable gastric banding (AGB, n=20) or Roux-en-Y-gastric bypass (RYGB, n=41), were enrolled. Twenty-four subjects were followed at 1, 3 and 12 months post-BS. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography mass spectrometry (LC-MS). Confirmation groups were included.

Results: Low gene richness (LGC) was present in 75% of patients and correlated with increased trunk-fat mass and comorbidities (type 2 diabetes, hypertension and severity). Seventy-eight metagenomic species were altered with LGC, among which 50% were associated with adverse body composition and metabolic phenotypes. Nine serum metabolites (including glutarate, 3-methoxyphenylacetic acid and L-histidine) and functional modules containing protein families involved in their metabolism were strongly associated with low MGR. BS increased MGR 1 year postsurgery, but most RYGB patients remained with low MGR 1 year post-BS, despite greater metabolic improvement than AGB patients.

Conclusions: We identified major gut microbiota alterations in severe obesity, which include decreased MGR and related functional pathways linked with metabolic deteriorations. The lack of full rescue post-BS calls for additional strategies to improve the gut microbiota ecosystem and microbiome-host interactions in severe obesity.

Trial registration number: NCT01454232.

Keywords: gastric surgery; intestinal bacteria; intestinal tract; obesity; obesity surgery.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1:. Microbial gene richness (MGR) in severe obesity:

A: Study flow-chart: baseline (MB or MB+MO) and MB follow-up cohorts. Two independent confirmation cohorts (EROIC and ATOX) were used for data confirmation, B: Microbial gene Richness (MGR) bimodal distribution in MB baseline cohort. C: Baseline MGR in AGB and RYGB patients, including four enterotype characteristics in each surgery groups.

Figure 2:. Links between MGR and bio-clinical characteristics in MO+MB subjects:

(A) MGR relationships with anthropometric parameters (B) MGR relation with metabolic comorbidities (hypertension and hypertension treatments and diabetes), N=non-diabetes, IG =glucose intolerance, D=diabetes, (C) MGR relation with OGTT-derived glucose-tolerance parameters (AUC area under the curve of glucose after OGTT with 75g glucose, and Stumvoll index), Adiponectin and adipocyte volume. Pearson correlations are performed (p=p-value, q=FDR and r2; Statistics include linear models (lm), Pearson and Spearman correlations, t-test and Kruskal-Wallis when appropriate.

Figure 3:. MGR-associated MGS at baseline

A: Heatmap of Spearman pairwise correlation coefficients between MGR-associated-MGS abundance and metabolic variables (body composition and corpulence and metabolic traits), and MGR-associated serum metabolites B: Venn diagram of metabolic parameters associated with MGR-related MGS. C: Heatmap of Spearman pairwise correlation coefficients between metabolic phenotypes and targeted serum metabolites. P-value significance denoted by (*) and FDR significance by (#).

Figure 4:. Microbial composition post-bariatric surgery

A: Mean changes in MGR in RYGB and AGB from baseline to Month 1 (M1) Month 3 (M3) and Month 12 (M12) B: Evolution of richness and enterotype composition of 24 patients with kinetics follow-up at M1, M 3 (M3) and M12 C: MGR with enterotype distribution at month 12 in AGB (N=10) and RYGB (N=14) patients with kinetics follow-up, D: richness evolution confirmed in another independent RYGB (ATOX) cohort followed at 5 years (*) significance between AGB and RYGB and (*) significance between baseline and T12M

Figure 5:. Significant MGS change post bariatric surgery:

A: 12 MGS significantly differ between baseline and T12M post both surgeries. Brown: RYBG (11 MGS); beige: AGB (2 MGS; 1 is common to RYGB-MGS); (*) significant p-value (in brown for RYGB and beige for AGB between T0 and T12) B: Heatmap of Spearman pairwise correlation coefficients between MGS delta and improvement in clinical outcomes. (*) significant p-value and (#) significant FDR.