微生物群与肠道炎症（英文）
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摘要
在数百万年的时间里,哺乳动物进化出与肠道菌群间一个精密的共生关系。不断增加的证据表明微生物群平衡失调可以促进人类疾病的发展,其中包括不断增加的炎性肠炎。修复宿主-微生物相互作用是一种有效的阻止和治疗疾病的策略。在本文中,我们着重描述了在正常生理状况和肠道炎症背景下肠道微生物群的功能,着眼于宿主和微生物复杂关系的机理和病原基础。尽管有目前研究进展,但肠菌研究还面临很多挑战,缩小基础科学和临床应用之间的差距仍然很困难。我们认识到如果缺少肠道菌群及其对哺乳动物生理影响的深入理解,共生菌用于治疗("从肠菌到药物")的前景便无从谈起,所以本文也讨论用于操控肠道微生物群的临床治疗策略。
Mammals have developed a delicate symbiotic relationship with gut flora over millions of years.Mounting evidence indicates that microbiome contributes to the development of human diseases,including the ever-increasing inflammatory bowel diseases( IBD).Restoring host-microbial interactions constitutes a promising therapeutic strategy to prevent and treat the illness.In this review,we highlighted our understandings of the intestinal microbiome in the context of physiological health and intestinal inflammation,focusing on the signaling pathways,such as the NF-κB,vitamin D receptor,and Toll-like receptors( TLRS),which underlies the host-microbe interactions.We also discussed the potential therapeutic strategies that can be used to manipulate the gut microbiota in IBD.Many challenges lie ahead that making it difficult to narrow the gap between the basic sciences and clinical applications.The promise of pharmabiotics( "bugs to drugs") is unlikely to be completely fulfilled without a greater understanding of enteric microbiota.
Mammals have developed a delicate symbiotic relationship with gut flora over millions of years.Mounting evidence indicates that microbiome contributes to the development of human diseases,including the ever-increasing inflammatory bowel diseases( IBD).Restoring host-microbial interactions constitutes a promising therapeutic strategy to prevent and treat the illness.In this review,we highlighted our understandings of the intestinal microbiome in the context of physiological health and intestinal inflammation,focusing on the signaling pathways,such as the NF-κB,vitamin D receptor,and Toll-like receptors( TLRS),which underlies the host-microbe interactions.We also discussed the potential therapeutic strategies that can be used to manipulate the gut microbiota in IBD.Many challenges lie ahead that making it difficult to narrow the gap between the basic sciences and clinical applications.The promise of pharmabiotics( "bugs to drugs") is unlikely to be completely fulfilled without a greater understanding of enteric microbiota.
引文
[1]Sartor R B.Mechanisms of disease:pathogenesis of Crohn's disease and ulcerative colitis[J].Nat Clin Pract Gastroenterol Hepatol,2006,3(7):390-407.
[2]Shanahan F.Crohn's disease[J].Lancet,2002,359(9300):62-69.
[3]O'Hara A M,Shanahan F.The gut flora as a forgotten organ[J].EMBO Rep,2006,7(7):688-693.
[4]Sha S,Liang J,Chen M,et al.Systematic review:faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children[J].Aliment Pharmacol Ther,2014,39(10):61003-61032.
[5]Qin J,Li R,Raes J,et al.A human gut microbial gene catalogue established by metagenomic sequencing[J].Nature,2010,464(7285):59-65.
[6]Guarner F,Malagelada J R.Gut flora in health and disease[J].Lancet,2003,361(9356):512-519.
[7]Yang L,Lu X,Nossa C W,et al.Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome[J].Gastroenterology,2009,137(2):588-597.
[8]Pedron T,Mulet C,Dauga C,et al.A crypt-specific core microbiota resides in the mouse colon[J].Mbio,2012,3(3):e00116-12.
[9]Walker A W,Duncan S H,McWilliam Leitch E C,et al.pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon[J].Appl Environ Microbiol,2005,71(7):3692-3700.
[10]Funkhouser L J,Bordenstein S R.Mom knows best:the universality of maternal microbial transmission[J].PLoS Biol,2013,11(8):e1001631.
[11]Dominguez-Bello M G,Costello E K,Contreras M,et al.Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns[J].Proc Natl Acad Sci USA,2010,107(26):11971-11975.
[12]Lepage P,Leclerc M C,Joossens M,et al.A metagenomic insight into our gut's microbiome[J].Gut,2013,62(1):146-158.
[13]Turnbaugh P J,Ley R E,Hamady M,et al.The human microbiome project[J].Nature,2007,449(7164):804-810.
[14]Jin D,Zhang H,Sun J.Manipulation of microbiome,a promising therapy for inflammatory bowel diseases[J].J Clin Cell Immunol,2014,5:234.doi:10.4172/2155-9899.1000234.
[15]Eckburg P B,Bik E M,Bernstein C N,et al.Diversity of the human intestinal microbial flora[J].Science,2005,308(5728):1635-1638.
[16]Sartor R B.Microbial-host interactions in inflammatory bowel diseases and experimental colitis[J].Nestle Nutr Workshop Ser Pediatr Program,2009,64:121-132.
[17]Umesaki Y,Okada Y,Matsumoto S,et al.Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class Ⅱmolecules and fucosyl asialo GM1 glycolipids on the small intestinal epithelial cells in the ex-germ-free mouse[J].Microbiol Immunol,1995,39(8):555-562.
[18]Sellon R K,Tonkonogy S,Schultz M,et al.Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice[J].Infect Immun,1998,66(11):5224-5231.
[19]Devkota S,Wang Y,Musch M W,et al.Dietary-fatinduced taurocholic acid promotes pathobiont expansion and colitis in Il10-/-mice[J].Nature,2012,487(7405):104-108.
[20]Abreu M T.Nod2 in normal and abnormal intestinal immune function[J].Gastroenterology,2005,129(4):1302-1304.
[21]Hooper L V.Laser microdissection:exploring hostbacterial encounters at the front lines[J].Curr Opin Microbiol,2004,7(3):290-295.
[22]Madara J.Building an intestine--architectural contributions of commensal bacteria[J].N Engl J Med,2004,351(16):1685-1686.
[23]Rakoff-Nahoum S,Paglino J,Eslami-Varzaneh F,et al.Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis[J].Cell,2004,118(2):229-241.
[24]Biswas A,Petnicki-Ocwieja T,Kobayashi K S.Nod2:a key regulator linking microbiota to intestinal mucosal immunity[J].J Mol Med(Berl),2011,90(1):15-24.
[25]Couturier-Maillard A,Secher T,Rehman A,et al.NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer[J].J Clin Invest.2013,123(2):700-711.
[26]Petrof E O,Kojima K,Ropeleski M J,et al.Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition[J].Gastroenterology,2004,127(5):1474-1487.
[27]White J H.Vitamin D signaling,infectious diseases,and regulation of innate immunity[J].Infect Immun,2008,76(9):3837-3843.
[28]Holick M F,Chen T C,Lu Z,et al.Vitamin D and skin physiology:a D-lightful story[J].J Bone Miner Res,2007,22 Suppl 2:V28-33.
[29]Lim W C,Hanauer S B,Li Y C.Mechanisms of disease:vitamin D and inflammatory bowel disease[J].Nat Clin Pract Gastroenterol Hepatol,2005,2(7):308-315.
[30]Bours P H,Wielders J P,Vermeijden J R,et al.Seasonal variation of serum 25-hydroxyvitamin D levels in adult patients with inflammatory bowel disease[J].Osteoporos Int,2011,22(11):2857-2867.
[31]Levin A D,Wadhera V,Leach S T,et al.Vitamin D deficiency in children with inflammatory bowel disease[J].Dig Dis Sci,2011,56(3):830-836.
[32]Abreu M T,Kantorovich V,Vasiliauskas E A,et al.Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density[J].Gut,2004,53(8):1129-1136.
[33]Wada K,Tanaka H,Maeda K,et al.Vitamin D receptor expression is associated with colon cancer in ulcerative colitis[J].Oncol Rep,2009,22(5):1021-1025.
[34]Kong J,Zhang Z,Musch M W,et al.Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier[J].Am J Physiol Gastrointest Liver Physiol,2008,294(1):G208-216.
[35]Lagishetty V,Misharin A V,Liu N Q,et al.Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis[J].Endocrinology,2010,151(6):2423-2432.
[36]Carlberg C,Seuter S.A genomic perspective on vitamin D signaling[J].Anticancer Res,2009,29(9):3485-3493.
[37]Schauber J,Gallo R L.The vitamin D pathway:a new target for control of the skin's immune response[J]?Exp Dermatol,2008,17(8):633-639.
[38]Wu S,Liao A P,Xia Y,et al.Vitamin D receptor negatively regulates bacterial-stimulated NF-kappaB activity in intestine[J].Am J Pathol,2010,177(2):686-697.
[39]Sun J,Kong J,Duan Y,et al.Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor[J].Am J Physiol Endocrinol Metab,2006,291(2):e315-322.
[40]Wu S,Zhang Y-g,Lu R,et al.Intestinal epithelial vitamin D receptor deletion Q1 leads to defective autophagy in colitis[J].Gut,2014.doi:10.1136/gutjnl-2014-307436.
[41]Sentongo T A,Semaeo E J,Stettler N,et al.Vitamin D status in children,adolescents,and young adults with Crohn disease[J].Am J Clin Nutr,2002,76(5):1077-1081.
[42]Verway M,Behr M A,White J H.Vitamin D,NOD2,autophagy and Crohn's disease[J].Expert Rev Clin Immunol,2010,6(4):505-508.
[43]Wang Y,Antonopoulos D A,Zhu X,et al.Laser capture microdissection and metagenomic analysis of intact mucosa-associated microbial communities of human colon[J].Appl Microbiol Biotechnol,2010,88(6):1333-1342.
[44]Lin J,Hackam D J.Worms,flies and four-legged friends:The applicability of biological models to the understanding of intestinal inflammatory diseases[J].Dis Model Mech,2011,4(4):447-456.
[45]Jostins L,Ripke S,Weersma R K,et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease[J].Nature,2012,491(7422):119-124.
[46]Uhlig H H.Monogenic diseases associated with intestinal inflammation:implications for the understanding of inflammatory bowel disease[J].Gut,2013,62(12):1795-1805.
[2]Shanahan F.Crohn's disease[J].Lancet,2002,359(9300):62-69.
[3]O'Hara A M,Shanahan F.The gut flora as a forgotten organ[J].EMBO Rep,2006,7(7):688-693.
[4]Sha S,Liang J,Chen M,et al.Systematic review:faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children[J].Aliment Pharmacol Ther,2014,39(10):61003-61032.
[5]Qin J,Li R,Raes J,et al.A human gut microbial gene catalogue established by metagenomic sequencing[J].Nature,2010,464(7285):59-65.
[6]Guarner F,Malagelada J R.Gut flora in health and disease[J].Lancet,2003,361(9356):512-519.
[7]Yang L,Lu X,Nossa C W,et al.Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome[J].Gastroenterology,2009,137(2):588-597.
[8]Pedron T,Mulet C,Dauga C,et al.A crypt-specific core microbiota resides in the mouse colon[J].Mbio,2012,3(3):e00116-12.
[9]Walker A W,Duncan S H,McWilliam Leitch E C,et al.pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon[J].Appl Environ Microbiol,2005,71(7):3692-3700.
[10]Funkhouser L J,Bordenstein S R.Mom knows best:the universality of maternal microbial transmission[J].PLoS Biol,2013,11(8):e1001631.
[11]Dominguez-Bello M G,Costello E K,Contreras M,et al.Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns[J].Proc Natl Acad Sci USA,2010,107(26):11971-11975.
[12]Lepage P,Leclerc M C,Joossens M,et al.A metagenomic insight into our gut's microbiome[J].Gut,2013,62(1):146-158.
[13]Turnbaugh P J,Ley R E,Hamady M,et al.The human microbiome project[J].Nature,2007,449(7164):804-810.
[14]Jin D,Zhang H,Sun J.Manipulation of microbiome,a promising therapy for inflammatory bowel diseases[J].J Clin Cell Immunol,2014,5:234.doi:10.4172/2155-9899.1000234.
[15]Eckburg P B,Bik E M,Bernstein C N,et al.Diversity of the human intestinal microbial flora[J].Science,2005,308(5728):1635-1638.
[16]Sartor R B.Microbial-host interactions in inflammatory bowel diseases and experimental colitis[J].Nestle Nutr Workshop Ser Pediatr Program,2009,64:121-132.
[17]Umesaki Y,Okada Y,Matsumoto S,et al.Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class Ⅱmolecules and fucosyl asialo GM1 glycolipids on the small intestinal epithelial cells in the ex-germ-free mouse[J].Microbiol Immunol,1995,39(8):555-562.
[18]Sellon R K,Tonkonogy S,Schultz M,et al.Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice[J].Infect Immun,1998,66(11):5224-5231.
[19]Devkota S,Wang Y,Musch M W,et al.Dietary-fatinduced taurocholic acid promotes pathobiont expansion and colitis in Il10-/-mice[J].Nature,2012,487(7405):104-108.
[20]Abreu M T.Nod2 in normal and abnormal intestinal immune function[J].Gastroenterology,2005,129(4):1302-1304.
[21]Hooper L V.Laser microdissection:exploring hostbacterial encounters at the front lines[J].Curr Opin Microbiol,2004,7(3):290-295.
[22]Madara J.Building an intestine--architectural contributions of commensal bacteria[J].N Engl J Med,2004,351(16):1685-1686.
[23]Rakoff-Nahoum S,Paglino J,Eslami-Varzaneh F,et al.Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis[J].Cell,2004,118(2):229-241.
[24]Biswas A,Petnicki-Ocwieja T,Kobayashi K S.Nod2:a key regulator linking microbiota to intestinal mucosal immunity[J].J Mol Med(Berl),2011,90(1):15-24.
[25]Couturier-Maillard A,Secher T,Rehman A,et al.NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer[J].J Clin Invest.2013,123(2):700-711.
[26]Petrof E O,Kojima K,Ropeleski M J,et al.Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition[J].Gastroenterology,2004,127(5):1474-1487.
[27]White J H.Vitamin D signaling,infectious diseases,and regulation of innate immunity[J].Infect Immun,2008,76(9):3837-3843.
[28]Holick M F,Chen T C,Lu Z,et al.Vitamin D and skin physiology:a D-lightful story[J].J Bone Miner Res,2007,22 Suppl 2:V28-33.
[29]Lim W C,Hanauer S B,Li Y C.Mechanisms of disease:vitamin D and inflammatory bowel disease[J].Nat Clin Pract Gastroenterol Hepatol,2005,2(7):308-315.
[30]Bours P H,Wielders J P,Vermeijden J R,et al.Seasonal variation of serum 25-hydroxyvitamin D levels in adult patients with inflammatory bowel disease[J].Osteoporos Int,2011,22(11):2857-2867.
[31]Levin A D,Wadhera V,Leach S T,et al.Vitamin D deficiency in children with inflammatory bowel disease[J].Dig Dis Sci,2011,56(3):830-836.
[32]Abreu M T,Kantorovich V,Vasiliauskas E A,et al.Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density[J].Gut,2004,53(8):1129-1136.
[33]Wada K,Tanaka H,Maeda K,et al.Vitamin D receptor expression is associated with colon cancer in ulcerative colitis[J].Oncol Rep,2009,22(5):1021-1025.
[34]Kong J,Zhang Z,Musch M W,et al.Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier[J].Am J Physiol Gastrointest Liver Physiol,2008,294(1):G208-216.
[35]Lagishetty V,Misharin A V,Liu N Q,et al.Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis[J].Endocrinology,2010,151(6):2423-2432.
[36]Carlberg C,Seuter S.A genomic perspective on vitamin D signaling[J].Anticancer Res,2009,29(9):3485-3493.
[37]Schauber J,Gallo R L.The vitamin D pathway:a new target for control of the skin's immune response[J]?Exp Dermatol,2008,17(8):633-639.
[38]Wu S,Liao A P,Xia Y,et al.Vitamin D receptor negatively regulates bacterial-stimulated NF-kappaB activity in intestine[J].Am J Pathol,2010,177(2):686-697.
[39]Sun J,Kong J,Duan Y,et al.Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor[J].Am J Physiol Endocrinol Metab,2006,291(2):e315-322.
[40]Wu S,Zhang Y-g,Lu R,et al.Intestinal epithelial vitamin D receptor deletion Q1 leads to defective autophagy in colitis[J].Gut,2014.doi:10.1136/gutjnl-2014-307436.
[41]Sentongo T A,Semaeo E J,Stettler N,et al.Vitamin D status in children,adolescents,and young adults with Crohn disease[J].Am J Clin Nutr,2002,76(5):1077-1081.
[42]Verway M,Behr M A,White J H.Vitamin D,NOD2,autophagy and Crohn's disease[J].Expert Rev Clin Immunol,2010,6(4):505-508.
[43]Wang Y,Antonopoulos D A,Zhu X,et al.Laser capture microdissection and metagenomic analysis of intact mucosa-associated microbial communities of human colon[J].Appl Microbiol Biotechnol,2010,88(6):1333-1342.
[44]Lin J,Hackam D J.Worms,flies and four-legged friends:The applicability of biological models to the understanding of intestinal inflammatory diseases[J].Dis Model Mech,2011,4(4):447-456.
[45]Jostins L,Ripke S,Weersma R K,et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease[J].Nature,2012,491(7422):119-124.
[46]Uhlig H H.Monogenic diseases associated with intestinal inflammation:implications for the understanding of inflammatory bowel disease[J].Gut,2013,62(12):1795-1805.