Abstract
Obesity and diabetes in humans are associated with increased rates of anxiety and depression. To understand the role of the gut microbiome and brain insulin resistance in these disorders, we evaluated behaviors and insulin action in brain of mice with diet-induced obesity (DIO) with and without antibiotic treatment. We find that DIO mice have behaviors reflective of increased anxiety and depression. This is associated with decreased insulin signaling and increased inflammation in in the nucleus accumbens and amygdala. Treatment with oral metronidazole or vancomycin decreases inflammation, improves insulin signaling in the brain and reduces signs of anxiety and depression. These effects are associated with changes in the levels of tryptophan, GABA, BDNF, amino acids, and multiple acylcarnitines, and are transferable to germ-free mice by fecal transplant. Thus, changes in gut microbiota can control brain insulin signaling and metabolite levels, and this leads to altered neurobehaviors.
Highlights
Over the past decade there has been a mounting body of evidence that gut microbiota can modulate host physiology in mice, humans and other species [1,2,3,4,5,6]
We have previously shown that treatment with vancomycin or metronidazole can decrease adipose and liver inflammation and the elevated serum tumor necrosis factor-α (TNFα) levels which occur in HFDfed C57Bl/6J mice, and that this can be transferred to GFmice [8]
Modifications in gut microbial composition induced by diet and other factors can play an important role in the metabolic changes associated with obesity, including glucose intolerance, insulin resistance and inflammation in fat and liver [1, 2, 8, 11]
Summary
Over the past decade there has been a mounting body of evidence that gut microbiota can modulate host physiology in mice, humans and other species [1,2,3,4,5,6]. Many factors can affect the composition of the gut microbiome, including colonization at time of birth, changes in the diet, and exposure to antibiotics [7,8,9,10] In both humans and mice, feeding a high fat diet (HFD) or over-eating due to a genetic mutation in the leptin axis induces robust alterations in gut microbial flora, reducing bacterial diversity and altering the overall bacterial composition [11, 12]. We [8] and others [13,14,15] have shown that treatment with prebiotics, probiotics or antibiotics, which modulate the gut microbiome, can reduce insulin resistance and inflammation in peripheral organs, such as liver, fat and muscle, in mice models
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