UCLA

The microbiota-gut-brain (MGB) axis is a complex communication network connecting the central nervous system (CNS) with the gut microbiota. Lifestyle factors, including diet, can have a profound impact on the composition and function of the gut microbiome and hence modulates the MGB axis. The high-fat diet (HFD) is a major contributor to the obesity pandemic and is associated with increased susceptibility to neurological disorders, including anxiety and depression. The HFD is shown to decrease the abundance of beneficial bacteria and increase systemic levels of proinflammatory cytokines and lipopolysaccharides. Animal and human studies have demonstrated that HFD can induce anxiety-like behavior, as measured by elevated plus maze and open field tests in mice and rats. The underlying mechanism of this effect is believed to involve alterations in the MGB axis and changes in the gut microbiota composition and metabolites. Obesity-induced chronic inflammation induces anxiety-like behavior by activating the immune system and altering neurotransmitter signaling. There is increasing focus on the role of limbic system inflammation in the pathogenesis of several metabolic and neurological disorders, especially concerning HFD. However, the biochemical mechanisms and pathways that link high-fat consumption and CNS homeostasis with the pathology of neurological disorders are not well understood. This thesis investigates the relationship between diet, specifically high-fat diet (HFD), and anxiety-like behavior in mice, focusing on the role of the microbiota-gut-brain (MGB) axis. A 10-week experiment was conducted, wherein male C57BL/6 mice were divided into HFD and control diet (CD) groups. The HFD group exhibited weight gain and increased anxiety-like behavior compared to the CD group, as assessed through various behavioral paradigms, including the open field test (OFT), elevated plus maze (EPM) test, and light/dark box (LDB) test. Notably, anxiety-like behavior was observed as early as three weeks into the HFD treatment. Additionally, the study explored the potential involvement of imidazole propionate (ImP), a microbiota-derived metabolite, in anxiety-like behavior. ImP supplementation induced anxiety-like behavior in mice, despite no significant differences in ImP levels between HFD-fed and CD-fed mice. Histological analysis suggests that ImP decreases cFOS expression in the hypothalamus, a brain region important in the regulation of appetite and insulin signaling. There were no changes in microglial morphology in specific brain regions associated with anxiety regulation in response to ImP. However, further investigations are needed to understand the precise mechanisms underlying the effects of ImP on the MGB axis. Overall, this thesis contributes to the understanding of the complex interplay between diet, the gut microbiota, and the CNS, highlighting potential therapeutic strategies targeting the MGB axis for anxiety and neurological disorders.