Assessment of the Effects of Dietary Vitamin D Levels on Olanzapine-Induced Metabolic Side Effects: Focus on the Endocannabinoidome-Gut Microbiome Axis

Abstract

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in Trpv1 expression and increases in the levels of its agonists, including various N-acylethanolamines and 2-monoacylglycerols, which are consistent with the observed improvement in adiposity and metabolic status. Furthermore, while global gut bacteria community architecture was not altered by olanzapine, we identified changes in the relative abundances of various commensal bacterial families. Taken together, changes of eCBome and gut microbiota families under our experimental conditions might contribute to olanzapine and vitamin D-mediated inhibition of weight gain in mice on a HFHS diet.

The regulatory effects of second-generation antipsychotics on lipid metabolism: Potential mechanisms mediated by the gut microbiota and therapeutic implications

“…The probiotic Bacteroides has also been shown to produce the endothelin-like molecule N-acyl-3-hydroxypalmitoyl-glycine (commendamide) ( Cohen et al, 2015 ; Lynch et al, 2017 ). Furthermore, olanzapine-induced metabolic effects have been shown to be dependent on the endogenous cannabinoid system ( Abolghasemi et al, 2021 ). Everard et al showed that treating obese mice with A. muciniphila increased intestinal 2-oleoylglycerol (2-OG), 2-arachidonoylglycerol (2-AG) and 2-palmitoylglycerol (2-PG) levels ( Everard et al, 2013 ).…”

Systematic Review on the Effects of Food on Mental Health via Gut Microbiome

“…Various studies find that healthy diets have a positive effect on the gut microbiome. The diversity of the gut microbiome can be affected by diets, which may influence one's mental health [17,36], leading to potential improvements in mental health [15][16][17][18][19][20][21][22][23][24][25][26][27]29]. A healthy diet commonly refers to the consumption of vegetables, fruits, fish, and whole-diet interventions instead of only examining individual nutrients or foods.…”

“…Positive effects: Other specific foods: Dietary vitamin D, unpasteurized milk, foods with a low omega-3 to omega-6 ratio, and Xiao Yan San [15,19,27,28], may also have a positive effect on the gut microbiome. Consuming a sufficient amount of vitamin D helps to regulate the gut microbiome and benefit gut health [53].…”

“…Foods rich in dietary vitamin D include salmon, egg yolks, mushrooms, and red meat. A lack of dietary vitamin D has been associated with mental illnesses, while extreme vitamin D deficiency is found in patients with acute schizophrenia [27]. Vitamin D heals the gut epithelium, hence maintaining the integrity of the epithelial barrier [55].…”