Yao Ping, Han Hailong
Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.
Biomedicines. 2025 Jun 5;13(6):1390. doi: 10.3390/biomedicines13061390.
The autophagy-lysosomal pathway (ALP) is crucial for neuronal health by clearing misfolded proteins and damaged organelles. While much research has focused on ALP dysfunction in the central nervous system, new evidence shows its importance in the gut, where it affects neurodegeneration via the gut-brain axis. Past reviews have mainly studied the ALP's direct neuroprotective effects or the gut microbiota's role in neurodegeneration separately. However, the two-way relationship between the ALP and the gut microbiota in neurodegenerative diseases is not well understood. We combine the latest findings on the ALP's role in gut health, microbial imbalance, and neuroinflammation, providing a comprehensive view of their combined effects in Alzheimer's, Parkinson's, and Huntington's diseases. This narrative review synthesizes evidence from preclinical, clinical, and translational studies (2014-2025) to explore the interplay between the autophagy-lysosomal pathway (ALP) and the gut-brain axis in neurodegeneration. The literature was identified via PubMed and Web of Science using search terms including autophagy, lysosome, gut microbiota, neurodegeneration, and gut-brain axis, with additional manual screening of reference lists. The inclusion criteria prioritized studies elucidating molecular mechanisms (e.g., ALP-microbiota crosstalk), while excluding case reports or non-peer-reviewed sources. The gut-brain axis facilitates bidirectional communication between the gut and the brain through neural, immune, and metabolic pathways. Autophagy dysfunction may disrupt intestinal homeostasis, promote gut microbiota dysbiosis, and trigger chronic neuroinflammation, ultimately accelerating neurodegeneration. Notably, strategies targeting the gut microbiota and restoring intestinal barrier function via the ALP have demonstrated promising potential in delaying the progression of neurodegenerative diseases. This review establishes the ALP as a dynamic regulator of gut-brain communication, highlighting microbiota-targeted therapies as promising strategies for neurodegeneration.
自噬-溶酶体途径（ALP）通过清除错误折叠的蛋白质和受损细胞器对神经元健康至关重要。虽然许多研究集中在中枢神经系统中的ALP功能障碍，但新证据表明其在肠道中也很重要，在肠道中它通过肠-脑轴影响神经退行性变。过去的综述主要分别研究了ALP的直接神经保护作用或肠道微生物群在神经退行性变中的作用。然而，在神经退行性疾病中，ALP与肠道微生物群之间的双向关系尚未得到充分理解。我们结合了关于ALP在肠道健康、微生物失衡和神经炎症中作用的最新发现，全面阐述了它们在阿尔茨海默病、帕金森病和亨廷顿病中的综合作用。这篇叙述性综述综合了临床前、临床和转化研究（2014 - 2025年）的证据，以探讨自噬-溶酶体途径（ALP）与肠-脑轴在神经退行性变中的相互作用。通过PubMed和Web of Science使用包括自噬、溶酶体、肠道微生物群、神经退行性变和肠-脑轴等检索词来识别文献，并对参考文献列表进行额外的人工筛选。纳入标准优先考虑阐明分子机制（如ALP-微生物群相互作用）的研究，同时排除病例报告或非同行评审来源。肠-脑轴通过神经、免疫和代谢途径促进肠道与大脑之间的双向通信。自噬功能障碍可能破坏肠道稳态，促进肠道微生物群失调，并引发慢性神经炎症，最终加速神经退行性变。值得注意的是，通过ALP靶向肠道微生物群和恢复肠道屏障功能的策略在延缓神经退行性疾病进展方面已显示出有前景的潜力。本综述将ALP确立为肠-脑通信的动态调节因子，强调以微生物群为靶点的治疗方法是神经退行性变的有前景策略。
