Effect of metformin in autistic BTBR T + Itpr3tf/J mice administered a high-fat diet

Abstract

The biological mechanisms linking diet-related obesity and autism-related behaviors remain unclear. We aimed to characterize these interactions, focusing on gut microbiota, 5-hydroxytryptamine (5-HT) levels, and autistic behaviors in an animal model for autism; a high-fat diet (HFD) BTBR T + Itpr3tf/J (BTBR) mouse. In this model, we also examined the medication effects of metformin (Met) which is known to ameliorate several symptoms of autism spectrum disorder (ASD). Therefore, we hypothesized that HFD exacerbates BTBR autistic symptoms, which can be alleviated by Met, and the effects are associated with serotonin and the microbiota. As expected, compared with mice fed a normal diet, ten-week HFD-fed mice showed increased body weight, adiposity, and glucose levels. HFD consumption markedly aggravated repetitive behaviors in the self-grooming test. Met reduced HFD-induced hyperactivity. Notably, HFD intervention rescued sociability in the three-chamber sociability test. Furthermore, HFD stimulated tryptophan production, which was inhibited by Met. In contrast, 5-HT levels were lower in the gut and higher in the cortex in the HFD group. Moreover, Met suppressed inflammation in the hippocampus of HFD-fed mice by significantly downregulating the expression of pro-inflammatory cytokines (NF-κB, IL-17A, and IL-6). HFD increased the Firmicutes/Bacteroidetes ratio, and Met supplementation decreased richness while increasing bacterial diversity. We found that the abundance of gut microbiota (Lachnoclostridium, Anaerotruncus, Mucispirillum, and Lactococcus) was correlated with behavior scores and 5-HT levels. Overall, HFD consumption improved sociality in BTBR mice, which was related to the modulation of 5-HT levels and the composition of the microbiota. Met did not show any significant positive effects on the autism phenotype associated with HFD.