The pathogenesis of primary pouchitis following ileal pouch-anal anastomosis: a review of current hypotheses

doi:10.4236/ojgas.2011.12002

Paper Menu >>

Journal Menu >>

Open Journal of Gastroenterology, 2011, 1, 7-12

doi:10.4236/ojgas.2011.12002 Published Online November 2011 (http://www.SciRP.org/journal/ojgas/ OJGas

Published Online November 2011 in SciRes. http://www.scirp.org/journal/OJGas

The pathogenesis of primary pouchitis following ileal

pouch-anal anastomosis: a review of current hypotheses

Sally Bath1, Christian P. Selinger1,2, Rupert W. L. Leong1,3

1Concord Repatriation General Hospital, Gastroenterology and Liver Services, Hospital Road, Concord, Australia;

2Salford Royal Hospital, Department of Gastroenterology, Stott Lane, Salford, UK;

3The Faculty of Medicine, The University of New South Wales, Sydney, Australia.

Email: [email protected]

Received 3 October 2011; revised 8 November 2011; accepted 19 November 2011.

ABSTRACT

Primary pouchitis is a common complication of ileal

pouch-anal anastomosis following proctocolectomy in

patients treated for ulcerative colitis (UC), but is un-

usual for those treated for familial adenomatous

polyposis (FAP). While a number of theories as to the

pathogenesis of this inflammatory condition have

been proposed, no single one has been wholly satis-

factory. Much research has been devoted to investi-

gating a link between the pathogenic factors involved

in UC, but not FAP, and those underlying pouchitis.

The contribution of sulfate-producing bacteria has

also been explored. The role of other intraluminal

factors, such as short chain fatty acids and unconju-

gated bile salts, has also been investigated. A unifying

theory of a multi-step process might explain the

pathogenesis of pouchitis, but further research is re-

quired to proof causation. It is likely that pouchitis

develops as a result of a combination of genetic, im-

munological, microbial and metabolic factors. Future

insight into the causes of pouchitis may eventually

allow for the development of more effective treat-

ments.

Keywords: Pouchitis; Ileo-Pouch Anal Anastomosis;

Pathogenesis

1. INTRODUCTION

Prior to the development of the ileal pouch-anal anasto-

mosis technique (IPAA) patients requiring proctocolec-

tomy were mandated to have an end-ileostomy. IPAA

restore the continuity of the lower GI tract by creating a

pouch of ileal loops directly anastomosed to the anal

canal, and preserving the anal sphincter function. Re-

storative proctocolecto my followed by IPAA is currently

the treatment of choice in the surgical management of

refractory ulcerative colitis (UC) and familial adenoma-

tous polyposis (FAP) [1,2]. Epidemiological studies

show that at least 10% of patients with UC will undergo

proctocolectomy during the course of their illness [3].

IPAA has been fou nd to have a positive impact on global

quality of life score as it provides symptomatic relief

while preserving fecal continence [4,5]. However, the

procedure is associated with significant short and long-

term morbidity, including immediate post-operative com-

ations, pouch failure, small bowel obstruction, sexual

dysfunction, irritable pouch syndro me and pouchitis [2].

Of these, pouchitis is the most common long-term

complication, occurring at a rate of 48% at 10 years and

70% at 20 years in patients with UC [6]. For patients

who have had one episode of pouchitis, there is a 64%

risk of recurrence [2]. In FAP, pouchitis is uncommon

and approximated 5% in those treated with restorative

proctoco lectomy with pouch [7]. Overall similar rates of

adverse post-operative outcomes have been reported in

patients treated for UC and those treated for FAP [8].

There is however a marked difference in the risk of fis-

tulisation and pouchitis [8]. Pouchitis is significantly

more common in patients treated for UC than FAP, and

this observation has formed the basis for a number of

hypotheses of pathogenesis.

Pouchitis is an inflammatory condition of the ileal

reservoir that is formed during IPAA [9]. It occurs as a

single acute episode in a third of cases but most have

recurrent acute episodes or a chronic course of disease

[10]. Acutely, it can be distressing with symptoms of

increased stool frequency, urgency, nocturnal inconti-

nence and abdomino-pelvic pain, often accompanied by

fever, weight-loss and bloody stools [5]. In chronic cases,

pouchitis may be associated with reduced quality of life

and the need for further surgery [9]. Currently, there are

no consensus guidelines for diagnosis and in most cases

a combination of clinical signs and symptoms and pou ch

S. Bath et al. / Open Journal of Gastroenterology 1 (2011) 7-12

endoscopy are utilised. For research purposes, a number

of detailed, standardised diagnostic tools have been de-

veloped which incorporate clinical, endoscopic and his-

tological criteria. The most commonly used version is

the Pouchitis Disease Activity Index (see Ta bl e 1 ) [11].

The complexity of these scores highlights the multifac-

eted nature of pouchitis.

Secondary pouchitis is diagnosed in 20% - 30% of pa-

tients presenting with pouchitis [12]. In these cases a

specific causative factor is identified, for example Can-

dida infection, Clostridium difficile infection, radio-

therapy, chemotherapy, CMV infection or collagen depo-

sition. The remainder of patients present with primary

(idiopathic) pouchitis. To date, the pathogenesis of pri-

mary pouchitis has not been fully elucidated, but a

number of theories have been proposed. The aim of this

paper is to review the evidence for and against each of

these theories.

The management of pouchitis includes confirmation

and exclusion of other inflammatory conditions include-

ing Crohn’s disease recurrence and secondary pouchitis.

Both metronidazole and ciprofloxacin are effective in

treating acute pouchitis [13,14] and continuous mainte-

nance antibiotic therapy may be required for chronic

pouchitis. Rifaximin, an oral broad-spectrum non-ab-

sorbed antib iotic was found be useful in an open-labelled

maintenance study in the maintenance of remission [15].

For patients with chronic pouchitis in remission, the

probiotic VSL#3 consisting of strains of lactobacilli,

biﬁdobacteria and Streptococcus salivarius subsp. ther-

mophilus significantly reduced recurrences of pouchitis

from 100% in the placebo group to 15% [16]. Topical

treatments using enemas may be effective. Resistant

cases may respond to immunosuppressive therapies and

infliximab has been used effectively in difficult-to-treat

cases [17]. Finally, surgical reconstruction and excision

may be required.

2. POUCHITIS AS A RECURRENCE OF

ULCERATIVE COLITIS

Following an IPAA, the section of ileum used to fashion

the fecal reservoir (pouch) takes on many of the histo-

logical features of colonic epithelium, probably as a re-

sult of prolonged fecal exposure [18]. These changes

may render the pouch susceptible to conditions that pri-

marily affect the colon. Thus, it has been suggested that

pouchitis is a recurrence of UC.

There is significant overlap between UC and pouchitis

at the clinical, endoscopic, histological and molecular

levels, suggesting a common mechanism of pathogenesis.

The characteristic endoscopic findings in pouchitis are

oedema, granularity, friability, loss of vascular pattern,

mucous exudates and superficial ulceration (see Table 1)

[11]. Clearly, there are commonalities between these

findings and the hallmarks of UC. At the molecular level,

Amasheh et al. [19] have demonstrated changes in the

expression of claudin-1 and claudin-2 in tissue taken from

Table 1. The pouchitis disease activity index. [10] Score range 0 - 18; >7 indicates pouchitis.

Criteria Score

Clinical

Stool frequency Usual postoperative frequency 0

1 - 2 stools/day more than postoperative norm 1

3 or more stools /day more than po stoperative norm 2

Fecal urgenc y/abdominal cramps None 0

Occasional 1

Usual 2

Rectal bleeding None or rare 0

Present daily 1

Fever (temp erature > 37.8˚C) Absent 0

Present 1

Endoscopic inflammation Oedema 1

Granularity 1

Friability 1

Loss of vascular pattern 1

Mucous exudates 1

Ulceration 1

Acute histological inflamm ation Polymorphonuclear leukocyte infiltration None 0

Mild 1

Moderate and crypt abscess 2

Severe and crypt abscess 3

Ulceration per low field (mean) None 0

<25% 1

25% - 50% 2

>50% 3

S. Bath et al. / Open Journal of Gastroenterology 1 (2011) 7-12 9

patients suffering acute pouchitis. These proteins are

components of epithelial tight junctions and altered ex-

pression of these proteins increases epithelial permeabil-

ity via the paracellular route. Similar changes have been

demonstrated in UC [20].

While pouchitis is prevalent in patients with a history

of UC, it is very infrequently seen in those with a history

of FAP. A large meta-analysis of studies comparing

post-IPAA outcomes in UC and FAP patients found sig-

nificantly higher rates of pouchitis in the UC population

(OR 6.44; 95% CI: 3.21 - 12.93) [8]. These results cer-

tainly support the theory that the pathological mecha-

nisms underlying UC, but not FAP, may be responsible

for the development of pouchitis. That pouchitis is more

common in patients with a history of pancolitis than

those with left-sided colitis also len ds weight to this the-

ory [21]. Ta bl e 2 lists some of the differences between

UC and FAP in the risk of developing pouchitis.

Immunological features of pouchitis often mimic UC.

CD19 + Ki-67 + cells and CD138 + Ki-67 + cells are

increased in UC and represent immature plasma cells

with increased proliferative activities. Similar cell phe-

notypes are found in pouchitis mucosa suggesting UC-

derived abnormalities in the pathogenesis of pouchitis

[22]. Pouchitis also correlated with decreased defensin

expression in UC in addition to high expr ession of cyto-

kines as opposed to FAP pouches that had increased ex-

pression of hBD-1 beta-defensin and low cytokine levels

[23]. Toll-like receptors (TLR) are members of the pat-

tern recognition family important involved in innate

immunity. TLR-4 is specifically activated by lipopoly-

saccharide, an endotoxin produced by gram-negative

bacteria. TLR-4 expression was found to be increased in

pouches of UC patients in comparison with FAP patients,

even in the absence of clin ical or histological inflamma-

tion. This may result in increased intracellular pathway

activity following activation by bacterial products in UC

patients. [24] The observation that extraintestinal mani-

festations of UC often occur in parallel with pouchitis

provides further support to a theory of common immu-

nological pathogenesis. Lohmuller et al. [25] found that

in a population of 734 pa tients who had undergone IPAA

for UC, 53% of those with postoperative extraintestinal

manifestations developed pouchitis compared to 25% of

those without extraintestinal manifestations (P < 0.001).

Seven patients with preoperative extraintestinal mani-

festations that resolved after IPAA had concomitant re-

currence of the extraintestinal manifestations and acute

pouchitis.

The most compelling refutation of this theory lies in

the role of antibio tics in the treatment of pouchitis. Short

courses of metronidazole and ciprofloxacin have tradi-

tionally been used in the treatment of acute cases [26]. It

has been shown that treatment of pouchitis with met-

ronidazole results in resolution of the characteristic his-

tological changes of the condition [18]. UC is not rou-

tinely responsive to antibiotic therapy. While there is

compelling evidence for a common pathogenesis be-

tween pouchitis and UC, the theory does not fully ac-

count for this discrepancy. Additionally, mucosal cyto-

kine alterations found in pouchitis may simply reflect

inflammatory activity independent to those underlying

CD or UC. That is, cytokine changes are the result of

inflammation rather than causative [27].

3. THE ROLE OF BACTERIA IN THE

PATHOGENESIS OF POUCHITIS

Pouchitis appears to correlate with the presence of

pouch dysbiosis. The efficacy of antibiotics in the

treatment of acute pouchitis strongly suggests that

Table 2. Pouchitis risk and association with restorative procto-colectomy for ulcerative colitis (UC) versus familial adenomatous

polyposis (FAP).

Pouchitis association with UC a s opposed to FAP

Epidemiology  more common wit h U C

Clinical  UC extraintestinal manifestations may occur in parallel with pouchitis

Endoscopic  macroscopic and microscopic features of pouchitis are in common with inflammatory bowel diseases

Bacteria  pouch dysbiosis and loss of microbial biodivers ity in culture and molecular identification similar to UC

 increased hydrogen sulfide-producing and sulfate-reducing organisms

Immune  serological markers (pANCA) similar to UC

 increased immature plasma cells with increased proliferative activities similar to UC

Molecular

 cytokine and defensin changes may reflect underlying UC pathogenesis

 increased toll-like receptor 4 expression in UC pouches

 altered tight junction proteins

Mucosal  increased sulphomucin in UC pouches

pANCA = Perinuclear anti-neutrophil cytoplasmic antibody.

S. Bath et al. / Open Journal of Gastroenterology 1 (2011) 7-12

bacteria play a role in the pathogenesis of the condi-

tion. Loss of biodiversity occurs in pouches of UC

patients but not in pouches following FAP. UC

pouches in contrast to FAP pouches, there was increase

in Proteobacteria (P = 0.019), decrease in Bacteroide-

tes (P = 0.001) and Faecalibacterium prausnitzii (P =

0.029). Furthermore, bacterial diversity was signifi-

cantly greater in UC non-pouchitis compared with UC

pouchitis (P = 0.009). [28] Mucosal Clostridiaceae spp

colony forming units were significantly increased in

patients with recurrent or chronic pouchitis compared

to those with no- or single-episode pouchitis (OR:14.

95% CI: 0.887 - 224.021; P = 0.045) [29]. VSL#3, a

probiotic, is effective in preventing relapse of chronic

pouchitis and may prevent episodes of acute pouchitis

[26]. Specific causative bacteria or differential bacte-

rial count were not identified in the faeces of patients

with or without pouchitis in another study [30]. How-

ever, negative findings may reflect older techniques in

defining the microbiome. Patients with pouchitis have

been found to have a greater anaerobe to aerobe ratio

than those without [30,31]. Thus, it may be qualitative

rather than quantitative differences in microflora that

lead to the development of pouchitis. More recently, a

role for sulfate-reducing bacteria has been proposed

[32,33]. These bacteria are native to the human colon

and produce hydrogen sulfide as a by-product of me-

tabolism. Hydrogen sulfide is believed to compete

with normal colonic metabolic substrates, leading to

disruption of colonocyte metabolism and injury to the

intestinal mucosa [32]. The quantity of hydrogen sul-

fide gas produced by the pouch contents of patients

with active pouchitis is significantly greater than that

produced by patients with no history of pouchitis and

those receiving antibiotic therapy. In patients with FAP,

the quantity of hydrogen sulfide produced is signifi-

cantly less than in any group of UC patients [32].

Duffy et al. [33] report that sulfate-reducing bacteria

are found in the pouches of patients with UC, but not

those with FAP. Thus, this theory accounts for a num-

ber of the observed features of pouchitis: the efficacy

of antibiotics, the lack of a single identifiable causa-

tive organism and the differences in incidence between

UC and FAP patients.

The chief argument against a bacterial theory of

pathogenesis is that there is no correlation between the

characteristic histological changes of pouchitis and fecal

aerobic or anaerobic coun ts [18]. Future studies examin-

ing the relationship between hydrogen sulfide production

and mucosal morphology will, no doubt, be valuable.

4. THE ROLE OF OTHER

INTRALUMINAL FACTORS

Pouch mucosal mucin characteristics appear to differ

between UC and FAP pouches. The expression of sul-

phomucin is increased in the mucous gel layer of UC

compared with FAP pouches. Differential mucin ex-

pression favours colonization by different organisms

and sulphomucin expression was associated with sul-

phate-reducing bacteria and increased chronic inflam-

mation [34].

Short-chain fatty acids (SCFAs) are produced by

anaerobic bacteria through the fermentation of dietary

fibre. They are the principle source of energy for

colonocytes and are important for mucosal homeosta-

sis. Clausen et al. [35] found that concentrations of

SCFAs in the faeces of patients with pouchitis are

lower than in those without pouchitis, albeit in a small

sample of patients. This finding has led to the hy-

pothesis that reduced availability of SCFAs in the ileal

pouch plays a role in the development of pouchitis.

However, this is unlike ly to be the pr imary mechan ism

responsible for pouchitis for a number of reasons.

Sandborn et al. [30] quan tified SCFA concen tration s in

the faeces of UC patients, both with and without

pouchitis, and FAP patients, finding no significant dif-

ferences between the groups. This finding calls into

question the role of SCFAs in the pathogenesis of

pouchitis. Furthermore, it highlights the fact that this

theory cannot account for the observed differences in

incidence of pouchitis between patients with UC and

FAP. Glutamine and butyrate suppositories have been

trialled as therapy for chronic pouchitis on the basis

that increasing concentrations of SCFAs in the pouch

may reduce epithelial permeability, leading to symp-

tomatic improvement. The clinical response rate in

small, uncontrolled studies has been very low [26],

further undermining this hypothesis.

Unconjugated bile acids are released from primary

bile salts by the actions of anaerobic bacteria. These

unconjugated bile acids are toxic to lipid membranes.

High levels of unconjugated bile acids have been

found in the feces of patients with ileal pouches, as

compared to those who have undergone conventional

ileostomy [36]. It has been suggested that this increase

may predispose to pouchitis but others have not con-

firmed these findings. As for SCFAs, the concentra-

tions of unconjugated bile acids are no different in UC

and FAP patients [30]. If bile acids were the primary

pathogenic factor, a similar incidence of pouchitis

would be expected in the two groups. Thus, it is

unlikely that bile acids are a major pathogenic factor in

the development of pouchitis.

5. MULTI-FACTORIAL, MULTI-STEP

HYPOTHESIS

None of the theories discussed above can explain the

development of pouchitis fully on its own merit. Cof-

S. Bath et al. / Open Journal of Gastroenterology 1 (2011) 7-12 11

fey et al. [37] have proposed that pouchitis is the re-

sults of a multi-step process rather than anyone single

factor. Their unifying theory is based on the following

steps: First colonic metaplasia develops in the ileal

pouch, which is followed by the production of sul-

phomycin by the goblets cells. Sulphomycin then pro-

vides the basis for sulfate-reducing bacteria colonisa-

tion. Hydrogen sulfide production by sulfate-reducing

bacteria may cause apoptosis and reactive crypt cell

hyperplasia. Hydrogen sulphide will then also cause

infl ammat io n and asso c iated s ympto ms [37].

While the multi-step theory unifies current isolated

findings, it does not fully explain the pathogenesis. It

remains unclear why greater rates of colonic metapla-

sia occur in UC compare to FAP patients. So far only

an association between sulfate-reducing bacteria colo-

nisation and colonic metaplasia has been found and

any causality is speculative.

6. CONCLUSIONS

Understanding of the pathogenesis of primary pouchitis

remains incomplete. While a number of theories have

been proposed, no single one fully explains the histo-

logical findings and the efficacy of certain treatments.

The evidence for a shared pathological basis between

UC and pouchitis is compelling, but it can not explain th e

therapeutic benefit of antibiotics. There is mounting

evidence that sulfate-reducing bacteria play a major role

in the condition, while it seems unlikely that SCFAs or

bile acid concentrations are the chief pathological cul-

prits. Certainly it seems plausible that all of these factors

may contribute to the development of pouchitis, in the

context of unknown immunological factors unique to

patients with UC. The multi-step process theory pro-

posed by Coffey et al. aims to unify the current find ings.

Future studies may elicit a unifying link between the

single hypotheses and proof or disproof the proposed

multi-step model. Regardless, further investigation into

the pathogenesis of primary pouchitis is warranted in the

search for more efficacious treatments and preventative

strategies.

REFERENCES

[1] Doherty, G.A. and Chiefetz, A.S. (2009) Management of

acute severe ulcerative colitis. Expert Review of Gastro-

enterology and Hepatology, 3, 395-405.

doi:10.1586/egh.09.24

[2] Meagher, A.P., Farouk, R., Dozois, R.R., et al. (1998) Ji-

leal pouch-anal anastomosis for chronic ulcerative colitis:

Complications and long-term outcome in 1310 patients.

British Journal of Surgery, 85, 800-803.

doi:10.1046/j.1365-2168.1998.00689.x

[3] Soberg, I.C, Lygren, I., Jahnsen, J., et al. (2009) Clinical

course during the first ten years of ulcerative colitis: Re-

sults from a population-based inception cohort (IBSE

Study). Scandinavian Journal of Gastroenterology, 44,

431-440. doi:10.1080/00365520802600961

[4] Somashekar, U., Gupta, S., Soin, A., et al. (2010) Func-

tional outcome and quality of life following restorative

protocolectomy for ulcerative colitis in Indians. Interna-

tional Journal of Colorectal Disease, 25, 967-973.

doi:10.1007/s00384-010-0974-x

[5] Coffey, J.C., Winter, D.C., Neary, P., et al. (2002) Quality

of life after ileal pouch-anal anastomosis: An evaluation

of diet and other factors using the Cleveland Global

Quality of Life instrument. Diseases of the Colon Rectum,

45, 30-38.

[6] Hahnloser, D., Pemberton, J.H., Wolff, B.G. , et al. (2007)

Results at up to 20 years after ileal pouch-anal anasto-

mosis for chronic ulcerative colitis. British Journal of

Surgery, 94, 333-340. doi:10.1002/bjs.5464

[7] Banasiewicz, T., Marciniak, R., Kaczmarek, E., et al.

(2011) The prognosis of clinical course and the analysis

of the frequency of the inflammation and dysplasia in the

intestinal J-pouch at the patients after restorative procto-

colectomy due to FAP. International Journal of Colorec-

tal Disease, 26, 1197-1203.

doi:10.1007/s00384-011-1241-5

[8] Lovegrove, R.E., Tilney, H.S., Heriot, A.G., et al. (2006)

A comparison of adverse events and functional outcomes

after restorative protocolectomy for familial adenoma-

tous polyposis and ulcerative colitis. Diseases of the Co-

lon & Rectum, 49, 1293-1306.

doi:10.1007/s10350-006-0608-0

[9] Navaneethan, U. and Shen, B. (2010) Diagnosis and

management of pouchitis and ileoanal pouch dysfunction.

Current Gastroenterology Reports, 12, 485-494.

doi:10.1007/s11894-010-0143-y

[10] Beliard, A. and Prudhomme, M. (2010) Ileal reservoir

with ileo-anal anastomosis: Long-term complications.

Journal of Visceral Surgery, 147, E137-E144.

doi:10.1016/j.jviscsurg.2010.07.001

[11] Sandborn, W.J., Tremaine, W.J., Batts, K.P., et al. (1994)

Pouchitis after ileal pouch-anal anastomosis: A pouchitis

disease activity index. Mayo Clinic Procedures, 69,

409-415.

[12] Navaneethan, U. and Shen, B. (2010) Secondary pouchi-

tis: Those with identifiable etiopathogenetic or triggering

factors. American Journal of Gastroenterology, 105,

51-64. doi:10.1038/ajg.2009.530

[13] Madden, M.V., McIntyre, A.S. and Nicholls, R.J. (1994)

Double-blind crossover trial of metronidazole versus

placebo in chronic unremitting pouchitis. Digestive Dis-

eases and Science, 39, 1193-1196.

doi:10.1007/BF02093783

[14] Shen, B., Achkar, J.P., Lashner, B.A., et al. (2001) A

randomized clinical trial of ciproﬂoxacin and metroni-

dazole to treat acute pouchitis. Inflammatory Bowel Dis-

eases, 7, 301-305.

doi:10.1097/00054725-200111000-00004

[15] Shen, B., Remzi, F.H., Lopez, A.R. and Queener, E.

(2008) Rifaximin for maintenance therapy in antibi-

otic-dependent pouchitis. B M C G a s t roe n t ero l og y , 23, 26.

doi:10.1186/1471-230X-8-26

[16] Gionchetti, P., Rizzello, F., Venturi, A., et al. (2000) Oral

bacteriotherapy as maintenance treatment in patients with

S. Bath et al. / Open Journal of Gastroenterology 1 (2011) 7-12

OJGas

chronic pouchitis: A double-blind, placebo-controlled tri-

al. G astroenterology, 119, 305-309.

doi:10.1053/gast.2000.9370

[17] Ferrante, M., D'Haens, G., Dewit, O., et al. (2010) Bel-

gian IBD Research Group. Efficacy of infliximab in re-

fractory pouchitis and Crohn’s disease-related complica-

tions of the pouch: A Belgian case series. Inflammatory

Bowel Diseases, 16, 243-249.

[18] Kmiot, W.A., Youngs, D., Tudor, R., et al. (1993) Muco-

sal morphology, cell proliferation and faecal bacteriology

in acute pouchitis. Br itish Journa l of Sur ger y, 80, 1445-1449 .

doi:10.1002/bjs.1800801132

[19] Amasheh, S., Dullat, S., Fromm, M., et al. (2009) In-

flamed pouch mucosa possesses altered tight junctions

indicating recurrence of inflammatory bowel disease. In-

ternational Journal of Colorectal Disease, 24, 1149-

1156.

[20] Heller, F., Florian, P., Bojarski, C., et al. (2005) Inter-

leukin-13 is the key effector Th2 cytokine in ulcerative

colitis that affects epithelial tight junctions, apoptosis and

cell restitution. Gastroenterology, 129, 550-564.

doi:10.1016/j.gastro.2005.05.002

[21] Simchuk, E.J. and Thirlby, R.C. (2000) Risk factors and

true incidence of pouchitis in patients after ileal

pouch-anal anastomoses. World Journal of Surgery, 24,

851-856. doi:10.1007/s002680010136

[22] Hirata, N., Oshitani, N., Kamata, N., et al . (2008) Prolif-

eration of immature plasma cells in pouchitis mucosa in

patients with ulcerative colitis. Inflammatory Bowel Dis-

eases, 14, 1084-1090. doi:10.1002/ibd.20447

[23] Kiehne, K., Brunke, G. and Wegner, F. (2006) Defensin

expression in chronic pouchitis in patients with ulcerative

colitis or familial adenomatous polyposis coli. World

Journal of Gastroenterology, 12, 1056-1062.

[24] de Paiva, N.M., Ayrizono, M.L., Milanski, M., et al.

(2011) Differential expression of TLR2, TLR4 and JNK

in mucosa of ileal pouches for ulcerative colitis. Is there

a role for bacterial antigen pathway in asymptomatic pa-

tients? International Journal of Clinical and Experimen-

tal Medicine, 4, 179-186.

[25] Lohmuller, J.L., Pemberton, J.H., Dozois, R.R., et al.

(1990) Pouchitis and extraintestinal manifestations of in-

flammatory bowel disease after ileal pouch-anal anasto-

mosis. Annals of Surgery, 211, 622-627.

[26] Holubar, S.D., Cima, R.R., Sandborn, W.J., et al. (2010)

Treatment and prevention of pouchitis after ileal

pouch-anal anastomosis for chronic ulcerative colitis.

Cochrane Database of Systematic Reviews, 6, CD00-

1176.

[27] Schmidt, C., Giese, T., Ludwig, B., Menges, M., Schil-

ling, M., Meuer, S.C., Zeuzem, S. and Stallmach, A.

(2006) Increased cytokine transcripts in pouchitis reflect

the degree of inflammation but not the underlying entity.

International Journal of Colorectal Disease, 21, 419-426.

doi:10.1007/s00384-005-0024-2

[28] McLaughlin, S.D., Walker, A.W., Churcher, C. et al. (2010)

The bacteriology of pouchitis: A molecular phylogenetic

analysis using 16S rRNA gene cloning and sequencing.

Annals of Surgery, 252, 90-98.

doi:10.1097/SLA.0b013e3181e3dc8b

[29] Scarpa, M., Grillo, A., Pozza, A., et al. (2011) TLR2 and

TLR4 up-regulation and colonization of the ileal mucosa

by Clostridiaceae spp. in chronic/relapsing pouchitis.

Journal of Surgery Research, 169, E145-154.

doi:10.1016/j.jss.2011.04.003

[30] Sandborn, W.J., Tremaine, W.J., Batts, K.P., et al. (1995)

Fecal bile acids, short-chain fatty acids, and bacteria after

ileal pouch-anal anastomosis do not differ in patients

with pouchitis. Digestive Diseases and Sciences, 40,

1474-1483. doi:10.1007/BF02285195

[31] Nasmyth, D.G., Godwin, P.G., Dixon, M.F., et al. (1989)

Ileal ecology after pouch-anal anastomosis or ileostomy.

A study of mucosal morphology, fecal bacteriology, fecal

volatile fatty acids, and their interrelationship. Gastroen-

terology, 96, 817-824.

[32] Ohge, H., Furne, J.K., Springfield, J., et al. (2005) Asso-

ciation between fecal hydrogen sulphide production and

pouchitis. Diseases of the Colon & Rectum, 48, 469-475.

doi:10.1007/s10350-004-0820-8

[33] Duffy, M., O’Mahoney, L., Coffey, J.C., et al. (2002)

Sulfate-reducing bacteria colonise pouches formed for

ulcerative colitis but not familial adenomatous polyposis.

Diseases of the Colon & Rectum, 45, 384-388.

doi:10.1007/s10350-004-6187-z

[34] Bambury, N., Coffey, J.C., Burke, J., Redmond, H.P. and

Kirwan, W.O. (2008) Sulphomucin expression in ileal

pouches: Emerging differences between ulcerative colitis

and familial adenomatous polyposis pouches. Diseases of

the Colon & Rectum, 51, 561-567.

doi:10.1007/s10350-008-9200-0

[35] Clausen, M.R., Tvede, M. and Mortensen, P.B. (1992)

Short-chain fatty acids in pouch contents from patients

with and without pouchitis after ileal pouch-anal anas-

tomosis. Gastroenterology, 103, 1144-1153.

[36] Nasmyth, D.G., Johnston, D., Williams, N.S., et al. (1989)

Changes in the absorption of bile acids after total colec-

tomy in patients with ileostomy or pouch-anal anastomo-

sis. Diseases of the Colon & Rectum, 32, 230-234.

doi:10.1007/BF02554535

[37] Coffey, J.C., Rowan, F., Burke, J., et al. (2009) Patho-

genesis of and Unifying Hypothesis for Idiopathic

Pouchitis. American Journal of Gastroenterology, 104,

1013-1023. doi:10.1038/ajg.2008.127