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

Davey KJ, Cotter PD, O'Sullivan O, Crispie F, Dinan TG, Cryan JF, O'Mahony SM - Transl Psychiatry (2013)

Bottom Line: The atypical antipsychotic olanzapine is often associated with serious metabolic side effects including weight gain and increased visceral fat.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland [2] School of Pharmacy, University College Cork, Cork, Ireland.

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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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; $$$P<0.001 compared with VEH+ABX-treated animals. N=9/10. Data represent mean±s.e.m.
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fig4: Effect of olanzapine (OLZ) 2 mg kg−1 and an antibiotic cocktail (ABX), alone and combined, on (a) plasma free fatty acid concentration and (b) quantitative insulin sensitivity check index (QUICKI). **P<0.01, ***P<0.001 compared with vehicle (VEH)+VEH group. #P<0.05 compared with OLZ+VEH; $$$P<0.001 compared with VEH+ABX-treated animals. N=9/10. Data represent mean±s.e.m.

Mentions: OLZ treatment had a significant effect on plasma FFAs (F(1,32)=6.393, P<0.01). Further analysis showed that animals receiving OLZ+VEH had significantly elevated levels of FFAs compared with the VEH+VEH group (P<0.01) OLZ (2 mg kg−1). This increase was not seen in rats receiving OLZ+ABX, which had reduced levels compared with OLZ+VEH-treated animals (P<0.05) (Figure 4a).


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

Davey KJ, Cotter PD, O'Sullivan O, Crispie F, Dinan TG, Cryan JF, O'Mahony SM - Transl Psychiatry (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818006&req=5

fig4: 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.
Mentions: OLZ treatment had a significant effect on plasma FFAs (F(1,32)=6.393, P<0.01). Further analysis showed that animals receiving OLZ+VEH had significantly elevated levels of FFAs compared with the VEH+VEH group (P<0.01) OLZ (2 mg kg−1). This increase was not seen in rats receiving OLZ+ABX, which had reduced levels compared with OLZ+VEH-treated animals (P<0.05) (Figure 4a).

Bottom Line: The atypical antipsychotic olanzapine is often associated with serious metabolic side effects including weight gain and increased visceral fat.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland [2] School of Pharmacy, University College Cork, Cork, Ireland.

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.

Show MeSH
Related in: MedlinePlus