School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, China; Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, PR China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang 550004, Guizhou, PR China; Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, PR China.
Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, PR China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang 550004, Guizhou, PR China.
Ecotoxicol Environ Saf. 2023 Mar 15;253:114660. doi: 10.1016/j.ecoenv.2023.114660. Epub 2023 Feb 20.
After intensive research on the gut-brain axis, intestinal dysbiosis is considered to be one of the important pathways of cognitive decline. Microbiota transplantation has long been thought to reverse the behavioral changes in the brain caused by colony dysregulation, but in our study, microbiota transplantation seemed to improve only behavioral brain function, and there was no reasonable explanation for the high level of hippocampal neuron apoptosis that remained. Butyric acid is one of the short-chain fatty acids of intestinal metabolites and is mainly used as an edible flavoring. It is commonly used in butter, cheese and fruit flavorings, and is a natural product of bacterial fermentation of dietary fiber and resistant starch in the colon, acting similarly to the small-molecule HDAC inhibitor TSA. The effect of butyric acid on HDAC levels in hippocampal neurons in the brain remains unclear. Therefore, this study used rats with low bacterial abundance, conditional knockout mice, microbiota transplantation, 16S rDNA amplicon sequencing, and behavioral assays to demonstrate the regulatory mechanism of short-chain fatty acids on the acetylation of hippocampal histones. The results showed that disturbance of short-chain fatty acid metabolism led to high HDAC4 expression in the hippocampus and regulated H4K8ac, H4K12ac, and H4K16ac to promote increased neuronal apoptosis. However, microbiota transplantation did not change the pattern of low butyric acid expression, resulting in maintained high HDAC4 expression in hippocampal neurons with continued neuronal apoptosis. Overall, our study shows that low levels of butyric acid in vivo can promote HDAC4 expression through the gut-brain axis pathway, leading to hippocampal neuronal apoptosis, and demonstrates that butyric acid has great potential value for neuroprotection in the brain. In this regard, we suggest that patients with chronic dysbiosis should pay attention to changes in the levels of SCFAs in their bodies, and if deficiencies occur, they should be promptly supplemented through diet and other means to avoid affecting brain health.
在深入研究肠-脑轴后，肠道菌群失调被认为是认知能力下降的重要途径之一。人们早就认为，菌群移植可以逆转菌群失调引起的大脑行为改变，但在我们的研究中，菌群移植似乎仅改善了大脑功能的行为，而对仍然存在的海马神经元凋亡高水平没有合理的解释。丁酸是肠道代谢物的短链脂肪酸之一，主要用作食用香料。它常用于黄油、奶酪和水果调味料，是细菌发酵膳食纤维和结肠抗性淀粉的天然产物，作用类似于小分子 HDAC 抑制剂 TSA。丁酸对大脑中海马神经元中 HDAC 水平的影响尚不清楚。因此，本研究使用低细菌丰度大鼠、条件敲除小鼠、菌群移植、16S rDNA 扩增子测序和行为学检测，证明了短链脂肪酸对海马组织组蛋白乙酰化的调节机制。结果表明，短链脂肪酸代谢紊乱导致海马中 HDAC4 表达升高，并调节 H4K8ac、H4K12ac 和 H4K16ac，促进神经元凋亡增加。然而，菌群移植并没有改变低丁酸表达的模式，导致海马神经元中持续的神经元凋亡，HDAC4 表达保持较高。总的来说，我们的研究表明，体内低水平的丁酸可以通过肠-脑轴途径促进 HDAC4 表达，导致海马神经元凋亡，并表明丁酸在大脑神经保护方面具有巨大的潜在价值。在这方面，我们建议慢性菌群失调的患者应注意体内 SCFAs 水平的变化，如果出现不足，应通过饮食等方式及时补充，避免影响大脑健康。
