Epithelial wound healing in inflammatory bowel diseases: the next therapeutic frontier

Abstract

Patients with one of the many chronic inflammatory disorders broadly classified as inflammatory bowel disease (IBD) now have a diverse set of immunomodulatory therapies at their disposal. Despite these recent medical advances, complete sustained remission of disease remains elusive for most patients. The full healing of the damaged intestinal mucosa is the primary goal of all therapies. Achieving this requires not just a reduction of the aberrant immunological response, but also wound healing of the epithelium. No currently approved therapy directly targets the epithelium. Epithelial repair is compromised in IBD and normally facilitates re-establishment of the homeostatic barrier between the host and the microbiome. In this review, we summarize the evidence that epithelial wound healing represents an important yet underdeveloped therapeutic modality for IBD. We highlight 3 general approaches that are promising for developing a new class of epithelium-targeted therapies: epithelial stem cells, cytokines, and microbiome engineering. We also provide a frank discussion of some of the challenges that must be overcome for epithelial repair to be therapeutically leveraged. A concerted approach by the field to develop new therapies targeting epithelial wound healing will offer patients a game-changing, complementary class of medications and could dramatically improve outcomes.

Fig 1.

Histological features of colonic epithelium during murine colitis and mucosal healing. Displayed are transverse colonic sections stained with hematoxylin and eosin. These tissues were obtained from HSP25−/− mice, which exhibit delayed wound healing responses and thereby facilitate visualization of different aspects of injury and healing within the same tissue section. The left panel shows a transverse section of uninjured mouse colon. Note that crypts are uniform and undistorted, and few immune cells are present in the lamina propria. In contrast, the right panel shows the colon 1 4 d after the induction of colitis via a 5-d treatment with 3% dextran sulfate sodium (DSS). DSS treatment caused thickening of the colon and severe epithelial damage. This colon is in various states of wound healing. Restitution, the rapid resealing of eroded mucosa by epithelial cells, is accompanied by a massive immune infiltration into the lamina propria at multiple sites. Lymphoid follicles are enlarged. Regenerative epithelial changes include the formation of 3-dimensional wound channels, the morphological distortion of crypts, including their adoption of bifurcating/branching structures, and crypt hyperplasia, which may be associated with expansion of the progenitor cell zone. Photomicrograph credit: Yun Tao, PhD.

Fig 2.

Schematic of key mucosal tissue systems involved in colonic epithelial wound healing. Interactions between these systems and the epithelium could be therapeutically leveraged to restore normal mucosal architecture and barrier function. The inflammatory process of 1BD induces ulcers and epithelial erosions. At the site of the open wound, crypts adopt a “wound channel” structure, through which intestinal epithelial cells quickly migrate to re-fonn a rudimentary barrier. This process is known as restitution and does not require cell proliferation. Rapid closure of ulcers is critical to prevent gut microbes from further entry into the host. Crypts undergo morphological changes associated with stem cell proliferation to sustain wound closure and to restore the normal pattern of epithelial structure, cellular differentiation, and barrier function. Signals associated with immune cells, wound-associated mesenchyme, and the microbiome promote epithelial wound healing. For example, growth factors, cytokines, microbial metabolites and short-chain fatty acids, and microbial-associated molecular patterns modulate wound healing responses. Further understanding of these cellular and molecular interactions, and distinguishing their pathological versus beneficial effects, will advance potential therapies for mucosal healing in 1BD. Created using Biorender (biorender.com).