Padhi Piyush, Worth Carter, Zenitsky Gary, Jin Huajun, Sambamurti Kumar, Anantharam Vellareddy, Kanthasamy Arthi, Kanthasamy Anumantha G
Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, United States.
Department of Physiology and Pharmacology, Center for Brain Sciences and Neurodegenerative Diseases, University of Georgia, Athens, GA, United States.
Front Neurosci. 2022 Feb 25;16:836605. doi: 10.3389/fnins.2022.836605. eCollection 2022.
The human gut microbiota is a complex, dynamic, and highly diverse community of microorganisms. Beginning as early as 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.
人类肠道微生物群是一个复杂、动态且高度多样化的微生物群落。早在胎儿发育阶段就已开始,并贯穿出生直至成年后期,肠道微生物群与大脑之间的相互作用对于调节各种代谢、神经发育和免疫相关途径至关重要。相反,肠道微生物失调(定义为丰富度和相对丰度的改变)与几种慢性神经和神经退行性疾病的发病机制有关。来自大规模人群队列研究的证据表明,患有神经退行性疾病的个体肠道微生物组成发生了改变,其微生物和血清代谢组学特征也与健康人群不同。微生物失调还与精神和胃肠道并发症相关——这些合并症通常与帕金森病(PD)和阿尔茨海默病(AD)的前驱期有关。研究已经确定了连接肠道微生物失调和神经疾病的潜在介质。最近的研究结果还阐明了在神经退行性变发作之前,肠道神经系统中疾病病理的潜在机制。这篇综述重点介绍了连接肠道微生物失调和神经退行性变的功能途径和机制,特别是肠道微生物诱导的慢性炎症、蛋白质错误折叠、疾病特异性病理的传播、蛋白质清除缺陷和自身免疫失调。此外,我们还讨论了微生物组成的致病性转变如何导致内毒素产生增加和有益代谢物减少,这两者都可能触发免疫细胞激活和肠道神经元功能障碍。这些会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募集免疫介质,导致神经炎症和神经退行性变。在理解微生物群-肠道-大脑轴方面持续的生物医学进展将拓展神经退行性疾病的研究前沿,并使人们能够利用新的诊断和治疗策略来减轻这些疾病的病理负担。
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