How often have we heard the phrase “my gut feeling is this person is mentally sick”? And how often have you seriously considered it to be true? Well as it appears, it might be a true phenomenon, where the gut is able to regulate factors in the brain, leading to possibly different mood states, psychiatric phenotypes and also physiology. While the effects of stress on food intake via centers in the hypothalamus are quite well-known, leading researchers are now considering a way via the gut to the brain. While almost all studies have been conducted on mice, there seems no margin of doubt that the development of mood symptoms could be regulated by microbes in our gut (collectively called microbiota) one derives from their birth, so on and so forth by different events in our lives. This small article is about the fact that there is another way to look at the peripheral interactions of our complex brain, i.e. through the microbiota in the gut and the products they secrete. I am entirely going to base my views from the perspective of neuroscience and psychiatry, the two streams, which I know little about and starting to explore. Most of the views are based on the three scientific articles I have cited, and many times I have used their information in all their originality.
The amount of influence our plethora of microbiota has on us as a general ecosystem is just beginning to be unraveled. One of the proposed mechanisms of how out this communication system affects our behavior and subsequently the brain is the neurohumoral communication system, known as the gut–brain axis. In addition to that, pathways of communication include the autonomic nervous system, enteric nervous system, neuroendocrine system and the immune system. We harbor two major types of bacterial populations, the genus Bacteroides and the phylum Firmicutes, accounting over 90% of the known intestinal microbiota. In particular, recent researches have hinted at the role of this microbiome in the development and function of our brains. It has been shown that psychiatric disorders frequently coexist with common gastrointestinal conditions, such as irritable bowel syndrome (IBS). It has also been suggested that microbiome plays an important role in the maintenance of healthy homeostasis, and influences the risk of diseases like mood disorders and anxiety.
Clinical depression is associated with the alterations of the hypothalamic-pituitaryadrenal axis. Studies have demonstrated a direct link between microbiota populations and elevated corticosterone (CORT) and adrenocorticotrophin (ACTH) response in comparison to microbiota-free mice (germ-free mice). It was presumed that the immunologic development in these animals was undeveloped. A recent study by our lab also demonstrated the effects of chronic CORT administration as a model of anxiety/depression like states, and the effects on olfaction. Olfactory deficits are a result of impaired endocrine functions, which could play a role in anxiety/depressive states. Floxetine, a well-known antidepressant and serotonin reuptake inhibitor, not only elevated the depression-like states, but also improved olfactory acuity, memory, and impaired adult neurogenesis. It is to be noted that adult neurogenesis in the olfactory bulb has adaptive significance in odor processing and odor-driven behaviors.
The interactions between the brain and the microbiota are often bi-directional. Stress induced in rats by maternal separation during neonatal phase was also shown to lead to long-term changes in the diversity and composition of the gut microbiota. While the exact mechanism of transmission is under investigation, the vagal sensory responses and the elevation of peripheral cytokines are suggested. In terms of behavioral manifestations, transient changes of microbiota in mice influence brain chemistry and behavior. Alterations in the microbial profile have been shown to influence exploratory (anxiolytic) behavior, and corresponding changes in brain derived neurotrophic factor (BDNF) levels in the hippocampus and amygdala. It so appears that these behavioral alterations are in fact transmissible. Behavioral traits of donor mice can be adoptively transferred into adult germfree mice of a different strain via the intestinal microbiota.
Examples of interaction between the brain and the gut microbiota abound in psychiatry. Emotional stress or depression has been associated with inflammatory bowel diseases like Crohn’s disease and ulcerative colitis. Stress is likely to alter the integrity of the gut epithelium and also gut motility, arterial vasoconstriction and also the habitat of resident bacteria and promoting changes in microbial composition or activity. In addition, stress induced release of catecholamines into the gut might influence the microbial community. Hypothesis of microbiota involvement has been proposed in the late onset of autism spectrum disorders. Initially, interest focused on Clostridium spp. because autism onset sometimes follows prolonged antibiotic usage, thus implying that there is a post antibiotic influence on brain development and/or function. Subsequent molecularbased approaches found a broader range of microorganisms that include Desulfovibrio spp., Bifidobacterium spp., the mucolytic bacterium Akkermansiamuciniphila, members of the phylum Bacteroidetes and genus Sutterella. To date, little is known about the mechanisms underlying this putative link, but studies exist showing propionic acid, a microbial metabolite, could produce autism-like behavior in rats. It is also possible that microorganisms could influence the development of the fetal brain. The mouse studies indicate that brain development is altered in the offspring of germfree progenitors, and it is therefore possible that the maternal urogenital and intestinal microbiota influences brain development, not only during and shortly after birth, but also in utero (via soluble factors crossing the placental barrier). However, there is no information correlating maternal microbial profiles with autism or other behavioral conditions in the offspring. Altered intestinal fermentation profiles and increases in cytokine levels have been implicated in major depressive disorder. There has also been speculation about the role of inflammation and the intestinal microbiota in schizophrenia.
Although the fields of psychiatry and probiotics are in their infancy, studies do indicate that probiotics have anti-depressive and anxiolytic effects in preclinical practice in human subjects. Significantly less psychologic distress was observed in probiotic-treated groups when assessed for anxiety, depression, stress, and coping mechanisms. Some of the major neurotransmitter involved in these pathways are inhibitory GABA signaling and serotonin. GABA receptor expressions are altered in the CNS-related stress disorders while increased hippocampal expression of 5-hydroxytryptamine-1A (5HT1A) receptors and 5HT2C receptor, which bind serotonin, have been observed in anxiety. As scientists, we are limited by associative links rather than causal links at the moment. The field is progressing at a rapid rate, and strides are made every day. While human beings are more and more predisposed to psychiatric disorders, we need to understand them at a more basic level, and that’s where animal models are indispensible. The time is not far when we would rather rely on our ‘gut feelings’ more than our actual brain.
1. Foster, J. A. & Neufeld, K.-A. M. Gut–brain axis: how the microbiome influences anxiety and depression. Trends in Neurosciences 36, 305–312 (2013).
2. Collins, S. M., Surette, M. & Bercik, P. The interplay between the intestinal microbiota and the brain. Nature Reviews Microbiology 10, 735–742 (2012).
3. Siopi, E. et al. Anxiety- and Depression-Like States Lead to Pronounced Olfactory Deficits and Impaired Adult Neurogenesis in Mice. Journal of Neuroscience 36, 518–531 (2016).
The author thanks Dr. Eleni Siopi and Dr. Biliana Todorova (both from Institut Pasteur, Paris) for encouraging discussions on the topic and wonderful company in and out of work.