The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered by C difficile toxins
The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered by C difficile toxins
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异生物质传感孕烷X受体调节艰难梭菌毒素引发的组织损伤和炎症
DOI：
10.1096/fj.201902083rr
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发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Hirota, Simon A.
中科院分区：
文献类型：
--
作者：
Erickson, Sarah L.;Alston, Laurie;Hirota, Simon A.
艰难梭菌（Clostridioides difficile）（以前的艰难梭菌;艰难梭菌（C difficile））是工业化世界中医院内获得性腹泻相关性结肠炎和腹泻的主要原因，其通过释放两种毒素（毒素A（TcdA）和毒素B（TcdB））（调节单体G蛋白功能并改变细胞骨架功能的葡糖基转移酶）来触发结肠疾病。宿主对艰难梭菌及其致病毒素的免疫应答的初始程度是疾病严重程度和感染复发的常见指标。因此，针对感染期间的肠道炎症反应可以显着降低疾病的发病率和死亡率。在目前的研究中，我们试图询问的影响，异生素和解毒反应的调节剂，它可以感知和响应微生物代谢产物和调节炎症活动，在暴露于TcdA和TcdB的胆甾烷X受体（PXR）。直肠内暴露于TcdA/B后，PXR缺陷小鼠（Nr 1 i2（-/-））表现出存活率降低，这种效应与先天免疫细胞流入水平增加有关。这种加剧的反应与Tlr 4表达的两倍增加有关。此外，虽然广谱抗生素治疗（以消耗肠道微生物群）不会改变Nr 1 i2（-/-）小鼠的反应，但阻断TLR 4信号传导显着降低了这些小鼠中TcdA/B诱导的疾病严重程度和免疫反应。最后，为了评估靶向PXR的治疗潜力，我们在野生型小鼠中用双烯醇酮16 α-腈（PCN）激活PXR，这大大降低了TcdA/B诱导的损伤和肠道炎症的严重程度。综上所述，这些数据表明PXR在宿主对TcdA/B的应答中起作用，并且可能提供抑制艰难梭菌感染中的炎性组织损伤的新靶点。
Clostridioides difficile (formerly Clostridium difficile; C difficile), the leading cause of nosocomial antibiotic-associated colitis and diarrhea in the industrialized world, triggers colonic disease through the release two toxins, toxin A (TcdA) and toxin B (TcdB), glucosyltransferases that modulate monomeric G-protein function and alter cytoskeletal function. The initial degree of the host immune response to C difficile and its pathogenic toxins is a common indicator of disease severity and infection recurrence. Thus, targeting the intestinal inflammatory response during infection could significantly decrease disease morbidity and mortality. In the current study, we sought to interrogate the influence of the pregnane X receptor (PXR), a modulator of xenobiotic and detoxification responses, which can sense and respond to microbial metabolites and modulates inflammatory activity, during exposure to TcdA and TcdB. Following intrarectal exposure to TcdA/B, PXR-deficient mice (Nr1i2(-/-)) exhibited reduced survival, an effect that was associated with increased levels of innate immune cell influx. This exacerbated response was associated with a twofold increase in the expression of Tlr4. Furthermore, while broad-spectrum antibiotic treatment (to deplete the intestinal microbiota) did not alter the responses in Nr1i2(-/-) mice, blocking TLR4 signaling significantly reduced TcdA/B-induced disease severity and immune responses in these mice. Lastly, to assess the therapeutic potential of targeting the PXR, we activated the PXR with pregnenolone 16 alpha-carbonitrile (PCN) in wild-type mice, which greatly reduced the severity of TcdA/B-induced damage and intestinal inflammation. Taken together, these data suggest that the PXR plays a role in the host's response to TcdA/B and may provide a novel target to dampen the inflammatory tissue damage in C difficile infections.