多组分药物 Spascupreel 可减轻应激诱导的大鼠肠道功能障碍。
- 作者列表："Theodorou V","Beaufrand C","Yvon S","Laforge G","Burmeister Y","Müller A","Seilheimer B","Bueno L","Eutamene H
BACKGROUND:Irritable bowel syndrome (IBS) is a common disorder worldwide. It is characterized by abdominal pain/discomfort and changes in bowel habits. Due to the multifactorial pathophysiology and the heterogeneity of IBS patients, appropriate treatment of IBS is still a challenge. Spascupreel (SP-11), as a multicomponent medication, has the potential to modulate multiple pathophysiological pathways simultaneously. Therefore, the objective of the current study was to investigate the effects of oral SP-11 treatment on stress-induced changes of peripheral and central functions in a rat model mimicking human IBS. METHODS:Naïve Wistar rats were treated with SP-11 (0.9 tab/kg) or NaCl 0.9% by oral gavage for 4 days before 2-hour partial restraint stress (PRS) procedure. Twenty minutes after PRS, central and peripheral stress-induced changes affecting IBS were assessed. These include the hypothalamic-pituitary-adrenal (HPA) axis response through plasma ACTH and corticosterone measurements, visceral pain in response to colorectal distension, gut permeability, colonic mast cell number, and sensitization as well as gut transit time. RESULTS:Treatment with SP-11 reduced the HPA axis activation in response to PRS. At the gut level, a reduction in colonic hypersensitivity to colorectal distension, a normalization of gut transit time acceleration, a reduced mast cell sensitization, and a trend toward reduced gut hyperpermeability were observed. CONCLUSIONS:These data suggest that stress-induced IBS signs can be reduced using SP-11 in rats. The observed effects and the good tolerability of the drug make SP-11 an innovative candidate in the management of IBS.
背景: 肠易激综合征 (IBS) 是世界范围内常见的疾病。它的特点是腹痛/不适和排便习惯的变化。由于多因素的病理生理和 IBS 患者的异质性，适当的治疗 IBS 仍然是一个挑战。Spascupreel (SP-11) 作为一种多组分药物，具有同时调节多种病理生理通路的潜能。因此，本研究的目的是探讨口服 SP-11 治疗对模拟人 IBS 大鼠模型应激引起的外周和中枢功能变化的影响。 方法: 以 SP-11 (0.9 tab/kg) 或 0.9% NaCl 灌胃 4 天，在部分束缚应激 (PRS) 前给予初始 Wistar 大鼠。PRS 后 20 min，评估中枢和外周应激引起的影响 IBS 的变化。这些包括通过血浆 ACTH 和皮质酮测量的下丘脑-垂体-肾上腺 (HPA) 轴反应，对结直肠扩张的内脏疼痛反应，肠通透性，结肠肥大细胞数, 致敏以及肠道转运时间。 结果: SP-11 治疗减轻了 PRS 引起的 HPA 轴激活。在肠道水平，观察到结肠对结直肠扩张的超敏反应减少，肠道通过时间加速正常化，肥大细胞致敏减少，肠道高通透性减少的趋势。 结论: 这些数据表明，在大鼠中使用 SP-11 可以减少应激诱导的 IBS 体征。所观察到的药物效果和良好的耐受性使 SP-11 成为 IBS 治疗的创新候选药物。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.