Unraveling the Gut-Brain-Immune Interplay in Herpes Simplex Virus-Associated Neurodegeneration.

Herpes simplex virus type 1 (HSV-1), a ubiquitous neurotropic virus, has been increasingly associated with neurodegenerative disorders through mechanisms extending beyond acute encephalitis to include chronic neuroinflammation, proteostatic disruption, and immune dysregulation. Simultaneously, the gut-brain-immune axis has gained recognition as a master regulator of central nervous system (CNS) homeostasis. In this review, we delineate how HSV-1 neurovirulence intersects with gut microbiota dynamics and immune signaling to shape neuropathological trajectories. We explore five interconnected domains: the gut-brain axis as a mediator of systemic inflammation and neurodegeneration in HSV-1 infection; the influence of gut microbial metabolites on blood-brain barrier (BBB) integrity and immune cell trafficking; microbiota-dependent modulation of microglial activation during HSV-1-induced neuroinflammation; gut-microbiota regulation of proteostasis under viral stress; and therapeutic strategies targeting the microbiota to attenuate HSV-1-associated cognitive decline. We synthesize multidisciplinary evidence demonstrating that microbial dysbiosis exacerbates neuroimmune dysfunction, while microbiota-derived signals, such as short-chain fatty acids (SCFAs), tryptophan catabolites, and postbiotics, exert protective effects by reinforcing barrier integrity, regulating glial responses, and restoring proteostatic balance. Finally, we advocate for integrative therapeutic approaches that combine antiviral interventions with microbiota-based strategies, offering a conceptual framework for precision neuroimmunology in viral encephalopathies. This study repositions HSV-1 not merely as a latent pathogen but as a dynamic instigator of neurodegeneration within a vulnerable host-microbe ecosystem.