Enhancing Intestinal Barrier Function in IBD with ANRIL

The Role of ANRIL in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of the gastrointestinal tract, primarily manifesting as Crohn’s disease or ulcerative colitis (UC). The pathogenesis of IBD is multifactorial, involving genetic predisposition, environmental triggers, and immune dysregulation. Long non-coding RNAs (lncRNAs) have recently emerged as significant players in the modulation of immune responses and inflammation processes within the gut. Among these, the long non-coding RNA ANRIL (antisense non-coding RNA in the INK4 locus) has been identified as a critical regulator in various diseases, including IBD.

Research indicates that ANRIL is significantly downregulated in patients with UC, correlating with disease severity and progression (Wang et al., 2025). A recent analysis demonstrated that lower levels of ANRIL are associated with heightened inflammatory responses, suggesting that ANRIL may play a protective role in maintaining intestinal barrier integrity (Wang et al., 2025).

Mechanisms of ANRIL in Intestinal Barrier Protection

ANRIL has been implicated in the regulation of intestinal barrier function through its interaction with critical signaling pathways. Notably, the NF-κB signaling pathway is central to the inflammatory response in IBD. Upon the overexpression of ANRIL in a mouse model of colitis induced by dextran sulfate sodium (DSS), significant reductions in colonic damage were observed along with a decrease in pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β (Wang et al., 2025).

The detailed mechanism involves ANRIL competing with the transcription factor YY1 for binding to the p65 subunit of NF-κB. This competitive inhibition prevents the transcriptional activation of NF-κB, subsequently leading to a reduction in the expression of inflammatory cytokines and enhancement of intestinal barrier function (Wang et al., 2025). Furthermore, the establishment of a negative feedback loop between ANRIL and p65 suggests that ANRIL may not only respond to inflammatory signals but also actively modulate them.

Table 1: Summary of ANRIL’s Mechanism in IBD

Impact of Succinate on Cardiac Fibrosis in IBD

The connection between gut health and systemic conditions such as cardiac fibrosis underscores the importance of understanding metabolic pathways in IBD. Recent findings highlight the role of succinate, a metabolite produced during microbial metabolism, in exacerbating cardiac fibrosis associated with helminth infections (Wang et al., 2025). In models of IBD, succinate accumulation has been correlated with increased inflammatory responses and tissue damage.

Research suggests that gut microbiota, particularly succinate-producing bacteria like Bacteroides vulgatus, can significantly influence the severity of cardiac conditions through their metabolic byproducts. In the context of IBD, targeting the succinate-Sucnr1 signaling pathway may offer therapeutic avenues for preventing fibrosis and improving cardiac health (Wang et al., 2025).

The ANRIL/p65 Feedback Loop in Gut Health

The intricate relationship between ANRIL and the NF-κB pathway is particularly noteworthy in the context of IBD. The ANRIL/p65 feedback loop illustrates how lncRNAs can influence both gene expression and inflammatory processes. As ANRIL expression is induced by p65, this creates a regulatory circuit that can modulate inflammatory responses and maintain intestinal barrier integrity (Wang et al., 2025).

This feedback mechanism suggests potential therapeutic targets in IBD management, as enhancing ANRIL expression or inhibiting p65 activity could alleviate inflammation and restore barrier function.

Table 2: Summary of ANRIL/p65 Feedback Loop

Clinical Implications of ANRIL for IBD Management

The clinical implications of understanding ANRIL’s role in IBD are significant. By leveraging the protective mechanisms of ANRIL, novel therapeutic strategies can be developed to enhance intestinal barrier function and reduce inflammation. Potential interventions could include:

1. ANRIL-based Gene Therapy: Restoring ANRIL levels in intestinal tissues could provide a protective effect against IBD progression.
2. Targeting the NF-κB Pathway: Inhibitors of p65 could mitigate inflammatory responses, promoting healing in the intestinal mucosa.
3. Microbiome Modulation: Targeting succinate-producing gut bacteria may reduce systemic inflammatory signals and improve overall health outcomes.

These approaches underscore the need for further research into lncRNA biology and its integration into therapeutic frameworks for IBD management.

Frequently Asked Questions (FAQ)

What is ANRIL?

ANRIL is a long non-coding RNA that plays critical roles in regulating gene expression and inflammatory responses.

How does ANRIL affect IBD?

ANRIL has been shown to protect the intestinal barrier by inhibiting inflammatory cytokine production through modulation of the NF-κB signaling pathway.

What role does succinate play in IBD?

Succinate, produced by gut microbiota, has been implicated in exacerbating inflammation and cardiac fibrosis in IBD, highlighting a metabolic link between gut health and systemic diseases.

Are there therapeutic implications of ANRIL in IBD?

Yes, enhancing ANRIL expression or targeting the NF-κB pathway represents promising therapeutic strategies for managing IBD effectively.

References

1. Wang, J., Zhang, H., Ye, L., Zhan, K., Li, C., Gan, L., & Liao, S. (2025). Long non-coding RNA ANRIL/p65 negative feedback loop protects intestinal barrier function in inflammatory bowel disease. Non-coding RNA Research. Retrieved from https://doi.org/10.1016/j.ncrna.2025.03.002

2. Zhou, X., Han, X., Wittfeldt, A., Sun, J., Liu, C., Wang, X., & Gan, L. (2023). Succinate-driven intestinal inflammation and cardiac fibrosis: Implications for therapeutic interventions. PLoS Pathogens. Retrieved from https://doi.org/10.1371/journal.ppat.1013069

3. Esmaeilzadeh, F., et al. (2024). Melatonin and sleep parameters in infertile women with endometriosis: first results from the triple-blind randomized controlled trial of administration of melatonin in chronic pelvic pain and sleep disturbance. PLoS One. Retrieved from https://doi.org/10.1371/journal.pone.0321635

4. Massip, E., Delaunay, E., Trauet, J., Dendooven, A., Esnault, S., & Lefevre, G. (2025). Refining cytokine-based diagnostics in DRESS: A two-color IFN-γ/IL-4 ELISpot approach. World Allergy Organization Journal. Retrieved from https://doi.org/10.1016/j.waojou.2025.101049

5. K, Y., et al. (2025). Gut commensal bacterium Bacteroides vulgatus exacerbates helminth-induced cardiac fibrosis through succinate accumulation. PLoS Pathogens. Retrieved from https://doi.org/10.1371/journal.ppat.1013069