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

BackgroundThe 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.MethodsConventionally 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.ResultsThe 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.ConclusionsCollectively, 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.