We read with interest the letter to the Editor by Dr Ribolsi and Dr Cicala with regard to our recent paper published in the journal. We thank them for their insightful contribution to the discussion around proton pump inhibitor (PPI) dependency and exacerbation of gastro‐esophageal reflux symptoms upon withdrawing PPIs.

In our study, rebound symptoms on stopping PPIs appeared to occur in patients with both normal and abnormal objective acid exposure. We agree that it would be fascinating to have pre‐PPI therapy data for these patients in order to better understand the effect of withdrawing PPIs compared with baseline. Nevertheless, the data we have presented shows that, at the time of heartburn symptom exacerbation, a significant proportion of patients have esophageal acid exposure and number of reflux events that can be considered completely normal. The mechanism for this requires further examination. Very few in our study demonstrated reflux hypersensitivity by pH‐impedance criteria.

The role of dilated intercellular spaces (DIS) in the esophageal epithelium is indeed, of interest in when considering the reason for increased perception in such patients. Over time, we have read with interest the studies by the authors of the letter.1, 2 We agree that the presence of DIS may allow H⁺ ions to permeate to the nerve endings. However, we have also shown recently that the location of such nociceptive nerves frequently lie in the superficial layers of the epithelium, above the anatomical location of DIS (particularly in patients with non‐erosive disease).3, 4 This suggests that the ability of acid to permeate to the deeper epithelium is not always required to trigger nociception. The more the mucosa in gastro‐esophageal reflux disease is investigated, the more multifactorial the pathogenesis appears. It is probable that acid exposure, nerve location and sensitivity, inflammation, DIS, and other factors all play an overlapping role in pathogenesis. We look forward to working alongside our international peers to unravel how these factors combine and interact.

我们饶有兴趣地阅读了Ribolsi博士和Cicala博士写给编辑的信，内容涉及该杂志最近发表的论文。我们感谢他们为围绕质子泵抑制剂（PPI）依赖性和撤回PPI后加重胃食管反流症状的讨论提供了有见地的贡献。

在我们的研究中，正常和异常的客观酸暴露患者均出现了停止PPI的反弹症状。我们同意，为这些患者准备PPI之前的治疗数据会很有趣，以便更好地了解撤回PPI与基线相比的效果。尽管如此，我们提供的数据表明，在胃灼热症状加重时，仍有相当一部分患者患有食管酸暴露和反流事件，可以认为这是完全正常的。该机制需要进一步检查。在我们的研究中，几乎没有人通过pH阻抗标准显示出反流性超敏反应。

当考虑到这种患者的知觉增加的原因时，确实需要关注食管上皮细胞间隙的扩张（DIS）的作用。随着时间的流逝，我们感兴趣地阅读了这封信作者的研究。1，2我们同意DIS的存在可能会使H ⁺离子渗透到神经末梢。但是，最近我们还发现，这种伤害性神经的位置通常位于上皮的浅层中，位于DIS的解剖位置之上（特别是在非糜烂性疾病患者中）。3 4这表明并非总是需要酸渗透到更深的上皮的能力来触发伤害感受。对胃食管反流病中的粘膜进行的研究越多，发病机理就越多。酸暴露，神经位置和敏感性，炎症，DIS和其他因素很可能在发病机理中起重叠作用。我们期待与国际同行一道，共同探讨这些因素如何结合和相互作用。