Abstract
Cryptococcal meningitis (CM) is a fatal central nervous system infection caused by Cryptococcus neoformans 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.