Our understanding of anxiety and depression has evolved over the years, leading to advancements in diagnosis, treatment, and clinical management. However, their prevalence has not lessened; in fact, it has heightened in recent years due to the COVID-19 pandemic. Its effects will last for years to come, so all mechanisms that can influence its incidence should be thoroughly considered, and the gut microbiota is the newest emerging target for antidepressant and anxiolytic effects.
Gut microbiota has been linked to many disease processes, including obesity, diabetes mellitus, and cancers. Our gut microbiome influences not only direct digestion and absorption but also radiates further downstream, creating physiologic changes. There are 700 million microorganisms (virus, bacteria, and fungi) that play benign or malignant roles in the intestinal microenvironment. Each individual’s microbiome represents the interplay of factors and is dependent on more than just diet and genetics. The careful composition of a certain microbiota, or lack thereof, is what researchers suggest may provide a therapeutic role in disease processes. Mental health disorders are one such disease process that has been highlighted as being influenced by certain microbiome habitation. A multitude of evidence has led researchers to further explore the relationship between the microbiota and behavior.
The microbiota-gut-brain axis is a signaling system between the gastrointestinal tract and the central nervous system. Many studies have shown that alterations in the microbiome lead to changes in behavior. One study demonstrated that when germ-free mice were transplanted with human stool, they had increased exploratory behavior compared to baseline analysis. Other germ-free rats with absent microbiomes displayed an exacerbation of behavioral responses to acute stress. Additionally, studies have shown that antibiotics can alter behavior, such as the onset of anxiety and depression, via modification of the microbiome. The microbiome clearly has a significant effect on behavior, but understanding the mechanisms responsible for this change is crucial to determining how to optimize the potential therapeutic benefits.
The vagus nerve, a cranial nerve that sends signals from the brain to the gut and back, is one pathway that allows microbiota to communicate with the brain. Vagal nerve pathways directed back towards the brain from the gut, the afferent portion of the nerve, release serotonin (a key neurotransmitter in anxiety and depression) and other gut hormones after receiving data from gut enteroendocrine cells. These cells line the gut wall and contribute to less than 1% of the total composition of the gut lining or epithelial layer. These cells have receptors that respond to different components of bacteria and send signals back to the brain via the afferent nerve. These connections allow gut information to travel to the central nervous system and generate both physiological and pathological responses.
As mentioned, communication between the central nervous system and bacteria relies on the presence of neurotransmitters. Some studies have described the interplay of microbiomes modulating the availability of circulating tryptophan, serotonin, kynurenine, and short-chain fatty acids, and the activation of immune cells, all of which have significant chemical influence on behavior. Alternatively, research has found binding sites for enteric neurotransmitters produced by the host present on bacteria, leading to measurable changes in the composition of the microbiota. These findings suggest a larger role for the microbiome in modulating behavior, as both systems have significant influence on neurotransmitter availability and responsiveness.
A deeper dive into the microbiome has found multiple associated microbiota that correlate with disease presentations. One such target is the genus Lactobacillus. Microbiota genera such as Prevotella, Lactobacillales, Sellimonas, Streptococcus, and Enterococcus have also been increased in those with anxiety. This alludes to the possible prevention and management of not only anxiety but also several mental health disorders through non-pharmaceutical means. However, the question remains unanswered on how to target these specific microbiomes.
Researchers have taken this connection to explore possible uses to prevent and treat mood disorders, including anxiety and depression. One such field of interest is the use of prebiotics and probiotics. A study reported the anxiolytic effects of galacto-oligosaccharides (GOS) prebiotic supplement intervention in healthy females. Their analysis indicates that dietary supplementation with a particular sugar-based prebiotic may improve pre-clinical anxiety. Additional human studies found that the administration of a supplement containing probiotics, prebiotics, plant extracts, and nutrients for four weeks led to a positive change in mental health. A separate study on rats found a statistically significant increase in serotonin mRNA expression as a result of supplementation with bioactive milk fractions and prebiotics. This means there was an increase in the genetic precursor that allows for the production of serotonin, a neurotransmitter pathologically reduced in anxiety and depression. All of these studies have promising results, encouraging a path forward for the optimization of gut microbiotas for behavioral benefits.
When gastrointestinal structure is compromised, the functionality of the protective barrier is impaired, leading to increased intestinal permeability and, consequently, penetration by substances that can alter physiological functions. The gut microbiota can influence host behavior via altering physiological processes, including vagus nerve signals and neurotransmitter interplay. Further studies are warranted to identify solutions capable of altering the trajectory of psychological diseases. The microbiota-gut-brain axis is not a new finding. However, researchers still need to accumulate better generalizable and objective data in humans, along with specific therapeutic means to alter specific microbiota species. While we look forward to those developments, we can continue to emphasize healthy diets with a greater focus on natural prebiotics and probiotics directly from the kitchen table to maximize the potential anxiolytic and antidepressant benefits.
Sumeet Dhillon and Jennifer Cesolini are medical students.
