School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Pharmacol Res. 2024 Oct;208:107361. doi: 10.1016/j.phrs.2024.107361. Epub 2024 Aug 17.
Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TβMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TβMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TβMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.
新出现的证据表明，肠道微生物群-胆汁酸（BA）轴的紊乱与神经退行性疾病的发展密切相关。然而，在衰老过程中对不同脑区 BA 空间分布的改变及其在与衰老相关的神经退行性疾病中的确切作用仍知之甚少。在这里，我们分析了年轻和自然衰老雌雄小鼠大脑皮层、海马体和下丘脑的 BA 图谱。结果表明，衰老以性别和区域依赖的方式改变了大脑 BA 图谱，其中 TβMCA 在雌雄衰老小鼠中持续升高，特别是在海马体和下丘脑。此外，我们发现衰老积累的-TβMCA 刺激体外小胶质细胞炎症，并缩短秀丽隐杆线虫的寿命，以及小鼠的行为障碍和神经炎症。此外，宏基因组分析表明，衰老过程中大脑 TβMCA 的积累部分归因于携带 BSH 的细菌减少。最后，通过将老年小鼠与年轻小鼠共同饲养来恢复肠道微生物群，恢复了大脑 BA 平衡，并改善了自然衰老小鼠的神经功能障碍。总之，我们的研究强调了通过靶向肠道微生物群-脑 BA 轴改善与衰老相关的神经损伤的潜力。
