Ileal Pouch–Anal Anastomosis and Pouchitis

Ileal Pouch–Anal Anastomosis and Pouchitis: Comparison

Please note this is a comparison between Version 1 by Arianna Dal Buono and Version 2 by Jessie Wu.

Inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, are life-long disorders characterized by the chronic relapsing inflammation of the gastrointestinal tract with the intermittent need for escalation treatment and, eventually, even surgery. The total proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the surgical intervention of choice in subjects affected by ulcerative colitis (UC). Although IPAA provides satisfactory functional outcomes, it can be susceptible to some complications, including pouchitis as the most common.

ileal pouch–anal anastomosis
microbiota
pouchitis

1. Introduction

In humans, a wide number of different microbial species are located in the bowel, which hosts several trillion microbial cells [1]. This ensemble of microbial species is generally called gut microbiota [2]. There is a profound interplay between the gut microbiota and the human biology [3]. Indeed, the gut microbiota is important for various physiological functions such as eliciting immune maturation [4], defending against pathogens colonization and overgrowth [5], influencing epithelial proliferation [6] and intestinal vascular density [7], modifying bile acids in the large bowel [8], promoting metabolic homeostasis [9] and hormone modulation [10], synthesizing vitamins [11] and neurotransmitters [12], supplying energy [1], and regulating bone metabolism [13]. The intestinal microbiota of a healthy subject is composed predominantly by Bacteroidetes and Firmicutes, with also other smaller sections comprised by Actinobacteria, Proteobacteria, Verrucomicrobia, methanogenic archaea, Eucarya, and various phages [1]. Modifications in the constitution and function of gut microbes lead to dysbiosis [1], and several diseases are associated with gut dysbiosis ^[1][14][1,14]. In particular, intestinal dysbiosis is an important feature of inflammatory bowel diseases (IBD) ^[14][15][14,15], playing a crucial role in the onset of the disease in predisposed subjects [16]. Indeed, some important alterations of intestinal microbiota have been identified in IBD, including an underrepresentation of Firmicutes (in particular Faecalibacterium prausnitzii) [17], Bacteroidetes, and Lactobacillus [16] with increased levels of Proteobacteria [18]. IBD are life-long disorders characterized by the chronic relapsing inflammation of the gastrointestinal tract ^[19][20][19,20] with the intermittent need for escalation treatment, eventually requiring surgical intervention [21]. In particular, although decreasing over time, subjects affected by UC still have a 5- and 10-year risk of colectomy of 7.0% and 9.6%, respectively [22]. Indications for colectomy comprise refractory acute severe UC, medically refractory disease, and colorectal cancer [19]. For these cases, restorative total proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the surgical intervention of choice ^[19][23][24][19,23,24]. Although IPAA provides a good quality of life and satisfactory functional outcomes ^[25][26][25,26], it can be subject to some complications, including pouchitis as the most common [27]. Pouchitis is an active, non-specific, idiopathic inflammation of the IPAA mucosa [28]. Approximately 25% of subjects develop pouchitis a year after IPAA with an increasing trend that reaches up to 45% at 5 years [29]. Approximately 10–20% of the pouchitis may also progress to chronic pouchitis, leading to antibiotic dependency or refractoriness requiring immunosuppressive therapy [30]. Furthermore, pouchitis is a risk factor for hospitalization [31] and pouch failure [32], which can occur in 5–10% of cases ^[33][34][35][33,34,35]. The etiology of pouchitis is mostly unclear. However, the efficacy of antibiotics in pouchitis suggests that the IPAA-related dysbiosis of the microbiota could play an important role in its pathogenesis ^[36][37][38][36,37,38].

2. Ileal Pouch–Anal Anastomosis (IPAA) AA Microbiota Evolution over Time

Although derived from the small intestinal tissue, the microbiota of the IPAA changes over time into a microbiota with a colonic profile ^{[39][40][41][42]}[39,40,41,42]. These modifications can arise as early as two months after surgery and achieve a more stable composition as the years go by after the creation of the IPAA ^[40][42][40,42]. Clostridium coccoides, Clostridium leptum, Bacteroides fragilis, Atopobium, E. coli, Klebsiella, Veillonella, Staphylococcus (coag-), and Enterobacter are the more counted bacterial species in functional IPAA ^[40][41][43][40,41,43]. In particular, it seems that the microbiota of healthy IPAAs try to recover to a composition comparable to that observed prior to surgery [43], and it has been hypothesized that the presence of Veillonella, Lachnospiraceae, Ruminococcus gnavus, and clostridial cluster IV (i.e., Faecalibacterium prausnitzii) might be a marker of regularity of the IPAA flora ^[37][43][44][37,43,44]. Furthermore, a comparison between the microbiota of IPAA in subjects with UC and subjects with familial adenomatous polyposis (FAP), which exhibit a low incidence of pouch inflammation, might help to understand the microbial families potentially implicated in the pathogenesis of pouchitis [37]. Indeed, a higher presence of sulfate-reducing bacteria (SRB) in UC-IPAA has been observed compared to FAP-IPAA ^[45][46][45,46]. SRB produce hydrogen-sulfide, which inhibits butyrate oxidation and prevents its utilization by the intestinal epithelial cells, potentially resulting in the damage of the mucosa of IPAA ^[37][46][37,46]. Other findings confirm the presence of differences between UC-IPAA and FAP-IPAA observing less bacterial diversity, an increased proportion of Proteobacteria, and decreased levels of Bacteroidetes and Faecalibacterium prausnitzii in the UC-IPAA group ^[47][48][47,48]. Table 1 shows the most common microorganisms and the main differences between healthy adults, IBD patients, UC-IPAA, and FAP-IPAA patients.

Table 1.

Most common microorganisms and main differences between healthy adults, IBD patients, UC-IPAA, and FAP-IPAA patients.

Healthy Adults	IBD	UC-IPAA	FAP-IPAA
Bacteroidetes *	↓ Bacteroidetes	↓ Bacteroidetes	↑ Bacteroidetes
Firmicutes *	↓ Firmicutes	↓ Firmicutes	↑ Firmicutes
Actinobacteria *	↓ Lactobacillus	↑ Proteobacteria	↓ Proteobacteria
Proteobacteria *	↑ Proteobacteria	Presence of SRB	Absence of SRB
Verrucomicrobia	↑ Enterobacteriaceae
Methanogenic archaea
Eucaria (i.e., yeasts)

* Representing about 90% of the bacterial phyla of the gut microbiota. IBD: inflammatory bowel disease; UC-IPAA: ulcerative colitis–ileal pouch–anal anastomosis; FAP-IPAA: familial adenomatous polyposis–ileal pouch–anal anastomosis; SRB: sulfate-reducing bacteria; ↓: reduced levels; ↑: increased levels.

3. Microbiota as a Target for the Treatment of Pouchitis

3.1. Antibiotics

Antibiotics represent the mainstay for the treatment of pouchitis ^[49][63] as they can induce remission by 74% in chronic pouchitis ^[50][64]. Ciprofloxacin and metronidazole are the first-line recommended antibiotics, although the best modality of treatment is still unclear ^[51][65]. A randomized clinical trial showed that both antibiotics produced a reduction in the total Pouchitis Disease Activity Index (PDAI) score in patients with acute pouchitis; however, ciprofloxacin produced a greater reduction in both symptom score and endoscopic score with fewer adverse events compared to metronidazole (0% vs. 33%, respectively) ^[52][66]. Furthermore, it has been shown that a combination of the two antibiotics can be effective also in patients with refractory/recurrent pouchitis ^[53][67]. The mechanisms implicated in the pouch microbiota’s changes after antibiotic therapy that are responsible for their favorable effects are not clearly understood [38]. In the study of Gosselink et al., ciprofloxacin could eradicate pathogens that are significantly increased during pouchitis (Clostridium perfringens, hemolytic Escherichia coli) while not disrupting most of the anaerobic bacteria that contribute to the stability of the IPAA’s flora [36]. Subsequently, Dubinsky et al. observed that the effectiveness of antibiotic therapy in pouchitis may be ascribed to the establishment of an intestinal microbiota with non-pathogenic, antibiotic-resistant bacteria with low inflammatory potential. This newly established microbiota may prevent more aggressive inflammatory bacteria from colonizing the pouch ^[54][68]. However, within three months after therapy discontinuation, most subjects relapsed, requiring additional antibiotic treatment ^[54][68]. Indeed, 7–20% of subjects that experience a first episode of pouchitis will eventually develop chronic pouchitis ^[55][69]. Therefore, further interventions following treatment with antibiotics should be contemplated (i.e., probiotics, diet) to support beneficial bacteria and prevent subsequent colonization by pathogenic species ^[54][68].

3.2. Probiotics

Randomized placebo-controlled trials (RCTs) showed that a probiotic mixture of Lactobacilli (four strains), Bifidobacteria (three strains), and Streptococcus thermophilus was effective in maintaining remission in subjects that suffered previous pouchitis. The treatment was generally well tolerated without significant serious adverse events (only one patient stopped medication complaining of abdominal cramps, vomiting, and diarrhoea) ^[56][57][70,71]. The same probiotic mixture led to increased fecal levels of lactobacilli, bifidobacteria, and Streptococcus salivarius in comparison to patients treated with placebo (p < 0.001) ^[56][70]. Similar findings were observed also in the RCT of Mimura et al. ^[57][71]. One of the potential mechanisms of the beneficial effect of the probiotic mixture could be its ability to increase tissue levels of the anti-inflammatory interleukin (IL)-10 and to reduce levels of tumor necrosis factor (TNF)-α, interferon-γ, and IL-1α. IL-10 may increase the tolerance of the intestinal immune system to resident pouch bacteria. Nevertheless, other mechanisms are probably involved in the anti-inflammatory effects of probiotics ^[58][72]. Indeed, Persborn et al. demonstrated that maintenance treatment with Ecologic 825 (another probiotic mixture containing strains of Lactobacilli and Bifidobacterium) after induction therapy with antibiotics restored the mucosal barrier to E.Coli in subjects with pouchitis ^[59][73]. Interestingly, some probiotics have been shown to be effective also as a prophylaxis therapy after surgery, reducing the rate of the first episode of pouchitis ^[60][61][74,75]. Therefore, some Authors suggest prescribing prophylaxis treatment with probiotics in subjects with high-risk factors of pouchitis after surgery (i.e., primary sclerosing cholangitis and extraintestinal manifestations) ^[55][69]. In addition to probiotics, other treatments have been studied to rebalance the intestinal flora in patients with IPAA.

3.3. Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) has been shown to be a successful treatment in other conditions of microbiota alteration, such as recurrent Clostridioides difficile infection ^[62][63][76,77]. As a result, there is increasing interest in the use of FMT to treat pouchitis. In the study of Kousgaard et al., FMT could increase the microbial diversity in subjects with chronic pouchitis and obtain clinical remission in 33% of the patients at 6 months of follow-up ^[64][78]. However, a recent systematic review observed that FMT seems ineffective in treating chronic pouchitis ^[65][79]. Indeed, two recent randomized controlled trials observed a low efficacy of FMT in chronic pouchitis. Interestingly, the majority of the relapses occurred during or shortly after the completion of FMT ^[66][67][80,81]. Overall, only a few studies have explored the role of FMT in chronic pouchitis so far, exhibiting some pitfalls such as the heterogeneity in study design and type of fecal transplant delivery [38]. Future specifically dedicated RCTs with large sample-sizes and standardized protocols (i.e., disease definitions, type of FMT delivery, dose, or duration) will help to ensure reproducible data and provide higher quality of evidence on the real efficacy of FMT in the treatment of chronic pouchitis ^[68][82].