Background NLRX1 activation reduces inflammation by decreasing oxidative stress and altering cellular metabolism within multiple cell types implicated in ulcerative colitis (UC). Colitis animal models demonstrated reduced disease severity and a phase 1b clinical trial showed signs of rapid symptom and endoscopic improvement in patients with active UC.1, 2 Abdominal pain driven by visceral hypersensitivity may persist in patients even after inflammation has resolved, negatively affecting their quality of life.3, 4 Therapeutic agents which address inflammation, epithelial healing, and visceral hypersensitivity concurrently may provide greater symptomatic relief and improved quality of life as many patients, even in remission, still complain of abdominal pain. We here describe the effects of oral NX-13 in a rat model of visceral hypersensitivity. Methods Rats (n=8) were dosed daily for a period of 3 days with NX-13 or vehicle. Under anesthesia, electrodes were positioned to monitor oblique abdominal muscle contraction and a colonic balloon catheter was inserted intra-anally. Visceral pain was assessed at baseline and 3 h post lipopolysaccharide injection (1 mg/kg subcutaneous) through measuring of visceromotor response (VMR) via electromyogram (EMG) recording and visual assessment of abdominal withdrawal reflex (AWR). Data are represented as median (IQR) and statistical significance determined by non-parametric Mann-Whitney U test. Results Compared to the vehicle control, oral NX-13 delayed the onset of muscle contraction in response to colonic distension in LPS-treated rats. Further, NX-13 treated rats experienced reduced contraction intensity and reduced sustained abdominal muscle contraction period compared to the vehicle control. Specifically, NX-13 decreased the number of AWR during colonic expansion compared to the control group (p=0.01, Fig1A). Moreover, NX-13 desensitized the VMR response by numerically increasing the minimum volume of the colonic distension balloon required to induce significant VMR. The mean minimum volume of water injected required to induce significant VMR increased 23%, from 650 μL in the vehicle group to 800 μL in the NX-13 treated rats (p=0.16, Fig1B). Lastly, NX-13 visually reduced the maximum abdominal EMG amplitude during colonic distention (p=0.19, Fig1C). Conclusion Adequate management of persistent pain in IBD patients with or without active bowel inflammation remains an unmet need in the treatment of IBD. The potential for NX-13 to specifically reduce visceral hypersensitivity and abdominal pain will be evaluated further in the ongoing phase 2 human NEXUS trial in patients with UC. 1Leber et al. J Immunol 203(12) 2Peyrin-Biroulet et al. JCC (17)Supp 3Abreu et al. JCC (14)Supp 4Wils et al. J Clin Med 11(15)

中文翻译：

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P114 NLRX1 激动剂 NX-13 在减少临床前胃肠道炎症中内脏超敏反应中的作用

背景 NLRX1 激活可通过减少氧化应激和改变与溃疡性结肠炎 (UC) 相关的多种细胞类型内的细胞代谢来减少炎症。结肠炎动物模型显示疾病严重程度降低，1b 期临床试验显示活动性 UC 患者的症状和内窥镜检查有快速改善的迹象。1, 2 即使在炎症消退后，由内脏过敏引起的腹痛也可能在患者中持续存在，从而对其质量产生负面影响3, 4 同时解决炎症、上皮愈合和内脏过敏的治疗药物可以提供更大的症状缓解和改善生活质量，因为许多患者即使在缓解期，仍然抱怨腹痛。我们在此描述口服 NX-13 在内脏过敏大鼠模型中的作用。方法 每天​​给大鼠 (n=8) 施用 NX-13 或媒介物，持续 3 天。在麻醉下，放置电极以监测腹斜肌收缩，并将结肠球囊导管插入肛门内。通过肌电图 (EMG) 记录测量内脏运动反应 (VMR) 和腹部撤回反射 (AWR) 的视觉评估，在基线和脂多糖注射 (1 mg/kg 皮下注射) 3 小时后评估内脏疼痛。数据表示为中值 (IQR) 和通过非参数 Mann-Whitney U 检验确定的统计显着性。结果与载体对照相比，口服 NX-13 延迟了 LPS 治疗大鼠响应结肠扩张的肌肉收缩的发生。此外，与载体对照相比，NX-13治疗的大鼠收缩强度降低，腹部肌肉持续收缩时间缩短。具体而言，与对照组相比，NX-13 减少了结肠扩张期间的 AWR 数量（p=0.01，图 1A）。此外，NX-13 通过在数值上增加诱导显着 VMR 所需的结肠扩张球囊的最小体积来降低 VMR 反应的敏感性。诱导显着 VMR 所需的平均最小水量增加了 23%，从载体组的 650 μL 增加到 NX-13 治疗组大鼠的 800 μL（p=0.16，图 1B）。最后，NX-13 在视觉上降低了结肠扩张期间的最大腹部肌电图振幅（p=0.19，图 1C）。结论 对伴或不伴活动性肠道炎症的 IBD 患者的持续性疼痛进行充分治疗在 IBD 治疗中仍然是一个未得到满足的需求。NX-13 特异性减轻内脏过敏和腹痛的潜力将在正在进行的 UC 患者 2 期人体 NEXUS 试验中得到进一步评估。1 莱伯等人。J 免疫学杂志 203(12) 2Peyrin-Biroulet 等人。JCC (17)Supp 3Abreu 等人。JCC (14)Supp 4Wils 等人。临床医学杂志11(15)