03659490

December 09, 2025, 15:28

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We are delighted to read the high-quality review by Zheng et al[1], published in the World Journal of Gastroenterology, which offers insightful perspectives on the neuroimmune mechanisms contributing to the pathogenesis of inflammatory bowel disease (IBD). The intricate interplay between the autonomic nervous system (ANS) and the immune response, particularly involving vagus nerve stimulation (VNS) and its effects on macrophages, provides a promising avenue for future therapeutic interventions in IBD. The review underscores the emerging concept of neuroimmune interactions, particularly the cholinergic anti-inflammatory pathway (CAIP), which regulates inflammation through the vagus nerve and its interaction with intestinal macrophages. This is an exciting area of research, especially in the context of IBD, where inflammation is at the heart of the disease's pathology. Macrophages, as highlighted in the review, play a crucial role in maintaining intestinal homeostasis, but when overactivated, they contribute to the excessive production of proinflammatory cytokines, exacerbating the condition. This review draws attention to how the cholinergic system can modulate macrophage activity, reducing the inflammatory burden through the activation of the α7 nicotinic acetylcholine receptor (α7nAChR). The role of VNS as an approach to activate the cholinergic pathway and regulate inflammation in IBD is a breakthrough concept. Studies showing the beneficial effects of VNS in reducing inflammation and enhancing immune tolerance are promising, offering a potential alternative to conventional treatments, especially in patients with refractory IBD. Furthermore, the use of VNS to modulate the autonomic nervous system offers a unique therapeutic strategy for restoring balance between sympathetic and parasympathetic tones in patients, whose autonomic dysfunction may contribute to disease exacerbation. While the current data on VNS in IBD are promising, the review rightly calls for further research to better establish the clinical applicability of VNS, especially through non-invasive techniques such as transauricular and transcervical VNS. These methods, as highlighted, may offer a safer and more accessible alternative to invasive VNS, which has shown positive effects in treating other inflammatory conditions. The ongoing exploration of VNS in clinical trials, coupled with advancements in understanding the mechanisms of cholinergic signaling in immune cells, opens new avenues for therapeutic interventions in chronic inflammatory diseases. However, as the review mentions, there are still challenges that need to be addressed. The precise mechanisms through which VNS modulates immune responses, particularly in macrophages, are still under investigation. Additionally, while VNS has shown potential in preclinical models, there is a need for larger, well-designed clinical studies to confirm the safety, efficacy, and long-term benefits of VNS in IBD patients. The heterogeneity of IBD, along with differences in patient responses to treatment, further complicates the development of standardized protocols for VNS treatment. In conclusion, the review provides an excellent overview of the current state of research on neuroimmune interactions in IBD, with a special focus on the potential of VNS as a novel therapeutic strategy. The integration of neuroimmune regulation, particularly through the cholinergic pathway, into the treatment of IBD represents an innovative approach that could offer significant improvements in patient outcomes. As we move forward, I hope that the continued research in this field will provide more concrete evidence to support the use of VNS in clinical practice, potentially offering a transformative treatment for IBD patients who have not responded to traditional therapies. LIMITATIONS OF THE REVIEW While the review provides a comprehensive overview of the potential therapeutic role of vagus nerve stimulation (VNS) in inflammatory bowel disease (IBD), there are some limitations that should be addressed in future research. First, while the article highlights the promising effects of VNS, particularly through the cholinergic anti-inflammatory pathway (CAIP), there is a lack of in-depth discussion regarding the specific cellular mechanisms involved. The exact signaling pathways through which VNS modulates macrophage activity and alters immune responses remain unclear, and more detailed mechanistic studies are needed to provide a clearer understanding. Additionally, the review does not fully address the challenges associated with the translation of VNS into clinical practice. For instance, the variability in patient response to VNS, the optimal stimulation parameters (e.g., frequency, duration, and intensity), and the potential side effects of VNS, particularly in IBD patients with coexisting conditions, are aspects that require more attention. Lastly, the review focuses primarily on the autonomic nervous system's role in IBD, but it overlooks other possible neuroimmune interactions that could also influence disease progression. A broader exploration of how other neural pathways or neuropeptides contribute to IBD would provide a more comprehensive view of the neuroimmune mechanisms at play. CONCLUSION The review provides an insightful exploration of the neuroimmune mechanisms involved in inflammatory bowel disease (IBD), particularly focusing on the role of intestinal macrophages and the cholinergic anti-inflammatory pathway. Vagus nerve stimulation (VNS) represents a promising non-invasive therapeutic approach for modulating the immune system and controlling inflammation in IBD. However, further research is needed to fully understand the mechanisms behind VNS and to establish its efficacy in clinical settings for treating chronic inflammatory diseases such as IBD. With the development of non-invasive VNS technologies, future therapies may offer safer and more effective treatments for patients suffering from IBD.

03769692

December 03, 2025, 16:22

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this review provides a clear and systematic overview of the interactions among intestinal macrophages, the enteric nervous system, and the cholinergic anti-inflammatory pathway in inflammatory bowel disease (IBD). By closely linking basic mechanistic insights with the potential clinical application of vagus nerve stimulation (VNS)—especially low-frequency, non-invasive VNS—the paper offers a fresh “neuroregulation–immune modulation” angle on IBD treatment, which is currently dominated by immunosuppressants and biologics. In terms of clinical practicality, the authors emphasize the promise of non-invasive VNS as a safer and more tolerable approach, while frankly acknowledging that current evidence still largely comes from animal models and a few pilot clinical studies, with a lack of large-scale randomized controlled trials. This “promising yet cautious” tone is valuable for clinical readers. On the one hand, the paper helps gastroenterologists and basic scientists understand why heart rate variability (HRV), emotional status, and autonomic imbalance may be linked to IBD course and relapse; on the other hand, it reminds readers that VNS and α7nAChR-targeted agents are still at the stages of proof-of-concept and early translation. In the short term, their main value lies in inspiring new research designs (for example, clinical trials stratified by HRV, combined with intestinal macrophage phenotype analysis), rather than immediately changing standard treatment pathways. Overall, this work reads like a forward-looking “blueprint” for neuro-immune therapies in IBD and is particularly thought-provoking for readers interested in IBD mechanisms and novel therapeutic strategies.