Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders.
Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders.
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肠道微生物群失调介导的神经免疫调节异常以及蛋白质错误折叠和清除在慢性神经退行性疾病发病机制中的机制见解
DOI：
10.3389/fnins.2022.836605
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发表时间：
2022
影响因子：
4.3
通讯作者：
Kanthasamy AG
中科院分区：
文献类型：
--
作者：
Padhi P;Worth C;Zenitsky G;Jin H;Sambamurti K;Anantharam V;Kanthasamy A;Kanthasamy AG
人类肠道微生物区系是一个复杂、动态和高度多样化的微生物群落。从胎儿宫内发育开始，一直持续到成年后期，肠道微生物群和大脑之间的串扰对于调节各种代谢、神经发育和免疫相关的途径是必不可少的。相反，肠道微生物失调--定义为丰富度和相对丰度的变化--与几种慢性神经和神经退行性疾病的发病机制有关。大量人群队列研究的证据表明，神经退行性疾病患者的肠道微生物组成以及微生物和血清代谢组特征与健康人群不同。生物失调还与精神和胃肠道并发症有关--这些并发症通常与帕金森氏病(PD)和阿尔茨海默病(AD)的前驱症状有关。研究已经确定了将肠道生物失调和神经疾病联系起来的潜在介质。最近的发现也阐明了在神经变性开始之前肠道神经系统疾病病理的潜在机制。本文着重介绍肠道微生物引起的慢性炎症、蛋白质错误折叠、疾病特异性病变的传播、蛋白质清除缺陷和自身免疫失调等功能途径和机制，将肠道微生物失调与神经退行性变联系起来。此外，我们还讨论了微生物成分的致病转化如何导致内毒素产生增加和有益代谢物减少，这两者都可以引发免疫细胞激活和肠神经元功能障碍。这些可进一步破坏肠道屏障通透性，加重全身促炎状态，损害血脑屏障通透性，并招募免疫介质，导致神经炎症和神经变性。在了解微生物-肠道-脑轴方面的持续生物医学进展将扩大神经退行性疾病的前沿，并使新的诊断和治疗策略的使用能够减轻这些疾病的病理负担。
The human gut microbiota is a complex, dynamic, and highly diverse community of microorganisms. Beginning as early as in utero fetal development and continuing through birth to late-stage adulthood, the crosstalk between the gut microbiome and brain is essential for modulating various metabolic, neurodevelopmental, and immune-related pathways. Conversely, microbial dysbiosis – defined as alterations in richness and relative abundances – of the gut is implicated in the pathogenesis of several chronic neurological and neurodegenerative disorders. Evidence from large-population cohort studies suggests that individuals with neurodegenerative conditions have an altered gut microbial composition as well as microbial and serum metabolomic profiles distinct from those in the healthy population. Dysbiosis is also linked to psychiatric and gastrointestinal complications – comorbidities often associated with the prodromal phase of Parkinson’s disease (PD) and Alzheimer’s disease (AD). Studies have identified potential mediators that link gut dysbiosis and neurological disorders. Recent findings have also elucidated the potential mechanisms of disease pathology in the enteric nervous system prior to the onset of neurodegeneration. This review highlights the functional pathways and mechanisms, particularly gut microbe-induced chronic inflammation, protein misfolding, propagation of disease-specific pathology, defective protein clearance, and autoimmune dysregulation, linking gut microbial dysbiosis and neurodegeneration. In addition, we also discuss how pathogenic transformation of microbial composition leads to increased endotoxin production and fewer beneficial metabolites, both of which could trigger immune cell activation and enteric neuronal dysfunction. These can further disrupt intestinal barrier permeability, aggravate the systemic pro-inflammatory state, impair blood–brain barrier permeability and recruit immune mediators leading to neuroinflammation and neurodegeneration. Continued biomedical advances in understanding the microbiota-gut-brain axis will extend the frontier of neurodegenerative disorders and enable the utilization of novel diagnostic and therapeutic strategies to mitigate the pathological burden of these diseases.
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