Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis.
Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis.
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DOI：
10.1093/ibd/izac219
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发表时间：
2023-03-01
影响因子：
4.9
通讯作者：
Swanson, Garth R.
中科院分区：
文献类型：
--
作者：
Jochum, Sarah B.;Engen, Phillip A.;Shaikh, Maliha;Naqib, Ankur;Wilber, Sherry;Raeisi, Shohreh;Zhang, Lijuan;Song, Shiwen;Sanzo, Gabriella;Chouhan, Vijit;Ko, Frank;Post, Zoe;Tran, Laura;Ramirez, Vivian;Green, Stefan J.;Khazaie, Khashayarsha;Hayden, Dana M.;Brown, Mark J.;Voigt, Robin M.;Forsyth, Christopher B.;Keshavarzian, Ali;Swanson, Garth R.
中枢昼夜节律的破坏可能由微生物群的变化和肠源性代谢物如短链脂肪酸（SCFA）的减少介导，对结肠屏障稳态产生负面影响。我们的目的是探讨孤立的外周结肠昼夜节律破坏对结肠炎小鼠模型结肠屏障的影响，并探讨其机制，包括肠道微生物群的结构和功能。结肠上皮细胞昼夜节律在小鼠中被条件性遗传破坏：TS 4Cre-BMAL 1 lox（cBMAL 1 KO）与TS 4Cre作为对照动物。通过5天的2%葡聚糖硫酸钠（DSS）诱导结肠炎。评估疾病活动指数和肠道屏障，以及粪便微生物群和代谢物。结肠炎症状在外周昼夜节律紊乱（cBMAL 1 KO）的小鼠中更严重。具体而言，与对照动物（TS 4Cre）相比，昼夜节律紊乱的小鼠的疾病活动指数和肠通透性显著更高（P <0.05）。结肠炎的恶化似乎部分地通过JAK（Janus激酶）介导的STAT 3（信号转导子和转录激活子3）介导，其在用DSS治疗的昼夜节律破坏（cBMAL 1 KO）小鼠中显著升高（P < .05）。与对照动物（TS 4Cre）相比，昼夜节律破坏（cBMAL 1 KO）小鼠的粪便中SCFA代谢物浓度也降低，SCFA产生细菌的相对丰度也降低。与单独DSS相比，结肠上皮细胞中肠道昼夜节律的破坏促进了更严重的结肠炎，增加了炎症介质（STAT 3 [信号转导和转录激活因子3]），并减少了肠道微生物群来源的SCFA。进一步研究阐明这些发现背后的分子机制可以为炎症性肠道疾病的治疗提供新的昼夜节律定向靶点和策略。
Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota–derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.
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影响因子：
50.3
作者：
Bromberg J;Wang TC
通讯作者：
Wang TC
影响因子：
5.1
作者：
Babickova, Janka;Tothova, L'ubomira;Celec, Peter
通讯作者：
Celec, Peter
DOI：
10.1084/jem.20082683
发表时间：
2009-07-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pickert G;Neufert C;Leppkes M;Zheng Y;Wittkopf N;Warntjen M;Lehr HA;Hirth S;Weigmann B;Wirtz S;Ouyang W;Neurath MF;Becker C
通讯作者：
Becker C
DOI：
10.1016/j.jcmgh.2019.10.011
发表时间：
2020-01-01
影响因子：
7.2
作者：
Bishehsari, Faraz;Engen, Phillip A.;Khazaie, Khashayarsha
通讯作者：
Khazaie, Khashayarsha
影响因子：
4.8
作者：
Chakradeo, Prachi S.;Keshavarzian, Ali;Swanson, Garth R.
通讯作者：
Swanson, Garth R.