Wen Sha, Liu Mu, Pan Chengyu, Zhang Linhai, Yan Rong, Xu Zucai
Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, China.
Front Neurosci. 2025 Jul 16;19:1622349. doi: 10.3389/fnins.2025.1622349. eCollection 2025.
Cryptococcal meningitis (CM) is a fatal central nervous system infection caused by breaching the blood-brain barrier (BBB), carrying a mortality rate approaching 100% in untreated individuals, while even survivors following treatment often experience neurological complications including optic nerve atrophy, memory impairment, hydrocephalus, and motor dysfunction. Current research has yet to fully elucidate the complex pathological mechanisms of CM, particularly leaving a significant gap in the systemic analysis within the dynamic interaction network of immunity, metabolism, and the gut microbiota. This article systematically integrates the interplay of immune responses, metabolic reprogramming, and the gut microbiome to reveal the pathogenesis of CM across multiple dimensions: in immune regulation, the phagocytic-inflammatory equilibrium in macrophages and CD4 + T cells defends against pathogen invasion, but hyperactivated immune responses may damage the BBB and exacerbate neural injury; metabolically, host iron overload induces ferroptosis, disrupting the BBB via lipid peroxidation, while inositol metabolism provides substrates for cryptococcal capsular synthesis, enhancing its virulence and promoting CNS invasion; the gut microbiota, meanwhile, modulates immune homeostasis via the "gut-brain axis," with its metabolites (e.g., short-chain fatty acids) enhancing BBB integrity and suppressing neuroinflammation through immunomodulation. We propose a combined therapeutic strategy of "immunomodulators + metabolic inhibitors + microbiota intervention," moving beyond traditional single-factor research paradigms to establish a multi-omics integrated framework for the precise treatment of CM-spanning molecular mechanisms to clinical translation-and propelling the field of neuroinfectious diseases towards a host-pathogen-microenvironment systemic regulation paradigm.
隐球菌性脑膜炎（CM）是一种因血脑屏障（BBB）被破坏而引发的致命性中枢神经系统感染，在未经治疗的个体中死亡率接近100%，而即使是接受治疗后的幸存者也常常会出现包括视神经萎缩、记忆障碍、脑积水和运动功能障碍在内的神经并发症。目前的研究尚未完全阐明CM复杂的病理机制，尤其是在免疫、代谢和肠道微生物群动态相互作用网络的系统分析方面存在重大差距。本文系统地整合了免疫反应、代谢重编程和肠道微生物群之间的相互作用，从多个维度揭示CM的发病机制：在免疫调节方面，巨噬细胞和CD4 + T细胞中的吞噬-炎症平衡抵御病原体入侵，但过度激活的免疫反应可能会损害血脑屏障并加重神经损伤；在代谢方面，宿主铁过载诱导铁死亡，通过脂质过氧化破坏血脑屏障，而肌醇代谢为隐球菌荚膜合成提供底物，增强其毒力并促进中枢神经系统入侵；与此同时，肠道微生物群通过“肠-脑轴”调节免疫稳态，其代谢产物（如短链脂肪酸）通过免疫调节增强血脑屏障完整性并抑制神经炎症。我们提出了一种“免疫调节剂+代谢抑制剂+微生物群干预”的联合治疗策略，超越传统的单因素研究模式，建立一个用于CM精准治疗的多组学整合框架——从分子机制到临床转化——推动神经感染性疾病领域向宿主-病原体-微环境系统调节模式发展。
