In our prospective study, the mean age of participants was 8.62 ± 4.4 years, with a median age of 9 years. Females constituted a slight majority, accounting for 51.9% of the study population. Bardella et al. (2005) investigated gender- and age-related symptoms of gluten intolerance in a cohort of 1436 patients and found a higher prevalence among females (69.4%) [34]. Similarly, a more recent study by Kara et al. (2021) involving 90 patients with CD reported a median age of 11 years (range = 3–18 years) and a female predominance (54.4%) [29].

In our study, patients exhibited a wide range of clinical features. The most common presenting symptom was abdominal distention (61.11%), followed by failure to thrive (59.26%), chronic abdominal pain (57.41%), and chronic fatigue (55.56%). Similarly, Kara et al. (2021) reported that the most common symptom in their cohort was abdominal pain (52%), followed by weight loss (42%) and malnutrition (28%) (29). In a cross-sectional study conducted by Dehbozorgi et al. (2020) involving 130 patients with CD, abdominal pain was also the most prevalent symptom (62%), followed by bone pain (53%) and chronic fatigue (49%) [35].

A study from Saudi Arabia by Al Sarkhi et al. (2016), which included 113 patients, revealed that the most common presentation of CD was chronic abdominal pain (59%), followed by poor weight gain (54%) and abdominal distention (46%) [36]. Similarly, an older study by Poddar et al. (2006) involving 300 confirmed CD patients reported that the most frequent presenting symptoms were failure to thrive (91%), wasting (87%), anemia (84%), and diarrhea (84%) [37]. These findings highlight the vast variability in the clinical manifestations of CD, which can present with a wide range of gastrointestinal and extra-gastrointestinal symptoms.

In the current study, we observed significantly elevated serum IL-15 levels in newly diagnosed CD patients compared to the control group. Aghamohamadi et al. found that IL-15 messenger ribonucleic acid levels were notably higher in CD patients with Marsh II lesions compared to healthy controls, as well as those with Marsh I and Marsh III lesions. The difference between Marsh II and Marsh I patients was statistically significant. While serum IL-15 concentrations were also elevated in Marsh II patients compared to Marsh I and Marsh III patients, these differences did not reach statistical significance [38]. However, the study suggested that tissue levels of IL-15 correlate with circulating IL-15 expression. This supports the potential of circulating IL-15 as a reliable biomarker for assessing intestinal damage in CD [38].

IL-15 overexpression was also demonstrated in patients with active CD in the study by Mention et al. [39]. Numerous studies have shown that the gluten-driven intestinal inflammatory disorder in CD is primarily caused by the upregulation of IL-15 expression in the intestinal mucosa. IL-15 acts on various cell types and influences distinct immune components and pathways, ultimately disrupting intestinal immune homeostasis [17].

In our study, the diagnostic power of IL-15 was evaluated, demonstrating its potential as a promising tool for detecting CD with a sensitivity of 98.15% in the cases group. Furthermore, a serum level of IL-15 exceeding 14.3 pg/ml could be considered evidence of CD when compared to healthy controls.

An Iranian study by Masaebi et al. assessed the diagnostic performance of various cytokines for CD and non-celiac gluten sensitivity (NCGS). Their findings, for the first time, highlighted that IL-8 and IL-15 exhibited the highest sensitivities, specificities, and predictive values (positive and negative) for detecting CD patients compared to the NCGS group and healthy controls [40].

Similarly, a study conducted by Di Sabatino et al. evaluated 46 CD patients and 22 healthy individuals. Their results indicated that IL-15 expression significantly increased in the intestinal tissues of CD patients compared to healthy individuals. This finding suggests that a lower immunological threshold of IL-15 in CD contributes to the initiation of other immune responses and the development of small bowel lesions [41].

Bernardo et al. obtained similar findings after evaluating 42 CD patients and 24 healthy individuals at a gastroenterology clinic for intestinal pathologies. However, they noted that IL-15 levels did not increase in the NCGS group [42].

In another study by Heydari et al., they enrolled 110 treated CD patients, 15 with NCGS, and 46 healthy children, despite the higher mean serum levels of IL-15 they reported in the CD patients group (69.4 ± 137.9) as compared with patients in the NCGS (27.9 ± 61.1) and control (17.0 ± 43.9) groups, these differences were not significantly different between the studied populations (p = 0.869) [43].

Additionally, a study by Escudero-Hernandez et al. analyzed the IL-15 and IL-15Rα genes in samples from the Spanish Consortium for Genetics of Celiac Disease. Their findings suggested that the IL-15 gene might contribute to the genetic predisposition to CD and refractory CD through less common variants with moderate effects. They identified two regulatory SNP associated with CD: rs4956400 (p = 0.0112, OR 1.21, 95% CI 1.04–1.40) and rs11100722 (p = 0.0087, OR 1.24, 95% CI 1.06–1.45), both located upstream of the IL-15 gene. These SNP were found to correlate with higher IL-15 protein expression [16]

In our study, comparing the IL-15 SNP (rs2857261) between the patient and control groups, we found that the A/A genotype was significantly more prevalent among the patients (48.15%) compared to the control group (6.8%) with statistical significance (p < 0.0001). In contrast, the A/G genotype was more frequent in the control group (56.8%) than in the patient group (35.2%) with a significant difference (p < 0.0001). These findings contradict those of Kara et al., who studied Turkish patients with CD and found a significantly higher frequency of the GG genotype in celiac patients compared to controls. In their study, the AA genotype was more common in the control group than in the celiac patients [29].

Furthermore, we analyzed the potential impact of this IL-15 SNP (rs2857261) on CD symptoms and histopathological grade, but found that none of the clinical symptoms or the histological grade was influenced by the presence of any of the genotypes of this SNP. These discrepancies in clinical manifestations may be explained by the presence of additional modifier genes that may influence the disease phenotype."

In addition, differences in genotype findings could be attributed to variations in genetic backgrounds, as population-specific allele frequencies can significantly influence results [44]. The presence of modifier genes and genetic linkage with other variants may further explain population-specific effects [45].

Currently, limited data exist regarding IL-15 gene polymorphisms and their variability among individuals from different ethnic backgrounds and diseases. However, IL-15 gene variants have been associated with several autoimmune disorders, including psoriasis, type 1 diabetes, ulcerative colitis, and rheumatoid arthritis. These findings highlight the importance of genetic studies investigating the involvement of the IL-15 gene in celiac disease (CD) [16, 17].

Given the central role of IL-15 in the immunopathogenesis of CD, there is growing interest in developing novel therapies to attenuate its actions. To inhibit IL-15 activity and prevent its harmful effects on oral tolerance and intraepithelial lymphocyte activation, several therapeutic agents have been developed, including IL-15-specific antibodies [17].

While HLA genes are a prerequisite for the development of CD, they are not sufficient on their own. Approximately 39% of the general population carries the DQ2 or DQ8 genes, yet only 3% of these individuals develop CD. This highlights the role of additional genetic factors in determining host susceptibility to the disease [46].

This study has several limitations. Its single-center design may limit the generalizability of the findings. Additionally, serum and tissue IL-15 levels were not assessed after GFD adherence, particularly in patients with the A/A genotype, restricting insights into IL-15 expression dynamics. Resource constraints prevented the analysis of additional IL-15 SNPs beyond rs2857261. Future large-scale studies should evaluate IL-15 levels before and after GFD adherence, especially in genetically predisposed individuals, and investigate multiple IL-15 SNP to better understand IL-15’s role in CD and its therapeutic potential.