HIV神经认知障碍如何治疗？肠脑轴调控与菌群干预新策略

Abstract: HIV-associated neurocognitive disorders (HAND) are common complications in individuals with HIV infection. As research has progressed, the pathogenesis of HAND has evolved from a single "virus-induced direct damage" model to a complex network involving multiple factors, pathways, and systems. This network is closely related to neuroinflammation induced by the HIV-1 envelope protein gp120, imbalances in glial-neuronal interactions, gut microbiota dysbiosis, and dysfunction of the gut-brain axis. The clinical characteristics of HAND have shifted from acute severe dementia to predominantly mild-to-moderate, insidious, chronic, and cumulative conditions. Consequently, the limitations of antiretroviral therapy (ART) have become more apparent, highlighting the urgent need for therapeutic strategies that combine inflammation suppression, neuroprotection, and systemic regulation. The gut-brain axis stands out as a research hotspot due to its advantages in early, non-invasive, long-term intervention, systemic inflammation modulation, and multi-target, multi-pathway neuroprotection without the need to cross the blood-brain barrier. Studies have shown that gp120 transgenic mice exhibit progressive cognitive impairment and reduced gut microbiome diversity during aging, particularly characterized by a decrease in the abundance of Akkermansia muciniphila. Oral administration of A. muciniphila can significantly improve gp120-induced neuronal pyroptosis and hippocampal damage by repairing intestinal barrier integrity, inhibiting eosinophil infiltration in the colon, and suppressing pro-inflammatory cytokine release. The mechanism primarily relies on the antagonistic action of kynurenic acid (KYNA), a tryptophan metabolite, on the α7nAChR receptor, which blocks the activation of the NF-κB signaling pathway and inhibits neuronal pyroptosis. Additionally, KYNA directly inhibits the transformation of astrocytes into the A1 neurotoxic phenotype through JAK2/STAT3 signal regulation, thereby reducing neuronal death and cognitive impairment. These findings not only elucidate the central role of gut microbiota regulation in the pathogenesis of HAND but also provide a theoretical basis for therapeutic strategies based on the gut-brain axis. They also offer insights into the mechanisms and intervention strategies for other neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).