Genetic and environmental factors influencing Crohn’s disease

Abstract

This editorial discusses Pellegrino and Gravina's essay. Crohn’s disease (CD) is a complex and multifactorial disease that is influenced by a combination of genetic and environmental factors. While genetic factors play a key role in the development of the disease, environmental factors also play a significant role in influencing the risk of developing CD. By looking at present understanding of CD pathogenesis, we emphasize the important factors involved in the development of this illness, such as nucleotide-binding oligomerization domain-2, smoking, and vitamin D. Understanding the interplay between genetic and environmental factors is crucial for developing effective strategies for preventing and treating this chronic inflammatory bowel disease.

Key Words: Crohn’s disease; Pathogenesis; Nucleotide-binding oligomerization domain-2; Smoking; Vitamin D

Core Tip: The link and complicated mechanisms between Crohn’s disease (CD), nucleotide-binding oligomerization domain-2, smoking, and vitamin D is complex and poorly understood. In addition to genetic and environmental factors, the interaction between the two is also thought to play a role in the development of CD. Furthermore, the consequences of CD differ from person to person, emphasizing the importance of individual therapy. Individualized treatment, including surgery and medications, is important.

INTRODUCTION

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that affects millions of individuals worldwide[1]. This debilitating condition is characterized by inflammation of the lining of the digestive tract, leading to a range of symptoms including abdominal pain, diarrhea, weight loss, and fatigue[2]. The exact cause of CD remains unknown, but it is believed to result from a complex interplay of genetic, environmental, and immune factors[3]. About 60%-70% of CD patients may experience complications such as abdominal abscess, intestinal obstruction, intestinal perforation, intestinal fistula, intestinal leakage, and gastrointestinal bleeding in the later stage, requiring one or even multiple surgical treatments[4]. A key feature of CD is dysregulation of the immune response, with an exaggerated inflammatory response to intestinal bacteria believed to play a central role in the development of the disease[5]. Genetic factors also contribute to the risk of developing CD, with certain genetic variations known to increase susceptibility to this condition[6]. Environmental factors such as diet, smoking, and the composition of the gut microbiota are also thought to play a role in triggering or exacerbating inflammation in individuals predisposed to CD[7]. The colonic bacterial composition in CD is altered compared to healthy individuals, and this dysbiosis, an imbalance in the microbial community, appears to contribute to both the onset and the exacerbation of inflammation in the gut. Table 1 summarized the potential factors influencing CD.

Table 1 The potential factors influencing Crohn’s disease.

Pathogenesis	Factors	Description
Genetic factors	NOD2	NOD2 is involved in recognizing bacterial components and activating innate immune responses. Mutations in NOD2 are one of the most well-established genetic risk factors for CD, particularly influencing the response to intestinal bacteria
	ATG16 L1	ATG16 L1 is critical for autophagy, the process by which cells degrade and recycle components. Variants in this gene impair autophagy, which can increase susceptibility to CD by disrupting immune tolerance and promoting chronic inflammation
	TLRs	TLRs are part of the innate immune system, helping to recognize pathogens and initiate immune responses. Dysregulated TLR signaling can lead to an exaggerated immune response to gut microbiota, contributing to CD
Environmental factors	Smoking	Smoking is a well-established environmental risk factor for CD. It alters immune responses and microbiome composition, and is associated with more severe disease progression and complications, such as strictures and fistulas
	Diet	A diet high in processed foods, fats, and sugar, and low in fiber, can promote gut inflammation and dysbiosis, which may trigger or exacerbate CD. Diets rich in omega-3 fatty acids and fiber may have protective effects
	Vitamin D	Low levels of vitamin D have been associated with an increased risk of developing CD and may affect immune function. Vitamin D plays a role in regulating the immune system and maintaining the intestinal barrier
Gut microbiota	Bacteria	Dysbiosis, or an imbalance in gut bacterial composition, is linked to CD. Pathogenic bacteria like Escherichia coli may promote inflammation, while beneficial bacteria like Faecalibacterium prausnitzii have anti-inflammatory effects
	Fungi	The gut mycobiome (fungal microbiota) has been found to differ in CD patients compared to healthy controls. Dysregulated fungal populations may interact with bacteria, affecting immune responses and intestinal barrier function
	Virus	Viral infections, particularly those that affect the gut, may trigger or exacerbate CD in genetically susceptible individuals. Viruses like enteric adenoviruses and Epstein-Barr virus have been implicated in IBD pathogenesis
	Parasite	Parasitic infections may modulate immune responses, potentially either triggering or protecting against inflammation. Some studies suggest that exposure to certain parasites may be protective against CD
Immune factors	Innate immunity	Innate immunity involves the body's first line of defense, including pattern recognition receptors. Dysregulation in innate immunity leads to an inappropriate immune response to normal gut bacteria, contributing to chronic inflammation in CD
	Acquired immunity	The acquired immune response involves T cells and antibodies. In CD, an imbalance of Th1 and Th17 responses can drive inflammation, while Tregs may be insufficient to control it. Abnormal cytokine production is a key feature of CD
Non-coding RNA	miRNA	miRNAs are small RNA molecules that regulate gene expression post-transcriptionally. In CD, altered miRNA expression can affect immune cell differentiation and response, potentially contributing to inflammation and disease progression
	lncRNA	lncRNAs are involved in the regulation of gene expression, chromatin remodeling, and immune cell differentiation. Their dysregulation in CD may impact immune function and contribute to intestinal inflammation
	siRNA	siRNAs regulate gene silencing and play a role in modulating immune responses. They have been explored as potential therapeutic agents for targeting specific genes involved in CD pathogenesis
	circRNA	circRNAs are a type of non-coding RNA that form closed loops. They are involved in regulating gene expression and protein activity. In CD, altered circRNA expression may influence immune responses and gut barrier integrity

NOD2: Nucleotide-binding oligomerization domain-2; ATG16 L1: Autophagy related 16 like 1; TLRs: Toll-like receptors; CD: Crohn’s disease; Tregs: Regulatory T cells; IBD: Inflammatory bowel disease.

GENETIC FACTORS

Genetic factors have long been recognized as playing a key role in the development of CD. In fact, having a first-degree relative with CD can increase the risk of developing the disease by up to 20 times. Variants in the nucleotide-binding oligomerization domain-2 (NOD2) gene, involved in the immune response to bacteria in the gut, could increase risk of developing CD.

NOD2 mutations are associated with some phenotypes of CD, such as fibrous stenosis or penetrating lesions[8]. NOD2 gene deficiency leads to intestinal inflammatory gene expression and dysfunction of goblet cells in the intestinal mucosa in mice. These abnormalities are related to excessive production of kinesin by intestinal mucosal intraepithelial lymphocytes. In addition, scholars also detected an increase in the number of pro-inflammatory microorganisms Bacteroides in the gut. The mice with NOD2 mutation have autophagy dysfunction and increased bacterial lipopolysaccharide, which leads to the activation of Toll like receptors, the massive release of a variety of inflammatory related factors and the waterfall like effect, and finally causes intestinal inflammatory response[9].

The identification of these genetic risk factors has helped to improve our understanding of the underlying mechanisms that drive the development of CD. For example, studies have shown that mutations in the NOD2 gene can lead to an abnormal immune response in the gut, leading to inflammation and damage to the intestinal lining. Other genetic variants have been linked to abnormalities in the gut microbiome, the community of bacteria that live in the intestines and play a crucial role in regulating the immune system.

GENETIC VARIANTS TO IMPROVE THE EFFECTIVENESS OF DIAGNOSIS AND TREATMENT

Over the last few decades, CD-associated genetic variants largely affect immune responses, intestinal barrier function, and microbial interactions. Variants in the IL23R gene, which play a crucial role in the regulation of T-cell responses, are also strongly associated with CD. The involvement of IL23R in immune cell regulation suggests a potential therapeutic target. ATG16 L1 and IRGM are involved in autophagy, a process critical for the immune response to pathogens. Mutations in these genes can lead to impaired autophagy and contribute to CD pathogenesis. Variants in TNF Superfamily Member 15 have been linked to an increased risk of CD, particularly in European and Asian populations, suggesting a role in the regulation of inflammation. While genetic testing for CD is not yet routine in clinical practice, it holds potential in early diagnosis. Identifying patients at high genetic risk could enable earlier intervention, potentially altering the disease course. Moreover, genetic variants such as those affecting drug metabolism can influence a patient's response to medications and their risk of adverse effects.

ENVIRONMENT FACTORS

Several environmental risk factors have been identified, including smoking, diet, and stress. Smoking is one of the most well-established environmental risk factors for CD, with smokers being twice as likely to develop the disease compared to non-smokers. Studies have shown that smoking can disrupt the balance of bacteria in the gut and increase inflammation, contributing to the development of CD.

Smoking as one environmental factor has long been recognized as a risk factor for several health conditions, including heart disease, lung cancer, and respiratory problems. Recently, smoking has been of particular interest in relation to CD. Several studies have suggested that smoking may have a significant impact on the development and progression of CD[10,11]. For instance, research has shown that smoking can increase the risk of developing CD in individuals with a genetic predisposition to the condition[12]. Additionally, smokers with CD may experience more severe symptoms, require more aggressive treatment, and have a higher risk of complications compared to non-smokers with the condition. Chronic smokers, particularly those who have smoked for many years, are at an increased risk of developing CD, with studies indicating that smoking may accelerate disease onset and increase the severity of symptoms. Smoking duration and intensity are important factors in modulating disease outcomes, with heavy smokers experiencing more frequent flare-ups and complications compared to non-smokers. Both active smoking and passive exposure to tobacco smoke have been associated with increased disease risk. However, the risk is significantly higher in active smokers. While the exact mechanisms remain unclear, smoking-induced changes in the gut’s immune system and microbiota are believed to play a key role in the pathogenesis of CD.

Diet is another important environmental factor that can influence the development of CD. Research has shown that a diet high in processed foods, sugar, and saturated fats can increase inflammation in the gut and disrupt the balance of bacteria, contributing to the development of the disease. In contrast, a diet high in fruits, vegetables, and fiber has been shown to reduce inflammation and promote a healthy gut microbiome, reducing the risk of developing CD.

Vitamin D plays an important role in the pathogenesis by participating in the regulation of intestinal immune function[13]. Most patients with CD are complicated with vitamin D deficiency, and the reduction of vitamin D is significantly correlated with the incidence of CD[14]. The 1,25-dihydroxyvitamin D3 can significantly increase the secretion of antimicrobial peptides by Paneth cells in the intestinal mucosa through binding with vitamin D receptor, and promote the development and differentiation of regulatory T cells and type 2 helper T cells[15]. Vitamin D also affects the function of natural killer T cells and reduces the production of related cytokines such as Thl7 cells. In addition, vitamin D can protect patients with CD by increasing the number and abundance of beneficial bacteria and regulating the polymorphism of bacteria in the gut[16]. And vitamin D supplementation can reduce the recurrence rate of CD. The threshold for vitamin D deficiency commonly used in clinical practice is typically below 20 ng/mL (50 nmol/L), which is consistent with the definition of deficiency from organizations like the Institute of Medicine and the Endocrine Society. Levels between 20-30 ng/mL are considered insufficient, while levels above 30 ng/mL are generally considered sufficient for bone and immune health. Most studies implicating vitamin D in CD have linked deficiency levels (under 20 ng/mL) with poorer disease outcomes, such as higher disease activity, increased flare-ups, and poorer response to treatment. Vitamin D deficiency may be associated with the development of CD[17].

There are also some other environmental factors such as smoking e-cigarettes, exposure to various food toxicants, etc. The use of e-cigarettes is increasingly common, and while it is considered less harmful than traditional smoking, emerging evidence suggests it may still have a detrimental effect on gut health. E-cigarette vapors contain various chemicals, such as nicotine, formaldehyde, and acrolein, which can alter the gut microbiota, increase oxidative stress, and trigger inflammatory responses. Nicotine, in particular, may exacerbate CD by promoting Th17-mediated inflammation and impairing mucosal immunity. The long-term effects of vaping on CD are not fully understood but may include the potential to exacerbate existing disease or trigger the onset in susceptible individuals. Exposure to environmental pollutants, including particulate matter (PM2.5), NO₂, and O₃, has been associated with an increased risk of inflammatory bowel diseases, including CD. These pollutants can promote systemic inflammation, affect the gut immune response, and disrupt the microbiome.

EFFECT OF UNHEALTHY DIET, AND LIFESTYLE

Diets high in sugar, processed foods, and refined carbohydrates (e.g., white bread, sugary drinks, and sweets) have been shown to promote inflammation in the body. These foods can trigger or worsen flare-ups of CD by aggravating the gut’s immune response. Diets rich in unhealthy fats, particularly trans fats and saturated fats, have been linked to increased intestinal inflammation. Excess fat intake can promote the production of pro-inflammatory cytokines, which increase gut inflammation and can contribute to the severity of Crohn's symptoms.

CLINICAL IMPLICATIONS

Despite these findings, the link between CD, NOD2, smoking, and vitamin D is complex and poorly understood. In addition to genetic and environmental factors, the interaction between the two is also thought to play a role in the development of CD. Similarly, environmental factors may influence the expression of certain genes that increase the risk of developing the disease. Furthermore, the consequences of CD differ from person to person, emphasizing the importance of individual therapy. The complicated mechanisms underlying the link between CD, NOD2, smoking, and vitamin D need to be studied further for therapeutic applications. Individualized management, including surgery and medicines, is significant[18].

CONCLUSION

While genetic factors play a key role in the development of the disease, environmental factors also play a significant role in influencing the risk of developing CD. By looking at present understanding of CD pathogenesis, we emphasize the important factors involved in the development of this illness, such as NOD2, smoking, and vitamin D. Understanding the interplay between genetic and environmental factors is crucial for preventing and treating this chronic inflammatory bowel disease.