The past decade in science has seen an influx of new research articles showing the relationship between the human gut microbiome and its direct or indirect effect on the Central Nervous System (CNS). Much of the current research points to microbial therapy as a potential treatment option for many mental health disorders and conditions. The purpose of this literature review paper is to show the treatment potential for microbial therapy by focusing specifically on the links between the human gut microbiome and beneficial effects on mental health. The layout for this paper will follow a crawl-walk-run format that will cover the Microbial-Gut-Brain Axis (MGBA) and then transition to concepts involving micro-ribonucleic acid (miRNA), microbial species of interest, microbial neurochemical synthesis, microbial influence on the CNS and finally the aforementioned concepts and their relationship to mental health. This review paper is written under the assumption that the reader has a basic understanding of human physiology and microbiology.

The MGBA is defined as the bidirectional interrelationship between microbial colonies of the small & large intestines and their influence on the enteric, sympathetic & parasympathetic nervous systems as well as the neuroimmune & neuroendocrine components of the CNS [1]. Moreover, the microbiome and its synthesis of neurochemicals appear to modulate CNS activity by influencing brain functions which in turn causes the brain to modulate gastrointestinal (GI) activity such as blood flow and intestinal permeability [1]. In another research article, Moloney et al. [2] further explained that the MGBA is a vital communication network that can easily become unbalanced by diet, modified gene expression and the environment which may be responsible for many metabolic, immune and psychiatric disorders. A Chinese research team sought to elucidate this concept by experimenting on germ free rats by exposing them to Chronic Unpredictable Mild Stress (CUMS) scenarios and then testing them for depressive and anxiety-like behaviors and analyzing their microbiome composition [3]. Additionally, the Chinese research team was able to show a relationship between the probiotic Faecalibacterium prausnitzii (ATCC^® 27766™) and a reduction in CUMS associated depression and anxiety, concluding its potential use as a novel therapeutic approach to neuropathological and psychiatric disorders [3]. However, much of the emerging research emphasizes the need for future experiments to explore regulating gene expression to elicit positive MGBA outcomes.

According to Moloney et al. [2], miRNAs are non-coding single stranded ribonucleic acids (ssRNAs) that regulate the gene expression of messenger RNAs (mRNAs) containing miRNA binding sites during the post-transcriptional phase of gene expression. Continuing, miRNA’s influence on cellular growth, differentiation and death involving the expression of thousands of different proteins alludes to their potential to mitigate mental health diseases & disorders related to stress as well as cancer & viral infections [2]. Furthermore, Moloney et al. [2] stated that since miRNAs are found in most body fluids and are essential for cell-cell communication, they therefore serve as important biomarkers for many diseases and conditions. Moreover, it was shown that cell-cell communication was mediated through miRNA containing endocytic vesicles called exosomes which act similar to hormones and influence the phenotype in the recipient cell, leading to the conclusion that miRNAs are critical for MGBA regulation and potentially treating many infectious diseases [2]. Recent research has also pointed to interesting relationships between gut microbiome species proportions and overall mental health.  

According to Hao et al. [3], the composition and balance of the gut microbiome has a direct relationship with dietary intake and environmental factors. Additionally, Hao et al. [3] showed how the composition of the microbiome can elicit a positive or negative effect on overall mood and on disorders such as depression and anxiety by regulating systemic inflammatory responses. Furthermore, Ross stated that adult gut microbial composition showed drastic differentiation between those children born vaginally versus caesarean due to certain maternal bacteria found only in the vagina [1]. Continuing, infants born vaginally and at full term showed complex colonies and factors derived from the maternal immune system and vaginal microbial composition, resulting in better health outcomes later in life compared to cesarean-born who acquired bacteria from other environmental sources [1]. A consistent finding in recent research articles is that specific microbial species have unique roles in the body.

Ross found that vaginally born infants contained higher levels of Lactobacillus, Bifidobacterium, Bacteroides fragilis and Clostridium compared to caesarean births which resulted in long-term and short-term health benefits [1]. Much of the recent research consistently shows that specific bacterial species influence mental health through the MGBA and synthesis of specific metabolites such as butyric acid and propionic acid [3-5]. According to Forsythe et al. [4], the genus Lactobacillus has been shown to be a prominent gut bacterium that converts nitrate to nitric oxide, a potent regulator of the immune system, as well as produce large amounts of Gamma-Aminobutyric Acid (GABA) which has been shown to reduces depression and anxiety symptoms. Another study conducted by Foster et al. [5] showed that during rat testing with CUMS assessments, the microbial synthesis of GABA was shown to be as effective as the selective serotonin reuptake inhibitor (SSRI) fluoxetine as an anti-depressant. In addition, Foster et al. also showed that a 14-day regimen of Lactobacillus rhamnosous resulted in a reduction of anxiety-like behavior caused by the parasite Trichuris muris. Similar to Lactobacillus, Bifidobacterium infantis colonization before week 6 postnatal has the ability to reverse the hypothalamic-pituitary-adrenal axis (HPA axis) set point in adulthood, a key player in basal homeostasis and physiological stress responses [4]. Furthermore, a 14-day regimen of Bifidobacterium longum by itself was shown to normalize anxiety-like behavior in patients suffering from dextran sodium sulfate induced ulcerative colitis, yet when combined with other bacterium showed a greater effect in depression and anxiety mitigation [5]. In the obligate anaerobe genus Clostridium, an anti-anxiety mechanism has been associated with butyric acid synthesis, also known as butyrate; Clostridium has also shown to relieve symptoms of major depression and bipolar disorder through propionic acid synthesis [4,5]. As fascinating as the previous examples of microbial influence on mental health are, one newly discovered bacterial species has been described as being the most promising for future microbial therapy.

One of the most promising new species recently discovered in the human gut microbiota is Faecalibacterium prausnitzii which is the only known microbe of the Faecalibacterium genus and surprisingly comprises 5% of the human microbiome [3]. Furthermore, F. prausnitzii colonial concentrations have been shown to be decreased in patients suffering from irritable bowel disease (IBD), irritable bowel syndrome (IBS), obesity, celiac disease, colorectal cancer and depression [3]. Continuing, Hao et al. [3] showed that there was a positive correlation in high F. prausnitzii colonial concentrations with patients who underwent at least 7 weeks of anti-depressant therapy and in patients who reported better overall moods. Additionally, Hao et al. [3] established a negative correlation in the F. prausnitzii colonial concentrations in patients with metabolic disorders and depression. Further, Hao et al. [3] tested the manufactured Faecalibacterium prausnitzii (ATCC^® 27766^™) in rats using the CUMS testing model and established a link between F. prausnitzii microbial neurochemical synthesis of butyrate with preventative and therapeutic effects on neurological disorders. There was one additional study that examined the microbial content of human fecal matter that yielded interesting results.

In a study conducted by Jiang et al. [6], the 16S rRNA gene was pyrosequenced from the fecal samples of 46 adults, the results showed increased microbial diversity among patients suffering with major depressive disorders (MDD) as well as bacterial concentrations unique to the control group which had no history of MDD. Furthermore, Jiang et al. [6] mentioned that the presence of greater microbial diversity may not necessarily result in mental health benefits; this was due to other research that found breast fed infants had less microbial diversity yet showed greater neurodevelopment and intelligence compared to formula fed infants with greater microbial diversity. Additionally, the microbial diversity in autistic children was shown to be greater than children without autism, however no definitive link has been officially declared between autism and microbial concentrations [6]. To compliment the information in the previous two paragraphs, the study by Jiang et al. [6] showed that specific bacteria present in higher concentrations led to intestinal barrier dysfunction which would normally prohibit pathogenic bacterial permeability. The bacteria Alistipes metabolizes the amino acid tryptophan, which is needed to synthesize serotonin, and is seen in higher concentrations in patients with prolonged abdominal pain and IBS, pointing to elevated concentrations of Alistipes correlating to negative health outcomes [6]. Moreover, Jiang et al. [6] showed that anaerobic Lachnospiraceae from the Clostridiales order ferments carbohydrates into short chain fatty acids such as butyric acid and acetic acid which are both important in maintaining selective permeability of gut enterocytes. A disruption of the synthesis of short chain fatty acids can potentially increase permeability of the enterocytes to inflammogenic enteric pathogens from facultative anaerobic Enterobacteriaceae such as Pseudomonas aeruginosa and Klebsiella pneumonia whose presence can induce behavioral and psychological changes in humans [6]. The study of microbial neurochemical synthesis however has been shown to have a dramatic effect on the MGBA.

As established by Ross [1], the human microbiota is home to more than one trillion (10¹²) cells that constitute 150 times more genetic material than the human genome itself. The symbiosis of the human microbiota is therefore an intricate relationship of neurochemical synthesis mediated by quorum sensing and microbial balance [1]. According to Forsythe et al. [4], the human body is almost entirely dependent on the synthesis of short chain fatty acids from anaerobic commensal microbes like the butyric acid producing Clostridium. Further research conducted by Hao et al. [3] showed that short chain fatty acids can not only cross the brain barrier but are essential in microglia function, morphology & maturation which in turn has an effect on the neurocircuitry in the brain specific to the expression of depression and anxiety related behaviors. Another important point made by Forsythe et al. [4] is that the omega-3 fatty acid (linolenic acid) promotes the sustainability of Bifidobacterium and that eicosapentanoic acid (EPA) supports the adhesion of Lactobacillus genera to the enterocytes of the gastrointestinal tract, preventing premature excretion. Continuing, some clinical studies have reported the benefit that EPA and docosahexaenoic acid (DPA) have on patients suffering from major depressive and bipolar disorders, however, this evidence is inconclusive and warrants further research [4]. One of the most influential fatty acids on CNS health is butyric acid.

Butyric acid has shown to demonstrate pleiotropic characteristics, immunological regulation and play key roles in the synthesis of serotonin and other gut hormones that elicit endocrine responses and therefore influencing mental health [3]. In addition, understanding of butyric acid function supports the argument previously mentioned regarding the importance of F. prausnitzii as a therapeutic probiotic, referred to as a psychobiotic [3]. The key role that butyric acid plays on serotonin synthesis has been shown to work alongside the neurotransmitter GABA.

GABA is a byproduct of certain bacteria such as Lactobacillus brevis and Lactobacillus rhamnosous has been shown to have therapeutic effects on patients suffering from depression and anxiety [5]. Additionally, Foster et al. [5] confirmed this idea by testing the serum levels of rats for GABA after completing a CUMS model assessment which showed that the rats treated with L. brevis and L. rhamnosous showed a reduction in depression and anxiety related behavior. Interestingly enough, some bacteria are shown to react differently inside of a host under stress.

Under a prolonged period of stress, humans can accumulate excess serum levels of epinephrine and norepinephrine, powerful neurotransmitters related to the Fight-or-Flight response that can propagate the proliferation of pathogenic bacteria [4]. Moreover, Forsythe et al. [4] explained that the growth of pathogenic Escherichia coli O157:H7 was metabolically supported via host accumulation of epinephrine, norepinephrine and quorum sensing molecules. These findings support the idea that dysbiosis of the human gut microbiome due to prolonged stress can lead to worsening symptoms and a cascade of other health issues [4]. Interestingly, Forsythe et al. [4] discovered that some microbes, including Borrelia fragilis, that had been killed using heat or gamma radiation still maintained a cell wall complex that elicited an immune and anti-inflammatory response suggesting new research applications for microbes. Biomarkers of inflammation are growing in popularity by aiding researchers in studying the MGBA.

Biomarkers of inflammation such as interleukin-6, tumor necrosis factor and C-reactive protein are associated with patients suffering depression and anxiety, suggesting a possible temporal association with inflammation and gut microbial dysbiosis [4]. Expanding on this idea, Forsythe et al. [4] used syphilis as an example of an infectious disease that elicits neurological deficits such as dementia and presents proinflammatory biomarkers such as cytokines that are associated with behavior changes. Furthermore, Forsythe et al. [4] explained that inflammatory cytokines have been shown to directly affect CNS pathways by inducing a pyrexical response to infection or endotoxins. The overall influence of the microbiota on the CNS is quite expansive and continues to broaden each year.

Microbial influence on the CNS has been explored further in experiments involving specific afferent-efferent nerve pathways. Moloney et al. [2] and Foster et al. [5] stated that the therapeutic effects on the brain from the commensal bacteria Lactobacillus rhamnosus’ production of GABA was completely inhibited by severing the afferent pathway to the brain via the Vagus Nerve, the 10^th cranial nerve. Additionally, Moloney et al. [2] explained research findings where fecal transplantation from a healthy mouse into a mouse suffering from microbial imbalance resulted in the expression of behavior traits in the recipient mouse parallel with the behavior traits of the donor mouse. In another study conducted by Forsythe et al. [4], Lactobacillus was administered to anesthetized rats which resulted in suppression of cardiac responses from pain, showing that the Lactobacillus may have an inhibiting effect on the perception of visceral and somatic pain. An interesting experiment described by Hao et al. [3] describes how intraduodenal injections of Lactobacillus johnsonii reduced blood pressure in a patient within minutes by altering autonomic neurotransmission, further showing the complex application that microbes can have on future medical treatment for various diseases and illnesses. There are however many variables and considerations to consider for further research.

A consideration made by Jiang et al. [6] is that the fecal samples used in their study came from patients in China who have different diets and environmental factors than patients from Europe, Africa or other areas in the world. Additionally, Jiang et al. [6] further explained that the use of chronic anxiolytic medication may also have an effect on microbiota composition.

In conclusion, the aforementioned information from six different articles and reviews support the idea that the human MGBA is an intricate network of pseudo-hormonal signaling and biochemical metabolite synthesis that has direct and indirect effects on mental health. Advances in genomic sequencing have opened the door to new fields of study related to the possibility of therapeutic modification of the gut microbiome to alleviate the growing prevalence of depression and anxiety. Many of the experiments discussed in this literature review yielded interesting results, but the authors conveyed the importance of further studies and repeated experiments to verify underlying factors that affect results. More research that will include human trials and a reduction in variability or results will shed light on the intricacy of the human gut microbiome. The role of epigenetic research will continue to spearhead the understanding of the human microbiome and how to harvest the potential benefits for individual mental & overall health.