Background/Aim: It is now clear that intestinal microbes are involved in many aspects of inflammatory bowel diseases (IBD) and that understanding how microbes lead to disease could present novel opportunities for diagnosis and treatment. Microbes are linked to most disease-associated genetic polymorphisms and are critical mediators of environmental effects (through food, hygiene, and infection). This paper reviews recent findings and future implications for targeting microbes in IBD. Methods: A comprehensive review of the literature is presented, with specific focus on how treating microbes could alter patient care in the future. Results: Human and animal-based research supports the central role of microbes in IBD pathogenesis at multiple levels. Antibiotics, probiotics, diet, and potentially fecal transplantation are all potential treatments for IBD. Animal models of IBD only develop in the presence of microbes and co-housing mice genetically susceptible to gut inflammation with normal mice can lead to the development of bowel injury. Key papers have used microbial sequencing and metagenomics to study the role of microbes in IBD and we are now on the cusp of expanding into clinically relevant fields, such as diagnosis and therapeutics. However, many challenges still remain in understanding how microbes can be manipulated to prevent or treat disease. Conclusions: In the future, we may be able to predict risk of disease, define biological subtypes, establish tools for prevention, and even cure IBD using microbes or their products. A broad spectrum of therapeutic tools, spanning from fecal transplantation, probiotics, prebiotics, microbial products to microbe-tailored diets, may replace current IBD treatments.

Keywords:
Fecal microbial transplantation, Inflammatory bowel diseases, Intestinal microbiota, Microbiome, Treatment
1.
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Jian M, Zhou Y, Li Y, Zhang X, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Bork P, Ehrlich SD: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59-65.
2.
Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA: Diversity of the human intestinal microbial flora. Science 2005;308:1635-1638.
3.
Sartor RB: Microbial influences in inflammatory bowel diseases. Gastroenterology 2008;134:577-594.
4.
D'Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P: Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998;114:262-267.
5.
Knights D, Lassen KG, Xavier RJ: Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 2013;62:1505-1510.
6.
Peterson DA, Frank DN, Pace NR, Gordon JI: Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 2008;3:417-427.
7.
Michail S, Durbin M, Turner D, Griffiths AM, Mack DR, Hyams J, Leleiko N, Kenche H, Stolfi A, Wine E: Alterations in the gut microbiome of children with severe ulcerative colitis. Inflamm Bowel Dis 2012;18:1799-1808.
8.
Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Dore J, Antolin M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Merieux A, Melo Minardi R, M'Rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P: Enterotypes of the human gut microbiome. Nature 2011;473:174-180.
9.
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Buning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH: Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012;491:119-124.
10.
Beamish LA, Osornio-Vargas AR, Wine E: Air pollution: an environmental factor contributing to intestinal disease. J Crohns Colitis 2011;5:279-286.
11.
Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S: Host-gut microbiota metabolic interactions. Science 2012;336:1262-1267.
12.
Wu GD, Lewis JD: Analysis of the human gut microbiome and association with disease. Clin Gastroenterol Hepatol 2013;11:774-777.
13.
Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K, Ferrante M, Verhaegen J, Rutgeerts P, Vermeire S: A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2013, Epub ahead of print.
14.
Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottiere HM, Dore J, Marteau P, Seksik P, Langella P: Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 2008;105:16731-16736.
15.
Chassaing B, Koren O, Carvalho FA, Ley RE, Gewirtz AT: AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition. Gut 2013, Epub ahead of print.
16.
Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS: Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 2013;339:1084-1088.
17.
Prorok-Hamon M, Friswell MK, Alswied A, Roberts CL, Song F, Flanagan PK, Knight P, Codling C, Marchesi JR, Winstanley C, Hall N, Rhodes JM, Campbell BJ: Colonic mucosa-associated diffusely adherent afaC+ Escherichia coli expressing lpfA and pks are increased in inflammatory bowel disease and colon cancer. Gut 2013, Epub ahead of print.
18.
Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J, Kau AL, Rich SS, Concannon P, Mychaleckyj JC, Liu J, Houpt E, Li JV, Holmes E, Nicholson J, Knights D, Ursell LK, Knight R, Gordon JI: Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 2013;339:548-554.
19.
Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, Marshall JK, Talley NJ, Moayyedi P: Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011;106:661-673.
20.
Whelan K, Quigley EM: Probiotics in the management of irritable bowel syndrome and inflammatory bowel disease. Curr Opin Gastroenteroly 2013;29:184-189.
21.
Levine A, Turner D: Combined azithromycin and metronidazole therapy is effective in inducing remission in pediatric Crohn's disease. J Crohns Colitis 2011;5:222-226.
22.
D'Argenio V, Precone V, Casaburi G, Miele E, Martinelli M, Staiano A, Salvatore F, Sacchetti L: An altered gut microbiome profile in a child affected by Crohn's disease normalized after nutritional therapy. Am J Gastroenterol 2013;108:851-852.
23.
Tjellstrom B, Hogberg L, Stenhammar L, Magnusson KE, Midtvedt T, Norin E, Sundqvist T: Effect of exclusive enteral nutrition on gut microflora function in children with Crohn's disease. Scand J Gastroenterol 2012;47:1454-1459.
24.
Levine A, Wine E: Effects of enteral nutrition on Crohn's disease: clues to the impact of diet on disease pathogenesis. Inflamm Bowel Dis 2013;19:1322-1329.
25.
Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HY, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, Cheng Y, Clark MJ, Im H, Habegger L, Balasubramanian S, O'Huallachain M, Dudley JT, Hillenmeyer S, Haraksingh R, Sharon D, Euskirchen G, Lacroute P, Bettinger K, Boyle AP, Kasowski M, Grubert F, Seki S, Garcia M, Whirl-Carrillo M, Gallardo M, Blasco MA, Greenberg PL, Snyder P, Klein TE, Altman RB, Butte AJ, Ashley EA, Gerstein M, Nadeau KC, Tang H, Snyder M: Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell 2012;148:1293-1307.
26.
Larsson E, Tremaroli V, Lee YS, Koren O, Nookaew I, Fricker A, Nielsen J, Ley RE, Backhed F: Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 2012;61:1124-1131.
27.
Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TT, Vary JC, Hawn TR, Dunstan SJ, Farrar JJ, Thwaites GE, King MC, Serhan CN, Ramakrishnan L: Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 2012;148:434-446.
28.
Roca FJ, Ramakrishnan L: TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 2013;153:521-534.
29.
van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ: Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407-415.
30.
Anderson JL, Edney RJ, Whelan K: Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012;36:503-516.
31.
Kunde S, Pham A, Bonczyk S, Crumb T, Duba M, Conrad H Jr, Cloney D, Kugathasan S: Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr 2013;56:597-601.
32.
Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI: Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013;341:1241214.
33.
Bach JF: The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911-920.
34.
Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K: Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013;500:232-236.
35.
Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS: The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013;341:569-573.
36.
Wesemann DR, Portuguese AJ, Meyers RM, Gallagher MP, Cluff-Jones K, Magee JM, Panchakshari RA, Rodig SJ, Kepler TB, Alt FW: Microbial colonization influences early B-lineage development in the gut lamina propria. Nature 2013;501:112-115.
37.
Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, Wainger B, Strominger A, Muralidharan S, Horswill AR, Bubeck Wardenburg J, Hwang SW, Carroll MC, Woolf CJ: Bacteria activate sensory neurons that modulate pain and inflammation. Nature 2013;501:52-57.
38.
Devkota S, Wang Y, Musch MW, et al: Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in ll10-/-mice. Nature 2012;487:104-108.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.