Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

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

References

  1. 1.

    Bariatric surgery: risks and rewards. J. Clin. Endocrinol. Metab. 93, S89–S96 (2008)

  2. 2.

    et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N. Engl. J. Med. 366, 1567–1576 (2012)

  3. 3.

    et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide-1 receptor deficiency. Diabetes 62, 2380–2385 (2013)

  4. 4.

    et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 141, 950–958 (2011)

  5. 5.

    , , & Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Ann. Surg. 247, 401–407 (2008)

  6. 6.

    , , , & All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr. Rev. 33, 595–622 (2012)

  7. 7.

    et al. Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and β-cell function in type 2 diabetic patients. Diabetes 62, 3027–3032 (2013)

  8. 8.

    et al. Gastric bypass and banding equally improve insulin sensitivity and β cell function. J. Clin. Invest. 122, 4667–4674 (2012)

  9. 9.

    et al. Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner. Obesity 22, 390–400 (2014)

  10. 10.

    et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity 17, 1671–1677 (2009)

  11. 11.

    et al. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 61, 1124–1131 (2012)

  12. 12.

    et al. The human colonic microflora influences the alterations of xenobiotic-metabolizing enzymes by catechins in male F344 rats. Food Chem. Toxicol. 41, 695–702 (2003)

  13. 13.

    , , & Differences in mucosal gene expression in the colon of two inbred mouse strains after colonization with commensal gut bacteria. PLoS ONE 8, e72317 (2013)

  14. 14.

    et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010)

  15. 15.

    et al. Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. J. Clin. Endocrinol. Metab. 98, E708–E712 (2013)

  16. 16.

    et al. Vertical sleeve gastrectomy improves glucose and lipid metabolism and delays diabetes onset in UCD-T2DM rats. Endocrinology 153, 3620–3632 (2012)

  17. 17.

    et al. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-y gastric bypass. Diabetes Care 36, 1859–1864 (2013)

  18. 18.

    et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 60, 1861–1871 (2011)

  19. 19.

    et al. The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology 144, 50–52.e5 (2013)

  20. 20.

    , & Central nervous system mechanisms linking the consumption of palatable high-fat diets to the defense of greater adiposity. Cell Metab. 15, 137–149 (2012)

  21. 21.

    et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005)

  22. 22.

    et al. Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice. Cell Metab. 17, 141–152 (2013)

  23. 23.

    et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl Acad. Sci. USA 106, 2365–2370 (2009)

  24. 24.

    et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59, 3049–3057 (2010)

  25. 25.

    et al. Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters. Pharmacogenom. J. 13, 514–522 (2012)

  26. 26.

    et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci. Transl. Med. 5, 178ra41 (2013)

  27. 27.

    et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006)

  28. 28.

    , , & Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008)

  29. 29.

    & Effect of bile salts on the DNA and membrane integrity of enteric bacteria. J. Med. Microbiol. 58, 1533–1541 (2009)

  30. 30.

    et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 141, 1773–1781 (2011)

  31. 31.

    et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-β-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013)

  32. 32.

    et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc. Natl Acad. Sci. USA 108 (Suppl. 1). 4523–4530 (2011)

  33. 33.

    & UniFrac: a new phylogenetic method for comparing microbial communities. Appl. Environ. Microbiol. 71, 8228–8235 (2005)

  34. 34.

    et al. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62, 1112–1121 (2013)

  35. 35.

    et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008)

  36. 36.

    et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012)

  37. 37.

    et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013)

  38. 38.

    et al. Dietary modulation of clostridial cluster XIVa gut bacteria (Roseburia spp.) by chitin-glucan fiber improves host metabolic alterations induced by high-fat diet in mice. J. Nutr. Biochem. 23, 51–59 (2012)

  39. 39.

    et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013)

  40. 40.

    et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–6.e7 (2012)

  41. 41.

    et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281, 11039–11049 (2006)

  42. 42.

    , , & Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116, 1102–1109 (2006)

  43. 43.

    et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl Acad. Sci. USA 103, 1006–1011 (2006)

  44. 44.

    , , & Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J. Lipid Res. 53, 1723–1737 (2012)

  45. 45.

    , , , & Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm. Res. 30, 1447–1457 (2013)

  46. 46.

    et al. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J. Biol. Chem. 286, 26913–26920 (2011)

  47. 47.

    , , , & Targeting bile-acid signalling for metabolic diseases. Nature Rev. Drug Discov. 7, 678–693 (2008)

  48. 48.

    , , , & Improved insulin-sensitivity in mice heterozygous for PPAR-γ deficiency. J. Clin. Invest. 105, 287–292 (2000)

  49. 49.

    et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000)

  50. 50.

    et al. QIIME allows analysis of high-throughput community sequencing data. Nature Methods 7, 335–336 (2010)

  51. 51.

    et al. Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. J. Microbiol. Methods 81, 127–134 (2010)

  52. 52.

    , , , & Error-correcting barcoded primers for pyrosequencing hundreds of samples in multiplex. Nature Methods 5, 235–237 (2008)

  53. 53.

    et al. PyNAST: a flexible tool for aligning sequences to a template alignment. Bioinformatics 26, 266–267 (2010)

  54. 54.

    , & FastTree: computing large minimum evolution trees with profiles instead of a distance matrix. Mol. Biol. Evol. 26, 1641–1650 (2009)

Download references

Acknowledgements

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

Affiliations

  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

Authors

  1. Search for Karen K. Ryan in:

  2. Search for Valentina Tremaroli in:

  3. Search for Christoffer Clemmensen in:

  4. Search for Petia Kovatcheva-Datchary in:

  5. Search for Andriy Myronovych in:

  6. Search for Rebekah Karns in:

  7. Search for Hilary E. Wilson-Pérez in:

  8. Search for Darleen A. Sandoval in:

  9. Search for Rohit Kohli in:

  10. Search for Fredrik Bäckhed in:

  11. Search for Randy J. Seeley in:

Contributions

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.

Extended data

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature13135

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing