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Cited by 143Gut microbiota and healthRegulation of Appetite and ObesityGastrointestinal motility and disorders

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Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure

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Bahr, Sarah M., Weidemann, Benjamin J., Castro, Ana N., Walsh, John W., deLeon, Orlando, Burnett, Colin M.L., Pearson, Nicole A., Murry, Daryl J., Grobe, Justin L., Kirby, John R.·2015·EBioMedicine
DOI 10.1016/j.ebiom.2015.10.018PMC PMC4740326
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Abstract

Risperidone is a second-generation antipsychotic that causes weight gain. We hypothesized that risperidone-induced shifts in the gut microbiome are mechanistically involved in its metabolic consequences. Wild-type female C57BL/6J mice treated with risperidone (80 μg/day) exhibited significant excess weight gain, due to reduced energy expenditure, which correlated with an altered gut microbiome. Fecal transplant from risperidone-treated mice caused a 16% reduction in total resting metabolic rate in naïve recipients, attributable to suppression of non-aerobic metabolism. Risperidone inhibited growth of cultured fecal bacteria grown anaerobically more than those grown aerobically. Finally, transplant of the fecal phage fraction from risperidone-treated mice was sufficient to cause excess weight gain in naïve recipients, again through reduced energy expenditure. Collectively, these data highlight a major role for the gut microbiome in weight gain following chronic use of risperidone, and specifically implicates the modulation of non-aerobic resting metabolism in this mechanism.

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Fig. 1 Chronic risperidone treatment results in increased weight gain and an altered microbiome. For all panels, color indicates risperidone treatment (red) vs. control (blue). A) Body masses were assessed daily in 10 C57BL/6 female mice maintained on standard chow with ad libitum access to water (n = 5) or water with risperidone (20 μg/ml, n = 5). B) Body masses were assessed during risperidone treatment at a 1000-fold lower dose of risperidone (20 ng/ml, n = 5). C) PCoA of UniFrac distances illustrating the association between gut bacterial community structure after treatment with risperidone. Day 0 (Gray), Day 58 risperidone (red), and Day 58 control (blue). Risperidone Day 58 samples were compared to all other samples by ANOSIM (R = 0.895, p = 0.002). D) Mean pairwise intra- and intergroup UniFrac distances of control and chronic RSP treatment at days 0 and 58. p < 0.05 based on 1000 permutations. E–H) Genus-level percent relative abundances of the microbiome during treatment with risperidone vs. controls over time. Data are representative of mean ± s.e.m. *p < 0.05. I) Discriminatory OTUs among treatment populations as determined by LEfSe analysis.
Fig. 1 Chronic risperidone treatment results in increased weight gain and an altered microbiome. For all panels, color indicates risperidone treatment (red) vs. control (blue). A) Body masses were assessed daily in 10 C57BL/6 female mice maintained on standard chow with ad libitum access to water (n = 5) or water with risperidone (20 μg/ml, n = 5). B) Body masses were assessed during risperidone treatment at a 1000-fold lower dose of risperidone (20 ng/ml, n = 5). C) PCoA of UniFrac distances illustrating the association between gut bacterial community structure after treatment with risperidone. Day 0 (Gray), Day 58 risperidone (red), and Day 58 control (blue). Risperidone Day 58 samples were compared to all other samples by ANOSIM (R = 0.895, p = 0.002). D) Mean pairwise intra- and intergroup UniFrac distances of control and chronic RSP treatment at days 0 and 58. p < 0.05 based on 1000 permutations. E–H) Genus-level percent relative abundances of the microbiome during treatment with risperidone vs. controls over time. Data are representative of mean ± s.e.m. *p < 0.05. I) Discriminatory OTUs among treatment populations as determined by LEfSe analysis.CC BY-NC-ND · PubMed Central
Fig. 2 Body mass gains in mice treated with risperidone result from suppression of energy efficiency via resting metabolic rate. A) Body mass gains were assessed daily in C57BL/6 female mice maintained on standard chow with ad libitum access to water (n = 5) or water with risperidone (20 μg/ml, n = 5) for nine weeks. B) Food intake behavior was measured daily during housing in metabolic cages. C) Digestive efficiency was determined by bomb calorimetry, and performed on desiccated food and feces. D) Energy absorbed was calculated as the subtraction of calculated fecal energy from energy consumed. E) Energy efficiency was calculated as the rate of weight gain per unit energy absorbed. F) Total resting metabolic rate, measured by direct calorimetry, was assessed in mice after treatment with water (n = 4) or water with risperidone (20 μg/ml, n = 4) for two weeks. Data are representative of mean ± s.e.m. *p < 0.05.
Fig. 2 Body mass gains in mice treated with risperidone result from suppression of energy efficiency via resting metabolic rate. A) Body mass gains were assessed daily in C57BL/6 female mice maintained on standard chow with ad libitum access to water (n = 5) or water with risperidone (20 μg/ml, n = 5) for nine weeks. B) Food intake behavior was measured daily during housing in metabolic cages. C) Digestive efficiency was determined by bomb calorimetry, and performed on desiccated food and feces. D) Energy absorbed was calculated as the subtraction of calculated fecal energy from energy consumed. E) Energy efficiency was calculated as the rate of weight gain per unit energy absorbed. F) Total resting metabolic rate, measured by direct calorimetry, was assessed in mice after treatment with water (n = 4) or water with risperidone (20 μg/ml, n = 4) for two weeks. Data are representative of mean ± s.e.m. *p < 0.05.CC BY-NC-ND · PubMed Central
Fig. 3 Additional xenobiotic-induced shifts in the microbiome do not prevent risperidone-induced weight gain through suppressed energy expenditure. 6-Week old female C57Bl/6 mice were maintained on standard chow with ad libitum access to water (n = 8) or risperidone (n = 8, 20 μg/ml) for 7 weeks. During the second week of treatment, all mice (n = 48) were treated for 10 days with ampicillin (142.5 mg/l) or ciprofloxacin (62.5 mg/l). A) Body mass gains were assessed daily. B) Food intake behavior was measured during housing in metabolic cages during the seventh week of treatment. C) Digestive efficiency was determined through bomb calorimetry during the seventh week of treatment. D) Energy absorbed was calculated as the subtraction of calculated fecal energy from energy consumed. E) PCoA of UniFrac distances illustrating the change in the microbiome due to risperidone treatment and the changes in the microbiome due to antibiotic perturbation during the seventh week of treatment. Data are representative of mean ± s.e.m. *p < 0.05.
Fig. 3 Additional xenobiotic-induced shifts in the microbiome do not prevent risperidone-induced weight gain through suppressed energy expenditure. 6-Week old female C57Bl/6 mice were maintained on standard chow with ad libitum access to water (n = 8) or risperidone (n = 8, 20 μg/ml) for 7 weeks. During the second week of treatment, all mice (n = 48) were treated for 10 days with ampicillin (142.5 mg/l) or ciprofloxacin (62.5 mg/l). A) Body mass gains were assessed daily. B) Food intake behavior was measured during housing in metabolic cages during the seventh week of treatment. C) Digestive efficiency was determined through bomb calorimetry during the seventh week of treatment. D) Energy absorbed was calculated as the subtraction of calculated fecal energy from energy consumed. E) PCoA of UniFrac distances illustrating the change in the microbiome due to risperidone treatment and the changes in the microbiome due to antibiotic perturbation during the seventh week of treatment. Data are representative of mean ± s.e.m. *p < 0.05.CC BY-NC-ND · PubMed Central
Fig. 4 Risperidone differentially suppresses growth of cultured gut microorganisms. Microorganisms were collected from stool and cultured either aerobically or anaerobically overnight at 37 °C in BPRM broth. A) Growth curves of aerobic and anaerobic organisms were determined in BPRM supplemented with risperidone at various concentrations. B) Differential growth due to risperidone treatment is observed at the five hour timepoint. C) The IC50 of risperidone for anaerobic and aerobic growth was determined. Data are representative of mean ± s.e.m. *p < 0.05.
Fig. 4 Risperidone differentially suppresses growth of cultured gut microorganisms. Microorganisms were collected from stool and cultured either aerobically or anaerobically overnight at 37 °C in BPRM broth. A) Growth curves of aerobic and anaerobic organisms were determined in BPRM supplemented with risperidone at various concentrations. B) Differential growth due to risperidone treatment is observed at the five hour timepoint. C) The IC50 of risperidone for anaerobic and aerobic growth was determined. Data are representative of mean ± s.e.m. *p < 0.05.CC BY-NC-ND · PubMed Central
Fig. 5 Fecal transfer via gavage results in suppression of non-aerobic resting metabolic rates. A) C57BL/6 female donor mice were maintained on standard chow with ad libitum access to water (n = 4) or water with risperidone (20 mg/ml, n = 5) for nine weeks. Fecal material from donor mice was transferred by gavage to naive recipients (n = 7 for risperidone and n = 6 for control) daily for 14 days. Risperidone measured by HPLC in donor stool indicated that recipient mice received only 8.7 ± 1 ng/ml risperidone/day. Following fecal transfer, total and aerobic RMR was measured in recipient mice. B) Total RMR in fecal transfer recipients. C) Combined calorimetry determined the aerobic and non-aerobic components of total resting metabolic rate. Data are representative of mean ± s.e.m. *p < 0.05.
Fig. 5 Fecal transfer via gavage results in suppression of non-aerobic resting metabolic rates. A) C57BL/6 female donor mice were maintained on standard chow with ad libitum access to water (n = 4) or water with risperidone (20 mg/ml, n = 5) for nine weeks. Fecal material from donor mice was transferred by gavage to naive recipients (n = 7 for risperidone and n = 6 for control) daily for 14 days. Risperidone measured by HPLC in donor stool indicated that recipient mice received only 8.7 ± 1 ng/ml risperidone/day. Following fecal transfer, total and aerobic RMR was measured in recipient mice. B) Total RMR in fecal transfer recipients. C) Combined calorimetry determined the aerobic and non-aerobic components of total resting metabolic rate. Data are representative of mean ± s.e.m. *p < 0.05.CC BY-NC-ND · PubMed Central
Fig. 6 Phage transfer via gavage results in increased body mass without affecting digestive efficiency. Naïve mice were treated daily with bacteriophage isolated from risperidone-treated mice (n = 7) or control (n = 6). A) Body mass gains were measured daily. B) Food intake behavior was measured during housing in metabolic cages. C) Digestive efficiency was determined through bomb calorimetry. D) Energy absorbed was calculated as the subtraction of calculated fecal energy from energy consumed. Data are representative of mean ± s.e.m. *p < 0.05.
Fig. 6 Phage transfer via gavage results in increased body mass without affecting digestive efficiency. Naïve mice were treated daily with bacteriophage isolated from risperidone-treated mice (n = 7) or control (n = 6). A) Body mass gains were measured daily. B) Food intake behavior was measured during housing in metabolic cages. C) Digestive efficiency was determined through bomb calorimetry. D) Energy absorbed was calculated as the subtraction of calculated fecal energy from energy consumed. Data are representative of mean ± s.e.m. *p < 0.05.CC BY-NC-ND · PubMed Central
Supplemental Fig. S1 Core body temperature and physical activity measured through radiotelemetry before and after 1 and 15 weeks of risperidone treatment. Data are representative of mean ± s.e.m.
Supplemental Fig. S1 Core body temperature and physical activity measured through radiotelemetry before and after 1 and 15 weeks of risperidone treatment. Data are representative of mean ± s.e.m.CC BY-NC-ND · PubMed Central
Supplemental Fig. S2 Relative abundance of the major phyla within the gut microbiome are shown before and after risperidone treatment. Data are representative of mean ± s.e.m.
Supplemental Fig. S2 Relative abundance of the major phyla within the gut microbiome are shown before and after risperidone treatment. Data are representative of mean ± s.e.m.CC BY-NC-ND · PubMed Central
Supplemental Fig. S3 Body mass, total and aerobic RMR in mice treated with risperidone for 2 weeks. Data are plotted as change from baseline, in Fig. 2F. Data are representative of mean ± s.e.m.
Supplemental Fig. S3 Body mass, total and aerobic RMR in mice treated with risperidone for 2 weeks. Data are plotted as change from baseline, in Fig. 2F. Data are representative of mean ± s.e.m.CC BY-NC-ND · PubMed Central
Supplemental Fig. S4 Body mass, total and aerobic RMR in naïve mice receiving fecal transplants from vehicle- or risperidone-treated donors. Data plotted as change from baseline, in Fig. 5B–C. Data are representative of mean ± s.e.m.
Supplemental Fig. S4 Body mass, total and aerobic RMR in naïve mice receiving fecal transplants from vehicle- or risperidone-treated donors. Data plotted as change from baseline, in Fig. 5B–C. Data are representative of mean ± s.e.m.CC BY-NC-ND · PubMed Central
Supplemental Fig. S5 Epifluorescent microscopy determined viral-particle concentration and purity. All images were taken at 600 × magnification with an oil immersion objective. A representative image is shown which shows the characteristic milky appearance of a filter loaded with virus particles.
Supplemental Fig. S5 Epifluorescent microscopy determined viral-particle concentration and purity. All images were taken at 600 × magnification with an oil immersion objective. A representative image is shown which shows the characteristic milky appearance of a filter loaded with virus particles.CC BY-NC-ND · PubMed Central
Supplemental Fig. S6 Observed OTUs in control and risperidone treated mice, before and after treatment (mean ± s.e.m.), calculated at a uniform depth of 6000 sequences/sample.
Supplemental Fig. S6 Observed OTUs in control and risperidone treated mice, before and after treatment (mean ± s.e.m.), calculated at a uniform depth of 6000 sequences/sample.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Bahr, S. M., Weidemann, B. J., Castro, A. N., Walsh, J. W., deLeon, O., Burnett, C. M. L., Pearson, N. A., Murry, D. J., Grobe, J. L., & Kirby, J. R.
Affiliations
University of Iowa (US)
Corresponding author
Kirby, John R.
ORCID
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2015-11
Volume
2
Issue
11
Pages
1725-1734
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2015.10.018
PMC
PMC4740326
OpenAlex
W1781074272
Cited by
143
References
54
Citations by year
2026: 12 · 2025: 12 · 2024: 11 · 2023: 16 · 2022: 14 · 2021: 16 · 2020: 15 · 2019: 17 · 2018: 10 · 2017: 17 · 2016: 2 · 2015: 1
FWCI
4.34
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Foundation (1244021)
  • American Diabetes Association (1-14-BS-079)
  • Alfred P. Sloan Foundation
  • American Heart Association (HL084207, 15SFRN23730000)
  • National Institutes of Health (HL098276, HL-084207)
  • National Heart, Lung, and Blood Institute (HL098276, HL-084207, P01HL084207, R00HL098276)
  • National Institute of Allergy and Infectious Diseases (R01AI108255)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U24DK100469)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
risperidone, antipsychotic-induced weight gain, gut microbiota, energy expenditure, resting metabolic rate, fecal microbiota transplantation, bacteriophages, anaerobic metabolism, atypical antipsychotics, metabolic side effects
MeSH terms
Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Animals, Energy Metabolism, Female, Antipsychotic Agents, Xenobiotics, Weight Gain, Risperidone, Mice, Metagenome, Metagenomics

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