User:Thomas K. Duncan/Gut-brain axis

Anxiety and mood disorders
Work is currently being performed on the relationship between gut microbiota and anxiety disorders and mood disorders. Much interest was generated in the potential role of gut microbiota in anxiety disorders, and more generally in the role of gut flora in the gut–brain axis, by studies published in 2004 showing that germ-free mice have an exaggerated HPA axis response to stress caused by being restrained, which was reversed by colonizing their gut with a Bifidobacterium species. Studies looking at maternal separation for rats shows neonatal stress leads to long-term changes in the gut microbiota such as its diversity and composition, which also led to stress and anxiety-like behavior. Additionally, while much work had been done as of 2016 to characterize various neurotransmitters known to be involved in anxiety and mood disorders that gut flora can produce (for example, Escherichia, Bacillus, and Saccharomyces species can produce noradrenalin; Candida, Streptococcus, and Escherichia species can produce serotonin, etc.) the interrelationships and pathways by which the gut microbiota might affect anxiety in humans were unclear.

There have been several attempts to influence the relationship between gut microbiota and anxiety and mood disorders using probiotics or prebiotics (called "psychobiotics"). One study used the maternal-separation model to induce early-life stress in rodents, whereby researchers were subsequently able to reverse the associated behavioral and inflammatory responses to stress (with respect to HPA axis activation) upon treatment with a probiotic, similar to the effects produced on control rodents treated with citalopram. A significant amount of research for psychobiotics as potential therapeutics for mood and anxiety disorders has utilized rodent models, which can provide insight into early clinical understandings of human diseases. However, limitations exist related to conclusively demonstrating causality of gut microbiota changes in anxiety and mood disorders, which (along with a limited number of studies in human models) has prompted the need for further studies on the efficacy of probiotic or prebiotic treatment for such disorders. People with anxiety and mood disorders tend to have gastrointestinal problems that may also be indicative of potential gut-brain axis disturbances, such as those associated with irritable bowel syndrome. Some small studies have been conducted to compare the gut microbiota of people with major depressive disorder and healthy people, but those studies have had contradictory results. Nevertheless, some trends in microbiota composition for those with MDD are starting to be identified, such as an increase in Bacteroidetes, Protobacteria, and Actinobacteria, and a decrease in Firmicutes in MDD patients compared to healthy controls. Some trends also have been suggested for those with generalized anxiety disorder (GAD), whereby a decrease in the prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricicoccus, and Sutterella has been suggested to compromise immune functions that may subsequently result in further brain dysfunction.

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 with microbes from humans without MDD. The taxonomic composition of microbiota between depressed patients and healthy patients, as well as between the respective mice, also differed. Furthermore, this study further supported that gut microbiota dysbiosis may play a role in the development of certain behaviors observed in depression. 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. These results are consistent with the aforementioned overactive HPA axis in response to stress in germ-free mice, as such results have been replicated several times, with the overactive HPA axis resulting in increased levels of corticosterone and adrenocorticotropic hormone (following exposure to stressful stimuli). Notably, physiological changes that likely result in changes in HPA axis activity have been suggested to be the hippocampus and cortex, as alterations in these structures have been observed in germ-free mice exhibiting such behavioral differences. 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.