The microbiome in inflammatory bowel diseases: from pathogenesis to therapy

Abstract

Inflammatory bowel disease (IBD) has become a global disease with accelerating incidence worldwide in the 21st century while its accurate etiology remains unclear. In the past decade, gut microbiota dysbiosis has consistently been associated with IBD. Although many IBDassociated dysbiosis have not been proven to be a cause or an effect of IBD, it is often hypothesized that at least some of alteration in microbiome is protective or causative. In this article, we selectively reviewed the hypothesis supported by both association studies in human and pathogenesis studies in biological models. Specifically, we reviewed the potential protective bacterial pathways and species against IBD, as well as the potential causative bacterial pathways and species of IBD. We also reviewed the potential roles of some members of mycobiome and virome in IBD. Lastly, we covered the current status of therapeutic approaches targeting microbiome, which is a promising strategy to alleviate and cure this inflammatory disease.

Keywords

inflammatory bowel disease / pathogenesis / etiology / microbiome / dysbiosis / therapy

References

[1] Abraham BP, Quigley EMM (2017) Probiotics in inflammatory bowel disease. Gastroenterol Clin N Am 46:769–782

[2] Agus A,Planchais J, Sokol H (2018) Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23:716–724

[3] Akram W, Garud N, Joshi R (2019) Role of inulin as prebiotics on inflammatory bowel disease. Drug Discov Ther 13:1–8

[4] Alhagamhmad MH, Day AS, Lemberg DA, Leach ST (2016) An overview of the bacterial contribution to Crohn disease pathogenesis. J Med Microbiol 65:1049–1059

[5] An D, Oh SF, Olszak T, Neves JF, Avci FY, Erturk-Hasdemir D, Lu X, Zeissig S, Blumberg RS, Kasper DL (2014) Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156:123–133

[6] Ansaldo E, Slayden LC, Ching KL, Koch MA, Wolf NK, Plichta DR, Brown EM, Graham DB, Xavier RJ, Moon JJ (2019) Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364:1179–1184

[7] Arthur JC, Perez-Chanona E, Muhlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–123

[8] Atherly T, Mosher C, Wang C,Hostetter J,Proctor A, Brand MW, Phillips GJ, Wannemuehler M, Jergens AE (2016) Helicobacter bilis infection alters mucosal bacteria and modulates colitis development in defined microbiota mice. Inflamm Bowel Dis 22:2571–2581

[9] Barnett MP, McNabb WC, Cookson AL, Zhu S, Davy M, Knoch B, Nones K, Hodgkinson AJ, Roy NC (2010) Changes in colon gene expression associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species. BMC Immunol 11:39

[10] Barnich N, Carvalho FA, Glasser AL, Darcha C, Jantscheff P, Allez M, Peeters H, Bommelaer G, Desreumaux P,Colombel JF (2007) CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Investig 117:1566–1574

[11] Bell A, Brunt J, Crost E, Vaux L, Nepravishta R, Owen CD, Latousakis D, Xiao A, Li W, Chen X (2019) Elucidation of a sialic acid metabolism pathway in mucus-foraging Ruminococcus gnavus unravels mechanisms of bacterial adaptation to the gut. Nat Microbiol 4:2393–2404

[12] Bian X, Wu W, Yang L, Lv L, Wang Q, Li Y, Ye J, Fang D, Wu J, Jiang X (2019) Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front Microbiol 10:2259

[13] Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, De Simone C, Sartor RB (2005) VSL#3 probioticmixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol 100:1539–1546

[14] Bjarnason I, Sission G,Hayee B (2019) A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic in patients with asymptomatic ulcerative colitis and Crohn’s disease. Inflammopharmacology 27:465–473

[15] Blandford LE, Johnston EL, Sanderson JD, Wade WG, Lax AJ (2019) Promoter orientation of the immunomodulatory Bacteroides fragilis capsular polysaccharide A (PSA) is off in individuals with inflammatory bowel disease (IBD). Gut Microbes 10:569–577

[16] Breban M, Tap J, Leboime A, Said-Nahal R, Langella P, Chiocchia G,Furet JP, Sokol H (2017) Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis 76:1614–1622

[17] Bringer MA, Glasser AL, Tung CH, Meresse S,Darfeuille-Michaud A (2006) The Crohn’s disease-associated adherent-invasive Escherichia coli strain LF82 replicates in mature phagolysosomes within J774 macrophages. Cell Microbiol 8:471–484

[18] Burrello C, Garavaglia F, Cribiu FM, Ercoli G, Lopez G, Troisi J, Colucci A, Guglietta S, Carloni S, Guglielmetti S (2018) Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. Nat Commun 9:5184

[19] Cammarota G,Ianiro G, Tilg H, Rajilic-Stojanovic M,Kump P,Satokari R, Sokol H, Arkkila P, Pintus C,Hart A (2017) European consensus conference on faecal microbiota transplantation in clinical practice. Gut 66:569–580

[20] Cammarota G, Ianiro G, Kelly CR, Mullish BH, Allegretti JR, Kassam Z, Putignani L, Fischer M, Keller JJ, Costello SP (2019) International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut 68:2111–2121

[21] Cao X(2017) Intestinal inflammation induced by oral bacteria. Science 358:308–309

[22] Castano-Rodriguez N, Kaakoush NO, Lee WS, Mitchell HM (2017) Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis. Gut 66:235–249

[23] Chai JN, Peng Y, Rengarajan S, Solomon BD, Ai TL, Shen Z, Perry JSA, Knoop KA, Tanoue T, Narushima S (2017) Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. Sci Immunol 2(13):eaal5068

[24] Chehoud C,Albenberg LG, Judge C,Hoffmann C, Grunberg S, Bittinger K,Baldassano RN, Lewis JD, Bushman FD, Wu GD (2015) Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 21:1948–1956

[25] Chiaro TR, Soto R, Zac Stephens W, Kubinak JL, Petersen C, Gogokhia L, Bell R, Delgado JC, Cox J,Voth W (2017) A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice. Sci Transl Med 9(380):eaaf9044

[26] Chua HH, Chou HC, Tung YL, Chiang BL, Liao CC, Liu HH, Ni YH (2018) Intestinal dysbiosis featuring abundance of Ruminococcus gnavus associates with allergic diseases in infants. Gastroenterology 154:154–167

[27] Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB (2018) Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe 23(203–214):e205

[28] Clooney AG, Sutton TDS, Shkoporov AN, Holohan RK, Daly KM, O’Regan O,Ryan FJ, Draper LA, Plevy SE, Ross RP (2019) Whole-virome analysis sheds light on viral dark matter in inflammatory bowel disease. Cell Host Microbe 26:764–778.e765

[29] Coker OO, Nakatsu G,Dai RZ, Wu WKK, Wong SH, Ng SC, Chan FKL, Sung JJY, Yu J(2019) Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut 68:654–662

[30] Colombel JF, Shin A, Gibson PR (2019) AGA clinical practice update on functional gastrointestinal symptoms in patients with inflammatory bowel disease: expert review. Clin Gastroenterol Hepatol 17:380–390.e381

[31] Connors J,Dunn KA, Allott J,Bandsma R, Rashid M, Otley AR, Bielawski JP, Van Limbergen J (2019) The relationship between fecal bile acids and microbiome community structure in pediatric Crohn’s disease . ISME J 14:702–713

[32] Cui B, Feng Q, Wang H, Wang M, Peng Z, Li P,Huang G, Liu Z, Wu P, Fan Z (2015) Fecal microbiota transplantation through mid-gut for refractory Crohn’s disease: safety, feasibility, and efficacy trial results. J Gastroenterol Hepatol 30:51–58

[33] Darfeuille-Michaud A (2002) Adherent-invasive Escherichia coli: a putative new E. coli pathotype associated with Crohn’s disease. Int J Med Microbiol 292:185–193

[34] Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C,Glasser AL, Barnich N, Bringer MA, Swidsinski A, Beaugerie L, Colombel JF (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127:412–421

[35] De Hertogh G, Aerssens J, Geboes KP, Geboes K (2008) Evidence for the involvement of infectious agents in the pathogenesis of Crohn’s disease. World J Gastroenterol 14:845–852

[36] Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J,Jacobs-Sera D, Schooley RT (2019) Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 25:730–733

[37] Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, Wu X, DeStefano Shields CE, Hechenbleikner EM, Huso DL (2018) Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359:592–597

[38] Derwa Y, Gracie DJ, Hamlin PJ, Ford AC (2017) Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease. Aliment Pharmacol Ther 46:389–400

[39] Dickson I (2018) Gut microbiota: oral bacteria: a cause of IBD? Nat Rev Gastroenterol Hepatol 15:4–5

[40] Dodd D, Spitzer MH, Van Treuren W, Merrill BD, Hryckowian AJ, Higginbottom SK, Le A, Cowan TM, Nolan GP, Fischbach MA (2017) A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551:648–652

[41] Draper LA, Ryan FJ, Smith MK, Jalanka J,Mattila E, Arkkila PA, Ross RP, Satokari R, Hill C (2018) Long-term colonisation with donor bacteriophages following successful faecal microbial transplantation. Microbiome 6:220

[42] Duan Y, Llorente C, Lang S, Brandl K, Chu H, Jiang L, White RC, Clarke TH, Nguyen K, Torralba M (2019) Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 575:505–511

[43] Duboc H, Rajca S, Rainteau D,Benarous D,Maubert MA, Quervain E, Thomas G, Barbu V, Humbert L, Despras G (2013) Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 62:531–539

[44] Duerkop BA, Kleiner M, Paez-Espino D, Zhu W, Bushnell B, Hassell B,Winter SE, Kyrpides NC, Hooper LV (2018) Murine colitis reveals a disease-associated bacteriophage community. Nat Microbiol 3:1023–1031

[45] Eaton K, Pirani A, Snitkin ES, Reproducibility Project: Cancer B, Iorns E,Tsui R, Denis A, Perfito N, Errington TM, Iorns E (2018). Replication Study: intestinal inflammation targets cancerinducing activity of the microbiota. Elife 7:e34364.

[46] el-Omar E,Penman I, Cruikshank G, Dover S, Banerjee S,Williams C, McColl KE (1994) Low prevalence of Helicobacter pylori in inflammatory bowel disease: association with sulphasalazine. Gut 35:1385–1388

[47] Erickson AR, Cantarel BL, Lamendella R, Darzi Y,Mongodin EF, Pan C, Shah M, Halfvarson J, Tysk C,Henrissat B (2012) Integrated metagenomics/metaproteomics reveals human hostmicrobiota signatures of Crohn’s disease. PLoS ONE 7:e49138

[48] Fedorak RN, Feagan BG, Hotte N, Leddin D, Dieleman LA, Petrunia DM, Enns R, Bitton A, Chiba N, Pare P (2015) The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn’s disease. Clin Gastroenterol Hepatol 13:928–935.e922

[49] Franzosa EA, Sirota-Madi A, Avila-Pacheco J, Fornelos N, Haiser HJ, Reinker S, Vatanen T, Hall AB, Mallick H, McIver LJ (2019) Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol 4:293–305

[50] Freedman SB, Williamson-Urquhart S,Farion KJ, Gouin S, Willan AR, Poonai N, Hurley K, Sherman PM, Finkelstein Y, Lee BE(2018) Multicenter trial of a combination probiotic for children with gastroenteritis. N Engl J Med 379:2015–2026

[51] Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–450

[52] Galtier M, De Sordi L, Sivignon A, de Vallee A, Maura D, Neut C, Rahmouni O, Wannerberger K, Darfeuille-Michaud A, Desreumaux P (2017) Bacteriophages targeting adherent invasive Escherichia coli strains as a promising new treatment for Crohn’s disease. J Crohns Colitis 11:840–847

[53] Garrett WS (2019) The gut microbiota and colon cancer. Science 364:1133–1135

[54] Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S, Karlsson M, Bry L,Glickman JN (2010) Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8:292–300

[55] Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C,Swanson KS, Cani PD (2017) Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 14:491–502

[56] Gogokhia L,Buhrke K, Bell R, Hoffman B, Brown DG, Hanke-Gogokhia C, Ajami NJ, Wong MC, Ghazaryan A, Valentine JF (2019) Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis. Cell Host Microbe 25:285–299. e288

[57] Hall AB, Yassour M, Sauk J,Garner A, Jiang X, Arthur T, Lagoudas GK, Vatanen T, Fornelos N, Wilson R (2017) A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med 9:103

[58] Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A (2012) Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 107:761–767

[59] Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, Ha S, Nelson BN, Kelly SP, Wu L (2019) Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576:143–148

[60] Hedin C, van der Gast CJ, Rogers GB, Cuthbertson L, McCartney S, Stagg AJ, Lindsay JO, Whelan K (2016) Siblings of patients with Crohn’s disease exhibit a biologically relevant dysbiosis in mucosal microbial metacommunities. Gut 65:944–953

[61] Henke MT, Kenny DJ, Cassilly CD, Vlamakis H, Xavier RJ, Clardy J (2019) Ruminococcus gnavus, a member of the human gut microbiome associated with Crohn’s disease, produces an inflammatory polysaccharide. Proc Natl Acad Sci USA 116:12672–12677

[62] Hill C,Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L,Canani RB, Flint HJ, Salminen S (2014) Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 11:506–514

[63] Hvas CL, Dahl Jørgensen SM, Jørgensen SRP, Storgaard M, Lemming L, Hansen MM, Erikstrup C, Dahlerup JF (2019) Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent Clostridium difficile infection. Gastroenterology 156:1324–1332.e1323

[64] Iliev ID, Funari VA, Taylor KD, Nguyen Q, Reyes CN, Strom SP, Brown J, Becker CA, Fleshner PR, Dubinsky M (2012) Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336:1314–1317

[65] Imhann F, Vich Vila A, Bonder MJ, Fu J, Gevers D, Visschedijk MC, Spekhorst LM, Alberts R, Franke L, van Dullemen HM (2018) Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 67:108–119

[66] Jergens AE, Wilson-Welder JH, Dorn A, Henderson A, Liu Z, Evans RB, Hostetter J,Wannemuehler MJ (2007) Helicobacter bilis triggers persistent immune reactivity to antigens derived from the commensal bacteria in gnotobiotic C3H/HeN mice. Gut 56:934–940

[67] Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P,Vandamme P, Vermeire S(2011) Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut 60:631–637

[68] Kalischuk LD, Buret AG (2010) A role for Campylobacter jejuniinduced enteritis in inflammatory bowel disease? Am J Physiol Gastrointest Liver Physiol 298:29

[69] Khoruts A, Sadowsky MJ (2016) Understanding the mechanisms of faecal microbiota transplantation. Nat Rev Gastroenterol Hepatol 13:508–516

[70] Khoruts A, Rank KM, Newman KM, Viskocil K, Vaughn BP, Hamilton MJ, Sadowsky MJ (2016) Inflammatory bowel disease affects the outcome of fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol 14:1433–1438

[71] Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH (2013) Shortchain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145(396–406):e391–e310

[72] Kirk KF, Nielsen HL, Thorlacius-Ussing O, Nielsen H(2016) Optimized cultivation of Campylobacter concisus from gut mucosal biopsies in inflammatory bowel disease. Gut Pathog 8:27

[73] Kostic AD, Xavier RJ, Gevers D (2014) The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146:1489–1499

[74] Kotlowski R, Bernstein CN, Sepehri S,Krause DO (2007) High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut 56:669–675

[75] Kruis W, Fric P, Pokrotnieks J, Lukas M, Fixa B, Kascak M, Kamm MA, Weismueller J, Beglinger C,Stolte M (2004) Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 53:1617–1623

[76] Kullberg MC, Rothfuchs AG, Jankovic D,Caspar P, Wynn TA, Gorelick PL, Cheever AW, Sher A (2001) Helicobacter hepaticusinduced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect Immun 69:4232–4241

[77] Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ (2006) IL-23 plays a key role in Helicobacter hepaticus-induced T celldependent colitis. J Exp Med 203:2485–2494

[78] Laharie D, Asencio C, Asselineau J,Bulois P, Bourreille A, Moreau J, Bonjean P, Lamarque D, Pariente A, Soule JC (2009) Association between entero-hepatic Helicobacter species and Crohn’s disease: a prospective cross-sectional study. Aliment Pharmacol Ther 30:283–293

[79] Lam S, Zuo T, Ho M, Chan FKL, Chan PKS, Ng SC (2019) Review article: fungal alterations in inflammatory bowel diseases. Aliment Pharmacol Ther 50:1159–1171

[80] Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee B,Lomer MCE, Parkes GC, Selinger C (2019) British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 68:s1–s106

[81] LaMont JT (2018) Probiotics for children with gastroenteritis. N Engl J Med 379:2076–2077

[82] Levy M, Thaiss CA, Zeevi D, Dohnalova L, Zilberman-Schapira G, Mahdi JA, David E, Savidor A, Korem T, Herzig Y (2015) Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163:1428–1443

[83] Li Q, Wang C, Tang C, He Q, Li N, Li J (2014) Dysbiosis of gut fungal microbiota is associated with mucosal inflammation in Crohn’s disease. J Clin Gastroenterol 48:513–523

[84] Li XV, Leonardi I, Iliev ID (2019) Gut mycobiota in immunity and inflammatory disease. Immunity 50:1365–1379

[85] Limon JJ, Tang J, Li D, Wolf AJ, Michelsen KS, Funari V, Gargus M, Nguyen C, Sharma P, Maymi VI (2019) Malassezia is associated with Crohn’s disease and exacerbates colitis in mouse models. Cell Host Microbe 25:377–388.e376

[86] Liu Z, Ramer-Tait AE, Henderson AL, Demirkale CY, Nettleton D, Wang C,Hostetter JM, Jergens AE, Wannemuehler MJ (2011) Helicobacter bilis colonization enhances susceptibility to Typhlocolitis following an inflammatory trigger. Dig Dis Sci 56:2838–2848

[87] Lloyd-Price J,Arze C, Ananthakrishnan AN, Schirmer M, Avila-Pacheco J,Poon TW, Andrews E, Ajami NJ, Bonham KS, Brislawn CJ (2019) Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569:655–662

[88] Lo Presti A, Zorzi F, Del Chierico F, Altomare A, Cocca S, Avola A, De Biasio F,Russo A, Cella E, Reddel S(2019) Fecal and mucosal microbiota profiling in irritable bowel syndrome and inflammatory bowel disease. Front Microbiol 10:1655

[89] Lynch SV, Pedersen O (2016) The human intestinal microbiome in health and disease. N Engl J Med 375:2369–2379

[90] Machiels K, Joossens M, Sabino J, De Preter V,Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K (2014) A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63:1275–1283

[91] Machiels K, Sabino J, Vandermosten L,Joossens M, Arijs I, de Bruyn M, Eeckhaut V,Van Assche G, Ferrante M, Verhaegen J (2017) Specific members of the predominant gut microbiota predict pouchitis following colectomy and IPAA in UC. Gut 66:79–88

[92] Mahendran V, Riordan SM, Grimm MC, Tran TA, Major J, Kaakoush NO, Mitchell H, Zhang L (2011) Prevalence of Campylobacter species in adult Crohn’s disease and the preferential colonization sites of Campylobacter species in the human intestine. PLoS ONE 6:e25417

[93] Mahendran V, Liu F, Riordan SM, Grimm MC, Tanaka MM, Zhang L (2016) Examination of the effects of Campylobacter concisus zonula occludens toxin on intestinal epithelial cells and macrophages. Gut Pathog 8:18

[94] Man SM, Kaakoush NO, Leach ST, Nahidi L, Lu HK, Norman J,Day AS, Zhang L, Mitchell HM (2010) Host attachment, invasion, and stimulation of proinflammatory cytokines by Campylobacter concisus and other non-Campylobacter jejuni Campylobacter species. J Infect Dis 202:1855–1865

[95] Mar JS, LaMere BJ, Lin DL, Levan S, Nazareth M, Mahadevan U,Lynch SV (2016) Disease severity and immune activity relate to distinct interkingdom gut microbiome states in ethnically distinct ulcerative colitis patients. mBio.https://doi.org/10.1128/mBio.01072-16

[96] Martin HM, Campbell BJ, Hart CA, Mpofu C, Nayar M, Singh R, Englyst H, Williams HF, Rhodes JM (2004) Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology 127:80–93

[97] Martin R, Miquel S, Benevides L, Bridonneau C,Robert V,Hudault S, Chain F, Berteau O, Azevedo V, Chatel JM (2017) Functional characterization of novel Faecalibacterium prausnitzii strains isolated from healthy volunteers: a step forward in the use of F. prausnitzii as a next-generation probiotic. Front Microbiol 8:1226

[98] Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–118

[99] Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625

[100] McCallin S, Alam Sarker S, Barretto C, Sultana S, Berger B, Huq S,Krause L, Bibiloni R,Schmitt B, Reuteler G (2013) Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. Virology 443:187–196

[101] Miele E, Pascarella F, Giannetti E, Quaglietta L, Baldassano RN, Staiano A (2009) Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol 104:437–443

[102] Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Onischi C, Armstrong D, Marshall JK, Kassam Z, Reinisch W (2015) Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149:102–109.e106

[103] Morgan XC, Tickle TL, Sokol H,Gevers D,Devaney KL, Ward DV, Reyes JA, Shah SA, LeLeiko N, Snapper SB (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13:R79

[104] Mukhopadhya I, Thomson JM, Hansen R, Berry SH, El-Omar EM,Hold GL (2011) Detection of Campylobacter concisus and other Campylobacter species in colonic biopsies from adults with ulcerative colitis. PLoS ONE 6:e21490

[105] Mylonaki M, Rayment NB, Rampton DS, Hudspith BN, Brostoff J (2005) Molecular characterization of rectal mucosa-associated bacterial flora in inflammatory bowel disease. Inflamm Bowel Dis 11:481–487

[106] Nattramilarasu PK, Bucker R, Lobo de Sa FD, Fromm A, Nagel O, Lee IM, Butkevych E, Mousavi S, Genger C, Klove S (2020) Campylobacter concisus impairs sodium absorption in colonic epithelium via ENaC dysfunction and claudin-8 disruption. Int J Mol Sci 21(2):373

[107] Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, Panaccione R, Ghosh S, Wu JCY, Chan FKL (2018) Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of populationbased studies. Lancet 390:2769–2778

[108] Ni J,Wu GD, Albenberg L, Tomov VT (2017) Gut microbiota and IBD: causation or correlation? Nat Rev Gastroenterol Hepatol 14:573–584

[109] Nishino K, Nishida A, Inoue R, Kawada Y,Ohno M, Sakai S, Inatomi O, Bamba S,Sugimoto M,Kawahara M (2018) Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease. J Gastroenterol 53:95–106

[110] Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, Kambal A, Monaco CL, Zhao G, Fleshner P (2015) Diseasespecific alterations in the enteric virome in inflammatory bowel disease. Cell 160:447–460

[111] Nougayrede JP, Homburg S,Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, Buchrieser C, Hacker J, Dobrindt U, Oswald E (2006) Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313:848–851

[112] Ohkusa T, Sato N, Ogihara T, Morita K, Ogawa M, Okayasu I(2002) Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody. J Gastroenterol Hepatol 17:849–853

[113] Ohkusa T, Okayasu I, Ogihara T, Morita K, Ogawa M, Sato N (2003) Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis. Gut 52:79–83

[114] Ohkusa T,Yoshida T, Sato N, Watanabe S, Tajiri H, Okayasu I (2009) Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis. J Med Microbiol 58:535–545

[115] Oliva S, Di Nardo G, Ferrari F,Mallardo S, Rossi P, Patrizi G, Cucchiara S, Stronati L (2012) Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis. Aliment Pharmacol Ther 35:327–334

[116] Ossa JC, Ho NK, Wine E, Leung N, Gray-Owen SD, Sherman PM (2013) Adherent-invasive Escherichia coli blocks interferongamma- induced signal transducer and activator of transcription (STAT)-1 in human intestinal epithelial cells. Cell Microbiol 15:446–457

[117] O'Toole PW, Marchesi JR, Hill C (2017) Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat Microbiol 2:17057

[118] Owen CD, Tailford LE, Monaco S, Suligoj T,Vaux L, Lallement R, Khedri Z, Yu H, Lecointe K, Walshaw J (2017) Unravelling the specificity and mechanism of sialic acid recognition by the gut symbiont Ruminococcus gnavus. Nat Commun 8:2196

[119] Palmela C,Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R,Barnich N, Ng SC, Colombel JF (2018) Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut 67:574–587

[120] Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, Leong RWL, Connor S, Ng W, Paramsothy R (2017a) Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebocontrolled trial. Lancet 389:1218–1228

[121] Paramsothy S,Paramsothy R, Rubin DT, Kamm MA, Kaakoush NO, Mitchell HM, Castano-Rodriguez N (2017b) Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis 11:1180–1199

[122] Paramsothy S, Nielsen S, Kamm MA, Deshpande NP, Faith JJ, Clemente JC, Paramsothy R, Walsh AJ, van den Bogaerde J, Samuel D (2019) Specific bacteria and metabolites associated with response to fecal microbiota transplantation in patients with ulcerative colitis. Gastroenterology 156:1440–1454. e1442

[123] Pittayanon R, Lau JT, Leontiadis GI, Tse F,Yuan Y, Surette M, Moayyedi P(2019) Differences in gut microbiota in patients with vs without inflammatory bowel diseases: a systematic review. Gastroenterology 158(4):930–946.e1

[124] Plovier H, Everard A, Druart C,Depommier C, Van Hul M, Geurts L, Chilloux J,Ottman N, Duparc T, Lichtenstein L (2017) A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 23:107–113

[125] Png CW, Linden SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, McGuckin MA, Florin TH (2010) Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 105:2420–2428

[126] Postler TS, Ghosh S(2017) Understanding the holobiont: how microbial metabolites affect human health and shape the immune system. Cell Metab 26:110–130

[127] Praveschotinunt P, Duraj-Thatte AM, Gelfat I,Bahl F, Chou DB, Joshi NS (2019) Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut. Nat Commun 10:5580

[128] Prindiville TP, Sheikh RA, Cohen SH, Tang YJ, Cantrell MC, Silva J Jr (2000) Bacteroides fragilis enterotoxin gene sequences in patients with inflammatory bowel disease. Emerg Infect Dis 6:171–174

[129] Prorok-Hamon M, Friswell MK, Alswied A, Roberts CL, Song F, Flanagan PK, Knight P,Codling C, Marchesi JR, Winstanley C (2014) Colonic mucosa-associated diffusely adherent afaC+ Escherichia coli expressing lpfA and pks are increased in inflammatory bowel disease and colon cancer. Gut 63:761–770

[130] Quevrain E,Maubert MA, Michon C,Chain F, Marquant R, Tailhades J, Miquel S, Carlier L, Bermudez-Humaran LG, Pigneur B (2016) Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut 65:415–425

[131] Ring C, Klopfleisch R, Dahlke K, Basic M, Bleich A, Blaut M (2019) Akkermansia muciniphila strain ATCC BAA-835 does not promote short-term intestinal inflammation in gnotobiotic interleukin-10-deficient mice. Gut Microbes 10:188–203

[132] Rokkas T, Gisbert JP, Niv Y,O’Morain C (2015) The association between Helicobacter pylori infection and inflammatory bowel disease based on meta-analysis. United Eur Gastroenterol J 3:539–550

[133] Rossi O, van Berkel LA, Chain F, Tanweer Khan M, Taverne N, Sokol H, Duncan SH, Flint HJ, Harmsen HJ, Langella P(2016) Faecalibacterium prausnitzii A2–165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses. Sci Rep 6:18507

[134] Round JL, Lee SM, Li J,Tran G, Jabri B, Chatila TA, Mazmanian SK (2011) The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974–977

[135] Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, Bourdin G, McCallin S, Ngom-Bru C, Neville T (2016) Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh. EBioMedicine 4:124–137

[136] Sarker SA, Berger B, Deng Y, Kieser S, Foata F, Moine D, Descombes P, Sultana S,Huq S, Bardhan PK(2017) Oral application of Escherichia coli bacteriophage: safety tests in healthy and diarrheal children from Bangladesh. Environ Microbiol 19:237–250

[137] Sassone-Corsi M, Nuccio SP, Liu H, Hernandez D,Vu CT, Takahashi AA, Edwards RA, Raffatellu M (2016) Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540:280–283

[138] Scaldaferri F, Gerardi V, Mangiola F,Lopetuso LR, Pizzoferrato M, Petito V, Papa A, Stojanovic J, Poscia A, Cammarota G (2016) Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of remission in ulcerative colitis patients: an update. World J Gastroenterol 22:5505–5511

[139] Schirmer M, Garner A, Vlamakis H, Xavier RJ (2019) Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol 17:497–511

[140] Schnadower D, Tarr PI, Casper TC, Gorelick MH, Dean JM, O'Connell KJ, Mahajan P, Levine AC, Bhatt SR, Roskind CG (2018) Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. N Engl J Med 379:2002–2014

[141] Seishima J,Iida N, Kitamura K, Yutani M, Wang Z, Seki A,Yamashita T, Sakai Y, Honda M, Yamashita T (2019) Gutderived Enterococcus faecium from ulcerative colitis patients promotes colitis in a genetically susceptible mouse host. Genome Biol 20:252

[142] Sekizuka T,Ogasawara Y, Ohkusa T,Kuroda M (2017) Characterization of Fusobacterium varium Fv113-g1 isolated from a patient with ulcerative colitis based on complete genome sequence and transcriptome analysis. PLoS ONE 12:e0189319

[143] Sepehri S,Khafipour E, Bernstein CN, Coombes BK, Pilar AV, Karmali M, Ziebell K, Krause DO (2011) Characterization of Escherichia coli isolated from gut biopsies of newly diagnosed patients with inflammatory bowel disease. Inflamm Bowel Dis 17:1451–1463

[144] Seregin SS, Golovchenko N, Schaf B, Chen J, Pudlo NA, Mitchell J, Baxter NT, Zhao L, Schloss PD, Martens EC (2017) NLRP6 protects Il10(−/−) mice from colitis by limiting colonization of Akkermansia muciniphila. Cell Rep 19:733–745

[145] Sinha SR, Haileselassie Y, Nguyen LP, Tropini C, Wang M, Becker LS, Sim D, Jarr K, Spear ET, Singh G (2020) Dysbiosisinduced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 27(4):659–670.e5

[146] Sivignon A, de Vallee A, Barnich N, Denizot J, Darcha C, Pignede G, Vandekerckove P, Darfeuille-Michaud A (2015) Saccharomyces cerevisiae CNCM I-3856 prevents colitis induced by AIEC bacteria in the transgenic mouse model mimicking Crohn’s disease. Inflamm Bowel Dis 21:276–286

[147] Sokol H, Pigneur B,Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux J-J,Blugeon S,Bridonneau C, Furet J-P, Corthier G (2008a) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 105:16731–16736

[148] Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G (2008b) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 105:16731–16736

[149] Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, Cosnes J, Corthier G, Marteau P, Dore J (2009) Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 15:1183–1189

[150] Sokol H, Leducq V, Aschard H, Pham HP, Jegou S, Landman C, Cohen D, Liguori G, Bourrier A, Nion-Larmurier I (2017) Fungal microbiota dysbiosis in IBD. Gut 66:1039–1048

[151] Song X, Sun X, Oh SF, Wu M, Zhang Y,Zheng W,Geva-Zatorsky N, Jupp R, Mathis D, Benoist C (2020) Microbial bile acid metabolites modulate gut RORgamma(+) regulatory T cell homeostasis. Nature 577:410–415

[152] Sonnenberg A, Genta RM (2012) Low prevalence of Helicobacter pylori infection among patients with inflammatory bowel disease. Aliment Pharmacol Ther 35:469–476

[153] Sonnenborn U (2016) Escherichia coli strain Nissle 1917-from bench to bedside and back: history of a special Escherichia coli strain with probiotic properties. FEMS Microbiol Lett 363(19): fnw212

[154] Tailford LE, Owen CD, Walshaw J, Crost EH, Hardy-Goddard J, Le Gall G,de Vos WM, Taylor GL, Juge N(2015) Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation. Nat Commun 6:7624

[155] Tang C, Kamiya T, Liu Y,Kadoki M, Kakuta S, Oshima K, Hattori M, Takeshita K,Kanai T, Saijo S (2015) Inhibition of Dectin-1 signaling ameliorates colitis by inducing Lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe 18:183–197

[156] Thiele Orberg E, Fan H, Tam AJ, Dejea CM, Destefano Shields CE, Wu S,Chung L, Finard BB, Wu X, Fathi P (2017) The myeloid immune signature of enterotoxigenic Bacteroides fragilisinduced murine colon tumorigenesis. Mucosal Immunol 10:421–433

[157] Tiago FC, Porto BA, Ribeiro NS, Moreira LM, Arantes RM, Vieira AT, Teixeira MM, Generoso SV, Nascimento VN, Martins FS (2015) Effect of Saccharomyces cerevisiae strain UFMG A-905 in experimental model of inflammatory bowel disease. Benef Microbes 6:807–815

[158] Underwood AP, Kaakoush NO, Sodhi N,Merif J,Seah Lee W, Riordan SM, Rawlinson WD, Mitchell HM (2016) Campylobacter concisus pathotypes are present at significant levels in patients with gastroenteritis. J Med Microbiol 65:219–226

[159] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 368:407–415

[160] Vich Vila A, Imhann F, Collij V, Jankipersadsing SA, Gurry T, Mujagic Z, Kurilshikov A,Bonder MJ, Jiang X, Tigchelaar EF (2018) Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Sci Transl Med 10(472):eaap8914

[161] Wagner J, Maksimovic J, Farries G, Sim WH, Bishop RF, Cameron DJ, Catto-Smith AG, Kirkwood CD (2013) Bacteriophages in gut samples from pediatric Crohn’s disease patients: metagenomic analysis using 454 pyrosequencing. Inflamm Bowel Dis 19:1598–1608

[162] Wang L, Tang L, Feng Y, Zhao S, Han M, Zhang C, Yuan G, Zhu J, Cao S, Wu Q (2020) A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8(+) Tcells in mice. Gut.https://doi.org/10.1136/gutjnl-2019-320105

[163] Wick EC, Rabizadeh S, Albesiano E, Wu X, Wu S, Chan J, Rhee KJ, Ortega G, Huso DL, Pardoll D (2014) Stat3 activation in murine colitis induced by enterotoxigenic Bacteroides fragilis. Inflamm Bowel Dis 20:821–834

[164] Wildt S, Nordgaard I, Hansen U, Brockmann E, Rumessen JJ (2011) A randomised double-blind placebo-controlled trial with Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp. lactis BB-12 for maintenance of remission in ulcerative colitis. J Crohns Colitis 5:115–121

[165] Williams BB, Van Benschoten AH, Cimermancic P,Donia MS, Zimmermann M, Taketani M, Ishihara A, Kashyap PC, Fraser JS, Fischbach MA (2014) Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16:495–503

[166] Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, Zheng Z, Jarnerot G, Tysk C,Jansson JK, Engstrand L (2010) A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139:1844–1854.e1841

[167] Wlodarska M, Luo C, Kolde R, d’Hennezel E, Annand JW, Heim CE, Krastel P, Schmitt EK, Omar AS, Creasey EA (2017) Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation. Cell Host Microbe 22:25–37. e26

[168] Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ, Galan C, Belkaid Y, Bonneau R, Littman DR (2018) c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554:373–377

[169] Yang I,Eibach D, Kops F, Brenneke B, Woltemate S, Schulze J, Bleich A, Gruber AD, Muthupalani S, Fox JG (2013) Intestinal microbiota composition of interleukin-10 deficient C57BL/6J mice and susceptibility to Helicobacter hepaticusinduced colitis. PLoS ONE 8:e70783

[170] Yilmaz B, Juillerat P, Oyas O, Ramon C, Bravo FD, Franc Y, Fournier N, Michetti P, Mueller C, Geuking M(2019) Microbial network disturbances in relapsing refractory Crohn’s disease. Nat Med 25:323–336

[171] Zamani S, Hesam Shariati S, Zali MR, Asadzadeh Aghdaei HSarabi Asiabar A, Bokaie SNomanpour B, Sechi LA, Feizabadi MM (2017) Detection of enterotoxigenic Bacteroides fragilis in patients with ulcerative colitis. Gut Pathog 9:53

[172] Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G,Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F (2013) Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–385

[173] Zhang L, Man SM, Day AS, Leach ST, Lemberg DA, Dutt S, Stormon M, Otley A, O’Loughlin EV, Magoffin A (2009) Detection and isolation of Campylobacter species other than C. jejuni from children with Crohn’s disease. J Clin Microbiol 47:453–455

[174] Zhang FM, Wang HG, Wang M, Cui BT, Fan ZN, Ji GZ (2013) Fecal microbiota transplantation for severe enterocolonic fistulizing Crohn’s disease. World J Gastroenterol 19:7213–7216

[175] Zhang L, Lee H, Grimm MC, Riordan SM, Day AS, Lemberg DA (2014) Campylobacter concisus and inflammatory bowel disease. World J Gastroenterol 20:1259–1267

[176] Zhu W, Winter MG, Byndloss MX, Spiga L,Duerkop BA, Hughes ER, Buttner L, de Lima Romao E, Behrendt CL, Lopez CA (2018) Precision editing of the gut microbiota ameliorates colitis. Nature 553:208–211

[177] Zhu W, Miyata N, Winter MG, Arenales A, Hughes ER, Spiga L, Kim J, Sifuentes-Dominguez L, Starokadomskyy P,Gopal P (2019) Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer. J Exp Med 216:2378–2393

[178] Zuo T, Wong SH, Cheung CP, Lam K, Lui R, Cheung K, Zhang F, Tang W, Ching JYL, Wu JCY (2018) Gut fungal dysbiosis correlates with reduced efficacy of fecal microbiota transplantation in Clostridium difficile infection. Nat Commun 9:3663

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