Anatomical, physiological, and luminal adaptations occurring in an ileoanal pouch: opportunities for improving outcomes

Abstract

Background

The ileal pouch represents a unique adaptation of the ileum to serve the dual roles of nutrient absorption, fecal storage, and evacuation in a new luminal microenvironment. However, the adaptation process produces early histological inflammation and therefore clues in the development of pouchitis may lie in how the ileal pouch adapts.

Aims

This narrative review explored anatomical and luminal ileal pouch adaptations, with a goal of designing clinical strategies that can strengthen the resilience of the pouch mucosa.

Methods

A comprehensive PubMed search was conducted, and findings were critically examined and summarized.

Results

Physiologically, the ileum must acquire key adaptive features, such as water and electrolyte reabsorption and distention capabilities to support optimal pouch function. However, other adaptations, such as severe villous blunting and alterations in bile acid metabolism, may accelerate an inflammatory environment. The benefits of retaining ileal type characteristics such as aspects of mucosal architecture are unclear, whereas changes in permeability and epithelial nutrient utilization remain incompletely characterized. Significant knowledge gaps remain regarding the optimal pouch microenvironment, including how the microbiome and its metabolites contribute to pouchitis development, and current therapies to manage pouchitis have yielded limited success. Mechanistically informed studies that explore the dynamic interplay between pouch structure, microbiota, and dietary influences are needed to better design targeted therapies.

Conclusions

The ileal pouch undergoes a series of adaptations that are not fully understood. This review integrates current evidence to better understand these adaptations, highlights clinically relevant implications, and identifies key areas where further mechanistic investigation is needed.

Key Messages.

What is already known? 

The ileal pouch is required to perform ileal and colonic functions and after ileostomy closure undergoes progressive adaptation within a new luminal microenvironment.

What is new here? 

This review critically examines features of pouch adaptation that support optimal pouch function, highlighting those that remain incompletely characterized but may accelerate a proinflammatory environment, and outlines relevant clinical implications.

How can this study help patient care? 

Better understanding of the physiology and microenvironment of the ileal pouch may help to guide mechanistic and translational research, including microbiome-targeted therapies such as dietary interventions to prevent and treat pouchitis.

Introduction

Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is the preferred surgical therapy for patients with medically refractory ulcerative colitis (UC) and in some patients with familial adenomatous polyposis (FAP).¹ Given that the colon is a metabolically active organ with a density of microbes, and its primary role is water and salt reabsorption, removal of the colon results in potential functional deficits. As the ileal mucosa within the pouch adapts to assume colonic functions, the ideal outcome is normal defecation without the development of de novo inflammation. The first 6-12 months following restoration of the fecal stream is generally considered the adaptation period, during which stool frequency normalizes and the pouch undergoes structural, microbial, and functional changes to serve its new reservoir role. A conceptual model of ileal pouch adaptation has been illustrated in Figure 1.

Figure 1.

Key physiological adaptations after ileostomy closure.

In reality, adaptation of the ileum to colonic conditions is often incomplete, which has implications for the structural integrity and function of the pouch, including the potential development of inflammatory complications. Pouchitis, the most common inflammatory complication of the pouch, is clinically characterized by increased pouch emptying, with possible nocturnal emptying, urgency, abdominal cramping, incontinence, and occasionally rectal bleeding or fever. Pouchitis is diagnosed based on clinical, histological, and endoscopic assessment,² often occurring before the adaptation process has matured, and develops in up to 70% of patients with UC within 12 months of closure of the protective ileostomy.³ A marked difference between the likelihood of pouchitis and the underlying disease has also been observed, with a prevalence of 32% in UC compared with 6% in FAP.⁴ Taken together, these data highlight roles of both intrinsic and extrinsic factors that contribute to risk of pouchitis. Understanding these factors may help identify those patients at greatest risk and potential opportunities for preventive therapeutic strategies.

Thus, the first aim of this review was to understand the functional, morphological, luminal, and immunological adaptations that take place in the ileal pouch in health; second, to identify factors that influence these outcomes in the context of patients with pouchitis; and third, to explore how clinical strategies may be designed to address these factors, with the goals of optimizing pouch function and preventing inflammatory complications.

Functional adaptations

Critical to better functional outcomes from an ileal pouch are pouch compliance and the ability to maintain anorectal function. Pouches that have maximal volumes or capacity to hold stool similar to that of a rectum have better functional and clinical outcomes, including decreased stool frequency and the ability to defer defecation for longer.^5–8 Pouch volume increases over the first 6 months to be similar to that of a rectum (300-400 mL) and stabilizes by the end of the first year.^5,9 Maintenance of healthy anal resting and squeeze pressures that are close to those in a healthy rectum are associated with better outcomes, such as improved pouch emptying frequency and reduced leakage.^8–10

On the contrary, a low initial pouch volume was found to be indicative of low pouch volume at 1 year postsurgery and was found to be associated with pouchitis.⁹ Additionally, failure to relax pelvic muscles and excessive straining are associated with poor pouch emptying and have been speculated to contribute to the development of pouchitis.¹¹

Pouch compliance and volume may be influenced by modifiable and nonmodifiable factors, including surgical characteristics or age. A longer length of ileal segment used for pouch construction was associated with a larger, more compliant pouch with better functional outcomes.⁹ The W-pouch was initially proposed to provide superior function due to its larger volume; however, although improved function compared with the J-pouch was observed 1 year postsurgery, these differences diminished over a 9-year follow-up.¹² Consequently, the J-pouch continues to be accepted as the preferred design due to ease of construction and satisfactory long-term functional outcomes. Additional patient-related nonmodifiable factors, such as age and sex, have been explored, although studies have not consistently demonstrated differences in pouch function across cohorts.^9,10 However, in a study of 125 patients assessed 6-8 months postoperatively, age was associated with reduced pouch compliance and impaired reservoir–sphincter pressure dynamics.⁸ In contrast, there are comparatively limited data evaluating the role of modifiable factors such as diet and smoking on pouch compliance and functional outcomes.

The reflex response of ileal motility to meals does not adapt following pouch formation.⁷ The presence and persistence of the postprandial increase in tone in the ileoanal pouch, in contrast to relaxation in the normal rectum, may negatively affect its function as a storage organ, as indicated by the association of suboptimal pouch functioning with greater postprandial reduction in pouch volume.¹³ The practical implication is that the urge to empty the pouch after meals is not likely to improve over time.

Epithelial adaptations

A consistent and prominent change in the mucosal architecture of the ileum after pouch surgery is the blunting of villi, a feature that makes the pouch mucosa more “colonic” in appearance. Figure 1 details the epithelial adaptions as the pouch progresses over time. Reductions in villous length, crypt elongation, and histological signs of inflammation are seen in the first 6-12 weeks after ileostomy closure, and this appearance persists after 6 months in healthy pouches.^14–16 Villous blunting becomes more severe if pouchitis develops. Patients with antibiotic-responsive pouchitis have subtotal or total villous atrophy, and those with chronic pouchitis appear to have severely disturbed villous architecture.^17–19 The villous changes can be transient and shift between a more flattened state during pouchitis and elongation after successful antibiotic treatment,^17,18 suggesting a microbiota-driven mechanism. The changes in epithelial and subsequent surface morphology could be related to the shortened lifespan of the epithelial cells due to inflammation (a response observed in active celiac disease) and the harsh luminal microenvironment.

Mucous layer

Adaptation of the ileal mucous layer in the ileal pouch is limited. The mucous does not form a double layer as seen in the colon, a finding indicating that bacteria and macromolecules within the lumen could more readily penetrate to the epithelium.²⁰ The mucins in the single layer are attached to the goblet cells and are released by an endogenous protease, which requires interaction with microbiota to be activated.²¹ Reductions in mucosal thickness, which can be related to increases in mucin-degrading bacteria, have been seen in UC.²¹ However, little information about the thickness of the mucous layer in ileal pouches is available to assess whether mucins are prematurely released by this system.

Mucous degradation by bacterial enzymes within the lumen appears to be heightened in pouchitis compared with mucous degradation in normal pouches, potentially affecting the structural integrity of the mucous layer.²² However, to our knowledge the rate of such degradation compared with that in the colon has not been investigated. The composition of the carbohydrate side chains of mucins differs in the ileum compared with the colon. Compared with the majority of goblet cells in the lower parts of the crypts in the colon, <3% of goblet cells express sulphomucins in the normal ileum, which typically produces sialomucin. However, in the J-pouch, this percentage increased to 10%.²³ Given that the degradation of sulphomucins yields sulfates, substrates that are utilized by sulfate-reducing bacteria. the relationship between the mucous structure, bacterial composition, and pouchitis warrants closer investigation.

Whether adaptations in the type of goblet cells are favorable to barrier function is not known. However, increases in the density of sulphomucin-producing goblet cells have been associated with poorer outcomes. For example, 12 patients with a UC pouch, who are more likely to develop pouchitis, had greater concentrations of sulphomucins in the pouch mucous layer compared with 9 patients with an FAP pouch.²⁴ Additionally, in a retrospective evaluation of 50 ileal pouch patients, those with poor outcomes defined as diffuse inflammation of the pouch body or pouch fistula had a greater percentage of sulphomucin-producing goblet cells than those without such complications.²³ It is challenging to see how adaptations to increase sulphomucin production are protective for mucosal homeostasis.

Adaptations in epithelial barrier function

Hypothetically, because it must cope with exposure to a microbe- and macromolecule-rich luminal environment, the barrier function exerted by the epithelium and mucous layer in a pouch must be more efficient than that in the normal ileum. However, the lack of adaptation of the pouch mucous layer places more demands on the epithelial barrier. Epithelial permeability, which is inherently greater in the small compared with the large intestine, has been examined by 2 studies with similar findings.^25,26 Different measures of permeability were applied in these studies; 1 study examined barrier function by directly administering ethylene diamine tetracetic acid (EDTA) with radioactive chromium (⁵¹Cr-EDTA) into the pouch and the amount passing through the epithelium was quantified in urine samples, ²⁵ while the other study examined tight junction protein expression.²⁶ In both studies, the pouch had evidence of increased permeability when protected by an ileostomy. However, permeability decreased once luminal flow (closure of the ileostomy) was established, as outlined in Figure 1. The reductions in permeability inversely correlated with the degree of villous atrophy and sulphomucin production as markers of epithelial injury.²⁵ Furthermore, permeability in a healthy pouch was similar to that in the rectum of patients with inactive UC.²⁵ When pouchitis develops, permeability increases as might be anticipated.^25,26 Both studies were limited by small sample sizes, but the consistency of findings was reassuring. Further studies in larger cohorts of patients using reliable methods, such as the lactulose:rhamnose dual sugar test, or plasma biomarkers, such as such as lipopolysaccharide and intestinal-type fatty acid binding protein (IFABP), to confirm such findings are required.

Adaptations in the mucosal immunological compartment

The mucosal immune system forms an important protective barrier in the pouch mucosa. While several immune components could plausibly change during adaptation or pouchitis, many remain poorly studied. Accordingly, features of immunological adaptation and abnormalities in pouchitis for which data exist are discussed below.

Paneth cells: These specialized epithelial cells increase in density from the proximal to distal small intestine but are not found in the normal colon. Their presence, however, can be induced in an inflamed colon. These cells play key roles in the secretion of trophic factors (to support stem cell differentiation) and a range of antibacterial molecules, such as α-defensins and lysozyme.²⁷ Paneth cell dysfunction, manifesting, for example, as reduced secretion of α-defensins, has been postulated to play pathogenic roles in Crohn disease.²⁷ A Paneth cell subtype, morphologically identifiable according to the size and distribution of their cytoplasmic granules, is commonly seen in Crohn disease and has been associated with defective secretory function,²⁸ providing a potential window to Paneth cell dysfunction in other conditions. In a large cohort of patients with UC having colectomy with creation of an ileoanal pouch, 27% had the abnormal type 1 phenotype and this was associated with subsequent complications, such as postsurgical diagnosis of Crohn disease of the pouch and time to first episode of pouchitis.²⁸ Hence, Paneth cell dysfunction may not be specific to Crohn disease but may play a role in pouchitis.

Paneth cells have received limited attention in the adaptation of the ileum after creation of a pouch. The secretion of α-defensins increases after pouch formation and there is a further 2-fold increase when pouchitis develops.²⁹ Lysozyme expression in pouchitis is reduced but transcription is increased—these changes may therefore be driven by the increased bacterial load within the pouch.²⁷ It seems reasonable to postulate that enhancement of Paneth cell secretory function prior to exposing the pouch to an increased bacterial load might be an effective preventive action.

Intraepithelial lymphocytes : There is a decreasing gradient of density of intraepithelial lymphocytes (and of eosinophils and mast cells) from the proximal to the distal ileum.³⁰ Within 5 days of pouch formation, the density of intraepithelial lymphocytes significantly decreases³¹ and reaches densities similar to those in the colon. This process could be an adaptation to the new microenvironment or due to increased crypt cell turnover in the pouch. However, their density healthy pouches is similar in to that in the presence of pouchitis,³² suggesting that this is an appropriate adaptation for the new microenvironment of the surface epithelium.

Dendritic cells: These cells are present in Peyer’s patches in the ileum and colonic lamina propria, and are key cells in antigen presentation. Dendritic cells are phenotypically heterogeneous and their functionality differs depending on their local environment: small-bowel dendritic cells encounter more dietary antigens, whereas colonic dendritic cells are exposed to a greater density of microbes.³³ Correspondingly, gut-homing markers differ, with CCR9 expressed in the small bowel and integrin β7 in the colon.³³ Few studies have been performed in ileoanal pouch mucosa, but expression of integrin β7 and increases in expression of CCR9 were reported during the first 12 months in 5 patients.²⁶ Expression of integrin β7 was also higher in patients with pouchitis compared with those without.²⁶ Thus, these changes to dendritic cells appear to parallel some of the colonic type adaptations, reflecting appropriate change in recognition of the microbial environment.

Toll like receptor-4: Toll like receptor-4 (TLR4) receptors recognize pathogen-associated molecular patterns (PAMPs) enabling them to initiate immune responses. Their expression is upregulated within the first 3-24 months postsurgery in UC pouches and further increase in patients with pouchitis.³⁴ Expression of TLR4 was also higher in UC pouches compared to FAP pouches.^34,35 This activation of TLR4 and consequential inflammatory cellular response could be one mechanism by which UC pouches are more prone to the development of pouchitis. This myriad of changes could reflect an appropriate response of the immune system to an increasing need for protection or an abnormal response to the new luminal environment.

Cytokines: Mucosal concentrations of inflammatory cytokines both prior to and following colectomy have been shown to be elevated. Increased expression of interferon- γ (IFN-γ) preoperatively was identified in a retrospective analysis (n = 68) to be an independent risk factor for the development of pouchitis, suggesting potential ileal immune activation prior to colectomy.³⁶ Similarly, a retrospective analysis (n = 417) found exposure to anti–tumor necrosis factor (TNF) therapy prior to surgery was an independent risk factor for the development of pouchitis.³⁷ The exact mechanisms underlying this finding are not clear—anti-TNF exposure may alter the immune-microbial environment and predispose the pouch to more inflammation, or alternatively, could be a marker of disease severity prior to colectomy. Furthermore, after pouch construction, concentrations of interleukin-1β (IL-1β), IL-6, IL-8, and TNF-α significantly increased within 3 months and remained elevated at 12 months after pouch construction even in patients who do not develop pouchitis.³⁸ Such studies have revealed no specific patterns or insights into the pathogenesis of pouchitis and almost certainly reflect responses to a more hostile environment. Nonetheless, the relationship between preoperative immune activation, prior exposure to immune-modifying therapies and subsequent immune adaption within the pouch represents an important opportunity for future study.

Lymphocytes: Lymphocyte behavior and phenotypic profiles change within the ileal mucosa after pouch formation. Phenotypic profiles of mucosal lymphocytes using flow cytometry have shown differences between patients with UC and FAP, but no outstanding differences in those with or without pouchitis.³⁹ Interpretation of such data in terms of what is “normal” vs potentially pathogenic is unclear.

Adaptations in the luminal compartment

Water and electrolyte reabsorption

Indicative volumes/weights of fecal or pouch output in various clinical situations is illustrated in Figure 2 and shows the adaptation that occurs.^40,41 Adaptive mechanisms may include increased surface area along with increased epithelial surface area with hyperplasia of villi, as demonstrated in rats,⁴² increased production of short-chain fatty acids (SCFAs) within the pouch over time after ileostomy closure that might stimulate sodium and water absorption in the ileal pouch, as it does in the colon,⁴³ and modulation of the aldosterone-renin system. Plasma concentrations of these hormones are elevated during ileostomy and normalize once continuity with the ileoanal pouch is re-established,⁴¹ suggesting an important role early after pouch creation, while other adaptive mechanisms are maturing.

Figure 2.

24-hour fecal/effluent output of patients with a colon compared to patients across pouch surgeries.

Pouch bile acid physiology

The absorption of primary bile acids, bacterial conversion of primary to secondary bile acids, and their subsequent absorption are processes that usually occur over a longer period in the colon. However, in the pouch, the loss of absorptive surface may impair absorption of bile acids, with a subsequent accumulation of primary bile acids causing damage to epithelial cells and increased loss of bile acids from the bile acid pool undergoing enterohepatic circulation.^44,45 The short transit time impairs the bacteria conversion of primary to secondary bile acids.⁴⁶ Indeed, fecal excretion from a small cohort of ileoanal pouch patients was found to have higher proportions of cholic acid and chenodeoxycholic acid compared with that from healthy controls,⁴⁵ and a reduced bile acid pool was observed in one small study.⁴⁷ Studies examining bile acid excretion, however, vary in their results, most likely due to heterogeneity in bile acid assessment methodology across studies.^44,48

Alterations in bile acid composition appear to influence pouch health and risk of pouchitis. These alterations are illustrated in Figure 1. One study reported that UC pouches (with and without a history of pouchitis) had lower levels of lithocholic and deoxycholic acid relative to those in FAP pouches. The other study found lithocholic acid to be lower in patients with chronic pouchitis and primary sclerosing cholangitis compared to those with chronic pouchitis alone or healthy pouches.^49,50 Decreased bacterial diversity in the pouch may also limit the ability to convert primary to secondary bile acids, thus reducing the antibacterial effects of secondary bile acids in the pouch and increasing the risk of mucosal inflammation.⁴⁹ Supporting these observations, lithocholic acid abundance was positively associated with species richness, while in contrast, cholic acid, a primary bile acid, was negatively associated with species richness.⁵⁰ Together, these data provide preliminary evidence that secondary bile acid composition, which is shaped by the gut microbiota, could play a part in protecting against pouchitis.

Pouch microbiome

Bacterial communities undergo dynamic changes following surgery. While the protective ileostomy is functioning, bacterial density is low; however, following stomal closure, there is a progressive increase in total abundance and diversity of species over time after stomal closure.⁵¹ Not surprisingly, an increase in “colonic” species, such as Clostridium coccoides, Clostridium leptum, Bacteroides fragilis, and Atopobium, albeit, in lower concentrations than in a healthy colon,⁵¹ with a concurrent decline in ileal-predominant species such as Enterococcus faecalis, has been observed.⁵² Following adaption, the ileal reservoir harbors a lower overall density compared to the normal colon, with compositional shifts including increased proportions of Proteobacteria and decreased Bacteroidetes and Lachnospiraceae.^53,54

The association of microbial composition with the development of pouch inflammation has been investigated by several groups. A “dysbiotic signature” in the feces prior to colectomy—characterized by the presence of the mucus-degrading Ruminococcus gnavus, Bacteroides vulgatus, and Clostridium perfringens and absence of saccharolytic bacteria, Blautia and Roseburia, was predictive of the subsequent development of pouchitis in a prospective evaluation of a cohort of patients with UC.⁵⁵ Sulfate-reducing bacteria were found exclusively in 80% of the UC pouches in patients who developed pouchitis, compared to FAP pouches without pouchitis.⁵² Subsequent studies identified that the risk of pouchitis applies to the abundance of specific sulfate-reducing bacterial families such as Desulfobulbaceae.^54,55

The community structure of luminal microbiota changes in the presence of pouchitis. In acute pouchitis, consistent associations of increased Clostridia and a decrease in Enterococcaacae were observed, while an increased density of Staphylococcus aureus and decreases in Faecalibacterium prausnitzii and Clostridia were seen in chronic pouchitis.⁵⁶ Mirroring the reduced relative abundance of saccharolytic bacteria in pouchitis, metagenomic analysis revealed a reduced abundance of the gene encoding butyryl-CoA: acetate CoA transferase, a key terminal enzyme in the dominant microbial butyrate synthesis pathway, when compared with that in association with a healthy pouch, UC, or Crohn disease.⁵⁷ Whether such changes represent a cause or effect of inflammation, or both, is not entirely clear. For example, oxidative stress from inflammatory events in pouchitis leads to greater abundance of microbes with greater oxygen tolerance and those that encode more oxygen-detoxifying enzymes.⁵⁷ Importantly, most of the research to date has failed to account for confounders such as diet, smoking, alcohol consumption, and medications, limiting interpretability of results. Additionally, there is heterogeneity across both microbial assessment techniques (culture-based methods, 16 s rRNA sequencing, and shotgun metagenomics) and patient populations studied, with a lack of reproducible microbial signals between studies. Thus, results must be interpreted with caution, and future well-designed multi-omic longitudinal studies are essential to fill these knowledge gaps.

Fuel for the epithelium

Adaptation to generating energy for the ileal epithelium is likely since the pouch ileal mucosa is exposed to higher concentrations of butyrate and less glutamine than the normal terminal ileum. This characteristic has been addressed in 3 small studies,^61–63 in which glutamine oxidation was reduced in the healthy pouch (n = 18) compared with that of the ileum in patients with UC and an intact colon (n = 9), but butyrate oxidation was similar in healthy ileum (n = 17) compared with healthy pouches (n = 7). Butyrate oxidation was, however, reduced in the presence of pouchitis (n = 15),⁵⁸ which potentially could lead to relative energy deficiency and subsequent weakened integrity of pouch epithelium, a situation similar to that in the rectum during active UC.⁵⁹

Metabolites

The pouch epithelium is exposed to multiple metabolites from bacterial pathways, the spectrum of which will change with adaptation. All metabolites may potentially influence function and health of the epithelium and mucosa.

Short-chain fatty acids

Upon pouch formation, there is a transient reduction on fecal SCFA concentrations, which tend to increase over time after the restoration of the fecal stream (closure of the protecting ileostomy) due to the delivery of malabsorbed or indigestible carbohydrates to the pouch (Figure 1).⁶⁰ This means that physiologically, a well-functioning adapted pouch needs to be able to handle a much larger load of SCFA than it would prior to the pouch creation. SCFA absorption in the normal ileum is rate limiting and reaches saturation at ∼40 mM, while colonic absorption did not reach saturation even at ∼90 mM.^43,61–64 Whether this adapts in the pouch is not known. This, together with the thinner mucous layer, puts the pouch epithelium at risk of being exposed to toxic concentrations of SCFA. Conversely, there is less time for the bacteria to generate SCFA and this might lead to energy deficiency of the epithelium and reduction of the anti-inflammatory effects of butyrate.

The concentration of butyrate in pouch effluent changes over time. Within the first 10 days after surgery, fecal concentrations of butyrate were 2 mM, this increased to ∼10 mM after 6 months of adaptation,⁶⁰ while established pouches have a concentration of ∼16mM.⁶⁵ However, concentrations of SCFA are lower in the presence of pouchitis (16.5 mM no pouchitis vs 6.5 mM pouchitis),⁶⁵ but the clinical importance of this observation is uncertain. Direct administration of SCFA into the pouch of patients with chronic pouchitis as a strategy for increasing SCFA delivery has yielded limited success. One small study was discontinued after both patients deteriorated (both endoscopically and clinically) following administration of SCFA enemas in relatively high concentrations (sodium acetate 60, sodium propionate 30, and sodium butyrate 40 mM).⁶⁶ In 19 patients with pouchitis, clinical improvements were observed in 30% using butyrate suppositories (40 mM sodium butyrate BD) compared with 60% response with glutamine suppositories (2 g L-glutamine BD).^66,67 The limited success of increasing intraluminal delivery of SCFAs could reflect their injurious effects at high concentrations and a reduced ability of pouch enterocytes to utilize doses that exceed the ileal absorptive capacity. The frequency of administration (twice daily vs continuous) may also be inadequate to produce sustained effects as observed in rats.⁶⁸

Metabolites of protein fermentation

Phenolic compounds (p-cresol, phenol), hydrogen sulfide (H₂S; see section below), nitric oxide, and ammonia can be putatively toxic at high concentrations and exert damage to colonocytes.⁶⁹ For example, viability of colonic epithelial cells was reduced when exposed to high concentrations of phenols.⁷⁰ Whether these compounds exert the same toxic effects in the ileoanal pouch is unknown, given its distinct microenvironment. Compared to healthy controls, concentrations of fecal ammonia and BCFA were lower in patients with an ileoanal pouch⁷¹ and as the pouch adapted over time, these concentrations increased compared to immediately after surgery, reflecting the increasing metabolic activity of the pouch microbiota.⁶⁰ Interestingly, in a study comparing fecal metabolite profiles in patients with UC or Crohn disease, healthy controls, and pouchitis, sulfur-containing compounds were less commonly found in stool of patients with a pouch.⁷² A proposed theory is that the short transit time within the pouch limits bacterial metabolic activities compared with the colon.

Hydrogen sulfide

Hydrogen sulfide has been hypothesized to play a role in pouch health and inflammation based on current understanding of UC pathophysiology. Colonic production of H₂S has been implicated in the development of inflammation in UC, where UC patients have increased numbers of sulfate-reducing bacteria and H₂S release and reduced ability to detoxify H₂S.⁷³

The association of sulfate-reducing bacteria and the > 3-fold elevation of concentrations of fecal hydrogen sulfide in pouchitis compared with individuals with no history of pouchitis have implicated H₂S in the pathogenesis of pouchitis.⁷⁴ However, a recent cross-sectional assessment of volatile organic compounds in the pouch effluent from a small cohort of patients with a UC-pouch compared with that from patients with UC and an intact colon found that volatile sulfur compounds were virtually absent from the pouch effluent of these patients.⁷⁵ Hence, whether H₂S plays a pathogenic role requires further study.

Clinical implications of adaptations occurring in the ileoanal pouch

Ileoanal pouches are associated with considerable morbidity that ranges from suboptimal function to pouchitis. Current strategies for prevention and treatment are limited, compounded by existing research being inherently limited by small, underpowered sample sizes with heterogeneous patient cohorts and methodological inconsistencies. Notably, the lack of longitudinal studies examining pouch adaptation over time makes it difficult to determine whether observed changes are transient or represent sustained adaptations. Understanding these adaptations that occur in the ileoanal pouch, from its formation to maturation, may provide opportunities for preventive or therapeutic interventions that should be utilized or avoided. There are 2 main targets—pouch function as a reservoir and the pouch microenvironment (Figure 3).

Figure 3.

Targets and nonpharmacological preventive strategies to improve pouch mucosal resilience and function.

Preparing for and improving pouch emptying/functioning as a reservoir

There are 2 clear strategies for preparing for and improving pouch emptying/functioning as a reservoir. First, postprandial effects on ileal motility leading to urgency and emptying appear to affect all patients and do not apparently adapt over time. All patients should be advised on simple approaches such as changes in meal patterns or timing. For example, scheduling an earlier evening meal or having larger meals earlier in the day are sensible options to prevent excessive emptying of the pouch overnight.

Second, pelvic floor muscle training may improve compliance and anal/sphincter pressures, leading to reduced frequency of pouch emptying and/or incontinence. Ideally, such training should be instituted prior to pouch construction, or at least prior to stomal closure, to prevent pouch dysfunction, particularly in those reporting preoperative fecal incontinence, straining, and incomplete emptying.⁷⁶ However, randomized controlled trials of balloon training and anal sphincter strengthening exercises prior to stomal closure showed no difference in volume or anal sphincter pressures compared with the no-treatment group.^77,78 Once pouchitis has occurred, biofeedback training has been associated, albeit in retrospective studies, with improvements in stool frequency, incontinence, abdominal pain, and pelvic dyssynergia in up to 90% of patients in 1 study.^11,79 Resolution of pouchitis following biofeedback therapy was observed in 3 of 9 patients, suggesting that pelvic dyssynergia and prolonged stool retention may contribute to inflammation mediated through the pouch microbiota, although further studies are needed to confirm this mechanism.¹¹

Targeting/“correcting” pouch immune response

The main opportunity to nonpharmacologically strengthen the barrier offered by the innate immune system of the ileal mucosa lies with the Paneth cells. If their adaptation (increased secretion of antibacterial molecules) could be enhanced ahead of, rather than as a protective response to, the exposure to increased bacterial load, injury may be prevented and outcomes improved. Paneth cell generation might be increased by treatment with a growth factor such as the Wnt agonist, R-Spondin1, that, in mice, induced stem cells to differentiate into functionally activity Paneth cells.⁸⁰ Paneth cell secretion/degranulation is modulated by many factors that include cholinergic (parasympathetic) stimulation and exposure to bacteria or their structural molecules, like lipopolysaccharide, monocytes and lymphocyte-derived cytokines, butyrate, and leucine. Hence, an intervention such as vagal nerve stimulation may enhance the antibacterial clout of the Paneth cells in preparation for the fecal stream after ileostomy is closed. Alternatively, orally administered α-defensins or lysozyme may be administered to correct for their inadequate secretion; lysozyme, for instance, ameliorates pouchitis in a rat model.⁸¹ Human trials are much needed.

Modulating the pouch microenvironment

Therapies targeting the structure of the pouch microbiota

The structure and function of the pouch microbiota are heavily implicated in the development and treatment of pouch complications, as shown by the efficacy of antibiotics in pouchitis (reviewed elsewhere⁸²). However, it is not known whether the microbiota work via reducing the bacterial load or changing the community structure and therefore function.

The composition of the microbiota can be altered by several strategies. First, selective assistance for the growth of “beneficial” bacteria may be achieved with prebiotics. In a double-blinded, cross-over randomized controlled trial, endoscopic and histological signs of improvement were observed with supplementation of a high dose of inulin (24 g/d) in patients without pouchitis⁸³; however, there have been no follow-up studies.

Second, the effects of potentially beneficial microbes (probiotics) have been investigated. Early correction of “dysbiosis” as a preventative strategy via probiotic administration may establish a pouch environment that is resilient against inflammatory changes. In a proof-of-concept study in 20 patients immediately postsurgery, only 2 patients provided with a specific multistrain probiotic formulation developed acute pouchitis, compared with eight on placebo.⁸⁴ In a 5-year retrospective analysis in 55 children post–pouch formation, the subgroup receiving the probiotic Clostridium butyricum had lower rates of pouchitis (11%) than the control group (58%).⁸⁵ An underpowered trial in adults also suggested benefit over 24 months with, on per-protocol analysis, 1 of 7 patients developing pouchitis with the probiotic compared with 4/8 with placebo.⁸⁶ However, probiotic treatment once chronic pouchitis has developed has shown mixed results. For example, Lactobacillus rhamnosus GG administration in antibiotic-responsive pouchitis failed.⁸⁷ In patients with chronic antibiotic-dependent or refractory pouchitis, a multi-strain formulation was effective in maintaining remission in 2 double-blinded clinical trials,^88,89 but subsequent real-world experience showed reduced efficacy and poor persistence of therapy (20% intake at 8 months).^90,91 In summary, such promise of the benefits of probiotics in preventive or therapeutic scenarios has not translated to well-powered studies or into clinical practice.

Third, the microbiota can be reshaped via fecal microbiota transfer (FMT). Three placebo-controlled randomized controlled trials in patients with chronic antibiotic-dependent and chronic antibiotic-refractory pouchitis have investigated FMT delivery through different routes—orally, via pouchoscopy, and via enema—from healthy donors. Low engraftment rates, low clinical remission rates, and high relapse rates were seen across all 3 studies.^92–94 It is important to examine why such an approach has failed. The aim of creating a colonic microenvironment from feces of those with a colon might be misdirected, especially given the differences in microbial functionality of colonic compared with ileal/pouch microbiota. The effluent from pouches of patients not prone to the development of pouchitis, such as those from patients with FAP, may be more suitable to investigate. The timing of FMT could also be important. Rather than waiting until pouchitis becomes chronic, FMT could be used as a prophylactic strategy in those who have increased risk such as patients with primary sclerosing cholangitis.

Modulating bile acids

The concept that changing bile acid composition to prevent or treat pouchitis is reasonable given current understanding of their role, but clinical studies are limited. There are 3 potential strategies. First, the use of bile-acid sequestrants to bind primary bile acids that accumulate in the pouch may, for example, mitigate the detergent-like effects of excessive concentrations of chenodeoxycholic acid, which are elevated in pouches from UC patients with a history of pouchitis or with chronic pouchitis.⁴⁹ In a retrospective cohort study of 1136 patients with recurrent pouchitis, treatment with bile acid sequestrants delayed onset of pouchitis, even though risk of relapse was similar to antibiotics.⁹⁵ Second, increasing secondary bile acid concentrations could be achieved via direct supplementation or via reshaping the microbiota.⁴⁹ In mice with colitis induced by dextran sodium sulfate, lithocholic acid in drinking water ameliorated the disease.⁴⁹ Human trials applying this approach are currently underway.⁹⁶ Enhancement of the microbiota to produce secondary bile acids that are lacking is an option that is limited by the short transit time of the pouch.

Altering intraluminal concentrations of short-chain fatty acids

Based on the aforementioned nutritional/metabolic/anti-inflammatory effects of SCFA within the ileal reservoir, there may indeed be a “sweet spot” for butyrate or SCFA to exert beneficial effects. Instead of instillation of SCFA or butyrate into the pouch (as described above), SCFA can be delivered to the ileal mucosa by promoting bacterial fermentation as achieved by inulin supplementation.⁸³ Concentrations of SCFA were enhanced in the pouch effluent by this approach and improved outcomes in patients without pouchitis were achieved, but further application of this approach has not been forthcoming. As a strategy for treating pouchitis, where SCFA concentrations may be reduced, this approach is limited by the fact that prebiotics are FODMAPs, whose intake are reduced to ameliorate pouch-related symptoms.⁹⁷ SCFA-optimizing strategies are challenged by lack of understanding what the target concentration (the “sweet spot”) is and the need for rigorous dietary control in any such studies. To address this lack of knowledge, a dietary trial investigating the effects of varying quantities of fermentable fiber on pouch function and microbial fermentation is currently underway, alongside complementary ex vivo fermentation studies examining microbial fermentative capacity (ACTRN12625000821493 and ACTRN12624000912583).

Altered protein fermentation/sulfate reduction

Reducing products of microbial protein fermentation, such as H₂S, has been proposed as a therapeutic target in ileoanal pouches, as it is in UC.⁹⁸ For example, the Monash Pouch Diet was designed to reduce the hypothesized increased pouch production of H₂S together with increased production of SCFA.⁹⁹ In a proof-of-concept/tolerability study, there were signals of efficacy.¹⁰⁰ However, in a subsequent double-blinded feeding trial, both the Monash Pouch and control diets were poorly tolerated, with worsening symptoms, leading to early termination of the trial.⁹⁹ It is likely that the design of the dietary trial underpinned the intolerance to both diets. However, analysis of metabolites in pouch effluent from 11 patients consuming their habitual diet showed reduced presence of protein fermentation and sulfur metabolites compared with those in feces from patients with UC and an intact colon, despite having very similar dietary protein consumption.⁷⁵ Although larger studies into these metabolites are needed, these data certainly raise interesting questions around translatability of UC pathogenesis to pouchitis.

Conclusion and future directions

The ileoanal pouch represents a unique and complex adaptation to serve ileal and colonic functions. This transformation encompasses extensive anatomical, physiological, immunological, and microbial changes. While many of these adaptations are beneficial and essential for optimal pouch function, others may accelerate existing histological inflammation to develop pouchitis. Evidence indicates that successful adaptation involves moderate morphological shifts, whereas exaggerated or aberrant changes, such as excessive villous atrophy, disrupted mucous layers, immune cell dysfunction, altered microbial communities, and impaired epithelial barrier function correlate with poor outcomes and increased risk of pouchitis. Despite the volume of descriptive research, there remains a substantial gap in understanding the causal mechanisms linking these alterations to disease onset and activity. Additionally, current therapies for pouchitis that aim to simulate the physiological or microenvironment of the colon have yielded limited success. Therefore, future research should prioritize longitudinal, mechanistically informed studies that explore the dynamic interplay between pouch structure, microbiota, immune responses, and dietary influences. This knowledge will be critical to developing prophylactic strategies, and tailored interventions that sustain pouch health and reduce the burden of pouchitis.

Author contributions

D.R.J. conceived the concepts and wrote the paper. C.K.Y., Z.S.A., P.R.G., E.P.H., and J.S. all conceived the concepts and edited the paper. All authors approved the final version of the manuscript.

Funding

No specific funding was received for this work. D.R.J. was in receipt of an RTP stipend from Monash University.

Conflicts of interest

E.H. declares research grants for investigator-driven studies from Mindset Health; received honoraria or consulted for Ferring, Janssen, Abbvie, Takeda, Shire, Sandoz, Dr Falk Pharm, and Mindset Health. Board member of GI DREAM Ltd. D.R.J. has received an honorarium from Yakult and Johnson & Johnson and conference support from Viatris. P.G declares consultant or advisory board member for Anatara and Comvita; research grants for investigator-driven studies from Mindset Health, and shareholder in Atmo Biosciences. Chu K. Yao has received research grants for investigator-driven studies from Atmo Biosciences and travel honoraria from Viatris, Yakult Australia, Dr Falk Pharma and Sandoz. The Department of Gastroenterology, which D.R.J., , E.P.H., P.R.G., and Z.M.A. are from, financially benefits from the sales of a digital application, booklets, and online courses on the FODMAP diet.

Data availability

No new data were generated or analyzed for this review.