Investigating the molecular, metabolic, and cognitive effects of a prebiotic in psychosis

Psychosis patients with lifetime exposure to antipsychotic medications often develop severe cardio-metabolic disorders and worsening cognitive impairments, therefore adjunct therapies that mitigate or attenuate these conditions would greatly enhance patient care. In recent years, the intestinal microbiome has emerged as an exciting area of research where gut microbial communities could influence cognitive and metabolic processes. However, experimental evidence of the molecular interactions between the gut and the brain as well as the translational potential into humans is currently unavailable. The main objective of this thesis was to investigate the molecular, metabolic and cognitive effects of the prebiotic BimunoTM galacto-oligosaccharide (B-GOS®) in psychosis. This was accomplished by establishing an olanzapine-induced weight gain rodent model and exploring the anti-obesity and pro-cognitive effects following daily prebiotics supplementation. Not only was increased levels of N-methy-D-aspartate receptor (NMDAR) subunit GluN1 observed, concomitant administration of prebiotics with olanzapine attenuated weight gain and increased circulating levels of acetate, a major product of prebiotics fermentation. The elevation of acetate imparts epigenetic changes involving the addition or removal of acetyl groups on histone molecules, therefore, an epigenetic effect of prebiotics was explored by comparing with direct sodium acetate administration. The prebiotic B-GOS® decreased brain activity of histone deacetylase (HDAC) and increased expression of HDAC-1 and HDAC-3, neither effects replicated by the supplementation of sodium acetate. Sodium acetate also did not attenuate olanzapine-induced weight gain and did not alter the expression of central NMDAR subunits suggesting that the therapeutic potential of the prebiotics B-GOS® may be mediated by alternative mechanisms. In psychosis patients after 12 weeks of BGOS ® supplementation, no significant changes on obesity-related anthropometric indices or serum immune biomarkers were observed. However, global cognitive functioning was beneficially affected and may have been driven by improvements in executive functioning, an NMDAR-dependent cognitive domain. The findings reported in this thesis provides preliminary support for the clinical potential of B-GOS® to address cognitive impairments and weight gain in psychosis, and provides further precedent for microbiome-based strategies at large. Additional exploration of the indirect effects of other short-chain fatty acids and the involvement of the immune system will be required to confirm and extend the findings presented in this thesis.