Terminal ileum (TI) refers to the intestinal tract from the ileocecal valve to the proximal end of the ileum, and its length is about 30–40 cm [1]. Feces tend to accumulate at the TI, more probably causing bacterial growth; meanwhile, there is a large amount of intestinal lymphoid tissue and Peyer’s patches within the TI [2, 3]. Therefore, it is more likely to develop ulcers in this region. Notably, if there was no ulcer at any other part of the intestines, isolated terminal ileal ulcers (ITIU) would be defined [1]. It has been reported that the detection rate of ITIU among individuals undergoing colonoscopy screening is 1.45% [4]. Among individuals with gastrointestinal symptoms, the detection rate of ITIU was observed to be 4.90% [5]. Until now, the etiology of ITIU has not been elucidated. It may be associated with infections, drugs, inflammatory bowel disease (IBD), eosinophilic gastroenteritis, ischemic bowel disease, and neoplasms [6, 7, 8, 9]. It has been reported that 1.07–34.5% of individuals with isolated terminal ileitis and ITIU may progress to Crohn disease (CD) during a long-term follow-up period, and the incidence of CD gradually increases over time [5, 8, 10, 11, 12]. Some investigators also suggest that nonspecific ITIU should be considered as an early stage of CD [5, 11, 12, 13], but it usually takes a relatively long time to progress from nonspecific ITIU to CD. Thus, early treatment and close monitoring may be required [5, 6, 8, 12]. However, there are no specific guidelines for the diagnosis and management of ITIU, because it is usually occult, asymptomatic, or nonspecific in symptoms.

Considering the clinical significance of ITIU, it is critical to understand the epidemiology of ITIU and recognize high-risk populations for developing ITIU. It has been reported that body mass index (BMI) may be associated with the number of small intestinal ulcers, but the association of BMI with ITIU was uncertain [14]. Additionally, other potential risk factors associated with ITIU have not been identified. The present study aimed to analyze the detection rate of ITIU and its associated risk factors to strengthen the knowledge of this disease and to explore the outcomes of nonspecific ITIU.

Our study showed that the detection rate of ITIU in individuals undergoing colonoscopy was 1.3% (123/9649). Among them, 4.1% (5/123) were diagnosed with IBD (2 with CD and 3 with UC). Common clinical manifestations of ITIU were formless stool and abdominal pain. In addition, age $\le$50 years was independently associated with ITIU. Subsequently, there was no difference in the follow-up outcomes between patients with nonspecific ITIU who received empiric therapy and those who received observational follow-up.

As well known, IBD often occurs in young adults, and the peak age of its onset is 18 to 49 years [17]. Considering a potential correlation between ITIU and IBD [5, 6], it is reasonable to believe that the age of individuals also influences the occurrence of ITIU, which is consistent with the findings of our current study. There are some possible explanations for this association, as follows. First, ITIU alone, without any involvement of the rest of the intestines, can be observed at the early stage of IBD [6, 18]. Specifically, nearly 30% of patients with CD have ulcers confined to the TI alone [19], and nearly 17% of patients with UC can be accompanied by ulcers in the TI [20]. Our study found that 10.7% (3/28) of patients with ITIU and concurrent ileocecal valvulitis/colitis were finally diagnosed with UC, probably because backwash ileitis resulted in ileal ulcers. Therefore, a higher risk of ITIU in individuals younger than 50 years old can be explained by a higher incidence of IBD in younger individuals [17]. Second, TI is a special part of the intestinal tract where feces tend to accumulate, and bacteria thrive. It contains a large amount of Peyer’s patches, which are responsible for the intestinal immune system or intestinal immunity. Notably, the number of Peyer’s patches gradually decreases with age, and peaks at the age of 15–25 years old. Once the bacteria thrive, the immune response would be strong at the TI owing to the presence of Peyer’s patches. Taken together, it is more likely to develop ulcers in the TI in young individuals [2, 3, 21, 22].

There seems to be a positive correlation between the number of small intestinal ulcers and BMI [14]. Previous studies suggest that the diversity of gut microbiota is lower in obese people [23, 24, 25]. Especially, most obese people have diets that are low in fiber but high in protein and fat. Notably, these diets can alter the ratios of microbes and metabolites that modulate inflammation [26, 27, 28]. Therefore, intestinal inflammation can be more easily increased in obese people. Moreover, the presence of certain bacteria in obese people can impair the function of intestinal tight junctions, allowing bacterial products to pass through the intestinal wall easily and then induce an inflammatory response [14, 23, 29]. By comparison, our study demonstrated only a marginally positive association between ITIU and BMI $\ge$28.0 kg/m². This issue can be further explored in large-scale studies.

At present, there is no consensus on routine TI intubation during screening colonoscopy. Traditionally, considering the time-consuming nature of TI intubation and a low detection rate of TI lesions, routine TI intubation is not recommended, and TI intubation is only recommended for individuals with gastrointestinal symptoms or suspected IBD [4, 30, 31]. However, our study showed that the detection rate of ITIU was 1.3% and that approximately 90% of individuals undergoing colonoscopy completed the TI intubation. Interestingly, we found that a relatively high proportion of ITIU individuals underwent screening colonoscopy, who did not have any obvious gastrointestinal symptoms and were asymptomatic. Thus, it seems that clinical manifestations are not associated with ITIU, and the necessity of TI intubation should be recognized in all individuals undergoing screening colonoscopy.

In a randomized controlled trial (RCT) enrolling 82 patients with ITIU, there was no significant difference in clinical efficacy or endoscopic outcome during short-term and 1-year follow-up periods between patients who received experimental treatment with mesalazine (orally, 4.0 g, quaque die [qd]) for 3 months and those who received observational follow-up [32]. Our current study also showed no significant difference in the efficacy between patients receiving empiric therapy and observational follow-up after 1-year follow-up. Recently, another RCT enrolling 60 patients with isolated terminal ileum abnormalities demonstrated no significant difference in clinical or endoscopic efficacy between patients who received combination antimicrobial therapy (rifaximin, orally, 550 mg, bid, for two weeks; albendazole, orally, 400 mg, as a single dose; tinidazole, orally, 1 g, bis in die [bid], for three days) and those who received symptomatic treatment (probiotics; proton pump inhibitors; prokinetic) during short-term and 3-month follow-up periods [33]. It has been reported that the rate of progression from ITIU to IBD is high, ranging from 29% to 54%, during a follow-up period of 4 to 7 years. Therefore, nonspecific ITIU should be considered as an early stage of IBD and treated early and monitored closely [13, 18, 34, 35, 36]. Considering that it is difficult to distinguish between IBD and ITIU, especially in asymptomatic individuals [10, 31], long-term follow-up and an adaptable treatment strategy seem to be necessary for patients with ITIU.

Our study has a few limitations. First, owing to the retrospective nature of this study, some baseline data, such as height, weight, and indications for colonoscopy, and follow-up information, were unavailable for all individuals. Second, in our study, some patients received probiotics or 5-ASA as empiric therapy for ileal ulcers. However, a systematic review and meta-analysis regarding the efficacy of aminosalicylic acid preparations for the treatment of CD revealed that the effectiveness of sulfasalazine for treating mild-to-moderate active CD was marginal. Additionally, olsalazine and mesalazine, at a low (1–2 g/d) or high (3.2–4.0 g/d) dosage, did not significantly differ from placebo in inducing remission of CD [37]. Furthermore, the current European Crohn’s and Colitis Organization guidelines do not recommend the use of oral 5-ASA for the treatment of ileal CD [38]. Finally, in our study, the BMI classifications are based on the China-specific criteria, which differ from the World Health Organization standards, particularly in establishing thresholds for overweight and obesity. This is primarily because the risk stratification of comorbidities and mortality in the Chinese population is dependent upon lower BMI cut-off values [39, 40, 41]. Further studies should validate this conclusion in population outside the China according to the World Health Organization standards of BMI.

In conclusion, ITIU is not rare during colonoscopy, and predominates in younger individuals with an age $\le$50 years. However, empiric therapy does not improve the outcomes of patients with nonspecific ITIU. Therefore, the cost-effectiveness or time-efficiency of TI intubation should be comprehensively evaluated in long-term follow-up studies.

• ITIU had a detection rate of 1.3% and is predominantly observed in younger individuals with an age $\le$50 years.

• The necessity of TI intubation should be recognized in all individuals undergoing screening colonoscopy.

• Younger age is an independent risk factor for ITIU.

• Empiric therapy does not improve the outcomes of patients with nonspecific ITIU.

All data included in this study are available from the corresponding authors upon reasonable request.

Conceptualization: XS, XQ; Formal analysis: DS, XS and XQ; Data curation: DS, RC, CL, YL, JH, SW, YS, KW, CG and XQ; Writing—original draft: DS, RC, JH, CL, CG, and XQ; Writing—review and editing: DS, RC, JH, CL, CG, YL, XS, XQ; Supervision: XS, XQ. All authors contributed to the important editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This work was approved by the medical ethical committee of General Hospital of Northern Theater Command [Approval number: Y (2023)196]. All of our patients signed their informed consent forms for colonoscopy before undergoing the examination. Considering the retrospective nature of this study, the use of anonymous data, the lack of direct intervention measures, and the extremely minimal risk to patients, the medical ethics committee of the General Hospital of the Northern Theater Command has waived the requirement for the patients’ written informed consents. This is in accordance with the principles outlined in the Declaration of Helsinki.

Not applicable.

This work was supported by the Independent Research Funding of General Hospital of Northern Theater Command (ZZKY2024018).

Given his role as Editorial Board member, Xingshun Qi had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to John Alcolado. Other authors declared no conflict of interest.