THC and CBD differentially modulated gut microbiota in the Poly I:C rat model of schizophrenia

Background: Disruptions in the gut-brain-microbiota axis are increasingly linked to psychiatric disorders. While cannabinoids possess immunomodulatory and neuroprotective properties, their impact on the microbial architecture during critical neurodevelopmental periods remains poorly understood. This exploratory study investigated whether adolescent treatment with delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) or their combination modulates dysbiosis in the maternal immune activation (MIA) rat model of schizophrenia.

Methods: Pregnant Wistar rats received Poly I:C or saline on gestational day 15. From the offspring of treated rats, eight groups were studied based on phenotype (Saline, MIA) and adolescent treatment (vehicle, CBD, THC, THC +CBD), with caecum contents analyzed via 16S rRNA sequencing.

Results: MIA-offspring exhibited reduced bacterial richness, which was further exacerbated by combined THC + CBD treatment. Notably, CBD was associated with beneficial shifts, including reductions in pro-inflammatory Pseudomonadota, Enterobacteriaceae and Pasteurellaceae. Furthermore, both cannabinoids decreased the pro-inflammatory Bilophila wadsworthia in MIA-offspring while promoting anti-inflammatory, short-chain fatty acid-producing taxa such as Oscillibacter, Roseburia and Prevotellaceae.

Discussion: Exploratory correlation analyses taken at PND120 revealed that THC and CBD differentially shape microbiotabrain structure and microbiota-brain oxidative/inflammatory relationships in a phenotype-dependent manner, with THC and CBD exerting distinct and sometimes opposing effects on redox and inflammatory status. Our findings highlight the microbiota-modulating potential of THC and CBD in a preclinic model of schizophrenia, underscoring the importance of the gut-brain axis given the high prevalence of adolescent cannabis use and its implications for psychiatric vulnerability.