Despite the tremendous advances in human immunodeficiency virus (HIV) therapies, HIV-associated neurocognitive disorders remain prevalent. In this study, we investigated the age-dependent progression of cognitive deficits in glycoprotein 120 transgenic (gp120tg) mice, with neuronal pyroptosis identified as a central mechanism in glycoprotein 120 (gp120) induced pathogenesis. Cognitive impairments were observed in 6-, 9-, and 12-month-old gp120 mice, and these deficits correlated with age-associated gut microbiota dysfunction. Notably, a significant reduction in the abundance of Akkermansia muciniphila was found in the gut microbiota of these mice compared to age-matched wild-type controls. Oral administration of A. muciniphila with tryptophan metabolic capacities alleviated cognitive impairment and neuronal pyroptosis in gp120tg mice. Kynurenic acid, a tryptophan metabolite with α7 nicotinic acetylcholine receptor (α7nAChR) inhibitory properties, attenuated gp120-induced neuronal pyroptosis via blockade of α7nAChR/NF-κB signaling. The α7nAChR, a receptor involved in neuroinflammation and neuronal survival, plays a pivotal role in the regulation of immune responses and neuronal excitability. This mechanism may account, in part, for the anti-pyroptosis effects observed in gp120 mice with A. muciniphila treatment. Our findings shed light on the therapeutic potential of A. muciniphila and strategies targeting α7nAChR inhibition against gp120-mediated neuropathology.