Elevated miR-124-3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T-synthase.
Elevated miR-124-3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T-synthase.
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衰老结肠中 miR-124-3p 升高会破坏粘液屏障，并通过靶向 T 合酶增加结肠炎的易感性
DOI：
10.1111/acel.13252
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发表时间：
2020-11
期刊：
影响因子：
7.8
通讯作者：
Zhou DS
中科院分区：
文献类型：
--
作者：
Huang L;Sun TY;Hu LJ;Hu SL;Sun HM;Zhao FQ;Wu B;Yang S;Ji FQ;Zhou DS
结肠炎和结直肠癌的风险在整个成年期显著增加，危及老年人的健康和生命。以往的研究认为细菌移位和感染是这些疾病的主要危险因素。因此，在本研究中，我们旨在通过关注粘液屏障功能和粘蛋白型O-糖基化来确定潜在机制。我们评估了2个月、16个月和24个月大的小鼠和老年人结肠粘液层的变化。老年结肠表现出肠粘膜屏障缺陷和粘液性质改变。老年人远端结肠黏膜中miR-124 - 3 p表达水平显著升高，并伴随病原菌增多和细菌移位。同时，T-合成酶，O-糖基化的限速酶，显示出与年龄相关的蛋白表达下降。进一步的实验表明，miR-124 - 3 p通过直接靶向T-合成酶来调节O-糖基化。此外，过表达miR-124 - 3 p的年轻小鼠表现出异常糖基化、早发性和更严重的结肠炎。这些数据表明，miR-124 - 3 p通过减少T-合成酶而易患老年性结肠炎，并且miR-124 - 3 p/T-合成酶/O-聚糖轴在维持结肠粘液的理化性质和肠道稳态中起着至关重要的作用。年轻的结肠显示出完整的内层和粘蛋白型O-糖基化，限制了微生物群进入上皮。miR-124 - 3 p/T-合成酶/O-聚糖轴的年龄相关改变和粘液厚度的减少削弱了粘液屏障，导致异常细菌侵入和老年性结肠炎易感性增加。
The risk of colitis and colorectal cancer increases markedly throughout adult life, endangering the health and lives of elderly individuals. Previous studies have proposed that bacterial translocation and infection are the main risk factors for these diseases. Therefore, in the present study, we aimed to identify the underlying mechanism by focusing on the mucus barrier function and mucin‐type O‐glycosylation. We evaluated alterations in the colon mucus layer in 2‐, 16‐, and 24‐month‐old mice and aged humans. Aged colons showed defective intestinal mucosal barrier and changed mucus properties. The miR‐124‐3p expression level was significantly increased in the aged distal colonic mucosa, which was accompanied by an increase in pathogens and bacterial translocation. Meanwhile, T‐synthase, the rate‐limiting enzyme in O‐glycosylation, displayed an age‐related decline in protein expression. Further experiments indicated that miR‐124‐3p modulated O‐glycosylation by directly targeting T‐synthase. Moreover, young mice overexpressing miR‐124‐3p exhibited abnormal glycosylation, early‐onset, and more severe colitis. These data suggest that miR‐124‐3p predisposes to senile colitis by reducing T‐synthase, and the miR‐124‐3p/T‐synthase/O‐glycans axis plays an essential role in maintaining the physiochemical properties of colonic mucus and intestinal homeostasis. Young colons show intact inner layer and mucin‐type O‐glycosylation, limiting microbiota access to the epithelium. Age‐related alteration in miR‐124‐3p/T‐synthase/O‐glycans axis and reduction in mucus thickness weakened the mucus barrier, leading to abnormal bacterial intrusion and increased susceptibility to senile colitis.
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DOI：
10.1038/nri.2016.88
发表时间：
2016-10
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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影响因子：
29.4
作者：
Bergstrom K;Liu X;Zhao Y;Gao N;Wu Q;Song K;Cui Y;Li Y;McDaniel JM;McGee S;Chen W;Huycke MM;Houchen CW;Zenewicz LA;West CM;Chen H;Braun J;Fu J;Xia L
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