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        The microbiome in inflammatory bowel disease and its modulation as a therapeutic manoeuvre
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Abstract

Inflammatory bowel disease (IBD) is increasing in incidence in both the developed and the developing world. Genetic, immunological and environmental factors are known to be involved. Genome-wide studies have examined the contribution played by host genetics in the development of IBD and have estimated that genetic factors are responsible for about 25 % of the disease risk. Having an IBD-associated genotype does not always lead to development of the disease phenotype, and hence it seems likely that environmental factors are key to triggering development of the disease in genetically susceptible individuals. The gut microbiota contains more cells than its human host, and mounting evidence attests to the importance of the microbiota in the development of several diseases, including IBD, metabolic syndrome and CVD. The present paper reviews the interplay between the microbiota and the mucosal immune system in health and in IBD; and discusses the evidence base for the use of therapeutic modulation of the microbiota to prevent and treat IBD.

A diverse community of micro-organisms inhabits the human intestine. The majority of these are bacteria, but eukaryotes, viruses and archaea are also present. Intestinal bacterial communities comprise up to 1000 different species constituting a diverse ecosystem( Reference Duerkop, Vaishnava and Hooper 1 ). It is estimated that the human microbiota contains up to 1014 bacterial cells, an order of magnitude greater than the number of human cells in our body( Reference Sekirov, Russell and Antunes 2 ). This perception of ourselves has given rise to the view of the microbiota as another organ and that we are ‘supraorganisms’ whose genome is a combination of human and microbial genes( Reference Peterson, Frank and Pace 3 ).

Our understanding of the microbiome has increased greatly with the introduction of high-throughput metagenomic processing( Reference Fraher, O'Toole and Quigley 4 ). The gut ecosystem is dominated by bacteria. More than fifty bacterial phyla have been described, although in the gut two phyla predominate: Bacteroidetes and Firmicutes. Proteobacteria and Actinobacteria are present in lesser proportions and other phyla are represented in minor extents( Reference Sekirov, Russell and Antunes 2 ). Significant differences exist between the magnitude and composition of bacteria both longitudinally from stomach to colon as well as laterally from the mucosal mucus layer to the intestinal lumen. Many species present in the intestinal lumen do not access the mucus layer and epithelial crypts( Reference Swidsinski, Loening-Baucke and Lochs 5 ).

Much of our knowledge of gut microbiota function is derived from studies of germ-free animals. These demonstrate that the commensal microbiota modulates nutrient absorption, mucosal barrier function, angiogenesis and intestinal maturation( Reference Hooper, Wong and Thelin 6 ). The mucosal immune system is required to be simultaneously tolerant of the microbiota while still able to prevent its overgrowth and translocation to systemic sites as well as able to respond appropriately to pathogens. This has led to the development of a finely tuned homoeostasis between the huge microbial load of the intestine and the host immune system.

The microbiota–mucosal immunity interface

The intestinal microbiota is protective against invasion by pathogens. Gut microbiota provide the host with a physical barrier against incoming pathogens by competitive exclusion such as: occupation of adherance sites; competitive consumption of nutrients; and stimulation of host production of antimicrobial substances( Reference Duerkop, Vaishnava and Hooper 1 , Reference Hooper, Wong and Thelin 6 ). The commensal microbiota enhance epithelial repair and cross-talk between components of the innate immune responses.

At the same time the intestinal immune system has developed a number of strategies to preserve ignorance as well as tolerance of the commensal microbiota. The inner layer of mucus secreted by goblet cells is resistant to bacterial penetration whereas the outer layer is colonised with bacteria( Reference Fraher, O'Toole and Quigley 4 ). The epithelial layer is bound together by tight junction proteins which allow nutrient flux into tissues whilst preventing bacterial penetration. Epithelial cells also produce a number of antimicrobial peptides including the cathelicidin, defensin and histatin classes( Reference Garrett, Lord and Punit 7 ). IgA-producing B cells secrete bacteria-specific IgA which is transcytosed to the apical layer of the epithelium, confining bacteria to the mucus layer( Reference Peterson, Frank and Pace 3 ). Symbiotic bacteria that do breach the mucosa are rapidly phagocytosed and killed by macrophages in contrast to pathogens which may actively interfere with macrophage function( Reference Garrett, Lord and Punit 7 ). Dendritic cells sample penetrating and apical bacteria and then present the sample to B and T cells which, in turn, direct appropriate immune responses, being either tolerance or inflammatory( Reference Garrett, Lord and Punit 7 ). Innate IL-22 producing lymphoid cells are also essential for the containment of lymphoid resident bacteria to the intestine, preventing their spread to systemic sites( Reference Garrett, Lord and Punit 7 ). Animal studies have revealed an immune-driven dysbiosis demonstrating the control the immune system exerts on the structure of the intestinal microbiota( Reference Garrett, Lord and Punit 7 ). Furthermore, human subjects with genetic polymorphism coding for immune components have an altered microbiota when compared with controls with wild-type alleles( Reference Biswas and Kobayashi 8 , Reference Secher, Normand and Chamaillard 9 ).

Despite advances in our understanding of the microbiota and host–microbiota relationships, much of the detail regarding structure and function of the microbiota are as yet unknown. The human microbiome project was established to enable comprehensive characterisation of the human microbiota and its role in health and disease. In the coming years, our knowledge of the microbiota will significantly expand. With the application of molecular techniques to the study of gut microbiology, mounting evidence is emerging regarding the relationship between dysbiosis of the human gut microbiota and a number of gastrointestinal diseases as well as diseases beyond the gut, including obesity and metabolic syndrome( Reference Peterson, Frank and Pace 3 , Reference Vrieze, Holleman and Zoetendal 10 ).

Dysbiosis in inflammatory bowel diseases

Inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis and pouchitis) are considered to be due to an inappropriate immune response to the intestinal microbiota. Genome-wide association studies have identified genes contributing to susceptibility to Crohn's disease and ulcerative colitis. Many of these susceptibility loci play a role in immune responses to microbial signalling and processing( Reference Xavier and Podolsky 11 ) as well as epithelial barrier integrity( Reference Barrett, Lee and Lees 12 , Reference Anderson, Boucher and Lees 13 ). Germ-free animal models of colitis indicate that the microbiota drives inflammation in genetically susceptible hosts( Reference Sartor 14 ). Knockout mouse models of colitis have also shown a transferrable colitogenic microbiota to wild-type mice( Reference Biswas and Kobayashi 8 ). Clinical evidence also points towards the microbiota-driving inflammation. Faecal diversion ameliorates inflammation in Crohn's disease while reintroduction of the ileal contents to the diverted bowel induces inflammation( Reference D'Haens, Geboes and Peeters 15 ). Pouchitis only occurs following closure of the ileostomy when the pouch is exposed to significantly higher concentrations of bacteria.

A number of theories exist regarding the role of the microbiota in IBD. These range from abnormalities of single organisms to a dysbiosis of the overall composition and diversity of the microbiota, to functional shifts in the microbiota. Mycobacterium avium ssp. paratuberculosis has long been associated with Crohn's disease; however, a blinded study showed no difference in the rate of culture recovery by two independent laboratories( Reference Sartor 14 , Reference Sartor, Blumberg and Braun 16 ) and clinical trials failed to show sustained response in Crohn's disease patients treated with combination antituberculous therapy( Reference Selby, Pavli and Crotty 17 ). Other investigators have demonstrated an increased persistence of adherent/invasive Escherichia coli in ileal Crohn's disease( Reference Darfeuille-Michaud, Boudeau and Bulois 18 ). Others suggest a reduction in protective species of bacteria such as Faecalibacterium prausnitzii ( Reference Sokol, Seksik and Furet 19 ). Molecular analyses suggest that the overall composition and diversity of the micriobiota is altered in IBD. More recent studies have assessed the functional metabolic outcomes of disease associated dysbiosis. These demonstrate alterations in bacterial carbohydrate metabolism, bacterial–host interactions, as well as human host-secreted enzymes. However, it remains uncertain as to whether any of these changes are primary or secondary events( Reference Erickson, Cantarel and Lamendella 20 ).

Modulating the microbiota to prevent and treat disease

The composition of the gut microbiota is determined by many interplaying factors including age, geographical location, host genetics, host immunity, diet and smoking status. Since it is widely accepted that IBD is driven by dysbiosis in genetically susceptible individuals, this list offers a number of potential opportunities to modify the microbiota and prevent or ameliorate the disease.

Moderating neonatal risk

A neonate is born with an immature microbiota which receives early modulation during birth and with feeding. The mode of delivery determines the makeup of the early microbiota, with Caesarean section delivered babies colonised with skin flora, and vaginally delivered babies colonised with bacteria from the birth canal( Reference Dominguez-Bello, Costello and Contreras 21 ). There is some evidence that Caesarean section is a risk factor for developing IBD( Reference Bager, Simonsen and Nielsen 22 ). Similarly, breast milk and formula feed will lead to establishment of differing microbiota profiles( Reference Cabrera-Rubio, Collado and Laitinen 23 ). There are conflicting data regarding whether breast-feeding is protective against IBD( Reference Khalili, Ananthakrishnan and Higuchi 24 , Reference Spooren, Pierik and Zeegers 25 ).

Diet and nutrition

Nutrition is vital in the management of adult and paediatric IBD, and modulates the microbiota, but its role in the development of the disease is still to be clarified( Reference Spooren, Pierik and Zeegers 25 ). Patients are prone to malnutrition for a number of reasons: intestinal malabsorption, post-surgical short gut length, strictured bowel lumen and food avoidance behaviour due to meal-related symptoms. Thus patients are routinely monitored from a nutritional viewpoint, and receive supplementary nutrition when required. Nutritional status determines key outcomes including surgical recovery rates. In the paediatric population, diet may be the only treatment required. Elemental and polymeric diets may be successful in not only healing the intestinal mucosa but also in achieving and maintaining remission in IBD( Reference Navas López, Blasco Alonso and Sierra Salinas 26 , Reference Akobeng and Thomas 27 ). In the adult population, a low-fibre diet is often employed to prevent obstruction of a narrowed lumen. The association between specific dietary components and IBD has been researched, but the data are frequently conflicting. Butyrate, a SCFA, is derived from microbial fermentation of dietary starches. It is the major energy source for colonocytes and both butyrate and butyrate producing bacteria have been shown to be deficient in the inflamed colon( Reference Thibault, Blachier and Darcy-Vrillon 28 Reference Marchesi, Holmes and Khan 30 ). Butyrate enemas, although not in common clinical use, have been used as a therapy in IBD, highlighting the importance of the microbiota( Reference Vieira, Leonel and Sad 31 ). Other studied nutrients include n 3 and n 6 fatty acids( Reference Farrukh and Mayberry 32 , Reference Yates, Calder and Ed Rainger 33 ) and vitamin D( Reference Mouli and Ananthakrishnan 34 ).

Antibiotics

The use of antibiotics to target the microbiota is well established in the management of IBD. Antibiotics, including metronidazole, are effective in prevention of post-operative recurrence of Crohn's disease( Reference D'Haens, Vermeire and Van Assche 35 , Reference Prantera, Lochs and Grimaldi 36 ) and antibiotics such as metronidazole, ciprofloxacin and rifaxamin are the mainstay of treatment for acute and chronic pouchitis( Reference Holubar, Cima and Sandborn 37 ).

Probiotics

Probiotics are generally considered to be safe, and do have some proven clinical therapeutic uses in IBD. They reduce the risk of disease onset( Reference Gionchetti, Rizzello and Helwig 38 ) and maintain disease remission( Reference Mimura, Rizzello and Helwig 39 ) in pouchitis. E. coli Nissle 1917 has similar efficacy to 5-aminosalicylic acid therapy in the maintenance of remission in ulcerative colitis( Reference Kruis, Schütz and Fric 40 ) and some studies suggest VSL#3 to be effective in the treatment of active mild-to-moderate ulcerative colitis( Reference Sood, Midha and Makharia 41 ). There is little evidence for the use of probiotics in Crohn's disease, however, possibly due to the smaller microbial load in the small bowel as compared with the colon( Reference Bourreille, Cadiot and Le Dreau 42 Reference Van Gossum, Dewit and Louis 45 ). One confounding factor of the probiotic approach is the comparatively low number and diversity of bacterial species available in a typical commercial probiotic in comparison with the gut microbiota. The commercially available products usually contain at least three orders of magnitude fewer bacteria than the microbiome which they are attempting to modify; for example a patient would need to take 1000 VSL#3 capsules to ingest a microbial load equivalent to the gut microbiota( Reference Sekirov, Russell and Antunes 2 ). Furthermore, probiotic bacterial strains may not be able to compete against the complex interactions of an established and adapted indigenous gut microbial community. The diversity of probiotic products on offer renders most meta-analyses irrelevant, as each trial should only be compared with trials studying the same species or combination of species.

Prebiotics

Prebiotics are non-digestible dietary components which promote the growth of beneficial gut micro-organisms. Fructo-oligosaccharides have been postulated to have a beneficial effect in active Crohn's disease, but initial trial success( Reference Lindsay, Whelan and Stagg 46 ) has not been reproduced in larger subsequent studies( Reference Benjamin, Hedin and Koutsoumpas 47 , Reference Joossens, De Preter and Ballet 48 ).

Faecal microbiota transplantation

The concept of transplantation of the whole gut microbiota has been described in ruminants for some time( Reference Rager, George and House 49 ). Use as therapy in human subjects was first reported by Eisemen et al. in 1958 in the treatment of fulminant pseudomembranous enterocolitis( Reference Eiseman, Silen and Bascom 50 ). Over the subsequent decades, there have been an increasing number of case reports and case series of the potential therapeutic uses of faecal transplantation not only for Clostridium difficile infection( Reference Van Nood, Vrieze and Nieuwdorp 51 ) but also for constipation, irritable bowel syndrome and IBD( Reference Borody and Khoruts 52 ). There also seems to be potential for faecal transplantation in the treatment of diseases beyond the gut such as metabolic syndrome( Reference Vrieze, Van Nood and Holleman 53 , Reference Kassam, Lee, Yuan and Hunt 54 ). The first randomised controlled trial of faecal transplantation for recurrent C. difficile demonstrated 94 % remission at 10 weeks following duodenal infusion of donor faeces( Reference Wong, de Souza and Kendall 29 ). Studies have shown a significant and durable change in the microbiota following faecal transplantation( Reference Grehan, Borody and Leis 55 ). In a mouse model of pseudomembranous colitis)( Reference Lawley, Clare and Walker 56 ) suppression of C. difficile following faecal transplantation was associated with a change of the recipients’ microbiota to a composition similar to that of the healthy input bacterial community and this was closely linked to a rapid increase in species diversity( Reference Lawley, Clare and Walker 56 ). There are case reports of the use of faecal microbiota transplantation in IBD, but currently there are no published randomised controlled data for faecal microbiota transplantation in IBD.

Faecal transplantation, a therapy used for more than half a century, could hold great promise as a future treatment in the many diseases where dysbiosis of the gut microbiota contributes to disease. While it appears that in the short-term this therapy is safe, there remains concern regarding the long-term health risks that may be posed by faecal transplantation.

Conclusions

Our understanding of the role of dysbiosis in the aetiology of many diseases is increasing, but is currently limited. The prospect of ‘mining the microbiota’ for novel therapies and to enhance the efficacy of present drug therapies is also a tantalising prospect for the future. The gut microbiota offers a vast undiscovered ecosystem with a wealth of potential opportunities for the treatment of intestinal and systemic diseases( Reference Shanahan 57 ). Enhanced knowledge and understanding of the gut microbiota as an ecosystem of importance comparable with other vital organs will likely lead to greater opportunities for the treatment of IBD, other intestinal disorders and diseases beyond the gut in the near future.

Financial Support

None.

Conflicts of Interest

None.

Authorship

A. L. Hart and P. Hendy co-wrote the paper.

References

1. Duerkop, BA, Vaishnava, S & Hooper, LV (2009) Immune responses to the microbiota at the intestinal mucosal surface. Immunity 31(3), 368376.
2. Sekirov, I, Russell, SL, Antunes, LCM et al. (2010) Gut microbiota in health and disease. Physiol Rev 90, 859904.
3. Peterson, DA, Frank, DN, Pace, NR et al. (2008) Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 3, 417427.
4. Fraher, MH, O'Toole, PW & Quigley, EMM (2012) Techniques used to characterize the gut microbiota: a guide for the clinician. Nat Rev Gastroenterol Hepatol 9, 312322.
5. Swidsinski, A, Loening-Baucke, V, Lochs, H et al. (2005) Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J Gastroenterol 11, 1131–140.
6. Hooper, LV, Wong, MH, Thelin, A et al. (2001) Molecular analysis of commensal host–microbial relationships in the intestine. Science 291(5505), 881884.
7. Garrett, WS, Lord, GM, Punit, S et al. (2007) Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 3345.
8. Biswas, A & Kobayashi, KS (2013) Regulation of intestinal microbiota by the NLR protein family. Int Immunol 25, 207214.
9. Secher, T, Normand, S & Chamaillard, M (2014) NOD2 prevents emergence of disease-predisposing microbiota. Gut Microbes 4, 353–336.
10. Vrieze, A, Holleman, F, Zoetendal, EG et al. (2010) The environment within: how gut microbiota may influence metabolism and body composition. Diabetologia 53, 606613.
11. Xavier, RJ & Podolsky, DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427434.
12. Barrett, JC, Lee, JC, Lees, CW et al. (2009) Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 41, 13301334.
13. Anderson, CA, Boucher, G, Lees, CW et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43, 246252.
14. Sartor, RB (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577594.
15. D'Haens, GR, Geboes, K, Peeters, M et al. (1998) Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114, 262267.
16. Sartor, RB, Blumberg, RS, Braun, J et al. (2007) CCFA microbial–host interactions workshop: highlights and key observations. Inflamm Bowel Dis 13, 600619.
17. Selby, W, Pavli, P, Crotty, B et al. (2007) Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology 132, 23132319.
18. Darfeuille-Michaud, A, Boudeau, J, Bulois, P et al. (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 127, 412421.
19. Sokol, H, Seksik, P, Furet, JP et al. (2009) Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 15, 11831189.
20. Erickson, AR, Cantarel, BL, Lamendella, R et al. (2012) Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease. PLoS ONE 7, e49138.
21. Dominguez-Bello, MG, Costello, EK, Contreras, M et al. (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 107, 1197111975.
22. Bager, P, Simonsen, J, Nielsen, NM et al. (2012) Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study. Inflamm Bowel Dis 18, 857862.
23. Cabrera-Rubio, R, Collado, MC, Laitinen, K et al. (2012) The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am J Clin Nutr 96, 544551.
24. Khalili, H, Ananthakrishnan, AN, Higuchi, LM et al. (2013) Early life factors and risk of inflammatory bowel disease in adulthood. Inflamm Bowel Dis 19, 542547.
25. Spooren, CEGM, Pierik, MJ, Zeegers, MP et al. (2013) Review article: the association of diet with onset and relapse in patients with inflammatory bowel disease. Aliment Pharmacol Ther 38, 11721187.
26. Navas López, VM, Blasco Alonso, J, Sierra Salinas, C et al. (2008) Efficacy of exclusive enteral feeding as primary therapy for paediatric Crohn's disease. An Pediatr (Barc) 69, 506514.
27. Akobeng, AK & Thomas, AG (2007) Enteral nutrition for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev, CD005984.
28. Thibault, R, Blachier, F, Darcy-Vrillon, B et al. (2010) Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis 16, 684695.
29. Wong, JMW, de Souza, R, Kendall, CWC et al. (2006) Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 40, 235243.
30. Marchesi, JR, Holmes, E, Khan, F et al. (2007) Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J Proteome Res 6, 546551.
31. Vieira, ELM, Leonel, AJ, Sad, AP et al. (2012) Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. J Nutr Biochem 23, 430436.
32. Farrukh, A & Mayberry, JF (2014) Is there a role for fish oil in inflammatory bowel disease? World J Clin Cases 2, 250252.
33. Yates, CM, Calder, PC & Ed Rainger, G (2014) Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol Ther 141, 272282.
34. Mouli, VP & Ananthakrishnan, AN (2014) Review article: vitamin D and inflammatory bowel diseases. Aliment Pharmacol Ther 39, 125136.
35. D'Haens, GR, Vermeire, S, Van Assche, G et al. (2008) Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn's disease: a controlled randomized trial. Gastroenterology 135, 11231129.
36. Prantera, C, Lochs, H, Grimaldi, M et al. (2012) Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn's disease. Gastroenterology 142, 473481. e4.
37. Holubar, SD, Cima, RR, Sandborn, WJ et al. (2010) Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev, CD001176.
38. Gionchetti, P, Rizzello, F, Helwig, U et al. (2003) Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 124, 12021209.
39. Mimura, T, Rizzello, F, Helwig, U et al. (2004) Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 53, 108114.
40. Kruis, W, Schütz, E, Fric, P et al. (1997) Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 11, 853858.
41. Sood, A, Midha, V, Makharia, GK et al. (2009) The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol 7, 12021209.e1.
42. Bourreille, A, Cadiot, G, Le Dreau, G et al. (2013) Saccharomyces boulardii does not prevent relapse of Crohn's disease. Clin Gastroenterol Hepatol 11, 982987.
43. Shen, J, Ran, HZ, Yin, MH et al. (2009) Meta-analysis: the effect and adverse events of Lactobacilli versus placebo in maintenance therapy for Crohn disease. Intern Med J 39, 103109.
44. Rahimi, R, Nikfar, S, Rahimi, F et al. (2008) A meta-analysis on the efficacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohn's disease. Dig Dis Sci 53, 25242531. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18270836.
45. Van Gossum, A, Dewit, O, Louis, E et al. (2007) Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1) on early endoscopic recurrence of Crohn's disease after lleo-caecal resection. Inflamm Bowel Dis 13, 135142.
46. Lindsay, JO, Whelan, K, Stagg, AJ et al. (2006) Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with Crohn's disease. Gut 55, 348355.
47. Benjamin, JL, Hedin, CRH, Koutsoumpas, A et al. (2011) Randomised, double-blind, placebo-controlled trial of fructo-oligosaccharides in active Crohn's disease. Gut 60, 923929.
48. Joossens, M, De Preter, V, Ballet, V et al. (2012) Effect of oligofructose-enriched inulin (OF-IN) on bacterial composition and disease activity of patients with Crohn's disease: results from a double-blinded randomised controlled trial. Gut 61, 958.
49. Rager, KD, George, LW, House, JK et al. (2004) Evaluation of rumen transfaunation after surgical correction of left-sided displacement of the abomasum in cows. J Am Vet Med Assoc 225, 915920.
50. Eiseman, B, Silen, W, Bascom, GS et al. (1958) Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44, 854859.
51. Van Nood, E, Vrieze, A, Nieuwdorp, M et al. (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile . N Engl J Med 368, 407415.
52. Borody, TJ & Khoruts, A (2012) Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 9, 8896.
53. Vrieze, A, Van Nood, E, Holleman, F et al. (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913916. e7.
54. Kassam, Z, Lee, CH, Yuan, Y & Hunt, RH (2013) Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 108, 500508.
55. Grehan, MJ, Borody, TJ, Leis, SM et al. (2010) Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol 44, 551561.
56. Lawley, TD, Clare, S, Walker, AW et al. (2012) Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog 8, e1002995.
57. Shanahan, F (2009) Therapeutic implications of manipulating and mining the microbiota. J Physiol 587, Pt 17, 41754179.