The Microbiome-Gut-Brain Communication Pathway: Impact on Mental and Physical Wellbeing

The gut-brain axis (GBA) has long been a concept in common language, with phrases such as ‘butterflies in the stomach,’ ‘gut instincts,’ and ‘gut feelings’, but until recently the biological pathways through which gut-brain communication occurs were not well understood. In the last decade, many researchers have focused on the mechanisms of the GBA, exposing the microbiome as a major player in this communication pathway, impacting both physiological and psychological health (Bruce-Keller, Salbaum, & Berthoud, 2018; Kennedy, et al., 2015; Lin & Li, 2017; Murphy, et al., 2015). This new found understanding of the integral role of the microbiome could bring about a paradigm shift in the treatment of many chronic disorders, such as anxiety, depression, obesity, autoimmune disorders, and gastrointestinal illnesses, using personalized medical treatments tailored to the composition of the individual microbiome (Bruce-Keller et al., 2018; Foster, Rinaman, & Cryan, 2017; Mason, 2017). There is strong evidential support for a relationship between the gut-microbiome and the mental and physical health of its host. This relationship is mediated by the bidirectional biological pathways of the gut-brain axis. Researchers are investigating interventions such as diet, microbial transplants, and pre- and probiotics as treatment strategies for psychiatric and physical conditions associated with gastrointestinal dysbiosis.

The human microbiome, weighing approximately as much as the human brain, is composed of an estimated 1000 species and 7000 strains of bacteria, along with viruses, bacteriophages, and fungi (Lin & Li, 2017). Of the known intestinal bacterial strains, current research mainly focuses on the Bifidobacterium and Lactobacillus genera, which have demonstrable effects on neuropsychiatric and physiological illnesses in human and animal models (Bruce-Keller et al., 2018; Foster et al., 2017; Kennedy et al., 2015; Lin & Li, 2017; Mason, 2017; Oriach, Stanton, Cryan, & Dinan, 2015; Sandhu et al., 2016; Sarkar et al., 2015). A balanced microbiome assists with overall metabolic functioning, playing an important role in digestion, metabolite synthesis, and stress regulation; however, when the microbiome falls into dysbiosis, these essential systems become disrupted. Many factors contribute to the composition of the microbiome, including physiological and psychological stress, dietary choices, antibiotic use, mode of delivery, and the condition of the maternal microbiome (Bruce-Keller et al., 2018; Foster et al., 2017; Mason, 2017).

The gut is first colonized by the maternal microbiome during delivery and breastfeeding. Compared to formula-fed infants, breastfed infants show a microbial profile containing higher levels of Bifidobacterium and Lactobacillus with lower level of pathogenic bacterial species, such as Escherichia coli and Clostridium difficile (Foster et al., 2017; Kennedy et al., 2015; Oriach et al., 2015; Sandhu et al., 2016; Sarkar et al., 2015). The composition of the microbiome during early life plays an important role in physical development, immune programming, and the maturation and functioning of the central nervous system microglia, suggesting an essential role in neurodevelopment (Bruce-Keller et al., 2018; Foster et al., 2017; Kennedy et al., 2015; Oriach et al., 2015; Sandhu et al., 2016). Since the early colonization of the individual microbiome has such a strong impact on development, the health of the maternal microbiome is essential for healthy development of offspring. Sandhu et al. referenced a study demonstrating the importance of the intergenerational health of the microbiome, in which mice fed a long-term low-fibre diet showed an irreversible reduction in microbial diversity, lasting up to four generations (2016).

The neurological pathways of gut-brain communication consist of afferent sensory spinal and vagal nerves sending visceral information from the enteric nervous system to the limbic system, and efferent signals pass from the cingulate and insular cortices, amygdala and hypothalamus, which regulate vagus nerve output signals to sensory motor neurons in the enteric nervous system (Mason, 2017). Alterations of the microbial composition influence hypothalamic-pituitary axis (HPA) activation set-point, resulting in an elevated stress response, anxiety, and depression-related behaviours, which in turn impact feeding behaviour, further influencing the composition of the microbiome. This feedback loop highlights the bidirectional nature of the gut-brain communication pathways (Foster et al., 2017).

Animal studies have been essential in understanding the relationship between stress, mood disorders, and the microbiome. Germ-free mice, raised without a microbiome, show an enlarged amygdala and hyperactive HPA set-point; however, administration of Bifidobacterium longum ameliorated the stress response and reduced HPA activation set-point (Mason, 2017). Chronic exposure to stress results in sustained HPA activation, which contributes to many chronic health conditions (Chrousos, 2009). Studies into microbiome transplants revealed that when inoculated with the microbial profile of stress prone mice, germ free mice showed increased anxiety-related behaviours, the microbial profile of normal mice decreased anxious behaviours in stress-prone mice, and microbes from depressed human patients increased anhedonia and anxiety-related behaviours in normal mice (Bruce-Keller et al., 2018; Foster et al., 2017; Kennedy et al., 2016; Mason, 2017; Sandhu et al., 2016; Sarkar et al., 2016). Animal research has also helped reveal the biological pathways through which the microbiome interacts with host physiology, uncovering the critical role of the vagus nerve in gut-brain communication. The bacterial strains Bifidobacterium longum and Lactobacillus rhamonosus have been effective in treating anxiety and depression-related behaviours in animal studies, but show no effect on behaviour when administered to vagotomized mice. Other research has shown that some bacterial strains do still have an effect on the physiology of vagotomized mice. The vagus nerve, although essential, is just one of many pathways for microbiome-gut-brain communication (Bruce-Keller et al., 2018; Foster et al., 2017; Kennedy et al., 2016; Mason, 2017; Oriach et al., 2015; Sandhu et al., 2016).

In addition to neural pathways, the microbiome interacts with host physiology via endocrine and humoral routes. The gut microbiota produce byproducts used by the body in metabolic processes impacting mood, cognition, pain perception, and gut motility and secretion (Lin & Li 2017; Mason, 2017; Oriach et al., 2015; Sandhu et al., 2016). Enteroendocrine cells (EEC) line the intestinal walls and are in direct contact with the intestinal flora that release metabolites that regulate EEC secretion. The EECs act as sensory cells in the GI tract, releasing peptide-hormones that send information about nutritional content and satiety to the CNS, impacting feeding behaviour as well as modulating digestive motility and secretion (Bruce-Keller et al., 2018; Jacka, 2017; Foster et al., 2017; Kennedy et al., 2016; Oriach et al., 2015; Sandhu et al., 2016; Sarkar et al., 2016). Another crucial function of the microbiota is to regulate serotonin synthesis, a neurotransmitter involved in psychiatric conditions, and digestive disorders such as IBS. Beyond serotonin, the gut flora contributes to the synthesis of neurotransmitters such as melatonin, GABA, epinephrine, dopamine, acetylcholine, and histamine (Bruce-Keller, 2017; Foster et al., 2018; Kennedy et al., 2016; Oriach et al., 2015; Sandhu et al., 2016; Sarkar et al., 2016).

Intestinal bacterial populations also play a role in vitamin synthesis, producing B-vitamins, vitamin-D, vitamin-K, biotin, and folate. These bacterial metabolites are absorbed into the bloodstream via the transport channels in the epithelium of the intestinal wall; however, dysbiosis can cause a weakening of the epithelial barrier, allowing bacteria and other compounds to pass between the cells of the intestinal wall (Foster et al., 2017; Oriach et al., 2015; Sandhu et al., 2016; Sarkar et al., 2015). Increased intestinal permeability and bacterial translocation cause a release of inflammatory cytokines, signalling cells that play an important role in the immune response. High levels of inflammatory cytokines are associated with anxiety and depression, and damage to both the gut lining and the blood-brain barrier, increasing the risk of inflammation and infection (Foster et al., 2017; Kennedy et al., 2016; Lin & Li, 2017; Sarkar et al., 2015). Consumption of commensal bacterial increases levels of anti-inflammatory cytokines, which assist in repairing the damage done by their pro-inflammatory counterparts (Foster et al., 2017; Sarkar et al., 2015). The microbiome has a strong relationship to the immune system, and research should focus on understanding the specific biological interactions of these communication pathways, and how to effect them using microbiome focused interventions.

Medical interventions focused on the condition of microbiome have shown promise for the treatment of many conditions, including autism spectrum disorder, attention deficit hyperactivity disorder, depression, IBS, cardiovascular issues, and many more acute and chronic conditions (Jacka, 2017; Kennedy et al., 2015; Oriach et al., 2015; Sandhu et al., 2016). Psychobiotics are a proposed class of psychotropic medications, pre- and probiotics designed to promote beneficial bacterial populations, targeted towards specific strains that show therapeutic value. Experimental animal research and small human trials have shown evidence for the efficacy of psychobiotics in treating stress, anxiety, and depression. Psychobiotics show potential for the treatment of other psychiatric conditions, and studies on microbiome focused treatments for psychosis and schizophrenia are underway (Bruce-Keller et al., 2018; Kennedy et al., 2015; Oriach et al., 2015; Sarkar et al., 2015; Jacka, 2017).

In the last half century the global dietary landscape has shifted away from traditional, whole food diets towards highly processed, high fat, high sugar, low fibre foods. This shift is correlated with an increase in many chronic conditions such as depression, anxiety, obesity, and gastrointestinal disorders such as irritable bowel syndrome (IBS) (Bruce-Keller et al., 2018; Foster et al., 2017; Jacka, 2017; Sandhu et al., 2016; Sarkar et al., 2015). Diet directly influences the composition of the microbiome and is responsible for approximately half of the variance in individual microbial composition (Jacka, 2017). Although the inability to double-blind research, and data being confounded with other lifestyle factors limits nutritional research in some ways, the consensus is clear that a well balanced diet rich in whole foods positively influences health.

Nutritional research often focuses on two main dietary compositions: the western diet and the Mediterranean diet. The western diet consists of high levels of fat, sugar, protein, carbohydrates, and low levels of fibre, with increased intake of processed foods, and is implicated gut dysbiosis, and the many conditions associated with microbial imbalance (Bruce-Keller et al., 2018; Jacka, 2017; Oriach et al., 2015; Sandhu et al., 2016). Whole vegetables and grains, healthy fats from oily fish and extra virgin olive oil, legumes, nuts, and moderate amounts of protein make up the Mediterranean diet, which has anti-inflammatory properties and improves gastrointestinal conditions, cardiovascular illness, anxiety, and depression. The high quality fat content combined with large quantities of prebiotic fibre from whole grains and vegetables feeds Bifidobacteria and other beneficial bacterial strains (Jacka, 2017; Oriach et al., 2015; Sandhu et al., 2016).

The most immediate way for an individual to influence the composition of their microbiome is through the foods they choose to consume. This is a complex process, as many individuals who suffer from digestive and mood disorders have a range of food sensitivities to consider when uncovering the optimal diet for their health. Some foods that are great sources of prebiotics can feed both the symbiont and pathobiont populations in the gut, so when treating dysbiosis it may be necessary to restrict consumption of certain fermentable carbohydrates until the epithelium can heal, while a balanced microbiome is reestablished. The low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet has shown promise in treating functional GI disorders (Staudacher & Whelan, 2017). Considering the high rates of comorbidity between IBS and mental health conditions, researchers should consider the possibility of using specialized diets to manipulate the composition of the microbiome as part of a treatment strategy to reestablish healthy microbial profiles in patients with comorbid mood and digestive conditions.

It is best to consult with a health practitioner or nutritionist to understand individual symptoms and sensitivities, but there are some general dietary strategies that contribute to the health of the microbiome. Fermented foods such as kefir, kimchi, miso, and sauerkraut are high in Lactobacillus, and high fibre vegetables such as asparagus, artichoke, banana, garlic and onion, as well as whole grains are good sources of prebiotics, feeding Bifidobacteria (Bruce-Keller et al., 2018; Foster et al., 2017; Jacka, 2017; Kennedy et al., 2015; Oriach et al., 2015; Sandhu et al., 2016; Sarkar et al., 2015). The microbiome ferments polyphenols, which are involved in processes such as immune modulation and regulation of neurotransmitters. Certain polyphenols, such as those found in green tea, enhance beneficial microbial populations, while suppressing pathogenic strains (Kennedy et al., 2015; Oriach et al., 2015; Sandhu et al., 2016).

The human organism consists of complex and interconnected systems, dependant upon the trillions of microorganisms residing within. If an imbalance in the microbiome occurs, the consequences are complex and far reaching, impacting both physical and mental wellbeing. Gut dysbiosis interrupts digestive functioning, resulting in malabsorption of nutrients, disrupted vitamin synthesis, dysfunctional neurotransmitter and hormone production, increased intestinal permeability, and both local and systemic inflammation. Due to the foundational role of the microbiome in health and wellness, physicians and mental health practitioners should consider the microbial condition of their patients while assessing the underlying causes of illness. Nutritional and psychobiotic interventions should be combined with evidence-based treatments such as exercise, lifestyle changes, psychotherapy, and medication if required. Moving forward, researchers should conduct clinical studies into the use of psychobiotics, using large sample sizes and double-blind conditions, to understand their potential use as psychotropic medications. Considering the strong relationship between diet, disease, and the health of the microbiome, public health strategies should include evidence-based nutritional education and improved access to affordable, high quality foods to reduce the individual and social consequences of chronic health disorders in the population.

References

Bruce-Keller, A. J., Salbaum, J. M., & Berthoud, H.R. (2018). Harnessing gut microbes for mental health: Getting from here to there. Biological Psychiatry, 83(3), 214-223. doi: 10.1016/j.biopsych.2017.08.014

Chrousos, G. (2009). Stress and disorders of the stress system. Nature Reviews Endocrinology, 5 (7), 374-381 DOI: 10.1038/nrendo.2009.106

Foster, J. A., Rinaman, L. & Cryan, J. F. (2017). Stress & the gut-brain axis: Regulation by the microbiome. Neurobiology of Stress, 7, 124-136. doi: 10.1016/j.ynstr.2017.03.001

Jacka, F. N. (2017). Nutritional psychiatry: Where to next? EBioMedicine, 17, 24-29. doi: 10.1016/j.ebiom.2017.02.020

Kennedy, P. J., Murphy, A. B., Cryan, J. F., Ross, P. R., Dinan, T. G. & Stanton, C. (2015) Microbiome in brain function and mental health. Trends in Food Science & Technology, 57, 289-301. doi:10.1016/j.tifs.2016.05.001

Lin, P. & Li Q. (2017). Can gut flora changes be new biomarkers for depression? Frontiers in Laboratory Medicine, 1(3), 129-134. doi:10.1016/j.flm.2017.08.002

Mason, B. L. (2017). Feeding systems and the gut microbiome: Gut-brain interactions with relevance to psychiatric conditions. Psychosomatics. 58(6), 574-580 doi:10.1016/j.psym. 2017.06.002

Oriach, C.S., Robertson, R. C., Stanton, C, Cryan, J. F., & Dinan, T. G. (2015) Food for thought: The role of nutrition in the microbiota-gut-brain axis. Clinical Nutrition Experimental, 6, 25-38. doi:10.1016/j.yclnex.2016.01.003

Sandhu, K. V., Sherwin, E., Schellekens, H., Stanton, C., Dinan, T. G., & Cryan, J. F. (2016) Feeding the microbiota-gut-brain axis: Diet microbiome and neuropsychiatry. Translational Research, 179, 223-244. doi:10.1016/j.trsl.2016.10.002

Sarkar, A., Lehto, S. M., Harty, S., Cryan, J. F.,  Dinan, T. G., & Burnet, P. W. J. (2015). Psychobiotics and the manipulation of gut-bacteria-brain signals. Trends in Neurosciences, 39(11), 763-781. doi: 10.1016/j.tins.2016.09.002

Staudacher, H., & Whelan, K. (2017). The low FODMAP diet: Recent advances in understanding its mechanisms and efficacy in IBS. Gut, 66(8), 1517-1527. doi: 10.1136/gutjnl- 2017-313750

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