Antipsychotics and the gut microbiome: olanzapine-induced metabolic dysfunction is attenuated by antibiotic administration in the rat

Abstract

The atypical antipsychotic olanzapine is often associated with serious metabolic side effects including weight gain and increased visceral fat. These adverse events are a considerable clinical problem and the mechanisms underlying them are multifactorial and poorly understood. Growing evidence suggests that the gut microbiota has a key role in energy regulation and disease states such as obesity. Moreover, we recently showed that chronic olanzapine altered the composition of the gut microbiome in the rat. It is thus possible that treatments that alter gut microbiota composition could ameliorate olanzapine-induced weight gain and associated metabolic syndrome. To this end, we investigated the impact of antibiotic-induced alteration of the gut microbiota on the metabolic effects associated with chronic olanzapine treatment in female rats. Animals received vehicle or olanzapine (2 mg kg−1 per day) for 21 days, intraperitoneal injection, two times daily. Animals were also coadministered vehicle or an antibiotic cocktail consisting of neomycin (250 mg kg−1 per day), metronidazole (50 mg kg−1 per day) and polymyxin B (9 mg kg−1 per day) by oral gavage, daily, beginning 5 days before olanzapine treatment. The antibiotic cocktail drastically altered the microbiota of olanzapine-treated rats, and olanzapine alone was also associated with an altered microbiota. Coadministration of the antibiotic cocktail in olanzapine-treated rats attenuated: body weight gain, uterine fat deposition, macrophage infiltration of adipose tissue, plasma free fatty acid levels, all of which were increased by olanzapine alone. These results suggest that the gut microbiome has a role in the cycle of metabolic dysfunction associated with olanzapine, and could represent a novel therapeutic target for preventing antipsychotic-induced metabolic disease.

Gut Microbiota: The Conductor in the Orchestra of Immune–Neuroendocrine Communication

“…6,99 In fact, when rats were administered the antipsychotic olanzapine in the presence of a cocktail of broad-spectrum antibiotics, the Firmicutes phylum was suppressed and the relative abundance of Bacteroidetes was increased while at the same time ameliorating the olanzapine-induced weight gain, uterine fat deposition, plasma free fatty acid levels, and macrophage infiltration of adipose tissue. 100 These findings of a microbiota-dependent, olanzapine-induced weight gain have recently been confirmed in GF mice, and in in vitro studies point to a direct interaction between olanzapine and microbes. 101 …”

Gut microbiota, metabolism and psychopathology: A critical review and novel perspectives

“…At baseline, when the fecal samples were collected, all but two patients were treated with antipsychotics. To what extent this may have impacted the findings is unclear, but antipsychotics have been found to influence microbiota composition [69][70][71].…”

The microbiome revolution

“…Yet today medical science also is moving in the direction of the microbiome (14,15), a diverse and rapidly evolving virome (16)(17)(18)(19)(20), metagenome (14), and the microbial mycome, transcriptome, proteome, and metabolome (21)(22)(23)(24)(25)(26)(27). There is increasing evidence that the microbiome and its output (our interactome) touch many, if not most, pathways that affect health, disease, and aging.…”