Systematic Review: Ileoanal pouch microbiota in health and disease

Authors: Jonathan P Segal, Siddhartha Oke, Georgina L Hold, Susan K Clark, Omar D Faiz, Ailsa L Hart

Jonathan P Segal (BSc) (Hons) MBChB (1,2)

Research fellow in Gastroenterology

Siddhartha Oke BSc (Hons) MBBS (1,2)

Research fellow in Gastroenterology

Georgina L Hold BSc (Hons) PhD (3)

Professor in Gastrointestinal Health

Omar D Faiz BSc (Hons) MBBS FRCS (GenSurg) MS (1,2)

Consultant Colorectal Surgeon and Honorary Senior Lecturer

Susan K Clark MA MB BChir MD FRCS (GenSurg) (1,2)

Consultant Colorectal Surgeon, Adjunct Professor

Ailsa L Hart BA (Hons) BMBCh FRCP PhD (1,2)

Consultant Gastroenterologist, Professor of Practice

1. St Mark’s Hospital, Harrow, United Kingdom

2. Department of Surgery and Cancer, Imperial College, London, United Kingdom

3. St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia.

Keywords: Microbiota; Ileoanal pouch; IPAA; dysbiosis; pouchitis; ulcerative colitis

Author for Correspondence:

Jonathan Segal

St Mark’s Hospital

Watford Road

Harrow

HA1 3UJ

Jonathansegal1@nhs.net

Abstract word count: 249

Main text word count: 3612

References: 1548

Tables:8

Figures: 1

Disclosures: none of the authors have any relevant disclosures.

Guarantor of the Article: Ailsa Hart

Author Contributions: JPS, SO reviewed the literature and prepared the manuscript. JPS, SO, GLH, ALH, SKC, and ODF have revised the manuscript critically and prepared the final version of the manuscript. All authors approved the final draft prior to submission.

Abstract

Background

The resident gut microbiota is essential for physiological processes; the disturbance of its balance is linked to intestinal inflammation. The ileoanal pouch is a model for the study of intestinal inflammation, as inflammation of the pouch is common and mostly develops within 12 months following ileostomy closure. This allows the longitudinal study of the microbiota, giving insight into the microbiota changes during transition from a normal to an inflamed pouch.

Aim

To explore the literature on the microbiota of the ileoanal pouch in health and disease.

Methods

A systematic computer search of the on-line bibliographic databases MEDLINE and EMBASE was performed between 1966 and February 2017. Randomised controlled trials, cohort studies and observational studies were included. Studies were included if they reported microbiota analysis on faecal samples or tissue from the ileoanal pouch.

Results

Twenty-six papers were eligible. Following ileostomy closure, anaerobic bacteria are the abundant species in the ileoanal pouch with presence of a diverse microbiota key to maintaining a healthy ileoanal pouch. Acute pouchitis is associated with an increase in Clostridia species, while chronic pouchitis is associated with an increase in Staphylococcus aureus. In the treatment of pouchitis, a decrease in Clostridia species appears to be associated with treatment response.

Conclusion

The microbiota plays an important role in both the inflamed and the healthy ileoanal pouch. A direct causal relationship between individual microbiota changes and inflammation has not yet been established, but manipulation of the ileoanal pouch microbiota may be a novel therapeutic avenue to explore.

Introduction

The resident gut microbiota is essential for a number of host physiological processes. These include digestion of dietary factors, development of the gut immune system and resistance to colonisation by pathogens1. The human gut microbiome is made up predominately of four major bacterial phyla: Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria2,3. Changes in, or imbalances of these are termed dysbiosis. Dysbiosis is linked to intestinal inflammation4, with a decrease in bacterial diversity, or richness, being the most consistent finding in relation to disease activity 5–8. Specifically, key changes have been identified in inflammatory bowel disease (IBD) such as a reduction in beneficial bacterial species including Faecalibacterium prausnitzii9 and increases in more pathogenic species including members of Enterobacteriaceae10,11. Furthermore, studies have shown that in patients with IBD, the microbiota is different from healthy controls longitudinally and across all IBD subtypes12. Currently it is not understood if dysbiosis is the cause of, or the result of, intestinal inflammation.

IBD can develop at any age but tends to occur in the majority of patients within the first two decades of life13,14. It is difficult to assess changes in the microbiota prior to the development of IBD, as currently we are unable to predict those individuals who will develop the disease. To help understand the underlying aetiology of inflammation, it may therefore be beneficial to use a model to study the evolution of the microbiota over time.

Restorative proctocolectomy with ileal pouch-anal anastomosis is performed in patients with ulcerative colitis (UC) refractory to medical therapy. This approach is popular amongst patients, since it restores intestinal continuity and avoids the need for a permanent ileostomy. The ileoanal pouch is a potential model to study pathogenesis of inflammation as pouchitis is common; moreover 40% of those that develop pouchitis do so within 12 months15. The relatively short time from ileoanal pouch formation to inflammation allows the convenient longitudinal study of the microbiota which gives insight into potential patterns occurring both in disease and non-diseased states. Interestingly, inflammation within the ileoanal pouch is rarely seen in patients who have the same operation for familial adenomatous polyposis (FAP)16,17, thus raising the possibility that pouchitis shares a similar pathogenesis to the inflammation that is seen in UC18.

The role of the microbiota has been suggested to contribute to the pathogenesis of pouchitis19, although its exact aetiology remains unclear. Novel laboratory techniques including next generation sequencing have transformed our understanding of the gut microbiota20 although the exact bacterial taxonomical shifts in the ileoanal pouch have been difficult to interpret due to the heterogeneity in study designs, sampling techniques and analysis. This systematic review will explore the literature on the microbiota of the ileoanal pouch both longitudinally and in health and disease.

Methods

Types of studies

Randomised controlled trials, cohort studies and observational studies were included. Studies which reported duplicate results were excluded. Those where data could not be extracted were also excluded.

Inclusion criteria

Studies were included if they reported microbiota analysis on either faecal samples or tissue from the ileoanal pouch, and provided information on specific bacterial taxa.

Exclusion criteria

Studies were excluded if they did not report on patterns of individual bacterial taxa differences in the ileoanal pouch or if they reported on the microbiota of Crohn’s disease or UC without any data on ileoanal pouch patients. We also excluded case reports and studies of fewer than ten patients.

Search methods for identification of studies

A search of the on-line bibliographic databases MEDLINE and EMBASE was carried out by two independent researchers (JPS and SO) to identify articles published between 1966 and February 2017. The following Medical Subject Heading (MeSH) terms were used, which included both the root term and text words; ulcerative colitis, inflammatory bowel disease, IBD, idiopathic proctocolitis, gastrointestinal microbiome, bacteria, microbiota, microbiome, dysbiosis, bacteriotherapy, pouchitis, restorative proctocolectomy, ileitis. Synonyms and word variations were combined using the AND and OR function. Manual searches of the reference list from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Abstracts from conferences of the American Gastroenterological Association, American Society of Colon and Rectal Surgeons, European Crohn’s and Colitis Organisation, United European Gastroenterology and the British Society of Gastroenterology from 1965-2017 were also manually searched in order to identify unpublished studies.

Grading of studies

The GRADE system was used to assess quality of the studies21. Two independent reviewers (JPS and SO) assessed each study against GRADE standards and assigned a quality of evidence score of very low, low, moderate and high. Any disagreement was then solved by discussion and consensus.

Results

The search strategy found 844 references that were imported for screening. Five duplicates were removed. We screened 839 studies against title and abstract and from this excluded 753 studies. Eighty-six studies were assessed for full-text eligibility. Of these, 61 studies were excluded; 39 because of study design that did not fulfil the inclusion criteria (20 were review articles, 19 were abstracts containing less than 10 subjects), 20 did not report the required outcomes (10 did not report on individual taxa, three reported on bacterial metabolites, three reported on genetic changes, two described endoscopic outcomes, one reported immunological changes and one described tissue sampling techniques), one did not address the required patient population and one was not in English. After full screening, 25 studies were included. Manual reference searching identified a further paper, meaning there was a total of 26 papers included in the analysis.

Figure 1: Prisma diagram

Microbiota pre-pouch formation vs pouch (Table 1a and 1b)

There were reported differences in the microbiota prior to undergoing the first stage of an ileoanal pouch operation (colectomy) between UC patients and FAP patients with lower bacterial diversity seen in mucosal samples in the colon prior to colectomy in UC patients compared with FAP patients22. Smith et al23 compared faeces from ileostomies in patients with UC and FAP prior to ileostomy closure and found there were significantly lower levels of Clostridium perfringens detected in the UC group23 . As colonic bacteria are predominately anaerobic, it would be expected that anaerobic bacteria would be present in patients prior to colectomy. Various studies have supported this highlighting that anaerobes mostly predominate in faecal samples pre-colectomy 24. Specifically, Almeida et al25 found that Veillonella was the most prevalent bacterial species in mucus from the terminal ileum, colonic segments and rectum25 from patients with UC. The authors suggest that the ongoing presence of Veillonella species in patients with UC may be associated with a persistently aberrant intestinal microbiota even in the presence of inflammation25. This study further characterised the differences in faecal microbiota across different colonic locations and found that both Klebsiella and Lactobacillus species were exclusive to a formed pouch and are not present pre-colectomy25. Further comparisons of faecal samples between a UC pouch and a UC ileostomy showed higher numbers of Bacteroides spp., Bifidobacteria spp. 24 and Enterococci spp. 23 in the UC pouch.

Table 1a: Microbiota pre-pouch formation: Ileostomy vs pouch

Table 1b: Microbiota pre-pouch formation: Pre-colectomy vs pouch

Summary: Microbiota pre-pouch formation vs pouch

Colonic bacteria are found in the ileostomy and continue to predominate in the ileoanal pouch. Following ileostomy closure, anaerobic bacteria appear to be more prevalent in the ileoanal pouch.

Microbiota in the UC pouch: Non-inflamed or “healthy” vs inflamed (Table 2)

A non-inflamed or healthy UC ileoanal pouch has been characterised as having a higher bacterial diversity (richness) then an inflamed ileoanal pouch27. When biopsies were compared between healthy UC ileoanal pouches and pouchitis, Bacteroides spp.28, Clostridia spp.28,29, enterics such as E. coli, Ruminoccoccus gnavus, Shigella and Streptococcus spp.29 were shown to be positively associated with a healthy ileoanal pouch. Another study, however, highlighted that Clostridium spp., Eubacterium spp., Roseburia spp., Escherichia spp., Streptococcus spp. and various sulphur-oxidising bacteria 30 were reduced in biopsies from a healthy ileoanal pouch.

Table 2: Microbiota in the UC pouch: Non-inflamed or “healthy” vs inflamed

Summary: Microbiota in the UC pouch: Non-inflamed or “healthy” vs inflamed

Bacterial diversity is important in maintaining a healthy ileoanal pouch with changes in Firmicutes and Bacteroidetes likely to play an important role in influencing a dysbiosis leading to disease.

Ileoanal pouch for ulcerative colitis vs Familial Adenomatous Polyposis (Table 3)

Smith et al23 made comparison between faecal samples from ileoanal pouches formed for FAP and UC, it was found that anaerobic bacteria predominated in the UC ileoanal pouch23. Duffy et al31 found significant decreases in aerobic bacteria in faeces when comparing a UC ileoanal pouch with an FAP ileoanal pouch including Lactobacilli spp.; another study highlighted decreases in Clostridium perfringens, Bacteroidetes and Bifidobacterium spp.31. On a phyla level, ileoanal pouch biopsies showed Bacteroidetes belonging to Bacteroidaceae and Prevotellaceae 27 and Firmicutes belonging to Ruminococcaceae 27 were lower in UC. Biopsy samples showed higher levels of Proteobacteria belonging to Comamonadaceae, Moraxellaceae and Alcaligenaceae27. Faecal samples showed higher levels of Enterococcaceae and Clostridia spp.23.

Table 3: Microbiota in UC vs FAP pouch

Summary: Microbiota in UC vs FAP pouch

Consistent findings in an un-inflamed UC ileoanal pouch compared with an un-inflamed FAP pouch include higher levels of Proteobacteria and lower levels of Bacteroidetes.

Microbiota in acute pouchitis (Table 4)

Similarly to IBD, bacterial diversity has been shown to be reduced in patients with pouchitis25,32–35 with changes in both anaerobic and aerobic bacteria noted36. Analysis of faecal samples has shown higher levels of aerobes and lower levels of anaerobes in patients with pouchitis when compared with controls without pouchitis (both UC and FAP)34,37.

Specifically, faecal samples30,34,38–41 and biopsy samples27,29,32,42 showed Bacteroidetes30,32,38,42, Enterococcaceae40,42, Lachnospiraceae38,39, Faecalibacterium spp. 39, Ruminococcaceae ,Streptococci spp. 27,29, Alcaligenaceae27 and Bifidobacterium spp. 38,41 were reduced in patients with pouchitis, whereas Enterobacteriaceae27, including E.coli 2734 Fusobacterium29 and Clostridia spp. 30,34,41 were increased in patients with pouchitis39. One study highlighted specific increases in Prevotella spp., Akkermansia spp., Firmicutes and Verrucomicrobia when comparing biopsy samples in acute pouchitis with FAP controls30. One study highlighted bacterial species that were exclusively found in pouchitis, including Pseudoalteromonas spp., Desulfosporosinus spp., Microcystis spp. and Methylobacter spp. 40. It is important to highlight that Microcystis is a genus of Cyanobacteria, which is likely to have been introduced to the ileoanal pouch via the subject's diet and in bioformatic studies are often removed. Furthermore, Methylobacter, Pseudoaltermonas and Desulfosporosinus are not usual commensals of the ileoanal pouch and are found in soil and water43 and therefore must be interpreted with caution.

Table 4: Microbiota in acute pouchitis

Summary: Microbiota in acute pouchitis

In acute pouchitis overall bacterial diversity is reduced. The consistent finding in acute pouchitis across studies is an increase in Clostridium species with more robust studies demonstrating a decrease in Enterococcaceae.

Chronic pouchitis (Table 5)

Chronic pouchitis defined by the Heidelberg pouchitis activity score44 or the need for long term medications to control symptoms45,46 was associated with a significantly higher numbers of Staphylococcus aureus in faecal cultures and it has been suggested that this may be a responsible pathogen for chronic pouchitis44. Furthermore, faecal cultures have shown Enterococcus spp. 45, Faecalibacterium prausnitzii 46, Clostridium spp., Ruminococcus spp., Eubacterium spp., Lachnospiraceae and Insertae Sedis XIV are found in significantly lower numbers in chronic pouchitis patients46. Komanduri et al,29 compared biopsies between an inflamed and non-inflamed pouch, they found reductions in both Streptococcus spp. and Clostridium spp. in chronic pouchitis29.

Table 5: Microbiota in chronic pouchitis

Summary: Microbiota in chronic pouchitis

Chronic pouchitis has been linked with an increase Staphylococcus aureus. In comparison with acute pouchitis, reductions in Clostridium species are a consistent finding in chronic pouchitis. As has been seen in ileal Crohn’s disease, Faecalibacterium prausnitzii is reduced in chronic pouchitis.

Longitudinal changes in microbiota in the pouch (Table 6)

The microbiota of the ileoanal pouch has been shown to evolve over both the short-term and long-term in a manner that is unique to each individual47. Early microbiota changes have been demonstrated within two months of restoration of intestinal continuity, with colon-predominant anaerobic bacteria present in higher proportions in faecal samples, alongside a decrease in numbers of ileum-predominant species 48. The most prevalent bacterial species found in faecal samples of the ileoanal pouch were Veillonella (90%), Enterobacter (70%), Klebsiella (70%), Staphylococcus (60%), Corynebacterium (60%), Peptococcus (60%), Clostridium (50%) and Lactobacillus (50%) 25. Of these, Enterobacter spp. showed the highest mean concentration25. Almeida et al25 compared faecal samples from the rectum pre-surgery and from patients with an ileoanal pouch two months post-surgery. They found Staphylococcus spp. and Corynebacterium spp. were found in less abundance (40% vs 70%) and (30% vs 60%) respectively, with increases in abundance of Bacteroidetes (30% vs 20%; p=0.049), Lactobacillus spp. (30% vs 0%; p=0.004) and Veillonella spp. (90% vs 30%; p=0.035) 25.

When the faecal microbiota of UC ileoanal pouch patients at two months after ileostomy closure was compared with the terminal ileum of healthy volunteer controls, Enterobacter spp. and Klebsiella spp., were significantly more prevalent whereas Enterococcus spp. and Staphylococcus spp. were more prevalent in controls25. There were decreases in the anaerobic bacteria Clostridium coccoides 25, Clostridium leptum subgroups, the Bacteroides fragilis group, and also in Atopobium spp. 48 when comparing their prevalence in faecal samples prior to colectomy and after closure of the loop ileostomy. By six to 12-months after closure of the ileostomy, the prevalent species present in faecal samples from the ileoanal pouch were E. coli, Veillonella spp., Enterobacter spp., Klebsiella spp. and Peptococcus spp. 25,44. Of these, E. coli and Enterobacter spp. had the highest mean concentration25. The authors of this study concluded that the microbiota composition found prior to ileoanal pouch surgery for UC patients was similar to the composition found in the healthy ileoanal pouch after both two and eight months, following ileostomy closure. This suggests that the non-inflamed ileoanal pouch tended to recover to a microbial composition similar to pre-surgery values25. Studies looking at the faecal microbial diversity one year following ileostomy closure have shown that the microbiota composition had stabilized to reflect a more colonic profile26,48. This is supported by the decrease in Lactobacillus spp. and Enterococcus spp., which predominate in the small bowel microbiota 48.

Table 6: Longitudinal changes in microbiota in the pouch

Summary: Longitudinal changes in microbiota in the pouch

The ileoanal pouch microbiota transforms from a microbiota profile typically found in the small bowel to a more “colonic” microbiota over-time with both Enterococcus spp. and Lactobacillus spp. reducing in numbers over-time. These changes can occur as early as two months, with more stability in the microbiota noted with increasing age of the ileoanal pouch.

Prevention and predictors of pouchitis

In analysis of faeces from patients with UC prior to ileoanal pouch formation, it has been seen that that a predominance of Ruminococcus gnavus, Bacteroides vulgatus and Clostridium perfringens and absence of Blautia spp. and Roseburia spp. can be predictive of pouchitis50. This was the first study to suggest that certain patterns in the microbiota can predict those who get pouchitis and those that do not. It will be important to repeat this study with larger numbers to potentially find patterns in the microbiota that predict those that may develop disease. This may help pre-operative counselling for a patient, whilst also giving a potential opportunity to alter the gut microbiota in order to prevent future complications with the ileoanal pouch.

Microbiota changes following treatment of pouchitis with antibiotics (Table 7)

The mainstay of pouchitis treatment is antibiotics. It is yet not fully understood the influence these have on disease course. Interestingly, Tannock et al46 found that antibiotic administration (either ciprofloxacin, ceftin, cefuroxime or metronidazole) did not reduce the total number of bacteria in faecal ileoanal pouch samples46. In contrast, Kuhbacher et al51, found that antibiotic use in pouchitis was associated with a lower bacterial richness and diversity in biopsies from patients who achieved remission51. Furthermore, biopsies from pouchitis patients have shown that antibiotics reduce specific bacterial groups including Bacteroides, Firmicutes and Tenericutes45. Faecal samples from pouchitis patients have shown reductions in Faecalibacterium spp., Roseburia spp., Coprococcus spp. and Lachnospiraceae39 Biopsies from pouchitis patients have shown increases in Enterococcaceae and Pasteurellaceae45.

When comparing faecal samples from pouchitis patients who were using antibiotics with those not doing so, it was found that those not taking antibiotics had fewer Firmicutes and higher numbers of Proteobacteria46. In faecal samples from patients taking maintenance antibiotics for chronic pouchitis, Caulobacteriaceae, Sphingomonadaceae, Comamonadaceae, Peptostreptococcaceae, were significantly reduced46.

With regards to the microbial impact of specific antibiotics, it has been shown that treatment with metronidazole resulted in complete eradication of anaerobic bacteria including Clostridium perfringens34. When pouchitis patients were treated with ciprofloxacin, Clostridium perfringens and all coliforms including haemolytic strains of E. coli disappeared34. Both ciprofloxacin and metronidazole are the first line treatments for pouchitis52 and result in clinical remission in about 60% of patients52. As both Clostridium perfringens and E. coli have been associated with pouchitis34,35 , this gives further credence to the concept that manipulating the gut microbiota to alter specific bacteria may help prevent this disease.

Table 7: Microbiota changes following treatment of pouchitis with antibiotics

Summary: Microbiota changes following treatment of pouchitis with antibiotics

Antibiotic treatment for pouchitis is associated with an overall reduction in bacterial richness within the ileoanal pouch. Reduction in both E. coli and Clostridia species appears to be important in treating pouchitis but this requires further clarification.

Microbiota changes following treatment with probiotics (Table 8)

Probiotics have been used to help maintain remission and treat pouchitis. The most widely used probiotic has been VSL#3. It has been shown that in ileoanal pouch biopsy samples, VSL#3 significantly increases bacterial richness and diversity within the ileoanal pouch51. VSL#3 has been shown to be associated with increase concentrations of Lactobacilli spp., Bifidobacterium spp. and E. coli51 in biopsy samples and Streptococcus salivarius in faecal samples from patients with pouchitis53. However, it has been shown that microbiota alterations after probiotic treatment were not sustained long-term33. Kuhbacher et al51 suggested that it was the increase in microbial diversity/richness that was responsible for maintenance of remission51. In a study using a different probiotic (MIYA-BM), it was found that treatment resulted in a reduction in Escherichia spp. and Bifidobacterium spp. in faecal samples 54.

Table 8: Microbiota changes following treatment with probiotics

Summary: Microbiota changes following treatment with probiotics

There is limited evidence for the use of probiotics in the treatment of pouchitis. There are no common microbiota signature changes induced by such treatments.

Discussion

This review has highlighted that undoubtedly the microbiota plays an important role in both the inflamed and the healthy ileoanal pouch with evidence suggesting that it may have a larger role in gut health55. Overtime the pouch microbiota transforms into a more “colonic” typical phenotype after ileostomy closure. Similar to findings in IBD, a decrease in bacterial diversity and dysbiosis are associated with both acute and chronic inflammation. Changes in Clostridium spp. and E. coli have been shown to be associated with inflamed pouches, non inflamed pouches and treatment response. Inconsistent findings across studies mean that it is difficult to assign a causative relationship of these changes with these phenomena.

There are many studies that highlight changes in bacterial composition in the ileoanal pouch, but these studies are limited by heterogeneity and in particular, analysis techniques and sampling strategies. On this basis, caution must be used when interpreting microbiota data. Studies used a variety of methods to define microbial diversity. These methods can be broadly split into culture vs culture-independent approaches. Culture-based studies are likely to have a bias towards culturing more aerobically friendly microbes than exist in a true ileoanal pouch environment, thus over-representing aerobic bacteria whilst possibly under-representing anaerobic bacteria. The use of 16S rRNA analysis methods will negate this effect and represents the future in determining the microbiota. However, it must be emphasized that such approaches do not accurately reflect bacterial viability.

The ileoanal pouch can be a good model in attempting to understand the role of the microbiota in gastrointestinal inflammation. It has been established that dysbiosis occurs in other forms of IBD and therefore deeper understanding of the roles of the microbiota using the ileoanal pouch as a model may help to clarify the aetiology and pathogenesis of IBD in general.

An important consideration, is understanding if the inflammatory process causes the change in the microbiota, or vice versa. Studies have shown that certain microbiota can predict the development of pouchitis, suggesting that it may be that these bacteria are present prior to the onset of inflammation 50. Interestingly, bacterial populations change over time with some signature changes being present in both inflamed and in non-inflamed tissue. Additional studies are needed to characterize the functional significance of these changes. Furthermore, in the inflammatory process, it may be that alterations in bacterial metabolic capabilities are more important than individual bacterial changes. Therefore, looking at functionality of the ensuing microbiota rather than trying to define the community composition may well allow a better understanding of the microbiota’s role in IBD.

A significant limitation of studies in ileoanal pouch microbiota is accounting for confounders that influence the gut microbiota such as medications56, diet57, smoking and age. It has been suggested that pouchitis is not caused by a single factor58 and the microbiota is just one of the factors that contribute to inflammation. This is obviously an issue with any disease and is something that cannot be avoided but should be considered when analysing the literature. This review has highlighted the heterogeneity of the gut microbiota between different patient populations. Given the relatively small numbers in each study, there is a need for a larger, more definitive study.

With advancing techniques in metagenomics, metaproteomics and metatranscriptomics we may be able to better understand the role of the microbiota in a ileoanal pouch both in health and disease.

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Supplementary materials

1.0 Search strategy details

A systematic search was done using Ovid. A search of the on-line bibliographic databases MEDLINE and EMBASE was carried out by two independent researchers (JPS and SO) to identify articles published between 1966 and February 2016. The search was performed separately on MEDLINE and repeated on EMBASE and then combined. COVIDENCE Systematic Review Software (Veritas Health Innovation, Melbourne, Australia (available at www.covidence.org) was used to remove duplicates and to individually screen articles

The search strategy is shown below:

Embase:

1. exp ulcerative colitis/

2. Inflammatory bowel disease*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

3. IBD.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

4. UC.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

5. idiopathic proctocolitis.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

6. 1 or 2 or 3 or 4 or 5

7. exp intestine flora/

8. exp bacterium/

9. Microbiota.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

10. Microbiome.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

11. Dysbiosis.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

12. Bacteria.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

13. Bacteriotherap*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

14. Gastrointestinal Microbiome.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

15. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14

16. ileitis/

17. proctocolectomy/

18. ileoanal anastomosis/

19. Pouch*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

20. RPC.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

21. reservoir*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

22. Proctocolectomy.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

23. ileitis.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

24. ileoanal anastomosis.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading]

25. 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24

26. 6 and 15 and 25

Medline search:

1. Colitis, Ulcerative/

2. Inflammatory bowel disease*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

3. IBD.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

4. UC.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

5. idiopathic proctocolitis.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

6. 1 or 2 or 3 or 4 or 5

7. Gastrointestinal Microbiome/

8. exp Bacteria/

9. Microbiota.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

10. Microbiome.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

11. Dysbiosis.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

12. Bacteria.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

13. Bacteriotherap*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

14. Gastrointestinal Microbiome.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

15. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14

16. Colonic Pouches/

17. Pouchitis/

18. Proctocolectomy, Restorative/

19. Ileitis/

20. Pouch*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

21. proctocolectomy.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

22. RPC.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

23. reservoir*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

24. ileitis.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

25. ileoanal anastomosis.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

26. 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25

27. 6 and 15 and 26

34