Inflammatory Bowel Disease is a complex and chronic illness characterized by an abnormal immune response against the microorganisms in the digestive system [1]. IBD encompasses two primary forms known as CD and UC. CD affects the entire digestive tract from the mouth to the anus, causing segmental and transmural inflammation. Common complications include intestinal narrowing and fistula formation, often requiring surgery. On the other hand, UC primarily affects the colon's surface and submucosa and is characterized by periods of exacerbation and remission with ulcers and inflammation. Its main symptoms include rectal bleeding, diarrhea, and abdominal pain, with complications such as toxic megacolon, strictures, dysplasia, and cancer [2]. IBD typically progresses with periods of relapse and remission. The prevalence of IBD is highest in Europe and North America, affecting approximately 11.2 million people worldwide [3].

The pathogenesis of IBD involves three main components: genetic predisposition, immunity, and microbiota. Understanding these mechanisms is crucial for researchers to fully comprehend the disease's pathogenesis [4], [5]. Identifying genetic variants associated with IBD is important for understanding the disease's development and developing targeted therapies. One such variant is the RNF186 gene, which is believed to play a role in regulating zonulin, a critical mediator of tight junction function [6].

Numerous studies have demonstrated that RNF proteins contribute to various biological processes. Genetic alterations that disrupt RNF protein function are often associated with diseases such as cancer, immunological disorders, and neuropsychiatric disorders [7], [8]. RNF186, a single-exon protein-coding gene, codes for the ring finger E3 ligase, which localizes to the endoplasmic reticulum and regulates caspase-dependent apoptosis induced by endoplasmic reticulum stress [9]. Recently, several RNF family members have been found to have a significant impact on regulating intestinal homeostasis. Genome-wide association studies have identified rare variants in RNF186 associated with UC. RNF186 has been shown to maintain intestinal homeostasis by regulating endoplasmic reticulum stress in colon epithelial cells [10], [11].

Multiple lines of evidence indicate a close connection between endoplasmic reticulum stress and intestinal inflammation. Increased expression of endoplasmic reticulum stress markers has been observed in patients with IBD [12], [13]. RNF186 has been found to mediate the response to endoplasmic reticulum stress. Its expression is linked to intestinal permeability and inflammation. However, it remains unclear whether RNF186 actively contributes to the pathogenesis of intestinal inflammation [11], [13].

Zonulin is considered the only physiological mediator that can affect intestinal permeability by modulating intercellular tight junctions (TJ). Human zonulin is a 47 kDa protein and increases intestinal permeability in the small intestine. Serum zonulin level is an indicator of intestinal permeability [14].

This study aimed to examine the possible role of RNF186 gene variants and zonulin levels in the pathophysiology of IBD.