The Pregnane X Receptor and Indole-3-Propionic Acid Shape the Intestinal Mesenchyme to Restrain Inflammation and Fibrosis.
The Pregnane X Receptor and Indole-3-Propionic Acid Shape the Intestinal Mesenchyme to Restrain Inflammation and Fibrosis.
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孕烷X受体和吲哚-3-丙酸塑造肠间质抑制炎症和纤维化。
DOI：
10.1016/j.jcmgh.2022.10.014
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发表时间：
2023
影响因子：
7.2
通讯作者：
Hirota, Simon A.
中科院分区：
文献类型：
--
作者：
Flannigan, Kyle L.;Nieves, Kristoff M.;Szczepanski, Holly E.;Serra, Alex;Lee, Joshua W.;Alston, Laurie A.;Ramay, Hena;Mani, Sridhar;Hirota, Simon A.
纤维化是炎症性肠病（IBD）的常见并发症。PXR（由NR 1 I2编码）抑制肠道炎症，并已被证明影响肝纤维化。在肠道中，PXR信号传导受到微生物来源的吲哚-3-丙酸（IPA）的影响。在这里，我们试图评估PXR在调节肠道炎症和纤维化中的作用。使用葡聚糖硫酸钠（DSS）诱导肠道炎症。在野生型（WT）、Nr 1 i2-/-、上皮特异性Nr 1 i2-/-和成纤维细胞特异性Nr 1 i2-/-小鼠中评估纤维化。通过流式细胞术定量免疫细胞流入，并通过Luminex定量细胞因子。用cytomix或脂多糖刺激从WT和Nr 1 i2-/-小鼠分离的肌成纤维细胞，并通过定量聚合酶链反应和Luminex评估介质产生。从DSS诱导的结肠炎中恢复后，WT小鼠表现出纤维化，这种反应在Nr 1 i2-/-小鼠中加剧。这与更大的中性粒细胞浸润和先天性细胞因子产生相关。成纤维细胞中PXR的缺失，而不是上皮细胞，概括了这种表型。炎症和纤维化通过IPA给药减少，而微生物群的消耗加剧了肠道纤维化。Nr 1 i2缺陷型肌成纤维细胞对刺激反应过度，与WT细胞相比，产生的炎症介质水平增加。在活动性克罗恩病（CD）和溃疡性结肠炎（UC）患者的活检中，NR 1 I2的表达减少，这与纤维化和先天免疫基因的表达增加相关。最后，CD和UC患者均表现出粪便IPA水平降低。这些数据强调了IPA及其与PXR的相互作用在调节间质以及炎症和纤维化发展中的作用，表明微生物群代谢物可能是IBD纤维化并发症进展的重要决定因素。
Fibrosis is a common complication of inflammatory bowel diseases (IBDs). The pregnane X receptor (PXR) (encoded by NR1I2) suppresses intestinal inflammation and has been shown to influence liver fibrosis. In the intestine, PXR signaling is influenced by microbiota-derived indole-3-propionic acid (IPA). Here, we sought to assess the role of the PXR in regulating intestinal inflammation and fibrosis. Intestinal inflammation was induced using dextran sulfate sodium (DSS). Fibrosis was assessed in wild-type (WT), Nr1i2-/-, epithelial-specific Nr1i2-/-, and fibroblast-specific Nr1i2-/- mice. Immune cell influx was quantified by flow cytometry and cytokines by Luminex. Myofibroblasts isolated from WT and Nr1i2-/- mice were stimulated with cytomix or lipopolysaccharide, and mediator production was assessed by quantitative polymerase chain reaction and Luminex. After recovery from DSS-induced colitis, WT mice exhibited fibrosis, a response that was exacerbated in Nr1i2-/- mice. This was correlated with greater neutrophil infiltration and innate cytokine production. Deletion of the PXR in fibroblasts, but not the epithelium, recapitulated this phenotype. Inflammation and fibrosis were reduced by IPA administration, whereas depletion of the microbiota exaggerated intestinal fibrosis. Nr1i2-deficient myofibroblasts were hyperresponsive to stimulation, producing increased levels of inflammatory mediators compared with WT cells. In biopsies from patients with active Crohn’s disease (CD) and ulcerative colitis (UC), expression of NR1I2 was reduced, correlating with increased expression of fibrotic and innate immune genes. Finally, both CD and UC patients exhibited reduced levels of fecal IPA. These data highlight a role for IPA and its interactions with the PXR in regulating the mesenchyme and the development of inflammation and fibrosis, suggesting microbiota metabolites may be a vital determinant in the progression of fibrotic complications in IBD.
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肠纤维化与克罗恩病中英夫利昔单抗治疗的反应有关。
影响因子：
3.7
作者：
de Bruyn JR;Becker MA;Steenkamer J;Wildenberg ME;Meijer SL;Buskens CJ;Bemelman WA;Löwenberg M;Ponsioen CY;van den Brink GR;D'Haens GR
通讯作者：
D'Haens GR
DOI：
10.1016/j.cgh.2018.09.008
发表时间：
2019-08
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
--
作者：
Ballengee CR;Stidham RW;Liu C;Kim MO;Prince J;Mondal K;Baldassano R;Dubinsky M;Markowitz J;Leleiko N;Hyams J;Denson L;Kugathasan S
通讯作者：
Kugathasan S
影响因子：
64.5
作者：
Kinchen J;Chen HH;Parikh K;Antanaviciute A;Jagielowicz M;Fawkner-Corbett D;Ashley N;Cubitt L;Mellado-Gomez E;Attar M;Sharma E;Wills Q;Bowden R;Richter FC;Ahern D;Puri KD;Henault J;Gervais F;Koohy H;Simmons A
通讯作者：
Simmons A
DOI：
10.3109/08977194.2011.595714
发表时间：
2011-10
期刊：
Growth factors (Chur, Switzerland)
影响因子：
--
作者：
Biernacka A;Dobaczewski M;Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
4.8
作者：
Erickson, Sarah L.;Alston, Laurie;Hirota, Simon A.
通讯作者：
Hirota, Simon A.