Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA.
Anesthesia and Brain Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China.
Mol Psychiatry. 2023 Oct;28(10):4421-4437. doi: 10.1038/s41380-023-02216-7. Epub 2023 Aug 21.
Spouses of Alzheimer's disease (AD) patients are at a higher risk of developing incidental dementia. However, the causes and underlying mechanism of this clinical observation remain largely unknown. One possible explanation is linked to microbiota dysbiosis, a condition that has been associated with AD. However, it remains unclear whether gut microbiota dysbiosis can be transmitted from AD individuals to non-AD individuals and contribute to the development of AD pathogenesis and cognitive impairment. We, therefore, set out to perform both animal studies and clinical investigation by co-housing wild-type mice and AD transgenic mice, analyzing microbiota via 16S rRNA gene sequencing, measuring short-chain fatty acid amounts, and employing behavioral test, mass spectrometry, site-mutations and other methods. The present study revealed that co-housing between wild-type mice and AD transgenic mice or administrating feces of AD transgenic mice to wild-type mice resulted in AD-associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment in the wild-type mice. Gavage with Lactobacillus and Bifidobacterium restored these changes in the wild-type mice. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of microbiota. The underlying mechanism of these findings includes that the butyric acid-mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation. Pending confirmative studies, these results provide insight into a potential link between the transmission of AD-associated microbiota dysbiosis and development of cognitive impairment, which underscore the need for further research in this area.
阿尔茨海默病（AD）患者的配偶发生偶发性痴呆的风险较高。然而，这种临床观察的原因和潜在机制在很大程度上仍不清楚。一种可能的解释与微生物失调有关，微生物失调与 AD 有关。然而，目前尚不清楚肠道微生物失调是否可以从 AD 个体传播到非 AD 个体，并导致 AD 发病机制和认知障碍的发展。因此，我们着手通过共饲养野生型小鼠和 AD 转基因小鼠进行动物研究和临床研究，通过 16S rRNA 基因测序分析微生物群，测量短链脂肪酸含量，并进行行为测试、质谱分析、位点突变等方法。本研究表明，野生型小鼠与 AD 转基因小鼠共饲养或给予 AD 转基因小鼠粪便会导致野生型小鼠出现与 AD 相关的肠道微生物失调、Tau 磷酸化和认知障碍。给予乳杆菌和双歧杆菌可恢复野生型小鼠的这些变化。AD 患者配偶的口腔和肠道微生物群与 AD 患者相似，但与健康对照组不同，表明微生物群的传播。这些发现的潜在机制包括，丁酸盐介导的 GSK3β 赖氨酸 15 乙酰化调节其丝氨酸 9 的磷酸化，从而影响 Tau 磷酸化。在确认性研究中，这些结果提供了 AD 相关微生物失调传播与认知障碍发展之间潜在联系的见解，这凸显了该领域进一步研究的必要性。
