Akkermansia muciniphila improve cognitive dysfunction by regulating BDNF and serotonin pathway in gut-liver-brain axis.

IF 13.8 1区生物学 Q1 MICROBIOLOGY Microbiome Pub Date : 2024-09-28 DOI:10.1186/s40168-024-01924-8

Eun Ji Kang, Min-Gi Cha, Goo-Hyun Kwon, Sang Hak Han, Sang Jun Yoon, Sang Kyu Lee, Moo Eob Ahn, Sung-Min Won, Eun Hee Ahn, Ki Tae Suk

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Abstract

Backrground: Akkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury.

Results: To investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila.

Conclusions: A. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment.

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Akkermansia muciniphila 可通过调节肠道-肝-脑轴的 BDNF 和血清素通路改善认知功能障碍。

背景：新一代益生菌Akkermansia muciniphila被认为是调节各种疾病中肠道-器官轴的基石，但其潜在机制仍不甚明了。在此，我们揭示了粘多糖对肝损伤中肠道-肝-脑轴的神经元和抗纤维化作用：为了研究神经系统功能障碍和特征性肠道微生物群，我们对肝硬化队列（154 名有或没有肝性脑病的患者）和社区认知队列（一个地区的 80 名参与者，为期三年）进行了研究，并在 3,5-二乙氧羰基-1,4-二氢环己烷诱导的肝损伤小鼠模型中验证了认知障碍的存在。在肝损伤动物模型中评估了候选菌株对认知能力的影响。根据肝纤维化等级和肝静脉压力梯度，访问了肝纤维化患者（100 名）的脑源性神经营养因子（BDNF）和血清素受体的表达情况。在肝性脑病和认知功能障碍人群中，粘多糖的比例有所下降。组织染色技术证实了肝损伤中的肠道-肝-脑损伤，肠道和大脑中的BDNF和5-羟色胺表达剧烈。服用 A. muciniphila 能明显减轻组织损伤，改善认知功能障碍以及 BDNF 和血清素的表达。离体迷走神经染色显示血清素的表达得到恢复，但不影响多巴胺通路。相反，在肝脏组织中，通过抑制血清素受体（5-羟色胺 2A 和 2B）的表达而抑制损伤的作用得到了证实。肝损伤的严重程度与血清素、BDNF 和 A. muciniphila 的丰度相关：结论：下一代益生菌 A. muciniphila 是缓解肝纤维化和认知障碍症状的候选疗法。

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来源期刊

Microbiome MICROBIOLOGY-

CiteScore

21.90

自引率

2.60%

发文量

198

审稿时长

4 weeks

期刊介绍： Microbiome is a journal that focuses on studies of microbiomes in humans, animals, plants, and the environment. It covers both natural and manipulated microbiomes, such as those in agriculture. The journal is interested in research that uses meta-omics approaches or novel bioinformatics tools and emphasizes the community/host interaction and structure-function relationship within the microbiome. Studies that go beyond descriptive omics surveys and include experimental or theoretical approaches will be considered for publication. The journal also encourages research that establishes cause and effect relationships and supports proposed microbiome functions. However, studies of individual microbial isolates/species without exploring their impact on the host or the complex microbiome structures and functions will not be considered for publication. Microbiome is indexed in BIOSIS, Current Contents, DOAJ, Embase, MEDLINE, PubMed, PubMed Central, and Science Citations Index Expanded.