Roux-en-Y gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype - PubMed (original) (raw)

doi: 10.1186/s40168-021-01086-x.

Hutan Ashrafian 2, Magali Sarafian 1, Daniel Homola 1, Laura Rushton 1 3, Grace Barker 1, Paula Momo Cabrera 1, Matthew R Lewis 3, Ara Darzi 2, Edward Lin 4, Nana Adwoa Gletsu-Miller 5, Stephen L Atkin 6, Thozhukat Sathyapalan 7, Nigel J Gooderham 1, Jeremy K Nicholson 8, Julian R Marchesi 1, Thanos Athanasiou 2, Elaine Holmes 9 10

Affiliations

Roux-en-Y gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype

Jia V Li et al. Microbiome. 2021.

Abstract

Background: Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations.

Methods: Three bariatric cohorts (n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome.

Results: Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine-N-oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients' bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery.

Conclusion: Altered bacterial composition and metabolism contribute to metabolic observations in biofluids of patients following RYGB surgery. The impact of these changes on the functional clinical outcomes requires further investigation. Video abstract.

Keywords: Bariatric surgery; Bile acids; Host-microbial metabolism, Metabolic profiling; Microbiome.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Fig. 1

Experimental design of three cohorts of bariatric surgery patients including sampling and the applied analytical methods (A). Body mass index (BMI) of patients who had undergone RYGB (B), gastric banding (C) and sleeve gastrectomy (D) at pre-op and post-operation time points. ****p < 0.0001, **p < 0.005, *p < 0.05. Data are presented in mean ± SEM

Fig. 2

Fig. 2

OPLS-DA cross-validated scores plots of urinary 1H NMR spectra of the RYGB patients from cohort 1 at pre-op, 2–6 months and 1–2 years post-op (A, Q2Y = 0.27; R2X = 17.2%; R2Y = 56.3%, CVANOVA p = 2.04 × 10−15), and cohort 2 at pre-op and 6-month post-op (B, Q2Y = 0.46; R2X = 25.3%; R2Y = 97.0%, p = 0.02). The metabolites that significantly contributed to the classification of different time points are shown in the heatmap (C). The correlation coefficient (r) was derived from OPLS-DA models and a positive correlation indicates higher relative concentrations of the metabolites in post-op compared to pre-op or in RYGB compared to LGB. q, the corrected p values using Benjamini-Hochberg multiple test correction are shown as #q < 0.0001, ‡_q_ < 0.001, †_q_ < 0.005, *_q_ < 0.05. a_p_ < 0.05 and q>0.05. ^ putatively assigned metabolites

Fig. 3

Fig. 3

Relative intensities of urinary bile acids from cohort 1 RYGB patients at pre-op (black), 2–6 months (green) and 1–2 years post-op (orange). Kruskal-Wallis test was used for group comparisons and Dunn’s test was used for adjusting multiple comparisons. The adjusted p values: ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05. Data are presented in mean ± SEM. The bile acids and their retention times (min) and m/z are given in the titles

Fig. 4

Fig. 4

Trajectory PCA scores plot of serum 1H NMR spectra of RYGB patients from cohort 3 at pre-op and 1, 3, 6, 9 and 12 months post-op (A). Data are presented in mean ± SEM. The metabolites that were significantly different between pre-op and each of the post-op time points are summarized in the heatmap (B). The last two columns show the metabolite changes between pre-op and 6 months post-op in cohort 2 alone and in combined analysis of cohorts 2 and 3. The correlation coefficient (r) was derived from OPLS-DA models (Figure S6) and a positive correlation indicates higher relative concentrations of the metabolites in post-op compared to pre-op. q, the corrected p values using Benjamini-Hochberg multiple test correction are shown as *0.005 < _q_ < 0.05. a_p_ < 0.05 and _q_ > 0.05

Fig. 5

Fig. 5

Shannon diversity index (A) and Chao1 diversity index (B) of faecal bacterial composition in different surgical groups at different time points (A, no statistical significance). An NMDS plot (C) of faecal bacterial composition of RYGB patients from cohort 1. PERMANOVA adjusted p = 0.0015 for pre-op vs. 2–6 months or 1–2 years post-op; p > 0.05 for 2–6 months vs. 1–2 years post-op. The natural log-transformed relative abundances of faecal bacteria from RYGB patients at pre-op (black), 2–6 months (green) and 1–2 years (orange) post-op (panel D). Data are presented in mean ± SEM. Kruskal-Wallis test was used for group comparisons and Dunn’s test was used for adjusting multiple comparisons. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05

Fig. 6

Fig. 6

OPLS-DA cross-validated scores plots of faecal 1H NMR spectra of the RYGB patients from cohort 1 at pre-op, and 1–2 years post-op (A, Q2Y = 0.18; R2X = 31.8%, R2Y = 61.2%, p = 0.002), and at 2–6 months and 1–2 years post-op (B, Q2Y = 0.2; R2X = 30.7%, R2Y = 65.3%, p = 0.002). The metabolites that significantly contributed to the classification of different time points are shown in the heatmap (C). The correlation coefficient (r) was derived from OPLS-DA models and a positive correlation indicates higher relative concentrations of the metabolites in 1–2 years post-op compared to either pre-op or 2–6 months post-op. q, the corrected p values using Benjamini-Hochberg multiple test correction are shown as ‡q < 0.001, †_q_ < 0.005, *_q_ < 0.05. a_p_ < 0.05 and _q_ > 0.05. Faecal pH of the RYGB patients at pre-op, 2-6 months and 1-2 Y post-op (D)

Fig. 7

Fig. 7

Spearman’s rank correlation of the significantly changed faecal bacterial abundances with faecal (F) and urinary (U) metabolites in RYGB patients from cohort 1 (A). The colour bar indicates the correlation coefficient r values and the p values post Benjamini-Hochberg multiple test correction are indicated as ***p < 0.001, **p < 0.01, *p < 0.05. Summary of metabolic pathways of tyrosine, phenylalanine, tryptophan and choline and associated gut bacteria (B). Bacteria and metabolite names depicted red indicate increased abundance or concentrations post-RYGB compared to pre-op. Bold solid red lines indicate metabolite production by the gut bacteria observed in the culture experiments. Red arrows between molecules indicate enhanced metabolic pathways following the RYGB surgery. The dashed line between the metabolites and gut bacteria indicates significantly positive (red) and negative (blue) correlation. The uneven dashed line indicates multiple reaction steps. The red ovals (RYGB microbiota) indicate metabolic transformation steps in the batch culture of faecal samples from RYGB donors

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