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Background Although there are developments in combination antiretroviral therapies, HIV-1-associated neurocognitive disorders (HAND) have no specific treatments. The HIV-1 envelope, gp120, induces neuropathological disorders like HAND. The association between these gut microbiota changes and HAND disease is unknown. It is vital to understand the relationship between gut microbiota changes and neuronal pyroptosis in gp120-induced neuropathology and find therapeutic targets for gut microbiota modulation. This study studies gut microbiota changes and gp120-induced HAND-related disorders, contending that the microbiota regulates metabolite production to mitigate the impacts.Methods HIV-1 gp120 transgenic mice were used to examine the relationship between gut microbial genera, neuronal pyroptosis, and cognition. Next, whole-genome sequencing of A. muciniphila and its effects on key tryptophan-related metabolites in mice after oral administration showed that higher KYNA levels in the brain protect against gp120-induced neuronal pyroptosis. This was confirmed in an animal model with higher cerebral KYNA levels. KYNA’s regulatory target, α7nAChR, was targeted in ‘rescue experiments’ utilizing specific inhibitors and NF-κB pathway inhibitors. In addition, α7-/-gp120tgm mice were used to investigate how KYNA reduces gp120-induced neuronal pyroptosis by inhibiting α7-nAChR and its downstream inflammatory signaling pathway.Results Cognitive deficits, decreased Akkermansia abundance, cerebral neuronal pyroptosis, and intestinal barrier injury were found in the gp120tgm (IDDF2026-ABS-0071 Figure 1. The abundance of Akkermansia genus is impaired during gp120-induced neurological deficits, IDDF2026-ABS-0071 Figure 2. Expression of intestinal barrier-related indexes, inflammation and immune response-related indexes and learning and spatial memory abilities in gp120tg mice and WT mice). Continuous oral A. muciniphila for six weeks improved intestinal barrier injury, cerebral neuronal pyroptosis, and behavioral performance in gp120tgm (IDDF2026-ABS-0071 Figure 3. Effects of A.muciniphila gavage on learning and spatial memory abilities and neuronal damage in 12-month-old gp120tg mice and WT mice, IDDF2026-ABS-0071 Figure 4. Effects of oral gavage of A.muciniphila on expression of gut barrier-related indexes in the colon of 12-month-old gp120tg mice and WT mice). Whole-genome sequencing showed that A. muciniphila enhanced serum tryptophan and brain KYNA levels, which may explain its protective effect (IDDF2026-ABS-0071 Figure 5. Administration of A.muciniphila promotes tryptophan metabolism and increases the KYNA synthesis in the brain). Meanwhile, A. muciniphila improves gp120-induced cognitive impairment via raising cerebral KYNA. KYNA protects neurons by inhibiting α7nAChR expression, which prevents neuronal pyroptosis caused by α7-nAchR signaling pathway activation, as demonstrated by Western blot and immunofluorescence staining. KYNA alleviates gp120-induced neuronal pyroptosis, as confirmed by ‘rescue experiments’ targeting α7-nAChR and NF-κB and α7-/-gp120tgm data (IDDF2026-ABS-0071 Figure 6. KYNA reduces gp120 -induced neuronal pyroptosis by blocking the α7nAChR expression).Conclusions In summary, our study indicates that A. muciniphila with tryptophan metabolic capacities alleviated cognitive impairment and neuronal pyroptosis in gp120 transgenic mice, and the mechanism may be related to the anti-pyroptosis effect of the tryptophan metabolite kynurenic acid through blockade of the α7nAChR signaling pathway.Abstract IDDF2026-ABS-0071 Figure 1Abstract IDDF2026-ABS-0071 Figure 2Abstract IDDF2026-ABS-0071 Figure 3Abstract IDDF2026-ABS-0071 Figure 4Abstract IDDF2026-ABS-0071 Figure 5Abstract IDDF2026-ABS-0071 Figure 6