Skip to main content

Short-Chain Fatty Acids Suppress Lipopolysaccharide-Induced Production of Nitric Oxide and Proinflammatory Cytokines Through Inhibition of NF-κB Pathway in RAW264.7 Cells

Inflammation volume 35, pages 1676–1684 (2012)Cite this article

Abstract

Short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber contribute a significant proportion of daily energy requirement. Furthermore, these compounds are modulators of macrophage function and potential targets for the development of new drugs. The aims of this study were to evaluate the effects of three types of SCFAs (sodium acetate (NaAc), sodium propionate (NaP), and sodium butyrate (NaB)) on the production of NO and inducible nitric oxide synthase (iNOS) and proinflammatory and antiinflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin (IL-1, IL-6, and IL-10)) and to observe the effect of NaAc on inhibiting lipopolysaccharide (LPS)-induced NF-κB activation in LPS-stimulated RAW264.7 cells. The results show that three types of SCFAs (acetate, propionate, and butyrate) reduced the production of proinflammatory factors, including TNF-α, IL-1β, IL-6, and NO, and inhibited the vitality of iNOS. Meanwhile, SCFAs enhanced the production of antiinflammatory cytokine IL-10 in lower concentrations (1–1,200 μmol/L). Like NaB, NaAC inhibited LPS-induced NF-κB activation. These results may hold promise on the role that SCFAs have on the prevention and treatment of various inflammatory conditions.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Duffield, J.S. 2003. The inflammatory macrophage: A story of Jekyll and Hyde. Clinical Science 104: 27–38.

    Article  PubMed  CAS  Google Scholar 

  2. Sergij Goerdt, O.P., K. Schledzewski, R. Birk, A. Gratchev, P. Guillot, N. Hakiy, C.-D. Klemke, E. Dippel, V. Kodelja, and C.E. Orfanos. 1999. Alternative versus classical activation of macrophages. Pathobiology 67: 5–6.

    Google Scholar 

  3. Cook, S.I., and J.H. Sellin. 1998. Review article: Short chain fatty acids in health and disease. Alimentary Pharmacology & Therapeutics 12(6): 499–507.

    Article  CAS  Google Scholar 

  4. Harig, J.M., K.H. Soergel, R.A. Komorowski, and C.M. Wood. 1989. Treatment of diversion colitis with short-chain-fatty acid irrigation. The New England Journal of Medicine 320: 23–28.

    Article  PubMed  CAS  Google Scholar 

  5. Scheppach, W., P. Bartram, A. Richter, F. Richter, H. Liepold, G. Dusel, G. Hofstetter, J. Rüthlein, and H. Kasper. 1992. Effect of short-chain fatty acids on the human colonic mucosa in vitro. Journal of Parenteral and Enteral Nutrition 16: 43.

    Article  PubMed  CAS  Google Scholar 

  6. Wong, J.M., R. de Souza, C.W. Kendall, A. Emam, and D.J. Jenkins. 2006. Colonic health: Fermentation and short chain fatty acids. Journal of Clinical Gastroenterology 40: 235–243.

    Article  PubMed  CAS  Google Scholar 

  7. Hijova, E., and A. Chmelarova. 2007. Short chain fatty acids and colonic health. Bratislavske Lekarske Listy 108: 354–358.

    PubMed  CAS  Google Scholar 

  8. Miller, S.J. 2004. Cellular and physiological effects of short-chain fatty acids. Mini Reviews in Medicinal Chemistry 4: 839–845.

    PubMed  CAS  Google Scholar 

  9. Meijer, K., P. de Vos, and M.G. Priebe. 2010. Butyrate and other short-chain fatty acids as modulators of immunity: What relevance for health? Current Opinion in Clinical Nutrition and Metabolic Care 13: 715–721.

    Article  PubMed  CAS  Google Scholar 

  10. Mohana Kumar, B., H.J. Song, S.K. Cho, S. Balasubramanian, S.Y. Choe, and G.J. Rho. 2007. Effect of histone acetylation modification with sodium butyrate, a histone deacetylase inhibitor, on cell cycle, apoptosis, ploidy and gene expression in porcine fetal fibroblasts. The Journal of Reproduction and Development 53: 903–913.

    Article  PubMed  Google Scholar 

  11. Ni, Y.F., J. Wang, X.L. Yan, F. Tian, J.B. Zhao, Y.J. Wang, and T. Jiang. 2010. Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice. Respiratory Research 11: 33.

    Article  PubMed  Google Scholar 

  12. Usami, M., K. Kishimoto, A. Ohata, M. Miyoshi, M. Aoyama, Y. Fueda, and J. Kotani. 2008. Butyrate and trichostatin A attenuate nuclear factor kappaB activation and tumor necrosis factor alpha secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells. Nutrition Research (New York, N.Y) 28: 321–328.

    Article  CAS  Google Scholar 

  13. Kawamura, T., A. Andoh, A. Nishida, M. Shioya, Y. Yagi, T. Nishimura, T. Hashimoto, T. Tsujikawa, H. Yasui, and Y. Fujiyama. 2009. Inhibitory effects of short-chain fatty acids on matrix metalloproteinase secretion from human colonic subepithelial myofibroblasts. Digestive Diseases and Sciences 54: 238–245.

    Article  PubMed  CAS  Google Scholar 

  14. Cavaglieri, C.R., A. Nishiyama, L.C. Fernandes, R. Curi, E.A. Miles, and P.C. Calder. 2003. Differential effects of short-chain fatty acids on proliferation and production of pro-and anti-inflammatory cytokines by cultured lymphocytes. Life Sciences 73: 1683–1690.

    Article  PubMed  CAS  Google Scholar 

  15. Park, J.S., E.J. Lee, J.C. Lee, W.K. Kim, and H.S. Kim. 2007. Anti-inflammatory effects of short chain fatty acids in IFN-[gamma]-stimulated RAW 264.7 murine macrophage cells: Involvement of NF-[kappa] B and ERK signaling pathways. International Immunopharmacology 7: 70–77.

    Article  PubMed  CAS  Google Scholar 

  16. Cox, M.A., J. Jackson, M. Stanton, A. Rojas-Triana, L. Bober, M. Laverty, X. Yang, F. Zhu, J. Liu, and S. Wang. 2009. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E2 and cytokines. World Journal of Gastroenterology: WJG 15: 5549–5557.

    Article  PubMed  CAS  Google Scholar 

  17. Vinolo, M.A.R., H.G. Rodrigues, E. Hatanaka, F.T. Sato, S.C. Sampaio, and R. Curi. 2010. Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils. The Journal of Nutritional Biochemistry 22: 849–855.

    Article  PubMed  Google Scholar 

  18. Hamer, H.M., D.M.A.E. Jonkers, G.M. Stein, M.W. Schmolz, F.J. Troost, A. Bast, K. Venema, and R.J.M. Brummer. 2009. C3–C6 but not C2 short chain fatty acids affect cytokine release in a co-culture system of Caco-2 cells and whole blood. In Short chain fatty acids and colonic health. Maastricht University. 49–69.

  19. Tedelind, S., F. Westberg, M. Kjerrulf, and A. Vidal. 2007. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: A study with relevance to inflammatory bowel disease. World Journal of Gastroenterology 13: 2826.

    PubMed  CAS  Google Scholar 

  20. Li, J., N. Xiao, J. Zhang, S. Cui, and Y. Liu. 2011. Protective effect of sodium acetate against endotoxic shock by D‐galactosamine and lipopolysaccharide. Jiangsu Medical Journal 37: 517–519.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. McOrist, A.L., G.C.J. Abell, C. Cooke, and K. Nyland. 2008. Bacterial population dynamics and faecal short-chain fatty acid (SCFA) concentrations in healthy humans. British Journal of Nutrition 100: 138–146.

    Article  PubMed  CAS  Google Scholar 

  23. Scheppach, W.M., C.E. Fabian, and H.W. Kasper. 1987. Fecal short-chain fatty acid (SCFA) analysis by capillary gas–liquid chromatography. The American Journal of Clinical Nutrition 46: 641–646.

    PubMed  CAS  Google Scholar 

  24. Vinolo, M.A.R., H.G. Rodrigues, E. Hatanaka, C.B. Hebeda, S.H.P. Farsky, and R. Curi. 2009. Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites. Clinical Science 117: 331–338.

    Article  PubMed  CAS  Google Scholar 

  25. Mirmonsef, P., M.R. Zariffard, D. Gilbert, H. Makinde, A.L. Landay, and G.T. Spear. 2012. Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with Toll-like receptor ligands. American Journal of Reproductive Immunology 67(5): 391–400. doi:10.1111/j.600-0897.2011.01089.x.

    Article  PubMed  CAS  Google Scholar 

  26. Macia, L., A.N. Thorburn, L.C. Binge, E. Marino, K.E. Rogers, K.M. Maslowski, et al. 2012. Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunological Reviews 245: 164–176.

    Article  PubMed  CAS  Google Scholar 

  27. Garland, S.H. 2011. Short chain fatty acids may elicit an innate immune response from preadipocytes: A potential link between bacterial infection and inflammatory diseases. Medical Hypotheses 76: 881–883.

    Article  PubMed  CAS  Google Scholar 

  28. Vinolo, M.A.R., E. Hatanaka, R.H. Lambertucci, P. Newsholme, and R. Curi. 2009. Effects of short chain fatty acids on effector mechanisms of neutrophils. Cell Biochemistry and Function 27: 48–55.

    Article  PubMed  CAS  Google Scholar 

  29. Mosser, D.M., and J.P. Edwards. 2008. Exploring the full spectrum of macrophage activation. Nature Reviews 8: 958–969.

    Article  PubMed  CAS  Google Scholar 

  30. Kim, E.Y., and K.D. Moudgil. 2008. Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunology Letters 120: 1–5.

    Article  PubMed  CAS  Google Scholar 

  31. Yoon, W.J., Y.M. Ham, B.S. Yoo, J.Y. Moon, J. Koh, and C.G. Hyun. 2009. Oenothera laciniata inhibits lipopolysaccharide induced production of nitric oxide, prostaglandin E2, and proinflammatory cytokines in RAW264.7 macrophages. Journal of Bioscience and Bioengineering 107: 429–438.

    Article  PubMed  CAS  Google Scholar 

  32. Moncada, S., R.M.J. Palmer, and E.A. Higgs. 1991. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacological Reviews 43(2): 109–142.

    PubMed  CAS  Google Scholar 

  33. MacMicking, J., Q.W. Xie, and C. Nathan. 1997. Nitric oxide and macrophage function. Annual Review of Immunology 15: 323–350.

    Article  PubMed  CAS  Google Scholar 

  34. Nathan, C. 1992. Nitric oxide as a secretory product of mammalian cells. The FASEB Journal 6(12): 3051–3064.

    CAS  Google Scholar 

  35. Detmers, P.A., M. Hernandez, J. Mudgett, H. Hassing, C. Burton, and S. Mundt. 2000. Deficiency in inducible nitric oxide synthase results in reduced atherosclerosis in apolipoprotein E-deficient mice. The Journal of Immunology 165(6): 3430–3435.

    PubMed  CAS  Google Scholar 

  36. Petros, A., D. Bennett, and P. Vallance. 1991. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. The Lancet 338: 1557–1558.

    Article  CAS  Google Scholar 

  37. Cavaillon, J.M. 1994. Cytokines and macrophages. Biomedicine and Pharmacotherapy = Biomedecine and Pharmacotherapie 48: 445–453.

    Article  CAS  Google Scholar 

  38. Brown, A.J., S.M. Goldsworthy, A.A. Barnes, M.M. Eilert, L. Tcheang, D. Daniels, A.I. Muir, M.J. Wigglesworth, I. Kinghorn, N.J. Fraser, N.B. Pike, J.C. Strum, K.M. Steplewski, P.R. Murdock, J.C. Holder, F.H. Marshall, P.G. Szekeres, S. Wilson, D.M. Ignar, S.M. Foord, A. Wise, and S.J. Dowell. 2003. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. The Journal of Biological Chemistry 278: 11312–11319.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Sciences and Technology subject for Returned Overseas Chinese Scholars (2008-199), the Key Project of Science and Technology for Universities in Hebei Province (ZD2010234), and the Key Basic Applied Research Program of Hebei Province (11966411D). The authors thank Mingshen Guo, Yuanyuan Wang, and Xu Cao for excellent technical assistance.

Author information

Authors and Affiliations

  1. Laboratory of Cell Pharmacology, College of Pharmaceutical Sciences, Hebei University, 180 East Wusi Road, Baoding, 071002, China

    Tengfei Liu, Jing Li, Yuxin Liu, Nan Xiao, Haitao Suo, Kun Xie & Chunliu Yang

  2. Drug Quality Control Key Laboratory of Hebei Province, Hebei University, 180 East Wusi Road, Baoding, 071002, China

    Yuxin Liu

  3. College of Life Sciences, Hebei University, 180 East Wusi Road, Baoding, 071002, China

    Chen Wu

Authors
  1. Tengfei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuxin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haitao Suo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kun Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chunliu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuxin Liu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, T., Li, J., Liu, Y. et al. Short-Chain Fatty Acids Suppress Lipopolysaccharide-Induced Production of Nitric Oxide and Proinflammatory Cytokines Through Inhibition of NF-κB Pathway in RAW264.7 Cells. Inflammation 35, 1676–1684 (2012). https://doi.org/10.1007/s10753-012-9484-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-012-9484-z

KEY WORDS

  • SCFAs
  • LPS
  • proinflammatory factors
  • inducible nitric synthase
  • NF-κB p65