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In one study, germ-free mice underwent fecal transplants with microbes from humans with or without major depressive disorder (MDD). Mice with microbes from humans with MDD displayed more behaviors associated with anxiety and depression than mice transplanted microbes from humans without MDD. Taxonomic composition of microbiotia between depressed patients and healthy patients, as well as between the respective mice, also differed. Germ-free mice i n another study also displayed behaviors associated with anxiety and depression as compared to mice with normal microbiota, and had higher levels of corticosterone after exposure to behavioral tests. Using rodents in microbiome and mental health studies allows researchers to compare behavior and microbial composition of rodents to humans, ideally to elucidate therapeutic application for mental disorders.

Additionally, there is a link between the gut microbiome, mood disorders and anxiety, and sleep. The microbial composition of the gut microbiome changes depending on the time of day, meaning that throughout the day, the gut is exposed to varying metabolites produced by the microbes active during that time. These time-dependent microbial changes are associated with differences in the transcription of circadian clock genes involved in circadian rhythm. One mouse study showed that altering clock gene transcription by disrupting circadian rhythm, such as through sleep deprivation, potentially has a direct effect on the composition of the gut microbiome. Another study found that mice that could not produce the CLOCK protein, made by a clock gene, were more likely to develop depression. Stress and sleep disturbances can lead to greater gut mucosal permeability via activation of the HPA axis. This in turn causes immune inflammatory responses that contribute to the development of illnesses that cause depression and anxiety.