尾吊模拟失重效应对小鼠结肠上皮的影响和机制研究

Spaceflight, in particular, microgravity, changes the muscle, bone, and immune system in many aspects. But microgravity-related intestinal mucosal changes and its clinical significance have not been well studied. Using the hindlimb unloading (HU) mouse model to simulate the microgravity condition, we found that 2-week HU mice had impaired mucosal immune homeostasis, altered microbiota, and increased susceptibility to dextran sulfate sodium-induced colitis; whereas 4-week HU mice had reduced colonic crypt length and goblet cell numbers and altered microbiota. Based on these data, the current project is going to investigate the mechanisms of goblet cell reduction by studying the tripartite cross-regulation of colonic epithelium, mucosal immune system, and microflora. The clinical significance of HU-induced goblet cell reduction will be also investigated. The results from these mouse studies will provide insights into the effects of microgravity on human intestinal mucosa and facilitate the development of monitoring approaches and counter measures to maintain the intestinal homeostasis.

航天飞行所带来的失重和多种应激可导致航天员骨肌系统和免疫系统发生多种改变，但对肠道粘膜组织，包括肠上皮、菌群和肠相关淋巴组织的影响还不清楚。前期工作中我们利用小鼠尾吊模型模拟失重效应，发现尾吊2周时肠道免疫稳态发生改变，肠道菌群失调、肠炎易感性增加；而尾吊4周时则主要表现为结肠隐窝缩短，杯状细胞减少和菌群失调。基于此，本项目将从结肠上皮、粘膜免疫和肠道菌群三个方面以及三者的相互调节探讨尾吊致结肠杯状细胞减少的原因以及其对粘膜屏障功能和肠炎发展和转归的影响。研究结果将有助于深入理解肠粘膜稳态的调控机制，为评估中长期失重对航天员肠道粘膜的影响提供实验依据和可能的检测手段，并为航天飞行中肠粘膜组织稳态的维护提供新的思路。

航天飞行可导致糖耐量异常和肠道的改变，但是具体机制并不清楚。我们利用小鼠尾吊模型模拟失重效应，探讨小鼠结肠的改变、机制及其对肠道和肠外组织的影响。我们发现尾吊4周小鼠肠道菌群失调，肠上皮防御能力减弱，更新减慢，粪便sIgA水平升高。这些肠道稳态的改变导致尾吊小鼠肠炎易感性增强。进一步的同笼饲养和粪菌转移实验发现尾吊小鼠肠上皮的稳态改变主要是由菌群失调导致。在此基础上，我们利用同笼模型发现，尾吊所致肠道菌群改变和肠上皮稳态改变可导致全身性的糖代谢异常、低度的内毒素血症和肝脏代谢异常。双歧杆菌的补充不仅改善了结肠上皮的稳态，而且缓解了尾吊鼠的葡萄糖不耐受。该研究在国际上不仅首次揭示了肠道菌群失调对尾吊导致肠上皮稳态改变的影响以及对全身性糖代谢异常的影响，也首次明确了双歧杆菌对尾吊鼠肠道和代谢异常的改善和治疗作用，并为进一步探讨模拟失重效应模型中肠道菌群紊乱与肠道外改变之间的关系和影响奠定坚实的基础，也为探讨失重效应所致多种异常表现的肠道机制和从肠道角度改善机体提供新的思路。一发表SCI论文12篇，包括FASEB J., Leukemia, Cell Mol. Immunol等，并多次在国际会议，如国际航天员联合会等会议上做口头报告。