丁酸介导下肠道菌群与宿主免疫互作机制的研究进展

doi:10.11843/j.issn.0366-6964.2021.010.003

摘要/Abstract

摘要： 肠道菌群或其代谢产物在动物机体生长发育与功能完善方面起重要作用，当宿主与肠道菌群间的动态平衡被打破，可诱发局部或全身性炎症反应。丁酸不仅作为能源物质为机体提供能量，还能调控宿主先天性免疫和适应性免疫状态，促进机体免疫应答；并影响宿主分泌抗菌肽（AMPs）等预防肠道病原菌易位，维持肠道菌群的稳态。本文将系统介绍丁酸介导下肠道菌群与宿主免疫系统间互作机制的研究进展，并阐明其在肠道健康稳态中的重要作用。

关键词: 肠道菌群, 丁酸, 宿主免疫, 互作机制

Abstract: The intestinal microbes and their metabolites play an important role in the growth and functional improvement of the animal. When the dynamic balance between the host and the intestinal microbes is broken, the local or systemic inflammation is induced. Butyrate not only provides energy for the body as an energy substance, but also regulates the host's innate immunity and adaptive immune state, promotes the body's immune response. Butyrate affects the host's secretion of antimicrobial peptides(AMPs) to prevent translocation of intestinal pathogenic bacteria and maintain steady state of intestinal microbes. This article will systematically introduce the research progress of the interaction mechanism between the intestinal microbes and the host immune system mediated by butyrate, and clarify their important role in the steady state of intestinal health.

Key words: intestinal microbes, butyrate, host immunity, crosstalk mechanism

中图分类号:

S852.4

梁开阳, 孙志洪, 谭支良, 刘勇. 丁酸介导下肠道菌群与宿主免疫互作机制的研究进展[J]. 畜牧兽医学报, 2021, 52(10): 2710-2720.

LIANG Kaiyang, SUN Zhihong, TAN Zhiliang, LIU Yong. Crosstalk Mechanism between Intestinal Microbes and Host Immunity Mediated by Microbial Metabolites-Butyrate[J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(10): 2710-2720.

参考文献 84

[1]	SCHULTHESS J,PANDEY S,CAPITANI M,et al.The short chain fatty acid butyrate imprints an antimicrobial program in macrophages[J].Immunity,2019,50(2):432-445.
[2]	ROBLES-VERA I,TORAL M,DE LA VISITACIÓN N,et al.Probiotics prevent dysbiosis and the rise in blood pressure in genetic hypertension:role of short-chain fatty acids[J].Mol Nutr Food Res,2020,64(6):1900616.
[3]	ESQUIVEL-ELIZONDO S,ILHAN Z E,GARCIA-PEÑA E I,et al.Insights into butyrate production in a controlled fermentation system via gene predictions[J].mSystems,2017,2(4):e00051-17.
[4]	VITAL M,HOWE A C,TIEDJE J M.Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data[J]. mBio,2014,5(2):e00889.
[5]	QIN P P,ZOU Y Q,DAI Y,et al.Characterization a novel butyric acid-producing bacterium Collinsella aerofaciens subsp.Shenzhenensis subsp. Nov[J].Microorganisms,2019,7(3):78.
[6]	CHEN D F,JIN D C,HUANG S M,et al.Clostridium butyricum,a butyrate-producing probiotic,inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota[J].Cancer Lett,2020,469:456-467.
[7]	FU X D,LIU Z M,ZHU C L,et al.Nondigestible carbohydrates,butyrate,and butyrate-producing bacteria[J].Crit Rew Food Sci Nutr,2019,59(S1):S130-S152.
[8]	KIM J S,LEE K C,SUH M K,et al.Mediterraneibacter butyricigenes sp. Nov.,a butyrate-producing bacterium isolated from human faeces[J].J Microbiol,2019,57(1):38-44.
[9]	MONTALBAN-ARQUES A,CHAPARRO M,GISBERT J P,et al.The innate immune system in the gastrointestinal tract:role of intraepithelial lymphocytes and lamina propria innate lymphoid cells in intestinal inflammation[J].Inflamm Bowel Dis,2018,24(8):1649-1659.
[10]	MARTÍNEZ-LÓPEZ M,IBORRA S,CONDE-GARROSA R,et al.Microbiota sensing by mincle-syk axis in dendritic cells regulates interleukin-17 and -22 production and promotes intestinal barrier integrity[J].Immunity,2019,50(2):446-461.e9.
[11]	VARADÉ J,MAGADÁN S,GONZÁLEZ-FERNÁNDEZ Á.Human immunology and immunotherapy:main achievements and challenges[J].Cell Mol Immunol,2021,18(4):805-828.
[12]	LIU L,LI L,MIN J,et al.Butyrate interferes with the differentiation and function of human monocyte-derived dendritic cells[J].Cell Immunol,2012,277(1-2):66-73.
[13]	KAISAR M M M,PELGROM L R,VAN DER HAM A J,et al.Butyrate conditions human dendritic cells to prime type 1 regulatory T cells via both histone deacetylase inhibition and G protein-coupled receptor 109A signaling[J].Front Immunol, 2017, 8:1429.
[14]	ISOBE J,MAEDA S,OBATA Y,et al.Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon[J].Int Immunol,2020,32(4):243-258.
[15]	FERNANDO M R,SAXENA A,REYES J L,et al.Butyrate enhances antibacterial effects while suppressing other features of alternative activation in IL-4-induced macrophages[J].Am J Physiol Gastrointest Liver Physiol,2016,310(10):G822-G831.
[16]	HOOD M I,SKAAR E P.Nutritional immunity:transition metals at the pathogen-host interface[J].Nat Rev Microbiol,2012,10(8):525-537.
[17]	CHANG P V,HAO L M,OFFERMANNS S,et al.The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition[J].Proc Natl Acad Sci U S A,2014,111(6):2247-2252.
[18]	RODRIGUES H G,TAKEO SATO F,CURI R,et al.Fatty acids as modulators of neutrophil recruitment,function and survival[J].Eur J Pharmacol,2016,785:50-58.
[19]	RAULET D H.Roles of the NKG2D immunoreceptor and its ligands[J].Nat Rev Immunol,2003,3(10):781-790.
[20]	ZHANG C,WANG Y P,ZHOU Z X,et al.Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis[J].Cancer Immunol Immunother,2009,58(8):1275-1285.
[21]	CORRĚA-OLIVEIRA R,FACHI J L,VIEIRA A,et al.Regulation of immune cell function by short-chain fatty acids[J].Clin Transl Immunology,2016,5(4):e73.
[22]	ROOKS M G,GARRETT W S.Gut microbiota,metabolites and host immunity[J].Nat Rev Immunol,2016 May 27;16(6):341-352.
[23]	KIMURA I,ICHIMURA A,OHUE-KITANO R,et al.Free fatty acid receptors in health and disease[J].Physiol Rev,2020,100(1):171-210.
[24]	FOLKERTS J,REDEGELD F,FOLKERTS G,et al.Butyrate inhibits human mast cell activation via epigenetic regulation of FcεRI-mediated signaling[J].Allergy,2020,75(8):1966-1978.
[25]	PETERSON L W,ARTIS D.Intestinal epithelial cells:regulators of barrier function and immune homeostasis[J].Nat Rev Immunol,2014,14(3):141-153.
[26]	KIM M,QIE Y Q,PARK J,et al.Gut microbial metabolites fuel host antibody responses[J].Cell Host Microbe,2016,20(2):202-214.
[27]	SANCHEZ H N,MORONEY J B,GAN H Q,et al.B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids[J].Nat Commun,2020,11(1):60.
[28]	ATARASHI K,TANOUE T,OSHIMA K,et al.Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota[J].Nature,2013,500(7461):232-236.
[29]	XU Z,ZAN H,PONE E J,et al.Immunoglobulin class-switch DNA recombination:induction,targeting and beyond[J].Nat Rev Immunol,2012,12(7):517-531.
[30]	MARTINS G,CALAME K.Regulation and functions of Blimp-1 in T and B lymphocytes[J].Annu Rev Immunol,2008,26:133-169.
[31]	LUO J,NIU X C,LIU H C,et al.Up-regulation of transcription factor Blimp1 in systemic lupus erythematosus[J].Mol Immunol,2013,56(4):574-582.
[32]	JIANG C C,ZHAO M L,DIAZ M.Activation-induced deaminase heterozygous MRL/lpr mice are delayed in the production of high-affinity pathogenic antibodies and in the development of lupus nephritis[J].Immunology,2009,126(1):102-113.
[33]	LAMAS B,RICHARD M L,LEDUCQ V,et al.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands[J].Nat Med,2016,22(6):598-605.
[34]	GAO J,XU K,LIU H,et al.Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism[J].Front Cell Infect Microbiol,2018,8:13.
[35]	GAUDINO S J,KUMAR P.Cross-talk between antigen presenting cells and t cells impacts intestinal homeostasis,bacterial infections,and tumorigenesis[J].Front Immunol,2019,10:360.
[36]	CAMPBELL C,MCKENNEY P T,KONSTANTINOVSKY D,et al.Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells[J].Nature,2020,581(7809):475-479.
[37]	KOPF M,BACHMANN M,MARSLAND B.Averting inflammation by targeting the cytokine environment[J].Nat Rev Drug Discov,2010,9(9):703-718.
[38]	NEURATH M F.Cytokines in inflammatory bowel disease[J].Nat Rev Immunol,2014,14(5):329-342.
[39]	PARK J,KIM M,KANG S G,et al.Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway[J].Mucosal Immunol,2015,8(1):80-93.
[40]	CHEN L,SUN M M,WU W,et al.Microbiota metabolite butyrate differentially regulates th1 and th17 cells' differentiation and function in induction of colitis[J].Inflamm Bowel Dis,2019,25(9):1450-1461.
[41]	LUU M,VISEKRUNA A.Short-chain fatty acids:bacterial messengers modulating the immunometabolism of T cells[J].Eur J Immunol,2019,49(6):842-848.
[42]	BACHEM A,MAKHLOUF C,BINGER K J,et al.Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T Cells[J].Immunity,2019,51(2):285-297.e5.
[43]	TROMPETTE A,GOLLWITZER E S,PATTARONI C,et al.Dietary fiber confers protection against flu by shaping Ly6c- patrolling monocyte hematopoiesis and CD8+ T cell metabolism[J].Immunity,2018,48(5):992-1005.e8.
[44]	IZCUE A,COOMBES J L,POWRIE F.Regulatory lymphocytes and intestinal inflammation[J].Annu Rev Immunol,2009,27:313-338.
[45]	KOH A,BÄCKHED F.From association to causality:the role of the gut microbiota and its functional products on host metabolism[J].Mol cell,2020,78(4):584-596.
[46]	SMITH P M,HOWITT M R,PANIKOV N,et al.The microbial metabolites,short-chain fatty acids,regulate colonic Treg cell homeostasis[J].Science,2013,341(6145):569-573.
[47]	SINGH N,GURAV A,SIVAPRAKASAM S,et al.Activation of Gpr109a,receptor for niacin and the commensal metabolite butyrate,suppresses colonic inflammation and carcinogenesis[J].Immunity,2014,40(1):128-139.
[48]	FURUSAWA Y,OBATA Y,FUKUDA S,et al.Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J].Nature,2013,504(7480):446-450.
[49]	MA X M,ZHOU Z H,ZHANG X J,et al.Sodium butyrate modulates gut microbiota and immune response in colorectal cancer liver metastatic mice[J].Cell Biol Toxicol,2020,36(5):509-515.
[50]	BELOTSERKOVSKY I,SANSONETTI P J.Shigella and enteroinvasive escherichia coli[J].Curr Top Microbiol Immunol,2018, 416:1-26.
[51]	LITVAK Y,MON K K Z,NGUYEN H,et al.Commensal enterobacteriaceae protect against salmonella colonization through oxygen competition[J].Cell Host Microbe,2019,25(1):128-139.e5.
[52]	LEE Y S,KIM T Y,KIM Y,et al.Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development[J]. Cell Host Microbe,2018,24(6):833-846.
[53]	SINGH A K,HERTZBERGER R Y,KNAUS U G.Hydrogen peroxide production by lactobacilli promotes epithelial restitution during colitis[J].Redox Biol,2018,16:11-20.
[54]	MARTIN-GALLAUSIAUX C,LARRAUFIE P,JARRY A,et al.Butyrate produced by commensal bacteria down-regulates indolamine 2,3-dioxygenase 1(IDO-1) expression via a dual mechanism in human intestinal epithelial cells[J].Front Immunol,2018,9:2838.
[55]	MACIA L,TAN J,VIEIRA A T,et al.Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome[J].Nat Commun,2015,6(1):6734.
[56]	KELLY C J,ZHENG L,CAMPBELL E L,et al.Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function[J].Cell Host Microbe,2015,17(5):662-671.
[57]	SAEEDI B J,KAO D J,KITZENBERG D A,et al.HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity[J].Mol Biol Cell,2015,26(12):2252-2262.
[58]	KELLY C J,GLOVER L E,CAMPBELL E L,et al.Fundamental role for HIF-1α in constitutive expression of human β defensin-1[J].Mucosal Immunol,2013,6(6):1110-1118.
[59]	LIU B,QIAN J M,WANG Q B,et al.Butyrate protects rat liver against total hepatic ischemia reperfusion injury with bowel congestion[J].PLoS One,2014,9(8):e106184.
[60]	WU J L,ZOU J Y,HU E D,et al.Sodium butyrate ameliorates S100/FCA-induced autoimmune hepatitis through regulation of intestinal tight junction and toll-like receptor 4 signaling pathway[J].Immunol Lett,2017,190:169-176.
[61]	VOLARIC A,GENTZLER R,HALL R,et al.Indoleamine-2,3-dioxygenase in non-small cell lung cancer:a targetable mechanism of immune resistance frequently coexpressed with PD-L1[J].Am J Surg Pathol,2018,42(9):1216-1223.
[62]	DONOHOE D R,COLLINS L B,WALI A,et al.The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation[J].Mol Cell,2012,48(4):612-626.
[63]	SATO T,VAN ES J H,SNIPPERT H J,et al.Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts[J].Nature, 2011,469(7330):415-418.
[64]	TAKAKUWA A,NAKAMURA K,KIKUCHI M,et al.Butyric acid and leucine induce α-defensin secretion from small intestinal Paneth cells[J].Nutrients,2019,11(11):2817.
[65]	SALZMAN N H,HUNG K,HARIBHAI D,et al.Enteric defensins are essential regulators of intestinal microbial ecology[J].Nat Immunol,2010,11(1):76-82.
[66]	XIONG H T,GUO B X,GAN Z S,et al.Butyrate upregulates endogenous host defense peptides to enhance disease resistance in piglets via histone deacetylase inhibition[J].Sci Rep,2016,6(1):27070.
[67]	NAKAMURA K,SAKURAGI N,TAKAKUWA A,et al.Paneth cell α-defensins and enteric microbiota in health and disease[J]. Biosci Microbiota Food Health,2016,35(2):57-67.
[68]	WANG S Z,YU Y J,ADELI K.Role of gut microbiota in neuroendocrine regulation of carbohydrate and lipid metabolism via the microbiota-gut-brain-liver axis[J].Microorganisms,2020,8(4):527.
[69]	DE PRETER V,GEBOES K P,BULTEEL V,et al.Kinetics of butyrate metabolism in the normal colon and in ulcerative colitis:the effects of substrate concentration and carnitine on the β-oxidation pathway[J].Aliment Pharmacol Ther,2011,34(5):526-532.
[70]	ZHAO H B,JIA L,YAN Q Q,et al.Effect of Clostridium butyricum and butyrate on intestinal barrier functions:study of a rat model of severe acute pancreatitis with intra-abdominal hypertension[J].Front Physiol,2020,11:561061.
[71]	KNUDSEN K E B,LAERKE H N,HEDEMANN M S,et al.Impact of diet-modulated butyrate production on intestinal barrier function and inflammation[J].Nutrients,2018,10(10):1499.
[72]	CHEN G X,RAN X,LI B,et al.Sodium butyrate inhibits inflammation and maintains epithelium barrier integrity in a TNBS-induced inflammatory bowel disease mice model[J].EBioMedicine,2018,30:317-325.
[73]	YE J Z,LV L X,WU W R,et al.Butyrate protects mice against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis by improving gut barrier function,attenuating inflammation and reducing endotoxin levels[J].Front Microbiol,2018,9:1967.
[74]	MACHIELS K,JOOSSENS M,SABINO J,et al.A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis[J].Gut,2014,63(8):1275-1283.
[75]	MCCARTY M F,LERNER A.Perspective:prospects for nutraceutical support of intestinal barrier function[J].Adv Nutr,2021, 12(2):316-324.
[76]	LIU L X,SUN D M,MAO S Y,et al.Infusion of sodium butyrate promotes rumen papillae growth and enhances expression of genes related to rumen epithelial VFA uptake and metabolism in neonatal twin lambs[J].J Anim Sci,2019,97(2):909-921.
[77]	CHUMBURIDZE-ARESHIDZE N,KEZELI T,AVALIANI Z,et al.The relationship between type-2 diabetes and tuberculosis[J]. Georgian Med News,2020(300):69-74.
[78]	KNIP M,SILJANDER H.The role of the intestinal microbiota in type 1 diabetes mellitus[J].Nat Rev Endocrinol,2016 Mar, 12(3):154-167.
[79]	MACHIELS K,JOOSSENS M,SABINO J,et al.A decrease of the butyrate-producing species roseburia hominis and faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis[J].Gut,2014,63(8):1275-1283.
[80]	DE GROOT P F,BELZER C,AYDIN O,et al.Distinct fecal and oral microbiota composition in human type 1 diabetes,an observational study[J].PLoS One,2017,12(12):e0188475.
[81]	FALONY G,VLACHOU A,VERBRUGGHE K,et al.Cross-feeding between Bifidobacterium longum BB536 and acetate-converting,butyrate-producing colon bacteria during growth on oligofructose[J].Appl Environ Microbiol,2006,72(12):7835-7841.
[82]	DE GROOT P F,NIKOLIC T,IMANGALIYEV S,et al.Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes:a randomised controlled trial[J].Diabetologia,2020,63(3):597-610.
[83]	XU J M,CHEN X,YU S Q,et al.Effects of early intervention with sodium butyrate on gut microbiota and the expression of inflammatory cytokines in neonatal piglets[J].PLoS One,2016,11(9):e0162461.
[84]	HUANG C,SONG P X,FAN P X,et al.Dietary sodium butyrate decreases postweaning diarrhea by modulating intestinal permeability and changing the bacterial communities in weaned piglets[J].J Nutr,2015,145(12):2774-2780.