The appendix and ulcerative colitis - an unsolved connection

Abstract

The appendix is thought to have a role in the pathogenesis of ulcerative colitis, but the nature and basis of this association remains unclear. In this Perspective, we consider the biology of the appendix with respect to its immunological function and the microbiome, and how this relates to evidence that supports the involvement of the appendix in ulcerative colitis. In experimental models, removal of the inflamed appendix prevents colitis, and in human observational studies, appendectomy is associated with protection against ulcerative colitis. Further, among people who develop ulcerative colitis, appendectomy before diagnosis might influence the course and outcomes of the disease - some evidence suggests that it protects against colectomy but could increase the risk of colorectal cancer. Appendectomy after onset of ulcerative colitis seems to have disparate consequences. Clinical trials to understand whether appendectomy has a role in the treatment of ulcerative colitis are ongoing. Major questions about the role of the appendix in the pathogenesis of ulcerative colitis remain unanswered, and further research is needed to establish whether the connection is clinically relevant.

Figure 1 |. The immunological composition and function of the appendix in health and ulcerative colitis.

a, A microcosm of the mucosal immune system in the appendix. In health, lymphoid aggregates are sites of immune priming. Microfold (M) cells, which permit ingress of luminal antigens, are in close proximity to antigen-presenting cells, such as dendritic cells, in the subepithelial dome, or lymphoid aggregate. Dendritic cell-mediated, non-inflammatory immune priming is accompanied by the induction of α4β7 integrin, such that the T cells and B cells that egress from the lymphoid tissues of the appendix are imprinted to localize back to the intestines. Other immune cells, including tissue-resident macrophages, maintain homeostasis in health. Finally, luminal bacteria ‘seed’ the colon (left), especially after depletion of colonic microbial communities. b, Proposed dysregulation in the immune function of the appendix in ulcerative colitis. The appendiceal microbiota and biofilm are altered. These changes are associated with non-physiological priming of immune responses, potentially via non-M-cell-dependent pathways as a result of epithelial disruption, leading to induction of pro-inflammatory T cells and B cells. After these cells egress from the appendix to the circulation, they localize back to the colon, owing to the induction of α4β7 integrin, and contribute to inflammation. The altered appendiceal microbiome could also contribute to colonic dysbiosis (left). Illustration by Jill K. Gregory, adapted with permission of © Mount Sinai Health System.

Figure 2 |. Proposed relationships between appendicitis, appendectomy and the risk of ulcerative colitis and its outcomes.

a, In healthy people, appendectomy as a result of appendicitis at a young age or of other indications for the procedure is associated with a reduced lifetime risk of ulcerative colitis relative to the risk in the general population. Whether appendicitis at a young age or appendicitis in a first-degree relative are associated with a reduced risk of ulcerative colitis independent of appendectomy is unknown, but some evidence indicates that these hypotheses should be studied further. b, In individuals with ulcerative colitis, appendectomy as a result of appendicitis at a young age is associated with a reduced risk of colectomy relative to individuals with ulcerative colitis who do not undergo appendectomy. Appendectomy in people with ulcerative colitis is also associated with an increased risk of colorectal dysplasia, although whether this association is a direct result of appendectomy or a consequence of the reduced risk of colectomy is unclear. Whether appendicitis itself is associated with the increased risk of colorectal dysplasia requires further investigation. Illustration by Jill K. Gregory, adapted with permission of © Mount Sinai Health System.