Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
Tianjin Neurological Institution, Tianjin Medical University General Hospital, Tianjin, China.
Brain Behav Immun. 2024 Jul;119:171-187. doi: 10.1016/j.bbi.2024.03.052. Epub 2024 Mar 31.
Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline.
肠道微生物组稳态对于老年人的认知健康至关重要。先前的研究表明，聚山梨酯 80（P80）作为食品工业和药物制剂中广泛使用的乳化剂，可直接改变人类肠道微生物群落组成。然而，长期暴露于 P80 是否会通过肠-脑轴加速与年龄相关的认知能力下降仍不清楚。因此，在这项研究中，我们使用衰老加速小鼠模型 8（SAMP8）小鼠模型来研究乳化剂 P80 摄入（饮用水中 1% P80，持续 12 周）对肠道微生物群和认知功能的影响。我们的结果表明，P80 摄入可显著加重 SAMP8 小鼠的认知能力下降，同时增加脑内病理蛋白沉积、破坏血脑屏障并激活小胶质细胞和神经毒性星形胶质细胞。此外，P80 摄入还可诱导肠道微生物群失调，特别是增加次级胆汁酸产生菌的丰度，如 Ruminococcaceae、Lachnospiraceae 和 Clostridium scindens。此外，从 P80 小鼠粪便中移植的微生物群也可加重 16 周龄 SAMP8 小鼠的认知能力下降、小胶质细胞激活和肠道屏障损伤。有趣的是，P80 暴露后肠道微生物组成的改变显著影响胆汁酸代谢谱，血清和脑组织中脱氧胆酸（DCA）水平明显升高。在机制上，DCA 可通过三磷酸腺苷结合盒转运蛋白 A1（ABCA1）导入溶酶体胆固醇激活小胶质细胞，并促进衰老相关分泌表型的产生。总之，乳化剂 P80 通过诱导肠道菌群失调、胆汁酸代谢改变、肠道屏障和血脑屏障破坏以及神经炎症，加速衰老小鼠的认知能力下降。这项研究提供了有力的证据，表明饮食诱导的肠道微生物群失调可能是与年龄相关的认知能力下降的一个风险因素。
