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.

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis

Abstract

Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein–coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.

This is a preview of subscription content, access via your institution

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: A low-fiber diet increased the severity of allergic airway inflammation.
Figure 2: A high-fiber diet decreased susceptibility to allergic airway inflammation.
Figure 3: Dietary fiber content alters the intestinal microbiota and both local and systemic levels of SCFAs.
Figure 4: Mice treated with propionate are protected against the development of allergic airway inflammation.
Figure 5: DCs from the lung-draining lymph nodes of mice treated with propionate are impaired in their ability to induce TH2 cell differentiation.
Figure 6: Propionate treatment increases the production of DC precursors in the bone marrow and results in lung-resident DCs that are less effective at reactivating effector TH2 cells.

References

  1. Devereux, G. The increase in the prevalence of asthma and allergy: food for thought. Nat. Rev. Immunol. 6, 869–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Nakaji, S. et al. Trends in dietary fiber intake in Japan over the last century. Eur. J. Nutr. 41, 222–227 (2002).

    Article  PubMed  Google Scholar 

  3. Roediger, W.E. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 21, 793–798 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Binder, H.J. & Mehta, P. Short-chain fatty acids stimulate active sodium and chloride absorption in vitro in the rat distal colon. Gastroenterology 96, 989–996 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Kaneko, T., Mori, H., Iwata, M. & Meguro, S. Growth stimulator for bifidobacteria produced by Propionibacterium freudenreichii and several intestinal bacteria. J. Dairy Sci. 77, 393–404 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Xie, S., Liu, J., Li, L. & Qiao, C. Biodegradation of malathion by Acinetobacter johnsonii MA19 and optimization of cometabolism substrates. J. Environ. Sci. (China) 21, 76–82 (2009).

    Article  CAS  Google Scholar 

  7. Flint, H.J., Bayer, E.A., Rincon, M.T., Lamed, R. & White, B.A. Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis. Nat. Rev. Microbiol. 6, 121–131 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Le Poul, E. et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278, 25481–25489 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Maslowski, K.M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sina, C. et al. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J. Immunol. 183, 7514–7522 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Aoyama, M., Kotani, J. & Usami, M. Butyrate and propionate induced activated or non-activated neutrophil apoptosis via HDAC inhibitor activity but without activating GPR-41/GPR-43 pathways. Nutrition 26, 653–661 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Jansen, M.S. et al. Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc. Natl. Acad. Sci. USA 101, 7199–7204 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim, H.J. et al. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J. Pharmacol. Exp. Ther. 321, 892–901 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Cummings, J.H., Hill, M.J., Bone, E.S., Branch, W.J. & Jenkins, D.J. The effect of meat protein and dietary fiber on colonic function and metabolism. II. Bacterial metabolites in feces and urine. Am. J. Clin. Nutr. 32, 2094–2101 (1979).

    Article  CAS  PubMed  Google Scholar 

  15. Cummings, J.H., Pomare, E.W., Branch, W.J., Naylor, C.P. & Macfarlane, G.T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221–1227 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Greger, J.L. Nondigestible carbohydrates and mineral bioavailability. J. Nutr. 129, 1434S–1435S (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Riedl, J., Linseisen, J., Hoffmann, J. & Wolfram, G. Some dietary fibers reduce the absorption of carotenoids in women. J. Nutr. 129, 2170–2176 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Scholz-Ahrens, K.E. & Schrezenmeir, J. Inulin and oligofructose and mineral metabolism: the evidence from animal trials. J. Nutr. 137, 2513S–2523S (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Hill, D.A. et al. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 3, 148–158 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Herbst, T. et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am. J. Respir. Crit. Care Med. 184, 198–205 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hill, D.A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–546 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Russell, S.L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440–447 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Noverr, M.C., Falkowski, N.R., McDonald, R.A., McKenzie, A.N. & Huffnagle, G.B. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect. Immun. 73, 30–38 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Noverr, M.C., Noggle, R.M., Toews, G.B. & Huffnagle, G.B. Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect. Immun. 72, 4996–5003 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Turnbaugh, P.J., Backhed, 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl. Acad. Sci. USA 107, 14691–14696 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Ulven, T. Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front. Endocrinol. (Lausanne) 3, 111 (2012).

    Article  Google Scholar 

  30. Lambrecht, B.N. & Hammad, H. Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat. Rev. Immunol. 3, 994–1003 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Lambrecht, B.N., Salomon, B., Klatzmann, D. & Pauwels, R.A. Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. J. Immunol. 160, 4090–4097 (1998).

    CAS  PubMed  Google Scholar 

  32. Plantinga, M. et al. Conventional and monocyte-derived CD11b+ dendritic cells initiate and maintain T helper 2 cell–mediated immunity to house dust mite allergen. Immunity 38, 322–335 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Liu, K. et al. In vivo analysis of dendritic cell development and homeostasis. Science 324, 392–397 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lambrecht, B.N. & Hammad, H. Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu. Rev. Immunol. 30, 243–270 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Erb-Downward, J.R. et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS ONE 6, e16384 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hilty, M. et al. Disordered microbial communities in asthmatic airways. PLoS ONE 5, e8578 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McNeil, N.I. The contribution of the large intestine to energy supplies in man. Am. J. Clin. Nutr. 39, 338–342 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Vinolo, M.A., Rodrigues, H.G., Nachbar, R.T. & Curi, R. Regulation of inflammation by short chain fatty acids. Nutrients 3, 858–876 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Blainey, P.C., Milla, C.E., Cornfield, D.N. & Quake, S.R. Quantitative analysis of the human airway microbial ecology reveals a pervasive signature for cystic fibrosis. Sci. Transl. Med. 4, 153ra130 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Madan, J.C. et al. Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. mBio 3, e00251–12 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work has been supported by the Swiss National Science Foundation grant 310030.130029 awarded to B.J.M. We thank R. Driscoll and the Fondation Placide Nicod for support and A. Genevaz, B. Berger and E. Rezzonico for scientific assistance related to microbiota analysis. B.J.M. is a Cloetta Medical Research Fellow.

Author information

Authors and Affiliations

Authors

Contributions

B.J.M. conceived the study. B.J.M. and A.T. designed the study. A.T., E.S.G., K.Y. and A.K.S. performed experiments. A.T. and E.S.G. analyzed data. N.S. performed SCFA analysis. C.N.-B., A.T. and B.J.M. performed microbiota analysis. T.J. provided Ffar3−/− and Ffar2−/− mice. T.J., C.B., N.L.H., L.P.N., E.S.G., A.T. and B.J.M. provided critical analysis and discussions. B.J.M. and A.T. wrote the paper.

Corresponding author

Correspondence to Benjamin J Marsland.

Ethics declarations

Competing interests

C.N.-B., C.B. and N.S. are employed by Nestec Ltd, Switzerland. T.J. is employed by Novartis Institutes for Biomedical Research.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 1650 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Trompette, A., Gollwitzer, E., Yadava, K. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 20, 159–166 (2014). https://doi.org/10.1038/nm.3444

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3444

This article is cited by

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