粪便微生物移植对仔猪肠道屏障功能的影响及作用机制进展

doi:10.11843/j.issn.0366-6964.2021.05.006

摘要/Abstract

摘要： 肠道屏障是抵御感染的重要防线。由肠道内微生物失调，屏障功能受损引起的仔猪腹泻给养猪业带来巨大损失。粪便微生物群移植在多种与肠道菌群相关的肠道疾病中显示出独特优势，被引入到操控仔猪肠道微生物以改善屏障功能的探索性研究中。本文介绍了肠道屏障的结构和功能，归纳了粪便微生物移植对仔猪肠道屏障的作用，并就可能的机制进行了探讨，以期为本领域的研究提供参考。

关键词: 粪便微生物移植, 仔猪, 肠道屏障功能, 机制, 微生物群落

Abstract: The intestinal barrier is an important defense against infection. Diarrhea in piglets, mainly caused by intestinal biological imbalance and damage of barrier function, has brought extreme losses to the porcine industry. Due to the unique advantages in various intestinal diseases related to intestinal microbiota, faecal microbiota transplantation has been introduced into exploratory researches on the improvement of the intestinal barrier function in piglets as a new microbiota manipulation strategy. This article reviews the structures and functions of the intestinal barrier and the effects of faecal microbiota transplantation on it in piglets, then discusses the possible inner mechanisms, with the expectation to provide some references in this field.

Key words: faecal microbiota transplantation, piglet, intestinal barrier function, mechanism, microbiota

中图分类号:

陈佳琦, 张晓迪, 顾招兵, 吕龙宝, 吴东旺, 王荣蛟, 毛华明. 粪便微生物移植对仔猪肠道屏障功能的影响及作用机制进展[J]. 畜牧兽医学报, 2021, 52(5): 1195-1207.

CHEN Jiaqi, ZHANG Xiaodi, GU Zhaobing, Lü Longbao, WU Dongwang, WANG Rongjiao, MAO Huaming. Effects and Mechanism of Faecal Microbiota Transplantation on Intestinal Barrier Function in Piglets[J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(5): 1195-1207.

参考文献 89

[1]	GUEVARRA R B, LEE J H, LEE S H, et al. Piglet gut microbial shifts early in life: causes and effects[J]. J Anim Sci Biotechnol, 2019, 10:1.
[2]	CAMMAROTA G, IANIRO G, TILG H, et al. European consensus conference on faecal microbiota transplantation in clinical practice[J]. Gut, 2017, 66(4):569-580.
[3]	KHO Z Y, LAL S K. The human gut microbiome-A potential controller of wellness and disease[J]. Front Microbiol, 2018, 9:1835.
[4]	VAN NOOD E, VRIEZE A, NIEUWDORP M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile[J]. N Engl J Med, 2013, 368(5):407-415.
[5]	HVAS C L, JØRGENSEN S M D, JØRGENSEN S P, et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent Clostridium difficile infection[J]. Gastroenterology, 2019, 156(5):1324-1332.e3.
[6]	DREW L. Microbiota: Reseeding the gut[J]. Nature, 2016, 540(7634):S109-S112.
[7]	ODENWALD M A, TURNER J R. The intestinal epithelial barrier: a therapeutic target?[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(1):9-21.
[8]	JULIO-PIEPER M, BRAVO J A. Intestinal barrier and behavior[J]. Int Rev Neurobiol, 2016, 131:127-141.
[9]	HIIPPALA K, JOUHTEN H, RONKAINEN A, et al. The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation[J]. Nutrients, 2018, 10(8):988.
[10]	SENDER R, FUCHS S, MILO R. Revised estimates for the number of human and bacteria cells in the body[J]. PLoS Biol, 2016, 14(8):e1002533.
[11]	HOOPER L V. Do symbiotic bacteria subvert host immunity?[J]. Nat Rev Microbiol, 2009, 7(5):367-374.
[12]	JOHANSSON M E, SJÖVALL H, HANSSON G C. The gastrointestinal mucus system in health and disease[J]. Nat Rev Gastroenterol Hepatol, 2013, 10(6):352-361.
[13]	WALTER J. Ecological role of lactobacilli in the gastrointestinal tract:implications for fundamental and biomedical research[J]. Appl Environ Microbiol, 2008, 74(16):4985-4996.
[14]	WANG K, WU L Y, DOU C Z, et al. Research advance in intestinal mucosal barrier and pathogenesis of Crohn’s disease[J]. Gastroenterol Res Pract, 2016, 2016:9686238.
[15]	WANG S N, XU M Q, WANG W Q, et al. Systematic review: adverse events of fecal microbiota transplantation[J]. PLoS ONE, 2016, 11(8):e0161174.
[16]	LOUIS N A, HAMILTON K E, CANNY G, et al. Selective induction of mucin-3 by hypoxia in intestinal epithelia[J]. J Cell Biochem, 2006, 99(6):1616-1627.
[17]	HALPERN M D, DENNING P W. The role of intestinal epithelial barrier function in the development of NEC[J]. Tissue Barriers, 2015, 3(1-2):e1000707.
[18]	MCGUCKIN M A, ERI R, SIMMS L A, et al. Intestinal barrier dysfunction in inflammatory bowel diseases[J]. Inflamm Bowel Dis, 2009, 15(1):100-113.
[19]	TURNER J R. Intestinal mucosal barrier function in health and disease[J]. Nat Rev Immunol, 2009, 9(11):799-809.
[20]	DELGADO M E, GRABINGER T, BRUNNER T. Cell death at the intestinal epithelial front line[J]. FEBS J, 2016, 283(14):2701-2719.
[21]	CAMARA-LEMARROY C R, METZ L, MEDDINGS J B, et al. The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics[J]. Brain, 2018, 141(7):1900-1916.
[22]	GUTTMAN J A, FINLAY B B. Tight junctions as targets of infectious agents[J]. Biochim et Biophys Acta, 2009, 1788(4):832-841.
[23]	GASSLER N. Paneth cells in intestinal physiology and pathophysiology[J]. World J Gastrointest Pathophysiol, 2017, 8(4):150-160.
[24]	MUNIZ L R, KNOSP C, YERETSSIAN G. Intestinal antimicrobial peptides during homeostasis, infection, and disease[J]. Front Immunol, 2012, 3:310.
[25]	ANDERSSON D I, HUGHES D, KUBICEK-SUTHERLAND J Z. Mechanisms and consequences of bacterial resistance to antimicrobial peptides[J]. Drug Resist Updat, 2016, 26:43-57.
[26]	KABAT A M, POTT J, MALOY K J. The mucosal immune system and its regulation by autophagy[J]. Front Immunol, 2016, 7:240.
[27]	AHLUWALIA B, MAGNUSSON M K, ÖHMAN L. Mucosal immune system of the gastrointestinal tract:maintaining balance between the good and the bad[J]. Scand J Gastroenterol, 2017, 52(11):1185-1193.
[28]	NEWBERRY B D, LORENZ R G. Organizing a mucosal defense[J]. Immunol Rev, 2005, 206(1):6-21.
[29]	MOWAT A M, AGACE W W. Regional specialization within the intestinal immune system[J]. Nat Rev Immunol, 2014, 14(10):667-685.
[30]	MACPHERSON A J, UHR T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria[J]. Science, 2004, 303(5664):1662-1665.
[31]	BRUNSE A, MARTIN L, RASMUSSEN T S, et al. Effect of fecal microbiota transplantation route of administration on gut colonization and host response in preterm pigs[J]. ISME J, 2019, 13(3):720-733.
[32]	HU L S, GENG S J, LI Y, et al. Exogenous fecal microbiota transplantation from local adult pigs to crossbred newborn piglets[J]. Front Microbiol, 2018, 8:2663.
[33]	GENG S J, CHENG S S, LI Y, et al. Faecal microbiota transplantation reduces susceptibility to epithelial injury and modulates tryptophan metabolism of the microbial community in a piglet model[J]. J Crohns Colitis, 2018, 12(11):1359-1374.
[34]	CHENG S S, MA X, GENG S J, et al. Fecal microbiota transplantation beneficially regulates intestinal mucosal autophagy and alleviates gut barrier injury[J]. mSystems, 2018, 3(5):e00137-18.
[35]	LIN C H, WAN J J, SU Y, et al. Effects of early intervention with maternal fecal microbiota and antibiotics on the gut microbiota and metabolite profiles of piglets[J]. Metabolites, 2018, 8(4):89.
[36]	陈雪, 任二都, 苏勇. 早期灌喂母源粪菌对新生仔猪肠道菌群发育的影响[J]. 微生物学报, 2018, 58(7):1224-1232.CHEN X, REN E D, SU Y. Effect of oral feeding maternal fecal microbiota on intestinal microbiota development of newborn piglets[J]. Acta Microbiologica Sinica, 2018, 58(7):1224-1232. (in Chinese)
[37]	岳晓敬, 胡栾莎, 扶雄锋, 等. 菌群移植对新生和K88攻毒仔猪生长、腹泻和肠道菌群的影响[C]//中国畜牧兽医学会动物营养学分会第十二次动物营养学术研讨会. 武汉, 2016.YUE X J, HU L S, FU X F, et al. Effects of microbiota transplantation on growth, diarrhea and intestinal flora of newborn and K88 challenged piglets[C]//Proceedings of the 12th Symposium on Animal Nutrition of the Animal Nutrition Branch of the Chinese Society of Animal Husbandry and Veterinary Medicine. Wuhan, 2016. (in Chinese)
[38]	DIAO H, YAN H L, XIAO Y, et al. Modulation of intestine development by fecal microbiota transplantation in suckling pigs[J]. RSC Adv, 2018, 8(16):8709-8720.
[39]	MCCORMACK U M, CURIÃO T, WILKINSON T, et al. Fecal microbiota transplantation in gestating sows and neonatal offspring alters lifetime intestinal microbiota and growth in offspring[J]. mSystems, 2018, 3(3):e00134-17.
[40]	MILANI C, DURANTI S, BOTTACINI F, et al. The first microbial colonizers of the human gut:composition, activities, and health implications of the infant gut microbiota[J]. Microbiol Mol Biol Rev, 2017, 81(4):e00036-17.
[41]	徐菊美, 范觉鑫, 张颖, 等. 早期菌群干预在仔猪肠道健康中的应用[J]. 畜牧与兽医, 2018, 50(10):137-141.XU J M, FAN J X, ZHANG Y, et al. Application of early microbial intervention in intestinal health of weaning piglets[J]. Animal Husbandry & Veterinary Medicine, 2018, 50(10):137-141. (in Chinese)
[42]	HU J, MA L B, NIE Y F, et al. A microbiota-derived bacteriocin targets the host to confer diarrhea resistance in early-weaned piglets[J]. Cell Host Microbe, 2018, 24(6):817-832.e8.
[43]	LI S S, ZHU A, BENES V, et al. Durable coexistence of donor and recipient strains after fecal microbiota transplantation[J]. Science, 2016, 352(6285):586-589.
[44]	CANIBE N, O’DEA M, ABRAHAM S. Potential relevance of pig gut content transplantation for production and research[J]. J Anim Sci Biotechnol, 2019, 10(1):55.
[45]	HU J, NIE Y F, CHEN J W, et al. Gradual changes of gut microbiota in weaned miniature piglets[J]. Front Microbiol, 2016, 7:1727.
[46]	KUMAR A, VLASOVA A N, DEBLAIS L, et al. Impact of nutrition and rotavirus infection on the infant gut microbiota in a humanized pig model[J]. BMC Gastroenterol, 2018, 18(1):93.
[47]	PANG X Y, HUA X G, YANG Q, et al. Inter-species transplantation of gut microbiota from human to pigs[J]. ISME J, 2007, 1(2):156-162.
[48]	GILBERT J A, BLASER M J, CAPORASO J G, et al. Current understanding of the human microbiome[J]. Nat Med, 2018, 24(4):392-400.
[49]	BIN P, TANG Z Y, LIU S J, et al. Intestinal microbiota mediates Enterotoxigenic Escherichia coli-induced diarrhea in piglets[J]. BMC Vet Res, 2018, 14(1):385.
[50]	KRISS M, HAZLETON K Z, NUSBACHER N M, et al. Low diversity gut microbiota dysbiosis:drivers, functional implications and recovery[J]. Curr Opin Microbiol, 2018, 44:34-40.
[51]	KUMP P, WURM P, GRÖCHENIG H P, et al. The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis[J]. Aliment Pharmacol Ther, 2018, 47(1):67-77.
[52]	SUEZ J, ZMORA N, ZILBERMAN-SCHAPIRA G, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT[J]. Cell, 2018, 174(6):1406-1423.e16.
[53]	DUVALLET C, GIBBONS S M, GURRY T, et al. Meta-analysis of gut microbiome studies identifies disease-specific and shared responses[J]. Nat Commun, 2017, 8:1784.
[54]	马晨, 张和平. 粪便菌群移植的研究与应用[J]. 中国微生态学杂志, 2016, 28(3):364-368.MA C, ZHANG H P. Research and application of fecal microbiota transplantation[J]. Chinese Journal of Microecology, 2016, 28(3):364-368. (in Chinese)
[55]	WILSON B C, VATANEN T, CUTFIELD W S, et al. The super-donor phenomenon in fecal microbiota transplantation[J]. Front Cell Infect Microbiol, 2019, 9:2.
[56]	SMILLIE C S, SAUK J, GEVERS D, et al. Strain tracking reveals the determinants of bacterial engraftment in the human gut following fecal microbiota transplantation[J]. Cell Host Microbe, 2018, 23(2):229-240.e5.
[57]	FALONY G, VIEIRA-SILVA S, RAES J. Richness and ecosystem development across faecal snapshots of the gut microbiota[J]. Nat Microbiol, 2018, 3(5):526-528.
[58]	BRON P A, KLEEREBEZEM M, BRUMMER R J, et al. Can probiotics modulate human disease by impacting intestinal barrier function?[J]. Br J Nutr, 2017, 117(1):93-107.
[59]	舒龙, 胡继. 粪便移植技术的应用研究[J]. 四川畜牧兽医, 2014(6):33-35.SHU L, HU J. Research on the application of faeces transplant[J]. Sichuan Animal & Veterinary Sciences, 2014(6):33-35. (in Chinese)
[60]	NIEDERWERDER M C, CONSTANCE L A, ROWLAND R R R, et al. Fecal microbiota transplantation is associated with reduced morbidity and mortality in porcine circovirus associated disease[J]. Front Microbiol, 2018, 9:1631.
[61]	WANG X F, TSAI T, DENG F L, et al. Longitudinal investigation of the swine gut microbiome from birth to market reveals stage and growth performance associated bacteria[J]. Microbiome, 2019, 7(1):109.
[62]	ROOS S, KARNER F, AXELSSON L, et al. Lactobacillus mucosae sp. nov., a new species with in vitro mucus-binding activity isolated from pig intestine[J]. Int J Syst Evol Microbiol, 2000, 50:251-258.
[63]	ARRIETA M C, WALTER J, FINLAY B B. Human microbiota-associated mice:a model with challenges[J]. Cell Host Microbe, 2016, 19(5):575-578.
[64]	SARTOR R B, WU G D. Roles for intestinal bacteria, viruses, and fungi in pathogenesis of inflammatory bowel diseases and therapeutic approaches[J]. Gastroenterology, 2017, 152(2):327-339.
[65]	STALEY C, KAISER T, VAUGHN B P, et al. Predicting recurrence of Clostridium difficile infection following encapsulated fecal microbiota transplantation[J]. Microbiome, 2018, 6(1):166.
[66]	LIBERTUCCI J, YOUNG V B. The role of the microbiota in infectious diseases[J]. Nat Microbiol, 2019, 4:35-45.
[67]	PARAMSOTHY S, NIELSEN S, KAMM M A, et al. Specific bacteria and metabolites associated with response to fecal microbiota transplantation in patients with ulcerative colitis[J]. Gastroenterology, 2019, 156(5):1440-1454.
[68]	MULLISH B H, MCDONALD J A K, PECHLIVANIS A, et al. Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infection[J]. Gut, 2019, 68(10):1791-1800.
[69]	ROAGER H M, LICHT T R. Microbial tryptophan catabolites in health and disease[J]. Nat Commun, 2018, 9:3294.
[70]	LAZAR V, DITU L, PIRCALABIORU G G, et al. Aspects of gut microbiota and immune system interactions in infectious diseases, immunopathology, and cancer[J]. Front Immunol, 2018, 9:1830.
[71]	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.
[72]	XIAO Y, YAN H L, DIAO H, et al. Early gut microbiota intervention suppresses DSS-induced inflammatory responses by deactivating TLR/NLR signalling in pigs[J]. Sci Rep, 2017, 7(1):3224.
[73]	SHANAHAN F. Probiotics in perspective[J]. Gastroenterology, 2010, 139(6):1808-1812.
[74]	KARCZEWSKI J, TROOST F J, KONINGS I, et al. Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier[J]. Am J Physiol Gastrointest Liver Physiol, 2010, 298(6):G851-G859.
[75]	HE B, XU W F, SANTINI P A, et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL[J]. Immunity, 2007, 26(6):812-826.
[76]	HAPFELMEIER S, LAWSON M A E, SLACK E, et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses[J]. Science, 2010, 328(5986):1705-1709.
[77]	IVANOV I I, ATARASHI K, MANEL N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria[J]. Cell, 2009, 139(3):485-498.
[78]	LIGGENSTOFFER A S, YOUSSEF N H, COUGER M B, et al. Phylogenetic diversity and community structure of anaerobic gut fungi (phylum Neocallimastigomycota) in ruminant and non-ruminant herbivores[J]. ISME J, 2010, 4(10):1225-1235.
[79]	ILIEV I D, FUNARI V A, TAYLOR K D, et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis[J]. Science, 2012, 336(6086):1314-1317.
[80]	GOGOKHIA L, BUHRKE K, BELL R, et al. Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis[J]. Cell Host Microbe, 2019, 25(2):285-299.e8.
[81]	REYES A, HAYNES M, HANSON N, et al. Viruses in the faecal microbiota of monozygotic twins and their mothers[J]. Nature, 2010, 466(7304):334-338.
[82]	LIN D M, LIN H C. A theoretical model of temperate phages as mediators of gut microbiome dysbiosis[J]. F1000Res, 2019, 8:F1000 Faculty Rev-997.
[83]	OTT S J, WAETZIG G H, REHMAN A, et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection[J]. Gastroenterology, 2017, 152(4):799-811.e7.
[84]	ZUO T, WONG S H, LAM K, et al. Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome[J]. Gut, 2018, 67(4):634-643.
[85]	CONCEIÇÃO-NETO N, DEBOUTTE W, DIERCKX T, et al. Low eukaryotic viral richness is associated with faecal microbiota transplantation success in patients with UC[J]. Gut, 2018, 67(8):1558-1559.
[86]	ALLEGRETTI J R, KAO D, SITKO J, et al. Early antibiotic use after fecal microbiota transplantation increases risk of treatment failure[J]. Clin Infect Dis, 2018, 66(1):134-135.
[87]	王宏刚. 粪菌移植治疗克罗恩病的临床安全性研究[D]. 南京:南京医科大学, 2019.WANG H G. The long term safety of fecal microbiota transplantation for Crohn’s disease[D]. Nanjing: Nanjing Medical Univerdity, 2019. (in Chinese)
[88]	FADDA H M. The route to palatable fecal microbiota transplantation[J]. AAPS Pharm Sci Tech, 2020, 21(3):114.
[89]	李晓蕾, 李地艳, 孙静. 以肠道菌群为靶向的粪菌移植法及其在畜牧业的应用潜能[J]. 中国实验动物学报, 2019, 27(1):124-128.LI X L, LI D Y, SUN J. Intestinal flora-targeted fecal microbiota transplantation and its potential applications in animal husbandry[J]. Acta Laboratorium Animalis Scientia Sinica, 2019, 27(1):124-128. (in Chinese)