A groundbreaking study by researchers at West China Hospital, Sichuan University, has unveiled a previously unknown mechanism linking Epstein–Barr virus (EBV) infection to the worsening of ulcerative colitis (UC). Published in Precision Clinical Medicine on January 21, 2025 (DOI: 10.1093/pcmedi/pbaf002), the research reveals that EBV can trigger inflammatory cell death—known as pyroptosis—in macrophages, a discovery that may pave the way for new, targeted treatments for UC.
Unraveling a Chronic Disease
Ulcerative colitis is a chronic, relapsing inflammatory bowel disease that causes painful inflammation and ulcers in the colon. Although its exact cause remains elusive, scientists have long suspected that viral infections may play a role in exacerbating the condition. Notably, elevated levels of EBV DNA and RNA have been detected in the colonic tissues of UC patients, correlating with more aggressive symptoms, increased risks of surgery, and poorer responses to treatment. However, until now, the precise mechanisms by which EBV influences UC progression have remained a mystery.
The Study: Methods and Models
To address these uncertainties, the research team led by Dr. Hu Zhang undertook a dual-pronged approach. First, they analyzed tissue samples from UC patients, looking for markers of EBV infection and correlating these with clinical outcomes. Second, the team conducted controlled experiments using mouse models infected with murine gamma‐herpesvirus 68 (MHV-68), a close relative of EBV. This animal model allowed the researchers to replicate the effects of EBV infection in a controlled environment and to observe its impact on intestinal tissues and immune responses.
READ MORE: Chemotherapy Linked to Persistent Physical Health Decline in Breast Cancer Survivors
The study focused on the role of macrophages—immune cells that play a crucial role in inflammation and tissue repair—in the progression of UC. Using advanced molecular techniques, the researchers examined the levels of key pyroptosis-related proteins, including Gasdermin D, NLRP3, interleukin-1β (IL-1β), and interleukin-18 (IL-18) in the colonic tissues of both human patients and mice. Pyroptosis is a form of programmed cell death that, unlike apoptosis, results in the release of pro-inflammatory factors, thus exacerbating inflammation.
Key Findings: The Role of Glycolysis and Pyroptosis
The results were striking. EBV infection was found to dramatically increase the expression of pyroptosis-related proteins in the colon. Macrophages infected with EBV displayed excessive inflammatory responses that led to severe intestinal damage and compromised gut integrity—a hallmark of exacerbated UC.
One of the most compelling discoveries was the identification of glycolysis as a central driver of this inflammatory process. Glycolysis, the metabolic pathway that converts glucose into energy, was found to fuel the heightened inflammatory response seen in EBV-infected macrophages. The researchers demonstrated that when glycolysis was blocked using the metabolic inhibitor 2-deoxy-D-glucose (2-DG), macrophage pyroptosis was significantly reduced, leading to decreased inflammation in the colitis-afflicted mice. This finding establishes a direct link between EBV-induced metabolic dysregulation and immune activation in UC, offering a novel target for therapeutic intervention.
Implications for Ulcerative Colitis Treatment
Current treatment strategies for ulcerative colitis primarily rely on immunosuppressants to control inflammation. While these medications can be effective, they also have the drawback of dampening the immune system broadly, which may leave patients more vulnerable to infections, including viral pathogens like EBV. The study’s findings suggest that targeting glycolysis could offer a more precise approach—one that specifically curbs the inflammatory cascade triggered by EBV without compromising overall immune function.
In addition to glycolysis inhibitors, the study raises the possibility of exploring antiviral therapies aimed directly at suppressing EBV replication as adjunct treatments for UC patients with elevated EBV levels. Such a dual approach—combining metabolic intervention with antiviral treatment—could potentially improve patient outcomes by addressing both the inflammatory and viral components of the disease.
Expert Commentary and Reactions
Dr. Hu Zhang, the corresponding author of the study, emphasized the significance of the findings: “Our research provides compelling evidence that EBV actively contributes to UC severity by triggering inflammatory cell death in macrophages. More significantly, we have identified glycolysis as a potential target for intervention. By disrupting this metabolic pathway, we may be able to curb EBV-driven inflammation and improve treatment outcomes for UC patients.”
Experts in the field have welcomed these insights as a major step forward. Professor Li Wei, a gastroenterologist not involved in the study, noted, “This research not only deepens our understanding of the pathogenesis of ulcerative colitis but also opens up new avenues for treatment that could be more effective and less harmful than current immunosuppressive therapies.”
Broader Implications: A Shift Toward Precision Medicine
The study is a significant contribution to the growing body of evidence that supports the shift toward precision medicine in the treatment of chronic inflammatory diseases. By pinpointing the specific pathways—such as glycolysis—that drive the inflammatory response in UC, clinicians may soon be able to tailor treatments to individual patients’ metabolic profiles. This approach could minimize side effects and improve the efficacy of treatments, ultimately leading to better quality of life for patients suffering from UC.
Moreover, the research underscores the potential of using animal models to replicate and understand human diseases. The successful use of MHV-68 to model EBV infection in mice provides a robust framework for future studies aimed at unraveling the complex interactions between viral infections and chronic inflammatory conditions.
The Future: Clinical Trials and Next Steps
While the findings from this study are promising, further research is essential to translate these discoveries into clinical practice. The next phase of research will likely involve clinical trials to test the efficacy and safety of glycolysis inhibitors like 2-deoxy-D-glucose in human subjects with ulcerative colitis. These trials will be critical in determining whether the reduction in inflammatory markers observed in mouse models can be replicated in patients.
Additionally, researchers will continue to explore the role of EBV in the broader context of inflammatory bowel disease. Understanding how viral infections interact with genetic and environmental factors in the progression of UC could lead to even more targeted and effective therapies. As scientists uncover more about the mechanisms of inflammatory cell death and metabolic dysregulation, it may become possible to develop a suite of precision-based interventions that address the unique needs of UC patients.
Challenges and Considerations
Despite the enthusiasm surrounding these findings, several challenges remain. The complexity of the human immune system means that interventions targeting glycolysis must be finely tuned to avoid unintended consequences. For instance, glycolysis is a fundamental process that occurs in all cells, and systemic inhibition could potentially affect normal cellular functions. Therefore, any potential treatment would need to be highly specific to the pathological processes occurring in EBV-infected macrophages.
Furthermore, the variability in EBV levels among UC patients suggests that a one-size-fits-all approach may not be feasible. Future therapies might need to be personalized based on the patient’s viral load and the extent of metabolic dysregulation in their colonic tissues.
Conclusion: New Hope for Ulcerative Colitis Patients
The study by West China Hospital, Sichuan University, and the Chinese PLA General Hospital represents a landmark in our understanding of ulcerative colitis and the role that Epstein–Barr virus plays in exacerbating the condition. By demonstrating that EBV triggers inflammatory cell death in macrophages through a glycolysis-dependent mechanism, the research offers a new perspective on disease progression and opens the door to innovative, targeted therapies.
While current treatments for UC have focused largely on suppressing the immune system, this new approach suggests that intervening in the metabolic pathways of immune cells could offer a more precise and effective strategy. With clinical trials on the horizon, there is renewed hope that these findings will soon translate into improved outcomes for the millions of patients living with ulcerative colitis.
As the field of precision medicine continues to evolve, this research highlights the critical importance of understanding the intricate interplay between viral infections, metabolism, and immune responses. For UC patients, these advancements represent not just a scientific breakthrough but a potential lifeline—a chance for a future where treatment is tailored to the unique biological processes underlying their condition.
