Cited by 762Gut microbiota and healthBariatric Surgery and OutcomesAdipokines, Inflammation, and Metabolic Diseases

The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index; none of the 42 sources its claims cite is checked for support yet.

Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation

Open access
Tremaroli, Valentina, Karlsson, Fredrik, Werling, Malin, Ståhlman, Marcus, Kovatcheva-Datchary, Petia, Olbers, Torsten, Fändriks, Lars, le Roux, Carel W., Nielsen, Jens, Bäckhed, Fredrik·2015·Cell Metabolism

Abstract

Bariatric surgery is currently the most effective procedure for the treatment of obesity. Given the role of the gut microbiota in regulating host metabolism and adiposity, we investigated the long-term effects of bariatric surgery on the microbiome of patients randomized to Roux-en-Y gastric bypass or vertical banded gastroplasty and matched for weight and fat mass loss. The two surgical procedures induced similar and durable changes on the gut microbiome that were not dependent on body mass index and resulted in altered levels of fecal and circulating metabolites compared with obese controls. By colonizing germ-free mice with stools from the patients, we demonstrated that the surgically altered microbiota promoted reduced fat deposition in recipient mice. These mice also had a lower respiratory quotient, indicating decreased utilization of carbohydrates as fuel. Our results suggest that the gut microbiota may play a direct role in the reduction of adiposity observed after bariatric surgery.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Bariatric surgery in women randomized to Roux-en-Y gastric bypass (RYGB) or vertical banded gastroplasty (VBG) produced similar, durable gut microbiome changes about 9 years later that were not explained by BMI. Transplanting these surgically altered microbiotas into germ-free mice reduced fat deposition, suggesting the microbiome contributes directly to post-surgery adiposity reduction.

Key findings

  • At 9.4 years after randomization, RYGB and VBG patients showed similar microbiome shifts; RYGB versus obese controls differed significantly, with 29 microbial genera differing in abundance, while VBG versus controls and RYGB versus VBG differences were not significant after multiple-testing correction.
  • Metagenomic functional content differed: 928 KOs were enriched and 60 depleted in RYGB versus OBS, and 682 KOs were enriched and 33 depleted in VBG versus OBS; only 17 KOs differed between RYGB and VBG, all enriched in VBG.
  • Fecal short-chain fatty acid/branched-chain fatty acid ratio decreased after surgery and was significant for RYGB; postprandial bile acid response was pronounced in RYGB, with increased total and conjugated bile acids and increased FGF19 response versus OBS.
  • Germ-free mice colonized with RYGB or VBG microbiota for 2 weeks accumulated 43% and 26% less body fat, respectively, than mice colonized with OBS microbiota; RYGB-colonized mice also had a lower respiratory quotient.

Methods

  • Cross-sectional human study of fecal samples from 14 women 9.4 years after randomization to RYGB (n = 7) or VBG (n = 7), matched for pre- and post-operative weight, BMI, and body composition, plus non-operated severely obese women (OBS, n = 7) and BMI-matched post-surgical controls (Ob, n = 9).
  • Shotgun metagenomic sequencing on Illumina HiSeq 2000; reads aligned to 2,382 reference genomes and the MetaHIT gene catalog, with KEGG ortholog/pathway analysis and multiple-testing correction.
  • Fecal SCFAs/BCFAs measured by GC-MS; plasma TMAO, choline, betaine, and bile acids measured by UPLC-MS/MS; fecal microbiota from three RYGB, three VBG, and three OBS patients transplanted into germ-free female mice for 2 weeks, with body composition and indirect calorimetry.

Limitations

  • The paper states that the small sample size may explain the lack of distinct microbiota profiles between RYGB and VBG, and that bile acid gene findings need validation in larger cohorts and at shorter time points after surgery.
  • The paper states that future studies of microbiome from patients achieving different levels of weight and fat loss are required to validate the findings.
  • Evident from the text: the human cohort was small, all female, and diabetes-free, and the human microbiome–adiposity link is supported by mouse transplantation rather than direct human causality.

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Integrity signals

Registry

Crossref · 10.1016/j.cmet.2015.07.009

Cites

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Statistics

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Figures

Graphical abstract
Graphical abstract CC BY-NC-ND · PubMed Central
Figure 1 Long-term Effects of Bariatric Surgery on Gut Microbiota Composition (A) Scatter plot of median species abundance in RYGB patients and severely obese subjects (OBS). (B) Scatter plot of median species abundance in VBG patients and OBS subjects. (C) Scatter plot of median species abundance in RYGB and VBG patients. The genus affiliations of differentially abundant species are indicated by color (Adj. p < 0.05, Wilcoxon rank-sum test). See also Table S3.
Figure 1 Long-term Effects of Bariatric Surgery on Gut Microbiota Composition (A) Scatter plot of median species abundance in RYGB patients and severely obese subjects (OBS). (B) Scatter plot of median species abundance in VBG patients and OBS subjects. (C) Scatter plot of median species abundance in RYGB and VBG patients. The genus affiliations of differentially abundant species are indicated by color (Adj. p < 0.05, Wilcoxon rank-sum test). See also Table S3.CC BY-NC-ND · PubMed Central
Figure 2 Functional Differences in the Microbiomes of RYGB, VBG and OBS Subjects as Measured by the Abundance of KOs (A) Comparison of RYGB versus OBS samples. (B) Comparison of VBG versus OBS samples. (C) Comparison of RYGB versus VBG samples. Each spot represents a KO, and red spots represent KOs whose abundance is significantly different. FC, fold change; CPM, counts per million. See also Table S4 and Figures S1 and S2.
Figure 2 Functional Differences in the Microbiomes of RYGB, VBG and OBS Subjects as Measured by the Abundance of KOs (A) Comparison of RYGB versus OBS samples. (B) Comparison of VBG versus OBS samples. (C) Comparison of RYGB versus VBG samples. Each spot represents a KO, and red spots represent KOs whose abundance is significantly different. FC, fold change; CPM, counts per million. See also Table S4 and Figures S1 and S2.CC BY-NC-ND · PubMed Central
Figure 3 Postprandial Bile Acid and FGF19 Responses in RYGB, VBG, and OBS Women (A) Circulating concentrations of total bile acids (Total BA), total conjugated primary (G+T primary), total conjugated secondary (G+T secondary), glycine-conjugated primary (G-primary), glycine-conjugated secondary (G-secondary), taurine-conjugated primary (T-primary), taurine-conjugated secondary (T-secondary), unconjugated primary, and unconjugated secondary bile acids. (B) Tukey box plots showing the area under the curve (AUC) as a measure of the bile acid postprandial responses. (C) Circulating concentrations of FGF19 and AUC showing FGF19 postprandial response in RYGB, VBG, and OBS women. Plasma samples were collected during fasting and every 30 min for 2.5 hr after a standard meal. Samples from colecystectomized patients (one in the RYGB and one in the VBG group) were excluded from the analysis, and plasma from one VBG woman could not be obtained, so the results represent the mean ± SEM for six RYGB, five VBG, and seven OBS women. a p < 0.05 according to one-way ANOVA with Tukey’s correction for multiple comparisons for RYGB compared to OBS. See also Figure S3.
Figure 3 Postprandial Bile Acid and FGF19 Responses in RYGB, VBG, and OBS Women (A) Circulating concentrations of total bile acids (Total BA), total conjugated primary (G+T primary), total conjugated secondary (G+T secondary), glycine-conjugated primary (G-primary), glycine-conjugated secondary (G-secondary), taurine-conjugated primary (T-primary), taurine-conjugated secondary (T-secondary), unconjugated primary, and unconjugated secondary bile acids. (B) Tukey box plots showing the area under the curve (AUC) as a measure of the bile acid postprandial responses. (C) Circulating concentrations of FGF19 and AUC showing FGF19 postprandial response in RYGB, VBG, and OBS women. Plasma samples were collected during fasting and every 30 min for 2.5 hr after a standard meal. Samples from colecystectomized patients (one in the RYGB and one in the VBG group) were excluded from the analysis, and plasma from one VBG woman could not be obtained, so the results represent the mean ± SEM for six RYGB, five VBG, and seven OBS women. a p < 0.05 according to one-way ANOVA with Tukey’s correction for multiple comparisons for RYGB compared to OBS. See also Figure S3.CC BY-NC-ND · PubMed Central
Figure 4 Gut Microbiome of RYGB and VBG Women in Comparison to Non-Operated Women (Ob) with BMI Matched to the Post-Surgical BMI of the Bariatric Surgery Patients (A) Gut microbiota composition. Scatter plot of median species abundance in RYGB and Ob, in VBG and Ob, and in Ob and OBS women. The genus affiliations of differentially abundant species are indicated by color (Adj. p < 0.05, Wilcoxon rank-sum test). (B) Functional differences in the microbiomes measured by the abundance of KOs. Each spot represents a KO, and red spots represent KOs whose abundance is significantly different. The number of KOs significantly increased (up) and depleted (down) is shown under each plot. The direction of change is defined as up being the title above and down being the title to the right of each plot. FC, fold change; CPM, counts per million. See also Table S5 and Figure S4.
Figure 4 Gut Microbiome of RYGB and VBG Women in Comparison to Non-Operated Women (Ob) with BMI Matched to the Post-Surgical BMI of the Bariatric Surgery Patients (A) Gut microbiota composition. Scatter plot of median species abundance in RYGB and Ob, in VBG and Ob, and in Ob and OBS women. The genus affiliations of differentially abundant species are indicated by color (Adj. p < 0.05, Wilcoxon rank-sum test). (B) Functional differences in the microbiomes measured by the abundance of KOs. Each spot represents a KO, and red spots represent KOs whose abundance is significantly different. The number of KOs significantly increased (up) and depleted (down) is shown under each plot. The direction of change is defined as up being the title above and down being the title to the right of each plot. FC, fold change; CPM, counts per million. See also Table S5 and Figure S4.CC BY-NC-ND · PubMed Central
Figure 5 The Gut Microbiota Influences Fat Accumulation and Metabolism in Colonized Mice (A) Fat gain in mice colonized with human stools from OBS, RYGB, and VBG women. Fat gain was calculated as the difference between fat content normalized over body weight at the end of the experiment (d14) and fat content normalized over body weight 1 day after colonization (d1). The results presented were obtained from colonization of GF mice with fecal microbiota from two patients in each of the RYGB, VBG, and OBS groups (four to five mice per donor microbiota). (B) RQ (ratio between CO2 produced and O2 consumed) calculated for the light and dark phases and for the overall 22 hr period in the Somedic chamber. (C) RQ in the resting phase (basal RQ, calculated as the average RQ for the lowest 10 min average of O2 consumption). The results presented in (B) and (C) were obtained from colonization of GF mice with fecal microbiota from three patients in each of the RYGB, VBG, and OBS groups (3–5 mice per donor microbiota). Bars show the results of colonization with the same donor microbiota, with black dots showing individual mice and lines indicating the mean. Statistical significance of differences between the means was tested by one-way ANOVA with Tukey’s correction for multiple comparisons (a p < 0.05 for RYGB compared to OBS, b p < 0.05 for VBG compared to OBS, and c p < 0.05 for RYGB compared to VBG). See also Figure S5.
Figure 5 The Gut Microbiota Influences Fat Accumulation and Metabolism in Colonized Mice (A) Fat gain in mice colonized with human stools from OBS, RYGB, and VBG women. Fat gain was calculated as the difference between fat content normalized over body weight at the end of the experiment (d14) and fat content normalized over body weight 1 day after colonization (d1). The results presented were obtained from colonization of GF mice with fecal microbiota from two patients in each of the RYGB, VBG, and OBS groups (four to five mice per donor microbiota). (B) RQ (ratio between CO2 produced and O2 consumed) calculated for the light and dark phases and for the overall 22 hr period in the Somedic chamber. (C) RQ in the resting phase (basal RQ, calculated as the average RQ for the lowest 10 min average of O2 consumption). The results presented in (B) and (C) were obtained from colonization of GF mice with fecal microbiota from three patients in each of the RYGB, VBG, and OBS groups (3–5 mice per donor microbiota). Bars show the results of colonization with the same donor microbiota, with black dots showing individual mice and lines indicating the mean. Statistical significance of differences between the means was tested by one-way ANOVA with Tukey’s correction for multiple comparisons (a p < 0.05 for RYGB compared to OBS, b p < 0.05 for VBG compared to OBS, and c p < 0.05 for RYGB compared to VBG). See also Figure S5.CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

58 Own result · 21 Not checked yet · 17 Own interpretation · 8 Own method · 1 Sources not found · 1 No basis given

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Show all 72 claims

  • It may state two separate claims as one. 22
  • Probably not a substantial claim. 18
34 of 34
  • The paper relies on this without support.

    There are no long-term investigations of the stability of gut microbiota changes after bariatric surgery or of the effects of different procedures on the human gut microbiota.

    “However, there are no long-term investigations of the stability of these changes or of the effects of different procedures on the human gut microbiota.”
  • The paper relies on this without support.

    The causal link between alterations to the microbiota and the reduction in adiposity observed after bariatric surgery has not been previously analyzed in humans.

    “Additionally, the causal link between the alterations to the microbiota and the reduction in adiposity observed after bariatric surgery has not been previously analyzed in humans.”
  • The paper relies on this without support.

    Both RYGB and VBG are associated with reduced luminal exposure to gastric acidity.

    “For example, increases in pH have been shown to promote the growth of E. coli in vitro (Duncan et al., 2009), and both RYGB and VBG are associated with reduced luminal exposure to gastric acidity.”
  • The paper relies on this without support.

    The observed microbiome shifts are attributable to bariatric surgery rather than to unmeasured differences in diet or other lifestyle factors.

    “Importantly, the changes in the microbiome were not dependent on BMI or degree of weight and fat mass loss, thus revealing shifts in the gut microbiota that were specific to bariatric surgery.”
4 of 4

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Metadata

Authors
Tremaroli, V., Karlsson, F., Werling, M., Ståhlman, M., Kovatcheva-Datchary, P., Olbers, T., Fändriks, L., le Roux, C. W., Nielsen, J., & Bäckhed, F.
Affiliations
  • University of Gothenburg (SE)
  • Chalmers University of Technology (SE)
  • Sahlgrenska University Hospital (SE)
  • University of Copenhagen (DK)
Corresponding author
Bäckhed, Fredrik
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2015-08
Volume
22
Issue
2
Pages
228-238
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2103218211
Cited by
757
References
59
Citations by year
2026: 26 · 2025: 37 · 2024: 43 · 2023: 68 · 2022: 79 · 2021: 72 · 2020: 100 · 2019: 86 · 2018: 76 · 2017: 82 · 2016: 73 · 2015: 14
FWCI
35.42
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
  • Chalmers Publication Library (Chalmers University of Technology) (submittedVersion)
  • Chalmers Research (Chalmers University of Technology) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
  • Hjärt-Lungfonden
  • Knut och Alice Wallenbergs Stiftelse
  • Vetenskapsrådet
  • Sahlgrenska Universitetssjukhuset
  • Göteborgs Universitet
  • Institut National Du Cancer
  • Novo Nordisk Fonden (NNF13OC0008163, NNF13SA0006017)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
Roux-en-Y gastric bypass, vertical banded gastroplasty, bariatric surgery, gut microbiota, obesity, adiposity, fecal metabolites, circulating metabolites, germ-free mice, fat deposition, respiratory quotient, carbohydrate utilization
MeSH terms
Animals, Female, Follow-Up Studies, Humans, Intestines, Obesity, Gastric Bypass, Body Mass Index, Adiposity, Mice, Microbiota

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