Time-restricted feeding mitigates Alzheimer's disease-associated cognitive impairments via a B. pseudolongum-propionic acid-FFAR3 axis

IF 23.7 Q1 MICROBIOLOGY

iMeta Pub Date : 2025-02-21 DOI:10.1002/imt2.70006

Yihang Zhao, Mengzhen Jia, Chen Ding, Bingkun Bao, Hangqi Li, Jiabin Ma, Weixuan Dong, Rui Gao, Xuhui Chen, Jiao Chen, Xiaoshuang Dai, Yuanqiang Zou, Jun Hu, Lin Shi, Xuebo Liu, Zhigang Liu

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Abstract

Time-restricted feeding (TRF) holds promise for alleviating cognitive decline in aging, albeit the precise mechanism via the gut-brain axis remains elusive. In a clinical trial, we observed, for the first time, that a 4-month TRF ameliorated cognitive impairments among Alzheimer's disease (AD) patients. Experiments in 5xFAD mice corroborated the gut microbiota-dependent effect of TRF on mitigating cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Multi-omics integration linked Bifidobacterium pseudolongum (B. pseudolongum) and propionic acid (PA) with key genes in AD pathogenesis. Oral supplementation of B. pseudolongum or PA mimicked TRF's protective effects. Positron emission tomography imaging confirmed PA's blood-brain barrier penetration, while knockdown of the free fatty acid receptor 3 (FFAR3) diminished TRF's cognitive benefits. Notably, we observed a positive correlation between fecal PA and improved cognitive function in an AD cohort, further indicating that TRF enhanced PA production. These findings highlight the microbiota-metabolites-brain axis as pivotal in TRF's cognitive benefits, proposing B. pseudolongum or PA as potential AD therapies.

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限时喂养通过 B. 假龙脑丙酸-FFAR3 轴减轻阿尔茨海默病相关的认知障碍

限时喂养（TRF）有望缓解衰老过程中的认知能力衰退，尽管通过肠道-大脑轴的精确机制仍然难以捉摸。在一项临床试验中，我们首次观察到，为期4个月的限时喂养能改善阿尔茨海默病（AD）患者的认知障碍。在 5xFAD 小鼠身上进行的实验证实了肠道微生物群对 TRF 缓解认知功能障碍、淀粉样蛋白-β沉积和神经炎症的影响。多组学整合将假双歧杆菌（B. pseudolongum）和丙酸（PA）与AD发病机制中的关键基因联系起来。口服假龙双歧杆菌或丙酸可模拟TRF的保护作用。正电子发射断层扫描成像证实了 PA 的血脑屏障穿透性，而敲除游离脂肪酸受体 3 (FFAR3) 则削弱了 TRF 对认知的益处。值得注意的是，我们观察到粪便中的 PA 与注意力缺失症队列中认知功能的改善呈正相关，这进一步表明 TRF 促进了 PA 的产生。这些发现凸显了微生物群-代谢物-脑轴在TRF的认知益处中的关键作用，从而提出了将假龙胆或PA作为潜在的AD疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iMeta

CiteScore

10.80

自引率

0.00%

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