Appendix in ulcerative colitis pathogenesis and therapy: An updated narrative review

Abstract

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon. Its pathogenesis has been linked to chronic intestinal inflammation stemming from genetic predisposition, immune dysregulation, changes in gut microbiome, and various environmental factors. There is emerging evidence for autophagy dysfunction in the UC setting, suggesting a compromise of the intestinal epithelial barrier and microbial clearance in patients, resulting in chronic activation of the immune system. There is growing evidence that the appendix functions as a critical priming site for UC. Dysregulation of various lymphocyte subsets, dysbiosis, propagation of inflammation into the colon, as well as autophagy dysfunction, have been listed as contributing to this early appendiceal priming phase. While initially thought of as a vestigial organ, current evidence points towards the appendix as an active immunological and microbial hub. Epidemiological data demonstrate an inverse association between early appendectomy and UC risk, suggesting its potential as a therapeutic strategy. According to recent ACCURE (2025) and COSTA (2026) clinical trials, improved remission outcomes were observed post-appendectomy in selected patients, particularly in patients unresponsive to biologic therapy. Together, the evidence positions appendectomy as a legitimate adjunctive treatment option for UC, warranting further mechanistic and clinical investigation. In this narrative review, current evidence on the pathogenesis and risk factors of UC are summarized, including the emerging role of the appendix and the therapeutic potential of appendectomy in UC.

Key Words: Ulcerative colitis; Therapeutic appendectomy; Autophagy; Xenophagy; Immune dysregulation

Core Tip: Recent clinical studies indicate the potential of the appendix as an immunological and microbial niche in ulcerative colitis pathogenesis. Induction of immune dysregulation and acceleration of inflammation are associated with autophagy dysfunction in colonic cells, and possibly the appendix. Current evidence suggests the potential of appendectomy as an adjunctive therapeutic strategy, improving remission in selected patients.

INTRODUCTION

Ulcerative colitis (UC) is a chronic, immune-mediated inflammatory bowel disease (IBD) characterized by a relapsing-remitting inflammation of the colonic mucosa. It typically starts in the rectum then propagates proximally[1]. The primary clinical manifestations are abdominal pain and repeated diarrhea with blood and mucus in the stools. Complications, including toxic megacolon, cancer, and extraintestinal manifestations, can occur in more than 25% of patients[2]. In the United States, UC necessitates approximately 250000 visits to healthcare providers each year. Medical costs directly associated to it are estimated to exceed more than four billion dollars a year[3]. UC, being a chronic lifelong disorder with no known cure, imposes a heavy burden on healthcare systems and patients alike[3]. Although the exact etiology and pathogenesis of UC are not fully understood, genetic, immunological, and environmental risk factors play fundamental roles in its development. Immunological factors, such as alterations in regulatory T cell (Tregs) function and pathways involving molecules such as interleukin (IL)-1β and IL-17, ultimately result in an inappropriate, prolonged immune response. Environmental factors, including dietary practices, alcohol intake, antibiotic and nonsteroidal anti-inflammatory use, as well as anxiety or depression, have long been established as risk factors in susceptible individuals[4]. Current smoking confers a protective effect, while former smoking positively correlates with disease[5]. The role of the appendix has emerged as a significant point of interest. Appendectomy performed before UC diagnosis has been shown to delay disease onset and produce a milder disease phenotype when compared with patients who have not had the procedure[5]. This narrative review examines the evolving evidence surrounding the appendix’s role in UC. It highlights biological mechanisms and clinical observations, as well as the potential role of autophagy dysregulation in UC pathogenesis. Finally, it explores appendectomy as a potential therapeutic intervention for sustaining or inducing remission and ameliorating symptoms.

METHODOLOGY AND REVIEW CRITERIA

This manuscript is a short, updated narrative review providing evidence of recent clinical studies on the appendix in the pathogenesis and treatment of UC. A literature search was conducted to capture relevant studies highlighting current trends and major findings on the appendix in UC setting. The keywords and combination of terms “appendix”, “appendectomy”, “pathogenesis”, “autophagy”, “therapy”, and others were entered into PubMed, Google Scholar, Directory of Open Access Journals, and ScienceDirect electronic databases. The search was limited to publications in the last ten years, and original research articles, clinical trials, systematic reviews, and meta-analyses published in English. However, the elements of systematic review, such as the preferred reporting items for systematic reviews and meta-analyses flow diagram, risk-of-bias assessment, and quantitative synthesis, were not applied.

UC: A FAILURE OF INTESTINAL HOMEOSTASIS

UC represents a pathological breakdown in the relationship between the host’s immune system and enteric commensals. In genetically predisposed individuals, exposure to certain environmental triggers induces an inappropriate and sustained immune response to the latter. The inflammatory cascade proceeds unchecked and the resulting cumulative damage to the bowel significantly increases the risk of hospitalization, surgical intervention, and colorectal cancer[1].

Pathogenesis of UC: The immune-microbiome interface

The pathogenesis of UC centers on a disrupted intestinal homeostasis. Microbial dysbiosis and structural failure of the colonic epithelial barrier synergistically precipitate a pathological overactivation of both the innate and adaptive immune systems[1,6]. Under normal circumstances, colonic epithelium is covered by a dense mucin layer, which acts as a barrier between the countless antigens that travel through the gut and the underlying immune cells[1]. In UC, mucin synthesis is impaired. Mucosal permeability to luminal antigens increases, allowing them to bypass the mucosa and stimulate the immune cells below[1]. A recent study by Kuwada et al[7] found that most enrolled UC patients (103 out of 112) had anti-integrin αvβ6 autoantibodies. The authors also demonstrated that higher titers correlated with more severe disease. Because αvβ6 integrin is crucial for preserving epithelial barrier integrity, these autoantibodies could very well represent yet another mechanism for the heightened mucosal permeability characteristic of UC[7]. An impaired expression of peroxisome proliferator-activated receptor gamma within colonic epithelial cells compounds the problem. Under-expression of these nuclear receptors precludes downregulation of inflammatory signals and lowers the threshold for activation of the immune system with subsequent tissue damage[1,8]. The gut microbiome simultaneously undergoes several hallmark changes due to disruption of the colonic mucous layer, which ordinarily harbours the gut commensals. There is a loss of bacterial diversity, accompanied by a reduction in beneficial commensals and an expansion of pathobionts and pathogens. The result is an imbalanced microbial ecosystem that promotes the overgrowth of harmful microbes capable of penetrating the thinned mucous layer[6]. Once they breach these compromised defences, antigens directly stimulate the innate immune response. Stimulated mature antigen-presenting dendritic cells (which in the setting of UC have heightened sensitivity and an increased number of Toll-like receptors) activate transcription factors like nuclear factor kappa-B and initiate an intense pro-inflammatory cascade[1]. The liberated cytokines, particularly IL-12, IL-23, and tumor necrosis factor alpha, augment lymphocyte activation and proliferation through signal transduction via intracellular proteins, e.g., Janus kinases (JAK). Ultimately, this cascade of events bridges the innate immune response to a sustained adaptive response[1]. This stage of persistent adaptive immune dysregulation is characterized by a critical imbalance between regulatory and effector T-cells, specifically effector T-helper 2 cells. These cluster of differentiation (CD) 4⁺ cells activate natural killer T (NKT) cells in the lamina propria, which secrete potent cytokines[1,6]. IL-13, for example, directly damages tissue by inducing apoptosis of epithelial cells and disrupting their tight junctions. The vicious cycle of mucosal barrier compromise and subsequent immune system activation thus continues[1]. Inflammatory cytokines also stimulate adhesion molecule expression by the vascular endothelium. These molecules recruit circulating leukocytes to the already-inflamed colonic mucosa. The inflammatory process intensifies and eventually evolves into the chronic mucosal inflammation that defines UC[1].

Environmental priming: The external catalysts of inflammation

Over the last decade, epidemiological evidence has solidified the role of the environment in the pathogenesis of UC. This is true for both individuals, through individual behavioral choices like diet, and for whole populations, where regional factors like urbanization and air pollution modify risk for an entire population. External exposures have cumulative disruptive effects on gut microbes, mucosal permeability, and immune responses from infancy to adulthood, and significantly alter the risk profile and clinical trajectory of the disease[1,9].

A troubling trend of increasing UC incidence in newly industrialized regions of South America, Asia, and Africa illustrates how environmental variables affect this disease. In China, the burden of disease surged from approximately 10000 diagnosed cases in 2000 to an estimated 266394 just one decade later. “Westernisation” (i.e., urbanization and a departure from traditional dietary practices) thereby appears to be a significant contributor to the disease process[1,9].

The hygiene hypothesis is another prime example of this “environmental priming”. It posits that the global surge in IBD incidence can be attributed to radical improvements in sanitation and hygiene. Children are “over-protected” from early exposure to common commensal microorganisms and infectious agents that are essential for normal development of the gut immune system[10]. When they subsequently encounter a pathogen later in life, the immune system reacts in an exaggerated manner that can trigger the abnormal inflammatory processes that underpin the development of IBD[1,10]. A growing body of evidence indicates that autophagy dysfunction may also play a major role in the pathogenesis of UC.

AUTOPHAGY: A PRO-SURVIVAL AND ANTI-INFLAMMATORY MECHANISM

Autophagy (also known as macroautophagy) is a pro-survival mechanism that facilitates the clearance and recycling of cellular components, including damaged organelles, misfolded proteins, and excessive lipid droplets (LDs), particularly under stress conditions such as inflammation, oxidative stress, and metabolic stress. Autophagy can selectively eliminate mitochondria (mitophagy), LDs (lipophagy), or pathogens such as bacteria (xenophagy)[11,12]. Therefore, autophagy is considered a prosurvival, anti-inflammatory, antibacterial, and antioxidative mechanism.

Autophagy is tightly regulated by autophagy-related (ATG) proteins and is initiated by suppression of the mechanistic target of rapamycin (mTOR) and activation of adenosine 5’-monophosphate-activated protein kinase (AMPK) in response to various stressors. Autophagy is characterized by the formation of Beclin-1-mediated autophagosomal membranes, which engulf pathogens, damaged mitochondria, and LDs within double-membrane vesicles called autophagosomes, in a process mediated by LC3 (a key autophagy marker). These autophagosomes subsequently fuse with lysosomes via lysosome-associated membrane protein 2 to form autolysosomes, where the cargo is degraded by lysosomal cathepsins[11-13].

Mechanistically, autophagy is a dynamic process assessed by measuring autophagic flux, defined as the rate of autophagic degradation[14]. In humans, autophagic flux can be evaluated by measuring LC3-II levels in peripheral blood mononuclear cells treated with lysosomal inhibitors such as chloroquine. Increased LC3-II levels accompanied by reduced p62 indicate enhanced autophagic flux[15].

AUTOPHAGY DYSFUNCTION IN UC

Recent studies indicate that mutations in ATG genes, such as ATG16 L1 and IRGM, are strongly associated with the pathogenesis of IBD. Notably, NOD2 functions as a key inducer of autophagy by recruiting ATG16 L1 to the plasma membrane[16,17]. In patients with active UC, the expression of activating transcription factor 4, a key ATG protein, has been reported to be significantly reduced in inflamed intestinal mucosa compared with normal mucosa, suggesting that impaired autophagy may contribute to UC pathogenesis[18].

In addition, mTOR-dependent impairment of autophagic flux has been demonstrated in intestinal epithelial cells from patients with active UC, further supporting the protective role of autophagy[19]. Importantly, defective clearance of Escherichia coli by macrophages via xenophagy has been shown to exacerbate intestinal inflammation in UC[20]. Moreover, recent studies indicate that enhancing autophagy through the AMPK-mTOR-p70S6K pathway attenuates UC symptoms and suppresses intestinal inflammation in dextran sulfate sodium-induced mouse models[21,22]. Therefore, autophagic clearance of microorganisms via xenophagy, particularly bacteria, plays a crucial role in protecting against IBD, such as UC.

Taken together, impaired autophagy in colonic cells contributes to persistent inflammation in UC, whereas activation of autophagy may exert protective effects. However, no studies have specifically investigated whether autophagy dysfunction in the appendix contributes to UC pathogenesis. Given that the appendix is part of the large intestine and contains cellular components similar to those of the colon, it is plausible that comparable ATG alterations may occur in this organ. Further research is required to confirm this hypothesis.

THE APPENDIX: FROM REMNANT TO REGULATOR

Traditionally dismissed as a vestigial remnant, the vermiform appendix is increasingly becoming recognized as a sophisticated immunological and microbial hub. Its historical reputation as a dispensable organ, reinforced by the common practice of incidental appendectomy, is being challenged by evidence of its pivotal role in the maturation of the gut immune system and development of gut-associated lymphoid tissue (GALT), as well as maintenance and calibration of the gut microbiome[23,24].

The breeding ground: The appendix as a reservoir for dysbiosis

The unique anatomy of the appendix (i.e., its narrow, tubular structure) confers some protection from the high-velocity fecal stream in the colon, and the deleterious effects of antibiotics and enteric infections on the microbiome. The appendix has been proposed to function as a reservoir for beneficial commensal bacteria, facilitating recolonization of the colon after intestinal infections or antibiotic exposure[24].

In the setting of UC, this reservoir function may become maladaptive; the appendix instead functions as a reservoir for dysbiosis. The organ appears to shelter pathobionts and pathogens that continuously reestablish an imbalanced microbial environment in the colon and perpetuate the cycle of inflammation. In an attempt to “cut off” the source of dysbiosis, appendectomy has been proposed as a potential treatment modality[6].

The appendix as a priming site for pathological immunity

The vermiform appendix is a specialized secondary lymphoid organ. The appendiceal wall is characterized by a dense concentration of multi-follicular GALT. These follicles are covered by an overlying specialized follicle-associated epithelium containing microfold (M) cells. M-cells sample luminal antigens and present them to adaptive immune cells in the GALT below. The appendiceal lamina propria and submucosa are noticeably enriched with NKT cells and activated T and B cells. This cellular landscape drastically shifts to one of active inflammatory signaling during the pathogenesis of UC. As intestinal homeostasis breaks down and fails, profound dysregulation of various lymphocyte subsets occurs[6].

In a healthy appendix, forkhead box protein 3 (FoxP3⁺ CD25⁺) Tregs suppress pro-inflammatory signals. In the setting of UC, their numbers do not rise sufficiently to effectively contain the inflammatory response and maintain immunological tolerance. Activated effector cells, specifically CD4⁺ CD69⁺ T cells, rise in parallel and worsen this relative deficiency of Tregs. A subpopulation of memory T cells, recently designated as tissue-resident memory T cells (TRM), quickly eliminate pathogens by proliferating, releasing cytokines, and recruiting other immune cells. Certain subgroups of TRM cells also have regulatory functions. In UC, the number of pro-inflammatory TRM cells rises, whereas regulatory subgroups decline[6,23]. Invariant NKT (iNKT) cells, naturally abundant in the appendix, can rapidly produce a broad array of cytokines upon activation. In patients with UC, iNKT cells exhibit increased levels of expression, fueling the sustained intestinal inflammation involved in the pathogenesis of UC.

Significant shifts in the B-cell population within the appendix during UC pathogenesis may undermine the organ’s protective function. CD5⁺ B lymphocytes (B1 cells), responsible for producing immunoglobulin M antibodies against both self-antigens and pathogens, exhibit a notable decrease in expression. This may allow for the persistence of pathogens that trigger a chronic inflammatory response. CD19⁺ B cells, responsible for inducing B-cell activation and function, conversely show increased expression and contribute to a heightened immune response within the colon[6].

Collectively, these cellular shifts, supported by murine models, suggest that the appendix in UC transitions from a site of immune education and maturation to a primary site of pathological priming and immune stimulation. The depletion of protective CD5⁺ B cells and the relative deficit of FoxP3⁺ CD25⁺ Tregs create a permissive environment for the over-activation of iNKT, TRM, and effector CD4⁺ CD69⁺ T cells which likely migrate distally to sustain inflammation in the colon[6]. These changes in the appendiceal cellular landscape also provide a potential mechanistic explanation for why early appendectomy (by removing this source of activated effector cells and inflammatory mediators) can alter the clinical trajectory of UC[25].

The organ’s role as a “priming site” is further evinced by the clinical observation of peri-appendiceal red patches (PARPs), also known as cecal patches. PARPs signify inflammation at the appendiceal orifice and have been reported in 12% to 87% of UC patient cohorts, including those with otherwise distal disease[26]. PARPs are essentially evidence of the “priming ground” theory; they potentially represent the point at which the inflammatory process spills over from the appendix into the colon[6,26].

A striking temporal relationship between the peak for disease onset and the lifecycle of appendiceal lymphoid tissue likewise supports removing the appendix to disrupt this early priming phase. The number of appendiceal lymphoid follicles peaks below 20 years of age and sets the stage for a peak onset of UC between the second and fourth decades of life[27]. The proposed mechanisms linking appendiceal inflammation to UC are illustrated in Figure 1.

Figure 1 Mechanisms of appendix-mediated ulcerative colitis pathogenesis. Appendiceal inflammation may initiate or exacerbate ulcerative colitis (UC) pathogenesis through multiple interconnected mechanisms, including dysregulation of T and B lymphocytes, impaired immune tolerance, and altered cytokine signaling. In addition, disruption of the appendiceal microbiota may promote gut dysbiosis and facilitate the persistence of pathogenic bacteria. Defective bulk autophagy and xenophagy in the appendix may represent mechanisms contributing to UC pathogenesis and warrant future exploration. GALT: Gut-associated lymphoid tissue; Th: T helper cell; Treg: Regulatory T cell; IBD: Inflammatory bowel disease; IL: Interleukin.

APPENDECTOMY AS A THERAPEUTIC STRATEGY IN UC

Altering the trajectory: Delaying onset and blunting disease severity

The association between the appendix and UC was first recognized in 1987. An observation was made that UC patients were far less likely to have had an appendectomy than their healthy counterparts[26]. A later meta-analysis reinforced the idea of the absence of the appendix as a protective factor against UC. It demonstrated that an appendectomy reduces the likelihood of developing UC by more than half (odds ratio = 0.44)[28]. Subsequent studies have refined this association; it appears as though the relationship between the appendix and UC not only depends on the surgical removal of the organ, but also on the specific indication and timing of the surgery. The risk reduction is particularly significant when the appendectomy is performed for acute appendicitis or mesenteric lymphadenitis. This effect is largely lost if the procedure is done after the age of 20 years[29].

These findings suggest that this protective effect is driven more by the intense immunological signaling of early-life appendicitis than by the simple absence of the organ itself[6]. Murine models support that appendicitis activates FoxP3⁺ CD25⁺ Tregs. The expression of these regulatory T-cells is age-limited, primarily occurring in childhood. They are thought to prevent auto-sensitization by promoting immune tolerance early on, which likely explains why the protective effect diminishes when an appendectomy is performed later in life[29].

Recent data from a 2024 study involving 313 newly diagnosed UC patients further substantiates this protective benefit. Cui et al[2] found that prior appendectomy not only significantly delayed the age of disease onset (with a mean interval of 14.72 years between surgery and diagnosis) but also positively altered disease severity. Patients who had undergone appendectomy presented with significantly lower disease activity, higher rates of clinical remission or mild disease, and a lesser extent of colonic involvement (primarily E1 and E2 per the Montreal classification) compared to the more extensive E3 lesions seen in non-appendectomized individuals[2].

Beyond the observation: Appendectomy as a targeted intervention

Expanding on these observational studies, recent clinical research has focused on therapeutic appendectomy as a means of inducing and maintaining remission in established UC. A large prospective case series by Bolin et al[30] yielded remarkable results in 30 adult patients with ulcerative proctitis who underwent appendectomy despite having no history of appendicitis. Following a median follow-up of 14 months, the Simple Clinical Colitis Activity Index score improved significantly from a median score of 9 to 2. Ninety percent of patients experienced clinical improvement, and 40% achieved a complete resolution of symptoms, allowing for total withdrawal of all pharmacological treatments by the 12-month mark. Notably, no patient required proctocolectomy during follow-up[30].

A prospective pilot study (PASSION, 2019) included 30 patients with therapy-refractory UC who were being considered for proctocolectomy. Therapy-refractory UC refers to active disease despite optimized treatment, including failure to respond to corticosteroids, inability to taper steroids without relapse (steroid dependence), or lack of response to 5-aminosalicylic acid and advanced therapies such as biologics or small molecules. All patients underwent laparoscopic appendectomy. The primary endpoints were clinical response at 3 months and 12 months, while secondary endpoints included endoscopic remission, treatment failure, and histopathological response. Appendiceal specimens and pre- and postoperative biopsies were assessed histologically. At one year of follow-up, approximately one-third of patients demonstrated sustained clinical response, with 17% achieving complete endoscopic remission[31]. Histological improvement was observed in nearly 50% of patients and was associated with active appendiceal inflammation, limited disease extent, and shorter disease duration. These findings suggest that a subset of UC patients may benefit from appendectomy.

The ACCURE study (2025) yielded even more robust evidence from a randomized controlled setting. The international, randomized controlled superiority trial was conducted across 22 centers in the United Kingdom, Ireland, and the Netherlands. Patients with diagnosed UC who were in remission but had had a relapse necessitating treatment within the prior 12 months were randomly allocated (1:1) to either appendectomy plus continued maintenance medical therapy (intervention group) or maintenance medical therapy alone (control group). Out of 1386 patients screened, 201 were finally assigned to either the appendectomy group (n = 101) or the control group (n = 100). Following four exclusions owing to violations of pre-established eligibility criteria, the final analysis comprised 99 patients and 98 patients in the appendectomy and control groups, respectively. The trial showed that appendectomy was superior to standard medical therapy alone in maintaining remission; the 1-year relapse rate was significantly lower in the surgical group (36% vs 56% in controls; relative risk = 0.65)[32].

The appendectomy group additionally exhibited favorable trends in medication sparing. Biological agents were initiated less frequently in the intervention group than in the control group. The most pronounced difference appeared at 6 months (0.0% vs 4.4%). Although this gap narrowed by 12 months (3.2% vs 5.5%), such a delay in the initiation of biologic therapy is still clinically and economically significant. Biologics drive a 10% annual increase in UC-related healthcare costs and, like any long-term maintenance medication, present the challenge of nonadherence. Adverse events occurred at similar rates in the appendectomy (11%) and control (10%) groups. The most frequent surgical complication was temporary, self-limiting abdominal pain, thereby positioning appendectomy as a safe and viable treatment option for maintaining remission in UC[32]. The authors demonstrated that appendectomy is superior to standard medical therapy alone in maintaining remission in patients with UC.

A subsequent multicenter interventional cohort study conducted across five hospitals in the Netherlands, the COSTA trial (2026)[33], investigated the role of appendectomy in inducing remission in a more challenging subset of UC patients. In this trial, patients were offered one of three treatment strategies: laparoscopic appendectomy while continuing their existing advanced therapy at a stable dose; switching to a JAK inhibitor; or colectomy. Between 2018 and 2023, a total of 211 patients were screened. Of these, 125 patients with a total Mayo score of 5-12 and persistent disease activity despite advanced therapy (i.e., a biologic or small molecule) were enrolled. The five patients who directly opted for colectomy only served as a non-comparative registry cohort for surgical outcomes and real-life patient preferences; they were not followed up for comparison and were excluded from subsequent analysis. Ultimately, 116 patients were included in the modified intention-to-treat analysis, of whom 67 underwent appendectomy as an adjunct to their current therapy and 49 switched to a JAK inhibitor[33].

The results demonstrated that laparoscopic appendectomy was significantly superior to JAK inhibitor therapy in inducing corticosteroid-free clinical remission at 12 months without therapy failure (defined as initiation or reintroduction of oral corticosteroids, switching to other advanced therapies, initiation of experimental treatment within a clinical trial, or colectomy) (32.8% vs 12.2%, respectively)[33]. This beneficial effect was also observed across key secondary endpoints. For instance, the appendectomy group showed higher endoscopic response rates (48.4% vs 25.6%)[33]. Safety outcomes were comparable between groups; adverse events were reported in 56.5% of the appendectomy group and 60.0% of the JAK inhibitor group. Appendectomy-related complications occurred in only 4.3% of patients and were all considered minor[33]. The authors suggested that appendectomy, as an adjunct to ongoing therapy, may represent a safe and potentially effective treatment strategy for patients with UC. A summary of the main clinical trials evaluating appendectomy in UC is presented in Table 1.

Table 1 Key clinical trials evaluating appendectomy in ulcerative colitis.

Trial	Study design	Population (sample size)	Intervention	Comparison	Outcome measures	Adverse effects	Key findings	Clinical implication	Strengths	Limitation	Level of evidence
PASSION (2019)[31]	Prospective pilot study conducted at two European tertiary IBD centres (Netherlands and Ireland)	Adults (> 18 years) with steroid-dependent or therapy-refractory. UC who have failed medical management and require colectomy n = 30	Laparoscopic appendectomy + patient’s baseline medical therapy (tapered postoperatively in case of response)	No comparison group	Primary: Clinical response at 12 months. Secondary: Endoscopic remission and pathologic response at 12 months	No major postoperative complications, e.g., skin rash, postoperative abdominal tenderness	Clinical response in 12 (30%) at 12 months. 5 of these additionally showed endoscopic remission, 50% pathological response. Complete steroid withdrawal in all patients who had not yet had colectomies at 12 months	Proof-of-concept that the appendix contributes to disease activity and hence the potential of appendectomy for UC patients with appendiceal inflammation	Consecutive sampling strategy. Prospective study design. Correlation of clinical, endoscopic, and pathological responses → ↓ placebo effect contribution to results	Short follow-up duration. Small sample size	Level IV
ACCURE (2025)[32]	Multicenter (22 centres across the Netherlands, United Kingdom, and Ireland), randomized controlled superiority trial, utilizing an open-label, pragmatic design	Adults (≥ 18 years) with established UCs currently in remission and a medically treated flare within 12 months. n = 197 (n = 99 appendectomy; n = 98 control)	Laparoscopic appendectomy + patient’s baseline medical therapy	Patient’s baseline medical therapy	Primary: 12-month relapse rate. Secondary: Annual relapse frequency, time-to-first relapse, disease activity, colectomy rate, medication use, and health-related quality-of-life	11% in the appendectomy group vs 10% in the control group. Self-limiting postoperative abdominal pain (n = 3). Major adverse events (n = 2), e.g., internal hernia requiring laparotomy, intra-abdominal hematoma	Significantly lower 12-month relapse rate in the appendectomy group (36% vs 56%). Lower mean total Mayo score at 12 months (1.2 vs 1.8), less frequent initiation of biologics, superior control of bowel symptoms in the appendectomy group	Supports appendectomy for the maintenance of remission in UC patients	High-quality RCT (3/5 on the Jadad scale. International multicenter pragmatic design. → ↑ External validity. Robust computer-generated randomization and allocation concealment. Masked outcome assessment via a dedicated blinded critical event committee → ↓ observer bias	Short follow-up duration (12 months). Open-label design and possible placebo effect contribution. Possible chronological bias owing to long study duration (September 2012 to September 2022). Possible participation bias. Possible expectation bias with the publication of encouraging appendectomy studies	Level II
COSTA (2026)[33]	Multicentre, prospective interventional cohort study utilizing a patient-preference design across five hospitals in the Netherlands	Biologic-exposed patients ≥ 16 years with active UC and ≥ 1 instance of biologic therapy failure. n = 116 (modified intention-to-treat) (appendectomy n = 67; JAK-inhibitor therapy n = 49)	Appendectomy + patient’s baseline medical therapy (including advanced medical therapies, e.g., anti-TNFs, JAK-inhibitors)	JAK-inhibitor + patient’s basal medical therapy (EXCLUDING biologics which were stopped)	Primary: 12-month failure-free clinical remission rate. Secondary: Steroid-free remission rate; time-to-first remission; clinical response; endoscopic response; therapy failure rate; colectomy rate	No significant difference in AEs between groups (56.5% vs 60.0% in the JAK-inhibitor and appendectomy groups, respectively; P = 0.70). Low postoperative complication rate (4%); minor postsurgical complications (n = 3)	33% failure-free remission with appendicectomy; significantly superior to JAK inhibitors (12%) at 12 months. Consistently higher rates of steroid-free remission, clinical response, and endoscopic improvement/response. No significant difference in time-to-remission or overall therapy failure rates. Well-tolerated; 4% postoperative complication rate	Potential of appendectomy as a promising adjunct or alternative for induction of remission in biologic-refractory patients	Patient preference design → ↓ patient preference bias. Centralized, blinded endoscopic assessments → ↓ observer bias and interobserver variability. Multicenter design → ↑ External validity	Non-randomized with differences in baseline characteristics. High probability of selection bias. Non-standardized escalation of medical therapy. Relatively small sample size (though the study maintained adequate power)	Level III

IBD: Inflammatory bowel disease; UC: Ulcerative colitis; RCT: Randomized controlled trial; JAK: Janus kinases; TNF: Tumor necrosis factor; AEs: Adverse events.

Although recent trials, such as ACCURE and COSTA, suggest that appendectomy may be considered as a therapeutic option for UC particularly given its favorable safety and tolerability profile in this setting available data indicate a complex relationship between the timing of appendectomy and clinical outcomes (Figure 2). The limitations and risks of these studies are discussed in the relevant section.

Figure 2 Appendectomy as a therapy for ulcerative colitis. The inflamed appendix may act as a niche for sustained inflammation, potentially driven by immune dysregulation, dysbiosis, and autophagy dysfunction in the colon and possibly in the appendix, thereby contributing to disease progression. Clinical studies, such as the ACCURE and COSTA trials, show that appendectomy can improve outcomes, reduce relapse rates, and achieve remission in selected patients, particularly those with refractory disease.

CHOLANGIOSCOPE-ASSISTED ENDOSCOPIC RETROGRADE APPENDICITIS THERAPY IN UC

A potential non-surgical treatment option for UC, cholangioscope-assisted endoscopic retrograde appendicitis therapy (ERAT), has been recently reported. The procedure facilitates endoscopic access to the appendiceal lumen for the removal of purulent material and the reduction of localized inflammation, resulting in enhanced clinical remission and mucosal healing. These findings provide evidence for the role of the appendix as a reservoir for inflammation, thus contributing to UC pathogenesis. Hence, ERAT represents a minimally invasive, non-surgical strategy that targets appendiceal inflammation[34-36].

Whereas appendectomy eradicates the source of inflammation, ERAT modulates local inflammation and restores appendiceal function. However, studies linking ERAT to UC are limited, and studies reporting its efficacy, durability, and patient selection criteria are still lacking[34-36]. Taken together, these surgical and endoscopic approaches highlight the appendix as a potential therapeutic target in UC. Figure 2 shows the role of the appendix in the pathogenesis and therapy of UC based on recent clinical trials.

AUTOPHAGY DYSFUNCTION IN THE APPENDIX IN OTHER DISEASES

The appendix has also been implicated in other diseases, including Parkinson’s disease (PD). Aberrant DNA methylation affecting genes of the autophagy-lysosome pathway (ALP) has been identified in the appendix of PD patients, with similar epigenetic alterations observed in the brain. Experimental models further demonstrate that chronic gut inflammation and α-synuclein pathology exacerbate these ALP-related changes, particularly in lysosomal genes[37,38]. These findings suggest that disruption of autophagy in the appendix may represent an important mechanism underlying the propagation of α-synuclein aggregates from the appendix to the brain in PD, thereby highlighting the role of the gut-brain axis in disease pathogenesis. Additionally, some studies have reported that appendectomy may be associated with a reduced risk of PD[39,40].

Whether dysregulation of autophagy in the appendix of patients with UC contributes to disease pathogenesis remains to be determined. Given the appendix’s role as an immunological and microbial niche, impaired autophagy may disrupt epithelial barrier integrity, alter microbial composition, and promote persistent immune activation. In particular, xenophagy dysfunction in colonic cells could compromise bacterial clearance, leading to persistent UC infection, upregulation of inflammatory cytokines, and impairment of immune tolerance[11,20]. However, direct evidence from pre-clincal and clinical studies, as well as mechanistic investigations, are still limited, and further research is required to clarify the role of autophagy dysfunction in the appendix during UC pathogenesis.

LIMITATIONS AND RISKS

Several limitations and risk factors should be considered prior to appendectomy for UC management. First, although appendectomy eradicates the source of inflammation, the role of the appendix as a reservoir for commensal microbiota and site for lymphocyte maturation suggests that the mucosal immunity might be disrupted, leading to dysbiosis in some individuals. Appendectomy may impair T-cell-mediated immunosurveillance, potentially increasing the risk of colorectal neoplasia[41]. Second, the therapeutic benefits of appendectomy for UC appear to be heterogeneous, with a proportion of patients failing to achieve stable remission. Third, the long-term consequences of appendectomy on disease course and immune functions remain to be elucidated. Fourth, a few studies have reported an increased risk of colorectal cancer following appendectomy[42]. Fifth, studies reporting the efficacy of ERAT in UC therapy, durability, and patient selection criteria are still limited. These considerations underscore the need for careful patient selection, and large scale studies in the future to determine if these risks outweigh the therapeutic benefits of appendectomy and ERAT for UC.

CONCLUSION

Growing evidence indicates that the appendix may have immunomodulatory and inflammatory functions beyond just a vestigial organ. Its role as a “priming site” for UC, through mechanisms including immune dysregulation, propagation of infection, dysbiosis, and possibly autophagy dysfunction, is supported by both murine models and clinical observations. This has led to the hypothesis that appendectomy may suppress colonic inflammation by removing a source of pro-inflammatory cytokines or an abnormal bacterial reservoir. Appendectomy before disease onset significantly reduces long-term colectomy risk and delays disease onset. In established disease, therapeutic appendectomy offers a promising bowel-sparing intervention for refractory UC. Ultimately, these findings warrant cautious optimism given the small sample size and justify further exploration of its therapeutic potential. Large-scale clinical studies are needed to determine how the timing of surgery relative to the diagnosis and the pathological state of the appendix (whether normal or inflamed) affect clinical outcomes. Further studies are needed to clarify the effects of appendicitis on the biofilm, microbiome, and mucosal immunity; the differential impact of removing inflamed vs non-inflamed appendices; and the optimal timing of appendectomy in relation to UC diagnosis. In addition, the potential association between appendectomy and colorectal cancer risk requires further investigation. Addressing these issues may improve our understanding of UC pathogenesis and inform therapeutic strategies. Further studies confirming the role of autophagy dysfunction and impaired autophagic flux in UC in both animal models and human studies are needed. Analysis of autophagy markers such as LC3 in peripheral blood mononuclear cells, as well as in diseased colonic and appendiceal tissues in animal models and patients with UC, may assist diagnosis and therapy via autophagy normalization with natural and pharmacological agents. Moreover, whether the immunomodulatory effects of appendectomy and autophagy dysregulation extend beyond the colon (as in the case of PD) needs to be explored.