The TNF-α antagonist etanercept reverses age-related decreases in colonic SERT expression and faecal output in mice.
The TNF-α antagonist etanercept reverses age-related decreases in colonic SERT expression and faecal output in mice.
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DOI：
10.1038/srep42754
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发表时间：
2017-02-15
影响因子：
4.6
通讯作者：
Yeoman MS
中科院分区：
文献类型：
--
作者：
Patel BA;Fidalgo S;Wang C;Parmar L;Mandona K;Panossian A;Flint MS;Ranson RN;Saffrey MJ;Yeoman MS
老年人慢性便秘的治疗具有挑战性，并且这种情况对生活质量有重大影响。对这种情况的原因缺乏了解阻碍了有效治疗的发展。5-HT是结肠中重要的促动力剂。我们研究了结肠5-HT信号的改变是否是小鼠粪便排出量年龄相关变化的基础，以及这些变化是否是由于TNF-α的增加。在对照条件下和依那西普（TNF-α抑制剂; 1 mg Kg−1）给药后，在3、12、18和24月龄小鼠的远端结肠中检查了5-HT信号系统（5-HT、5-HIAA、SERT）的组分和TNF-α表达，并监测了粪便排出量和含水量。老年动物的粪便排出量和含水量减少。年龄增加了粘膜5-HT的利用率和TNF-α的表达，降低了粘膜SERT的表达和5-HIAA。依那西普治疗老年小鼠逆转了这些变化，表明TNFα表达的年龄相关变化是老年小鼠粘膜5-HT信号传导和颗粒输出和含水量的重要调节剂。这些数据表明，“抗TNF α”药物是治疗年龄相关性慢性便秘的潜在药物。
Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life. A lack of understanding about the causes of this condition has hampered the development of effective treatments. 5-HT is an important pro-kinetic agent in the colon. We examined whether alterations in colonic 5-HT signalling underlie age–related changes in faecal output in mice and whether these changes were due to an increase in TNF-α. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-α expression were examined in the distal colon of 3, 12, 18 and 24-month old mice and faecal output and water content monitored under control conditions and following the administration of etanercept (TNF-α inhibitor; 1 mg Kg−1). Faecal output and water content were reduced in aged animals. Age increased mucosal 5-HT availability and TNF-α expression and decreased mucosal SERT expression and 5-HIAA. Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to “anti-TNFα” drugs as potential treatments for age-related chronic constipation.