<i>Fto</i> Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice via Alterations in Gut Microbiota

Abstract

Depression and obesity have high concurrence within individuals, which may be explained by sharing the same risk factors, including disruption of the intestinal microbiota. However, evidence that delineated the causal connections is extremely scarce. <b>Methods:</b> Mice lacking fat mass- and obesity-associated gene (<i>Fto</i>) were generated. <i>Fto</i>-deficient and wild-type control mice were subjected to novel conditions with or without chronic unpredictable mild stress (CUMS) for 6 weeks. Some mice were treated with antibiotics via their drinking water for 6 weeks in order to deplete their microbiota. Behavioral tests were performed to evaluate anxiety- and depression-like behaviors. 16S rRNA amplicon and metagenomic sequencing were employed to analyse fecal microbiota. Plasma levels of inflammatory cytokines and lipopolysaccharides (LPS) were also compared. <b>Results:</b> Deletion of <i>Fto</i> led to lower body weight and decreased anxiety- and depression-like behaviors, <i>Fto</i>+/- mice were also less susceptible to stress stimulation, highlighting the essential role of <i>Fto</i> in pathogenesis of depression. With regard to gut microbiota, <i>Fto</i> deficiency mice harbored specific bacterial signature of suppressing inflammation, characterized with higher abundance of <i>Lactobacillus</i>, lower Porphyromonadaceae and <i>Helicobacter</i>. Critically, behavioral alterations of <i>Fto</i>^+/- mice are mediated by shift in gut microbiota, as such changes can be partially attenuated using antibiotics. Exposure to CUMS increased serum IL-6 level while <i>Fto</i> deficiency reduced its level, which may be explained by a lower LPS concentration. <b>Conclusion:</b> Together, our findings uncover the roles of <i>Fto</i> on depression and provide insights into microbiota-related biological mechanisms underlying the association between obesity and depression.