Elsevier

Biological Psychiatry

Volume 77, Issue 7, 1 April 2015, Pages 607-615
Biological Psychiatry

Priority Communication
Obese-type Gut Microbiota Induce Neurobehavioral Changes in the Absence of Obesity

https://doi.org/10.1016/j.biopsych.2014.07.012Get rights and content

Abstract

Background

The prevalence of mental illness, particularly depression and dementia, is increased by obesity. Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice.

Methods

Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to comprehensive behavioral and biochemical analyses.

Results

The mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota in the absence of significant differences in body weight. Sequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in α- and β-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxa. HFD microbiota also disrupted markers of intestinal barrier function, increased circulating endotoxin, and increased lymphocyte expression of ionized calcium-binding adapter molecule 1, toll-like receptor 2, and toll-like receptor 4. Finally, evaluation of brain homogenates revealed that HFD-shaped microbiota increased neuroinflammation and disrupted cerebrovascular homeostasis.

Conclusions

Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.

Section snippets

Animals and Treatments

The Pennington Biomedical Research Center Institutional Animal Care and Use Committee approved all experimental protocols, which were compliant with National Institutes of Health guidelines. To generate microbiota donor material, 8-week-old male C57BL/6 mice (Jackson Laboratories, Bar Harbor, Maine) were given regular chow diet (13% fat calories, Purina LabDiet 5001; LabDiet, St. Louis, Missouri) or high-fat diet (60% fat calories, Research Diets D12492; Research Diets, Inc., New Brunswick, New

HFD-Derived Gut Microbiota Impair Behavioral Performance in Mice

All animals tolerated the antibiotic regimen with no overt effects other than a mild, approximate 10% loss of body weight (Figure 1A). Quantitative real-time polymerase chain reaction based analyses of 16S RNA levels in fecal samples collected from mice midway through the antibiotic treatment revealed an approximate 90% to 95% reduction in fecal bacteria burden compared with matched but untreated mice (fecal DNA concentration 82,502.1 ± 18,255 µg/g in control samples, 3417.4 ± 1212 µg/g in

Discussion

The present findings represent the first definitive evidence that high-fat diet-induced changes to the gut microbiome are sufficient to disrupt brain physiology and function in the absence of obesity. Specifically, data show that transplantation of microbiota shaped by high-fat diet, but not control low-fat diet, caused significant and selective disruptions in exploratory, cognitive, and stereotypical behavior in conventionally housed, nonobese, diet-naïve mice. Overall, these data are in

Acknowledgments and Disclosures

This work was supported by the National Institutes of Health (DK047348 to HRB) and also used Pennington Biomedical Research Center (Animal Phenotyping) and Louisiana State University (Microbial Genomics Resource Center), which are funded, in part, by the National Institutes of Health (P20-RR021945, P30-DK072476, and P60-AA009803).

We thank Dr. Barry Robert for expert veterinary assistance related to antibiotic administration.

The authors declare no biomedical financial interests or potential

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