Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium.
Laboratory of Ion Channel Research and Transient Receptor Potential Channel Research Platform, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven , Leuven , Belgium.
Am J Physiol Gastrointest Liver Physiol. 2019 Mar 1;316(3):G338-G349. doi: 10.1152/ajpgi.00116.2018. Epub 2019 Jan 10.
Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (HR) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca responses to cinnamaldehyde and GSK1016790A, an effect prevented by HR antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by HR antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via HR activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore HR antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (HR) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of HR antagonism in IBS.
先前，我们已经证实，在肠易激综合征（IBS）患者中，组胺可使瞬时受体电位香草酸 1 型（TRPV1）致敏。在躯体疼痛的临床前模型中，TRP 锚蛋白 1（TRPA1）和 TRP 香草酸 4（TRPV4）的致敏也与异常疼痛感知有关。在这里，我们假设，与 TRPV1 类似，组胺也可使 TRPA1 和 TRPV4 致敏，从而导致 IBS 患者内脏疼痛增加。我们从 IBS 患者和健康对照者（HS）中收集直肠活检组织，使用细胞内 Ca2+成像来研究 TRPA1 和 TRPV4 激动剂（肉桂醛和 GSK1016790A）对神经元的敏感性。此外，我们还评估了直肠活检组织的上清液对 IBS 患者和 HS 中鼠背根神经节（DRG）感觉神经元中 TRPA1 和 TRPV4 反应的影响。最后，我们评估了组胺和组胺 1 受体（HR）在 TRPA1 和 TRPV4 致敏中的作用。与 HS 相比，TRPA1 和 TRPV4 激动剂的应用在 IBS 患者的活检组织中诱发了更高的峰值幅度和响应的黏膜下神经元百分比。在 HS 中，组胺预处理显著增加了肉桂醛和 GSK1016790A 引起的 Ca2+反应，而 HR 拮抗作用可防止这种反应。IBS 上清液但不是 HS 的上清液可致敏 DRG 神经元上的 TRPA1 和 TRPV4。这种作用可以通过组胺复制，并通过 HR 拮抗作用预防。我们证明，IBS 中的黏膜微环境包含介质，如组胺，通过 HR 激活使 TRPV4 和 TRPA1 致敏，这可能导致 IBS 中内脏疼痛感知增加。这些数据进一步强调了 HR 拮抗作用作为 IBS 的潜在治疗方法。
我们提供了证据，证明组胺通过组胺 1 受体（HR）激活介导肠易激综合征（IBS）中的瞬时受体电位（TRP）锚蛋白 1 和 TRP 香草酸 4 致敏，这可能导致内脏疼痛感知增加。我们的结果揭示了感觉性 TRP 通道作为组胺效应器在 IBS 病理生理学中的一般作用，并为 HR 拮抗作用在 IBS 中的治疗潜力提供了新的机制见解。
