Ketogenic diet derived faecal microbiota transplantation improved sensorimotor gating deficit in an acute NMDA-receptor antagonist model of schizophrenia in mice

Abstract

Ketogenic diet (KD) shows promise as a novel treatment for schizophrenia, although its mechanisms of action are still unclear. KD has been shown to modify the gut microbiota and may exert some of its brain-directed effects through that. We hypothesised that KD-induced changes in the gut microbiota mediate some of the therapeutic effects of KD in a preclinical model of schizophrenia. To test this hypothesis, we transplanted the gut microbiota through faecal matter obtained from mice maintained on KD to standard diet-fed mice (faecal microbiota transplantation; FMT) and assessed its effect on a translationally validated endophenotype of psychotic disorders, the sensorimotor gating deficit induced by the NMDA-receptor antagonist MK-801, in mice. Faecal samples were collected from male C57Bl/6 mice fed a KD for 4 months and prepared into a liquid for inoculation. Ten-week-old male C57Bl/6 mice maintained on standard diet (SD) received 3 inoculations every second day. One week after the last inoculation, animals received 0.2 mg/kg MK-801 (dizocilpine) to induce schizophrenialike sensorimotor getting deficit as measured by the pre-pulse inhibition (PPI) of startle. MK-801 reduced PPI, which was attenuated by the faecal microbial transplant derived from mice fed with KD. We showed that FMT through inoculation with KD faeces improved a highly translatable behavioural endophenotype of schizophrenia. Our novel findings confirm that some of the beneficial effects of KD in schizophrenia are mediated by the gut microbiota.