Inulin ameliorates chronic ketamine-induced anxiety-like behaviors and impairments in spatial learning and memory: involvement of gut microbiota, microbial metabolite short-chain fatty acids, and the BDNF-TrkB-ERK1/2-CREB pathway

Chronic ketamine exposure for 28 days in an animal model disrupts gut microbiota, reduces short-chain fatty acids (SCFAs) and BDNF signaling, damages neurons, and causes anxiety-like behaviors, prepulse inhibition deficits, and spatial learning and memory impairments. Dietary inulin reversed these gut microbiota changes, increased SCFAs, repaired gut barrier damage, and restored BDNF-TrkB-ERK1/2-CREB signaling, which improved the behavioral deficits. Inulin may be a promising candidate for treating chronic ketamine-associated behavioral symptoms and schizophrenia with dysbiosis.

Study at a glance

Abstract

Chronic ketamine exposure results in psychotic and cognitive symptoms that resemble those found in patients with schizophrenia. Emerging evidence suggests that patients with schizophrenia exhibit gut microbiota dysbiosis and decreased levels of short-chain fatty acids (SCFAs) and BDNF, which are related to the severity of psychotic and cognitive symptoms. Dietary inulin can regulate gut microbiota, SCFAs, and BDNF. However, the role of gut microbiota, SCFAs, and BDNF in chronic ketamine-induced schizophrenia-like behaviors is unclear. In this study, we found that chronic ketamine exposure for 28 days caused gut microbiota dysregulation, reduced the expression of SCFAs in serum, hippocampus, and feces, elevated gut permeability, downregulated the BDNF-TrkB-ERK1/2-CREB signaling pathway, caused neuronal damage, and decreased the expression of synaptic proteins Syn and PSD-95, which may lead to anxiety-like behaviors, prepulse inhibition (PPI) deficits, and spatial learning and memory deficits. In addition, inulin intervention reversed gut microbiota dysbiosis by decreasing the abundance of Colidextribacter, Oscillibacter, Alistipes, and Desulfovibrio, while increasing the abundance of Lachnospiraceae_NK4A136_group, Faecalibaculum, and Blautia. It also increased the expression of SCFAs, alleviated gut barrier damage, and upregulated the BDNF-TrkB-ERK1/2-CREB signaling pathway to reduce neuronal damage and enhance the expression of Syn and PSD-95, which may improve chronic ketamine-induced anxiety-like behaviors, PPI impairments, and spatial learning and memory deficits. Our findings provide additional evidence that inulin may be a promising candidate for treating chronic ketamine-associated anxiety-like behaviors and deficits in spatial learning and memory, as well as behavioral deficits in schizophrenia with dysbiosis.