Until recently, the appendix was considered a rudimentary component of the human intestine with no discernible function. However, a recent systematic review, The link between the appendix and ulcerative colitis: clinical relevance and potential immunological mechanisms,¹ has changed that thinking. The aim of this review is to understand the proposed immunological role of the appendix in both health and disease, in particular ulcerative colitis (UC).

Evolutionary perspective

The commonly held view of the function of the appendix was that its primary job was to ferment plant-derived cellulose by creating a home for particular cellulose-degrading symbiotic bacteria. This resulted in a longstanding view that the human appendix is no more than a vestigial remnant – an organ that lost its function during the evolution of our species. However, recent studies have suggested that the appendix functions as a ‘safe-house’ for normal colonic flora, and that it may act as a reservoir from which normal microbial diversity could rapidly recover after gastrointestinal infections.

Appendectomy and risk of developing IBD

The correlation between appendectomy and inflammatory bowel disease (IBD) was first reported in 1987, when a large case-control study reported a significantly lower appendectomy rate in patients with UC compared to healthy controls, with reverse findings in Crohn’s disease. This finding was paid little attention until other studies consistently found these results in UC patients compared to controls. More recent studies show that the decreased incidence of UC after appendectomy is seen mostly in patients under the age of 20 years. The review evaluated 38 case-control studies, which included 15,114 UC patients, overall showing there was a significant inverse association between an appendectomy and the development of UC with an overall odds ratio of 0.39 (95% CI: 0.29 to 0.52). However, caution was advised with this data due to the retrospective character and small sample sizes of some studies while studies published in the 1990s did not always match their controls to the cases or control for confounding factors.

As well as the case-control studies, four population-based studies evaluated the incidence rate ratios of UC post-appendectomy. Three of these studies showed a significantly lower UC incidence rate in patients post-appendectomy compared to control patients. The largest population-based study showed a significant finding addressing the question of whether the preventive effect of appendectomy is connected to an underlying pathology or to the operation itself. This study had 709,353 participants from Sweden and Denmark and demonstrated there was a significantly reduced risk of UC in patients who underwent an appendectomy for appendicitis (0.45, 95% CI: 0.39 to 0.53), while an appendectomy without underlying inflammation showed no reduced risk (1.04, 95% CI: 0.95 to 1.15).

The association of appendectomy and Crohn’s disease patients remains difficult to establish as clearly, most likely due to issues with the differential diagnosis between appendicitis and Crohn’s disease.

Effect of appendectomy on established disease

There has been discussion about the potential therapeutic effect of appendectomy on the course of UC, but the results are limited and conflicting. Six observational studies were identified, totalling 2,532 IBD patients, with the majority of these studies showing a beneficial effect of appendectomy while a few studies showed no effect or even a detrimental effect.

However, more recent studies have shown a moderate decline in hospital admission rates for disease recurrence and a moderate decline in steroid use post-appendectomy.  The review highlights a case-series study by Bolin et al, which show results from a prospective cohort of ulcerative proctitis patients; 30 patients were treated with appendectomy, resulting in 90% showing significant improvement in their clinical colitis activity index. A total of 40% of those patients experienced complete resolution of their symptoms resulting in withdrawal of pharmacological treatments.

Overall, the majority of studies show some benefits for the course of UC following appendectomy, but no studies have been performed in a controlled prospective manner and thus only such a study will give the definitive answer.

The appendix and Clostridium difficile

While the systematic review mainly discussed the association between the appendix and UC, it mentioned that there are growing reports of a possible link between the appendix and Clostridium difficile colitis. 

Upon review of a handful of these reports, it is clear that there is conflicting evidence in terms of appendectomy and recurrent C. difficile colitis. 

However, many of these reports agreed that thorough level I research should be carried out in order to establish if there is a link.

The mechanistic link between appendix and UC

Despite strong epidemiologic evidence of the protective effects of appendectomy, the molecular mechanism between appendectomy and UC is unknown. However multiple theories have been proposed, including: 

Dysbiosis

Aberrant IgA-producing B cell and 

Role of natural killer T (NKT) cells.

Dysbiosis

Dysbiosis is a microbial imbalance in or on the body. In UC, the depletion of goblet cells and a defective inner mucin layer may allow bacteria to penetrate the lumen. It is speculated that aberrant interaction of gut flora contributes to the inflammatory response in UC. Due to the hypothesis in which the appendix may be a reservoir for commensal bacteria, an appendectomy may be beneficial in preventing re-colonisation of the gut.

IgA-producing B cell

Murine studies have shown that the appendix operates in a critical capacity in the generation of IgA-producing B cells that home to the colon, but not the small intestine. It has been suggested that UC patients have an aberrant range of IgA-producing B cells which may encourage a colitogenic microbiome associated with a causative role in UC.

NKT cells

The role of these cells in IBD is elusive, however increasing evidence suggests NKT involvement in UC. A previous study has shown a correlation between UC and abnormal Th2-type response, mediated by interleukin-13 (IL-13), producing NKT cells. This is due to the effect of IL-13 in which epithelial barrier function is impaired therefore increasing the contact to luminal content and UC predisposition. This is relevant to the appendix as it has a higher proportion of NKT cells than the colon and small intestine. However, a recent clinical trial in which IL-13 was blocked in patients with UC has been convincingly negative.

Conclusion

The epidemiological data shows strong evidence that appendectomy is protective against the development of UC and has shown benefits in terms of decreasing relapse rates, lower colectomy rates and moderate decline in hospital admissions for disease relapse as well as steroid use. A well designed prospective study is required for level I evidence to be generated, only then will we be able to definitively restore the appendix to the status of organ of influence.

References

1. Sahami S, Kooij IA, Meijer SL et al. The link between the appendix and ulcerative colitis: clinical relevance and potential immunological Mechanisms. Am J Gastroenterol 2016 (Feb);111(2):163-9