Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice

Abstract

The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health1. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia2. This was associated with a pro-inflammatory T helper type 1 (TH1) immune response and increased incidence of colitis in genetically susceptible Il10−/− , but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10−/− mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Saturated MF-induced colitis is associated with bloom of B. wadsworthia in Il10 −/− mice.
Figure 2: B. wadsworthia mono-association in GF Il10 −/− mice can only be established with consumption of MF diet, resulting in a T H 1 immune response and development of colitis.
Figure 3: Induction of TC bile acid following consumption of MF promotes bloom of B. wadsworthia both in vitro and in SPF Il10 −/− mice, resulting in colitis.
Figure 4: Mono-association with B. wadsworthia in GF Il10 −/− mice is successful only if accompanied by TC gavage.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Data have been deposited in GenBank under accession numbers JQ890637–JQ894320.

References

  1. Walter, J. & Ley, R. The human gut microbiome: ecology and recent evolutionary changes. Annu. Rev. Microbiol. 65, 411–429 (2011)

    CAS  Article  PubMed  Google Scholar 

  2. Baron, E. J. Bilophila wadsworthia: a unique Gram-negative anaerobic rod. Anaerobe 3, 83–86 (1997)

    CAS  MathSciNet  Article  PubMed  Google Scholar 

  3. Molodecky N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012)

    Article  PubMed  Google Scholar 

  4. Maslowski, K. M. & Mackay, C. R. Diet, gut microbiota and immune responses. Nature Immunol. 12, 5–9 (2011)

    CAS  Article  Google Scholar 

  5. NHANES. Trends in intake of energy and macronutrients—Unites States 1971–2000 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5304a3.htm (2004)

  6. Turnbaugh, P., Bäckhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Hildebrandt, M. A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137, 1716–1724 (2009)

    CAS  Article  PubMed  Google Scholar 

  8. Baron, E. J. et al. Bilophila wadsworthia, a unique Gram-negative anaerobic rod recovered from appendicitis specimens and human faeces. J. Gen. Microbiol. 135, 3405–3411 (1989)

    CAS  PubMed  Google Scholar 

  9. Attene-Ramos, M. S., Wagner, E. D., Plewa, M. J. & Gaskins, H. R. Evidence that hydrogen sulfide is a genotoxic agent. Mol. Cancer Res. 4, 9–14 (2006)

    CAS  Article  PubMed  Google Scholar 

  10. Loubinoux, J., Bronowicji, J.-P., Peireira, I. A. C., Mougenet, J. L. & Le Faou, A. E. Sulphate reducing bacteria in human faeces and their association with inflammatory diseases. FEMS Microbiol. Ecol. 40, 107–112 (2002)

    CAS  Article  PubMed  Google Scholar 

  11. Rowan, F. E., Docherty, N. G., Coffey, J. C. & O’Connell, P. R. Sulphate-reducing bacteria and hydrogen sulphide in the etiology of ulcerative colitis. Br. J. Surg. 96, 151–158 (2009)

    CAS  Article  PubMed  Google Scholar 

  12. Beech, I. B. & Zinkevich, V. Screening of sulfate-reducing bacteria in colonoscopy samples from healthy and colitic human gut mucosa. FEMS Microbiol. Ecol. 2, 147–155 (2000)

    Google Scholar 

  13. Gibson, G. R., Cummings, J. H. & Macfarlane, G. T. Growth and activities of sulphate-reducing bacteria in gut contents of healthy subjects and patients with ulcerative colitis. FEMS Microbiol. Ecol. 86, 103–112 (1991)

    CAS  Article  Google Scholar 

  14. Scanlan, P. D., Shanahan, F. & Marchesi, J. Culture-independent analysis of desulfovibrios in the human distal colon of healthy, colorectal cancer and polypectomized individuals. FEMS Microbiol. Ecol. 69, 213–221 (2009)

    CAS  Article  PubMed  Google Scholar 

  15. Arzese, A., Mercuri, F., Trevisan, R., Menozzi, G. & Botta, G. Recovery of Bilophila wadsworthia from clinical specimens in Italy. Anaerobe 3, 219–224 (1997)

    CAS  Article  PubMed  Google Scholar 

  16. Baron, E. J. et al. Bilophila wadsworthia isolates from clinical specimens. J. Clin. Microbiol. 30, 1882–1887 (1992)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Laue, H., Denger, K. & Cook, A. M. Taurine reduction in anaerobic respiration of Bilophila wadsworthia RZATAU. Appl. Environ. Microbiol. 63, 2016–2021 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lindstedt, S., Avigan, J., Goodman, D. S., Sjovall, J. & Steinberg, D. The effects of dietary fat on the turnover of cholic acid and on the composition of the biliary bile acids in man. J. Clin. Invest. 44, 1754–1765 (1965)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Rueda, A. et al. Conjugated bile acids and intestinal flora during the preruminant stage in goat: influence of a lamb milk replacer. Arch. Physiol. Biochem. 104, 246–251 (1996)

    CAS  Article  PubMed  Google Scholar 

  20. Graham, T. O., Van Thiel, D. H., Little, J. M. & Lester, R. Synthesis of taurocholate by rat fetal liver in organ culture: effects of cortisol in vitro . Am. J. Physiol. 237, E177–E184 (1979)

    CAS  Article  PubMed  Google Scholar 

  21. Ananieva, O., Nilsson, I., Vorobjova, T., Uibo, R. & Wadström, T. Immune responses to bile-tolerant Helicobacter species in patients with chronic liver diseases, a randomized population group, and healthy blood donors. Clin. Vaccine Immunol. 9, 1160–1164 (2002)

    Article  Google Scholar 

  22. Dussurget, O., Cabanes, D., Dehoux, P. & Lecuit, M. Listeria monocytogenes bile salt hydrolase is a PrfA-regulated virulence factor involved in the intestinal and hepatic phases of listeriosis. Mol. Microbiol. 4, 1098–1106 (2002)

    Google Scholar 

  23. Wang, a. l. Regional mucosa-associated microbiota determine physiological expression of TLR2 and TLR4 in murine colon. PLoS ONE 5, e13607 (2010)

    ADS  Article  PubMed  PubMed Central  Google Scholar 

  24. Wang, Y. et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME 3, 944–954 (2009)

    CAS  Article  Google Scholar 

  25. Berg, D. J. et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4+ TH1-like responses. J. Clin. Invest. 4, 1010–1020 (1996)

    Article  Google Scholar 

  26. Rossi, S. S., Converse, J. L. & Hofmann, A. F. High pressure liquid chromatographic analysis of conjugated bile acids in human bile: simultaneous resolution of sulfated and unsulfated lithocholyl amidates and the common conjugates bile acids. J. Lipid Res. 28, 589–595 (1987)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Center for Research Resources and the NIDDK, NIGMS and NCCAM of the National Institutes of Health through grant number DK-42086 (E.B.C.), DK47722 (E.B.C.), UH3DK083993 (E.B.C.), F31AT006073 (S.D.). Also, the Gastrointestinal Research Foundation, Crohns and Colitis Foundation of America (Y.W.), the Peter and Carol Goldman Family Research Fund, and the Harry and Leona Helmsley Trust Foundation (SHARE). We are also indebted to S. Finegold for his suggestions on successful culture of B. wadsworthia and Alistipes, J. Tiedje and M. Vital for dsrA primer sequences, L. Hagey for mass spectrometry, E. Huang, B. Theriault and J. Stencel for assistance with experiments, and R. Bouziat for T-cell purification.

Author information

Authors and Affiliations

Authors

Contributions

S.D. and E.B.C. were involved in all aspects of this study, especially in the development of the hypothesis, experimental plan and data analysis. Y.W., M.W.M., V.L., H.F.-P. and A.N. helped perform the experiments. D.A.A. and B.J. provided critical feedback and expertise and assisted in the analysis of data.

Corresponding author

Correspondence to Eugene B. Chang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-8 and Supplementary Tables 1-4. (PDF 4720 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Devkota, S., Wang, Y., Musch, M. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012). https://doi.org/10.1038/nature11225

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11225

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.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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