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

  • ️Tue Jan 01 2013

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

K J Davey et al. Transl Psychiatry. 2013.

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.

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Figures

Figure 1
Figure 1

Effect of olanzapine (OLZ) coadministered with vehicle (VEH) or an antibiotic cocktail (ABX) on the faecal microbiota of female rats. N=6.

Figure 2
Figure 2

(a) Effect of olanzapine (OLZ) 2 mg kg−1 coadministered with vehicle (VEH) or an antibiotic cocktail (ABX) on body weight gain in female rats. (b) Area under the curve analysis. *P<0.05, ***P<0.001 versus VEH+VEH, #P<0.05 versus OLZ+VEH. N=9/10. Data represent mean±s.e.m.

Figure 3
Figure 3

Effect of olanzapine (OLZ) 2 mg kg−1 and an antibiotic cocktail (ABX), alone and combined, on (a) periuterine fat percentage and (b) CD68 mRNA expression in adipose tissue. **P<0.01 versus vehicle (VEH)+VEH group. #P<0.05, ##P<0.01 versus OLZ+VEH group. N=9/10. All data represent mean±s.e.m.

Figure 4
Figure 4

Effect of olanzapine (OLZ) 2 mg kg−1 and an antibiotic cocktail (ABX), alone and combined, on (a) plasma free fatty acid concentration and (b) quantitative insulin sensitivity check index (QUICKI). **P<0.01, ***P<0.001 compared with vehicle (VEH)+VEH group. #P<0.05 compared with OLZ+VEH; $$$P<0.001 compared with VEH+ABX-treated animals. N=9/10. Data represent mean±s.e.m.

Figure 5
Figure 5

Effect of olanzapine (OLZ) 2 mg kg−1 and an antibiotic cocktail (ABX), alone and combined, on (a) sterol-regulatory element binding protein (SREBP)-1c; (b) fatty acid synthase (FAS); and (c) acetyl-CoA-carboxylase (ACC) mRNA expression in hepatic tissue. **P<0.01 versus vehicle (VEH)+VEH group; #P<0.05 versus OLZ+VEH group. N=9/10. Data represent mean±s.e.m.

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