Ulster University, Life and Health Sciences, Belfast, UK.
Cell Mol Neurobiol. 2024 Oct 8;44(1):64. doi: 10.1007/s10571-024-01496-z.
The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut-brain axis. The gut-brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation-a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders.
神经退行性疾病（如阿尔茨海默病、帕金森病和多发性硬化症）的患病率不断上升，这对全球健康构成了重大挑战。尽管进行了广泛的研究，但这些疾病的确切发病机制仍难以捉摸，目前的治疗方法主要针对症状，而不是根本原因。新出现的证据表明，肠道通透性和犬尿氨酸途径与这些神经疾病的发病机制有关，为新的治疗和预防策略提供了有希望的靶点。肠道通透性是指肠壁选择性地允许必需营养素进入血液，同时阻止有害物质的能力。多种因素，包括不良饮食、压力、感染和遗传易感性，都可能损害肠道完整性，导致通透性增加。这种情况促进了毒素和细菌向全身循环的易位，通过肠道-大脑轴引发广泛的炎症，从而影响神经健康。肠道-大脑轴（GBA）是肠道和中枢神经系统之间的复杂通讯网络。肠道微生物群落的失衡（即肠道菌群失调）会增加肠道通透性和全身炎症，加剧神经炎症——这是神经疾病的一个关键因素。犬尿氨酸途径是色氨酸代谢的主要途径，在这个过程中起着重要作用。在炎症的情况下，犬尿氨酸途径的失调导致产生神经毒性代谢物，如喹啉酸，这有助于神经元损伤和神经退行性疾病的进展。本综述强调了理解这些机制的潜力和进展。通过饮食、益生菌和生活方式改变来干预犬尿氨酸途径和维持肠道微生物群落的平衡，显示出在减轻神经炎症和支持大脑健康方面的前景。此外，直接调节犬尿氨酸途径的药物方法，如吲哚胺 2,3-双加氧酶抑制剂，为新的治疗方法提供了潜在途径。理解和靶向这些相互关联的途径对于开发预防和管理神经退行性疾病的有效策略至关重要。
