Cellular and molecular mechanisms in the pathogenesis of pouchitis: more than just the microbiota

Abstract

Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis. Antibiotics remain the first line of therapy for pouchitis, but the majority of patients develop subsequent episodes and some are refractory to antibiotic therapy. This highlights the need for more effective treatment options and points to a more complex pathophysiology beyond the role of th pouch microbiome, similar to what is seen in inflammatory bowel disease. In this review, we outline the putative mechanisms of pouchitis, including genetic predisposition, microbiome alterations, dysfunction of the intestinal barrier and the immune system and review the available animal models of pouchitis. In addition, we introduce the concept of pouchitis as a possible transmural disease and discuss the potential role of non-immune cells, including stromal cells, in perpetuating inflammation and intestinal barrier dysfunction. We discuss future directions, implications for novel therapies and propose novel multicellular disease models that can better capture the complexity of pouchitis pathogenesis.

Keywords: GASTROINTESTINAL PHYSIOLOGY; ILEOANAL POUCH; POUCHITIS; ULCERATIVE COLITIS.

Figure 1.. Adaptation of intestinal mucosa after J pouch creation (colectomy followed by IPAA).

Physiological small bowel microbiome, comprised of predominantly facultative anaerobic bacteria, and epithelium, comprised of enterocytes, stem cells, Paneth cells, Tuft cells and Enteroendocrine cells. In contrast, the colonic microbiota is composed of predominantly obligate anaerobic bacteria. Following colectomy and pouch creation, there is a shift in the bacterial composition, which becomes predominantly anaerobic. Illustration of small bowel (A), with characteristic Paneth cells, and the large bowel (B), with characteristic mucus-producing Goblet cells, and the pouch epithelium (C) with colon-like features including villus atrophy and a mix of Paneth cells and Goblet cells. Abbreviations: IPPA (ileal pouch-anal anastomosis).

Figure 2.. Animal models of pouchitis.

A. Rat models of pouchitis. Colectomy is performed and the small bowel tissue is used to create a J-shaped pouch and anastomosis performed at the distal rectum. Three to 4 weeks after surgical procedure, rats are then treated with DSS orally (3–7 days) or TNBS rectally (once). B. Mouse model of pouchitis. Sefl-filling intestinal loops (SFL) were surgically created using 2.5 cm of ileal tissue, 3 cm proximal to the ileocecal valve. In this model fecal stasis in the SFL loop is achieved. Inflammation of the intestinal loop can then be induced by oral administration of 2% DSS for 3 days or IL10 knockout. Abbreviations: DSS (Dextran sodium sulfate); KO (knockout); TNBS (2,4,6-trinitrobenzenesulfonic acid).

Figure 3.. Pathogenesis of pouchitis with cell-cell interaction model.

The pathogenesis of pouchitis is complex and multifactorial involving the microbiome (dysbiosis), metabolite composition, variety of cell types (immune cells and non-immune cells) and tissue layers (mucosa, submucosa and possibly deeper layers) in a genetically predisposed individual. Following J pouch creation (using ileal tissue), fecal stasis occurs triggering a shift in the bacterial composition (from aerobic to anaerobic) and nutrient microenvironment (changes in availability of short chain fatty acids) to which the small bowel-derived epithelium is exposed. This leads to adaptation of the small bowel epithelium, which transitions to a colon-like epithelium over time. Dysbiosis likely plays a major role in the pathogenesis of pouchitis. The intestinal barrier, composed of tight junctions (occludin, claudins, ZO-1), adherens junctions and junction-associated actomyosin cytoskeleton, is disrupted in pouchitis. Downregulation of tight junction proteins has been demonstrated, while it is unclear if pouchitis-associated barrier dysfunction involves modulation of adherens junctions and/or junction-associated actomyosin cytoskeleton. Activation of both the innate and adaptive arms of the immune system occurs, resulting in upregulation of pro-inflammatory cytokines. Stromal cells (fibroblasts) likely play an important role in perpetuating inflammation and contributing to intestinal epithelial barrier. Abbreviations: TJ (tight junctions); AJ (adherens junction); AMC (actomyosin cytoskeleton); TNFSF15 (tumor necrosis factor superfamily member NOD2 (nucleotide-binding oligomerization domain-containing protein 2); TLR9 (toll-like receptor 9); ZO-1 (zonula occludens 1).