Inulin alleviates chronic ketamine-induced impairments in memory and prepulse inhibition by regulating the gut microbiota, inflammation, and kynurenine pathway.

Chronic ketamine administration causes cognitive impairments similar to those observed in schizophrenia. Growing evidence suggests that patients with schizophrenia show alterations in gut microbiota, which is associated with cognitive impairments. Inulin could regulate gut microbiota. However, it is unclear whether chronic ketamine exposure causes cognitive impairments by mediating gut microbiota and whether inulin ameliorates these impairments. In this study, we found that chronic ketamine exposure for 14 days induced gut dysbiosis, thereby increasing gut permeability, upregulating LPS-activated TLR4-NF-κB-NLRP3 inflammatory pathway, causing hippocampal neuroinflammation and neuronal damage, activating tryptophan (TRP)-kynurenine (KYN)-kynurenic acid (KYNA) pathway in the hippocampus, peripheral serum, and feces, and thus leading to deficits in recognition memory and prepulse inhibition (PPI). In addition, inulin treatment restored gut dysbiosis by increasing the abundance of Turicibacter and Ileibacterium and decreasing the abundance of Alistipes, Alloprevotella, Desulfovibrio, and Parasutterella, which may improve gut barrier damage by upregulating tight junction protein expression, suppress LPS-mediated TLR4-NF-κB-NLRP3 inflammatory pathway to reduce neuroinflammation and neuronal damage, inhibit TRP-KYN-KYNA metabolism pathway, and thus alleviate chronic ketamine-associated impairments in PPI and memory. Our findings provide additional evidence that inulin treatment is a potential intervention strategy for treating chronic ketamine-associated cognitive impairments and cognitive deficits in schizophrenia.