Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

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Raw and normalized RNA-seq data have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE53782.


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We thank J. Berger, A. Haller, B. Li, E. Orr and M. Toure for technical assistance. This work was supported by grants from the UNIK Food Fitness and Pharma for Health and Disease research programme (C.C.), the Torsten Söderberg and NovoNordisk foundations (F.B.), Ethicon Endo-Surgery (R.K., D.A.S., R.J.S.) and the NIH (DK082173, HL111319 to K.K.R., DK093848 to R.J.S. and the Bioinformatics Core of the Digestive Disease Research Core Center in Cincinnati DK078392).

Author information


  1. Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA

    • Karen K. Ryan
    • , Christoffer Clemmensen
    • , Hilary E. Wilson-Pérez
    • , Darleen A. Sandoval
    •  & Randy J. Seeley
  2. Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, S-413 45 Gothenburg, Sweden

    • Valentina Tremaroli
    • , Petia Kovatcheva-Datchary
    •  & Fredrik Bäckhed
  3. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark

    • Christoffer Clemmensen
  4. Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Andriy Myronovych
    •  & Rohit Kohli
  5. Divison of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Rebekah Karns
  6. Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark

    • Fredrik Bäckhed


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K.K.R. conceptualized, designed, performed and analysed the experiments and wrote the manuscript. C.C., A.M., H.E.W.-P., D.A.S. and R. Kohli performed experiments and edited the manuscript. R. Karns performed the bioinformatics analysis of the RNA-seq data. V.T. and F.B. designed and performed the microbiota analysis and edited the manuscript. P.K.-D. and F.B. designed and performed the analysis of caecal metabolites and edited the manuscript. R.J.S. conceptualized, designed and analysed the experiments and wrote the manuscript.

Competing interests

D.A.S. receives research support from Ethicon Endo-Surgery, Novo Nordisk, and Boehringer-Ingelheim, is a consultant for Givaudan and is on the scientific advisory board for Ethicon Endo-Surgery. R. Kohli receives research support from Ethicon Endo-Surgery. F.B. is a founder of and owns equity in Metabogen AB. R.J.S. has received research support from Ethicon Surgical Care, Novo Nordisk, Ablaris, Roche, Boehringer-Ingelheim and Zealand. He has served as a consultant or paid speaker for Ethicon Surgical Care, Eissai, Forrest and Givaudan. He has a small equity position in Zafgen. The other authors have nothing to declare.

Corresponding author

Correspondence to Randy J. Seeley.

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