This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Lu-Xuan Wang, Undergraduate Student of 2015 '5+3' Program of Oral Medicine, Beijing Capital Medical University, Beijing 100069, China
Yue-Hong Liu, Undergraduate Student of 2013 Clinical Medicine, Beijing Capital Medical University, Beijing 100069, China
Ji-Kai Zhu, Yu Zhong, Undergraduate Student of 2015 '5+3' Program of Clinical Medicine, Beijing Capital Medical University, Beijing 100069, China
Li-Sheng Li, Function Experiment Platform Center, Beijing Capital Medical University, Beijing 100069, China
Jing-Dong Xu, Department of Physiology and Pathophysiology, Beijing Capital Medical University, Beijing 100069, China
Supported by: National Natural Science Foundation of China, Nos. 81274173, 81673671 and 81270443; Beijing Natural Science Foundation, No. 7122017.
Correspondence to: Jing-Dong Xu, Associate Professor, Department of Physiology and Pathophysiology, Beijing Capital Medical University, 10 Xitoutiao You'anmenwai, Fengtai District, Beijing 100069, China. xujingdong@163.com
Received: March 6, 2017 Revised: March 21, 2017 Accepted: April 5, 2017 Published online: May 8, 2017
Short chain fatty acids (SCFAs) are found in the intestine at high concentrations. In addition to acting as local substrates for energy production to promote cell growth, reduce environmental pH value in the colon, and reduce the growth of harmful bacteria, SCFAs can also regulate host physiology and immunity, suppress colon neoplasm cell proliferation by inducing their apoptosis and differentiation, and affect proto-oncogene expression. In this review, we discuss how SCFAs interact with G protein-coupled receptors to inhibit histone deacetyltransferase and thereby cause response of neutrophils and regulatory T cells to regulate intestinal immune responses and host physiological function. SCFAs can strengthen the epithelial barrier, suppress colon neoplasm cell proliferation, and be used to treat nonalcoholic fatty liver disease and obesity.
Citation: Wang LX, Liu YH, Zhu JK, Zhong Y, Li LS, Xu JD. Role of short-chain fatty acids in disease treatment. Shijie Huaren Xiaohua Zazhi 2017; 25(13): 1179-1186
Pinto A, Fidalgo P, Cravo M, Midões J, Chaves P, Rosa J, dos Anjos Brito M, Leitão CN. Short chain fatty acids are effective in short-term treatment of chronic radiation proctitis: randomized, double-blind, controlled trial.Dis Colon Rectum. 1999;42:788-795; discussion 795-796.
[PubMed] [DOI]
Scheppach W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas. A placebo-controlled trial. German-Austrian SCFA Study Group.Dig Dis Sci. 1996;41:2254-2259.
[PubMed] [DOI]
8.
Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease.Adv Immunol. 2014;121:91-119.
[PubMed] [DOI]
Schilderink R, Verseijden C, de Jonge WJ. Dietary inhibitors of histone deacetylases in intestinal immunity and homeostasis.Front Immunol. 2013;4:226.
[PubMed] [DOI]
11.
Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M, Yang X, Zhu F, Liu J, Wang S. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines.World J Gastroenterol. 2009;15:5549-5557.
[PubMed] [DOI]
Garland SH. Short chain fatty acids may elicit an innate immune response from preadipocytes: a potential link between bacterial infection and inflammatory diseases.Med Hypotheses. 2011;76:881-883.
[PubMed] [DOI]
Park JS, Lee EJ, Lee JC, Kim WK, Kim HS. Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: involvement of NF-kappaB and ERK signaling pathways.Int Immunopharmacol. 2007;7:70-77.
[PubMed] [DOI]
16.
Zhang WH, Jiang Y, Zhu QF, Gao F, Dai SF, Chen J, Zhou GH. Sodium butyrate maintains growth performance by regulating the immune response in broiler chickens.Br Poult Sci. 2011;52:292-301.
[PubMed] [DOI]
17.
Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, Mason LJ, Roberts LK, Wong CH, Shim R, Robert R. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites.Nat Commun. 2015;6:7320.
[PubMed] [DOI]
18.
Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, Li B, Turka LA, Olson EN, Greene MI. Deacetylase inhibition promotes the generation and function of regulatory T cells.Nat Med. 2007;13:1299-1307.
[PubMed] [DOI]
19.
Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.Nature. 2013;504:451-455.
[PubMed] [DOI]
20.
Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013;341:569-573.
[PubMed] [DOI]
21.
Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.Nature. 2013;504:446-450.
[PubMed] [DOI]
22.
Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity.Nat Rev Immunol. 2016;16:341-352.
[PubMed] [DOI]
23.
Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses.Nat Immunol. 2011;12:5-9.
[PubMed] [DOI]
24.
Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43.Nature. 2009;461:1282-1286.
[PubMed] [DOI]
25.
Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis.Immunity. 2014;40:128-139.
[PubMed] [DOI]
26.
Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine.FEMS Microbiol Lett. 2009;294:1-8.
[PubMed] [DOI]
27.
Field M, Rao MC, Chang EB. Intestinal electrolyte transport and diarrheal disease (1).N Engl J Med. 1989;321:800-806.
[PubMed] [DOI]
28.
Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome.Nat Commun. 2015;6:6734.
[PubMed] [DOI]
29.
Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis.Cell. 2011;145:745-757.
[PubMed] [DOI]
30.
Vinolo MA, Rodrigues HG, Hatanaka E, Sato FT, Sampaio SC, Curi R. Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils.J Nutr Biochem. 2011;22:849-855.
[PubMed] [DOI]
31.
Wrzosek L, Miquel S, Noordine ML, Bouet S, Joncquel Chevalier-Curt M, Robert V, Philippe C, Bridonneau C, Cherbuy C, Robbe-Masselot C. Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent.BMC Biol. 2013;11:61.
[PubMed] [DOI]
32.
Dekker J, Rossen JW, Büller HA, Einerhand AW. The MUC family: an obituary.Trends Biochem Sci. 2002;27:126-131.
[PubMed] [DOI]
33.
Porchet N, Buisine MP, Desseyn JL, Moniaux N, Nollet S, Degand P, Pigny P, Van Seuningen I, Laine A, Aubert JP. [MUC genes: a superfamily of genes? Towards a functional classification of human apomucins].J Soc Biol. 1999;193:85-99.
[PubMed] [DOI]
34.
Williams SJ, Munster DJ, Quin RJ, Gotley DC, McGuckin MA. The MUC3 gene encodes a transmembrane mucin and is alternatively spliced.Biochem Biophys Res Commun. 1999;261:83-89.
[PubMed] [DOI]
35.
Gaudier E, Jarry A, Blottière HM, de Coppet P, Buisine MP, Aubert JP, Laboisse C, Cherbut C, Hoebler C. Butyrate specifically modulates MUC gene expression in intestinal epithelial goblet cells deprived of glucose.Am J Physiol Gastrointest Liver Physiol. 2004;287:G1168-G1174.
[PubMed] [DOI]
36.
Willemsen LE, Koetsier MA, van Deventer SJ, van Tol EA. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts.Gut. 2003;52:1442-1447.
[PubMed] [DOI]
Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM, Bunger MK, Bultman SJ. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.Cell Metab. 2011;13:517-526.
[PubMed] [DOI]
39.
Mangian HF, Tappenden KA. Butyrate increases GLUT2 mRNA abundance by initiating transcription in Caco2-BBe cells.JPEN J Parenter Enteral Nutr. 2009;33:607-617; discussion 617.
[PubMed] [DOI]
40.
Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41.Proc Natl Acad Sci USA. 2004;101:1045-1050.
[PubMed] [DOI]
41.
Fukuda S, Toh H, Hase K, Oshima K, Nakanishi Y, Yoshimura K, Tobe T, Clarke JM, Topping DL, Suzuki T. Bifidobacteria can protect from enteropathogenic infection through production of acetate.Nature. 2011;469:543-547.
[PubMed] [DOI]
Chen YX, Fang JY, Lu J, Qiu DK. [Regulation of histone acetylation on the expression of cell cycle-associated genes in human colon cancer cell lines].Zhonghua Yixue Zazhi. 2004;84:312-317.
[PubMed] [DOI]
44.
Mandal M, Wu X, Kumar R. Bcl-2 deregulation leads to inhibition of sodium butyrate-induced apoptosis in human colorectal carcinoma cells.Carcinogenesis. 1997;18:229-232.
[PubMed] [DOI]
45.
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications.Hepatology. 2010;51:679-689.
[PubMed] [DOI]
46.
Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C, Choi KC, Feng DD, Chen C, Lee HG. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43.Endocrinology. 2005;146:5092-5099.
[PubMed] [DOI]
Pirlich M, Schütz T, Kemps M, Luhman N, Burmester GR, Baumann G, Plauth M, Lübke HJ, Lochs H. Prevalence of malnutrition in hospitalized medical patients: impact of underlying disease.Dig Dis. 2003;21:245-251.
[PubMed] [DOI]