The Gut-Brain Connection: Exploring the Microbiome-Gut-Brain Axis

The microbiome has emerged at the forefront of research in the gut-brain connection, with an increased understanding on how the enteric nervous system (ENS) function is related to the gut microbiota and the gut-brain axis. Evidence shows that gut microbiota are capable of producing neurotransmitters, influencing biochemistry, and impacting mood, behavior, anxiety, and stress responses. With the ability of the gut microbiota to communicate with the brain and regulate normal function through the microbiome-gut-brain axis, their synergistic role has the ability to significantly impact human health and overall well-being.

What is the gut-brain axis?

The gut-brain axis is a two-directional communication network that links the brain and the gut through extensive interconnected pathways. (28)

Gut-brain axis pathways include:

• Central nervous system (CNS)
• Enteric nervous system (ENS)
• Gut-associated lymphoid tissue (GALT)
• Hypothalamic-pituitary-adrenal axis (HPA axis)
• Neuroendocrine gut hormone signalling system
• Sympathetic and parasympathetic branches of the autonomic nervous system (ANS)
• Vagus nerve as a main nerve fiber connecting the gut and brain (5)(6)(24)

Communication within the gut-brain axis network occurs through chemical messengers in the form of neurotransmitters (e.g., dopamine, serotonin, GABA, acetylcholine), as well as neurotransmitter metabolites and precursors (e.g., tryptophan, choline, acetyl-CoA).

Gut-brain interactions have been studied for decades, and the negative health effects of stress on the brain and digestive system have been understood for centuries. (24) It was once thought that the gut-brain axis only interacted within specific networks. Significant advances in research now allow us to understand the vital role that the gut microbiota play in influencing the gut-brain axis interactions. (6)

The emergence of the microbiome-gut-brain axis

The gut microbiota is a population of microorganisms found within the gastrointestinal tract. In contrast, the human microbiome (or megagenome) encompasses all the microorganisms and their genetic material found on and within a human host. (42)

Termed the super-organism, a human gut hosts between ten and 100 trillion microorganisms with 150 times as many genes as our genome and ten times more bacterial cells than cells within the human body. (13)(42) With current research showing a 281% increase of evolutionary diversity of the genetic material of gut microorganisms in the collective human gut microbiota, (2) there is still more to learn about the diverse implications of the microbiome-gut-brain axis in health and disease.

Until very recently, microorganisms of the human microbiome were not considered significant in the development and function of the CNS or in the pathophysiology of chronic brain diseases and mood disorders. (5)(25)(28)

However, in 2012, the Human Microbiome Project Consortium was published on the structure, function, and diversity of the healthy human microbiome. (18) This discovery of the gut microbiome provided a missing link between the complex signaling between the microbiome-gut-brain axis. (31) A significant paradigm shift occurred with a new understanding of many psychiatric and neurological diseases, including gut microbiota factors influencing mood and stress-related behaviors as well as the expression of anxiety and depression. (5)(9)(14)(25)

The gut microbiota influence on the gut-brain axis

During the birthing process, a newborn will become inoculated with the mother’s microbiota. This is essential for the development and maturation of the CNS, ENS, and HPA axis early in life, as well as creating responsive stress reactivity and resilience. (13)(14)(27) Setting the stage for lifelong health includes a healthy and balanced gut microbiota, which is crucial for normal function of the gut-brain axis and regulating essential immune, endocrine, and metabolic functions. (13)(27)..

Newborns adopt their mother’s healthy microbiota.

It is important to understand that the microbiome is a dynamic entity that can be negatively altered by several factors, including genetics, diet, gut permeability, the mucosal immune response, metabolism, age, geography, antibiotic treatment, and stress. (3)(13) Specifically, increased exposure to stressors has been linked to increased intestinal permeability (leaky gut) and altered gut microbiota. (3)(16)(36)

In addition, the composition of the gut microbiota can influence disease expression, as seen in decreased mucosal immunity resulting in chronic inflammatory diseases. (17)(20)(22)(34)(37)(38)

A significant body of scientific evidence supports the vital role the gut microbiota plays in multiple neuro-chemical communication pathways to the brain through the microbiome-gut-brain axis. Researchers have gone so far as to coin the term psychobiotics to describe microbiota that influences the bacteria-brain relationship, as seen due to the influence of probiotics on psychiatric, mental, and brain health. (9)(33)

How to nurture your microbiome

A targeted approach using food elimination, immune support, specific high-quality prebiotics and probiotics, including fermented foods (9), and targeted supplementation effectively supports intestinal health and a healthy gut microbiome.

Eliminate major inflammatory food groups

Eliminate foods including gluten-containing grains (e.g., wheat), cow’s dairy, and refined sugars that may stress the HPA axis and contribute to increased gut permeability and chronic inflammation. (7)(11)(29)

Take high-quality probiotics

Taking high-quality probiotics is essential, as research suggests that specific probiotic species can be beneficial for rebuilding a healthy microbiome-gut-brain axis, including normalizing anxiety-like behaviors in the brain, after exposure to stressors. (4)

Examples of high-quality probiotics include:

• Lactobacillus rhamnosus R0011 (15)
• Lactobacillus helveticus R0052 (1)(15)
• Bifidobacterium longum NCC3001/R0175 (1)(4)

Incorporate naturally occurring probiotics from fermented foods

Several fermented foods and beverages contain naturally occurring probiotics, including: (9)(32)

• Fermented vegetables (e.g., sauerkraut, kimchi) (12)(26)
• Fermented dairy products (e.g., kefir and yogurt from goat or sheep dairy) (12)(26)
• Fermented tea (e.g., kombucha) (12)

Consuming natural dietary sources of probiotics, such as yogurt, can help support a healthy gut microbiome.

Incorporate naturally occurring prebiotics into your diet

Include prebiotic foods in your diet as they act as “food” for the probiotics. Additionally, some intestinal bacteria can turn resistant starches into short-chain fatty acids (SCFAs) that act like fiber to feed healthy bacteria. Examples of naturally occurring probiotics and their sources include:

• Prebiotic inulin: asparagus, garlic, Jerusalem artichoke, jicama, onions (39)
• Prebiotic arabinogalactans: carrots, leeks, radishes, tomatoes, turmeric (35)
• Resistant starches: cooked beans/legumes, sweet potato, yam, pumpkin, potato, cooked rice (10)

Consume healthy fats

Research suggests that consuming healthy fats, including omega-3 fatty acids, can support the intestinal tract and gut microbiota, which can have a positive influence on the gut-brain axis. (8) Sources of healthy fats include avocados, nuts, seeds, flaxseed oil, hemp oil, coconut oil, and extra-virgin olive oil. (8)

Consider targeted supplementation

In addition to consuming a healthy diet, targeted supplementation may help improve gut health. Dietary supplements to consider may include:

• Beta-glucans to help decrease permeability of the intestinal mucosa (23)
• L-glutamine to help improve intestinal permeability and intestinal barrier function (40)
• N-acetyl glucosamine (NAG) to heal the gut mucosal lining (41)

Support the immune system in the gut

Immune complexes known as the gut-associated lymphoid tissue (GALT) are located in the gut. This includes the Peyer’s patches, which are dedicated to providing immune defense against continual exposure to pathogens, food-derived antigens, and non-harmful microorganisms. (19)(21)(30) Peyer’s patches organotherapy can be used to re-educate and strengthen the gut-associated lymphoid tissue (GALT) (19)(21)(30)

The bottom line

Research continues to increase our collective understanding of the gut-brain connection and how ENS function is related to the gut microbiota within the microbiome-gut-brain axis. This understanding has represented a major paradigm shift in many branches of science. Opportunities continue to emerge to successfully address stress and mental health in relation to gut health and to rebalance the gut microbiota for better overall health and well-being.

REFERENCES

1. Ait-Belgnaoui, A., Payard, I., Rolland, C., Harkat, C., Braniste, V., Théodorou, V., & Tompkins, T. A. (2018). Bifidobacterium longum and Lactobacillus helveticus Synergistically Suppress Stress-related Visceral Hypersensitivity Through Hypothalamic-Pituitary-Adrenal Axis Modulation. Journal of neurogastroenterology and motility, 24(1), 138–146.
2. Almeida, A., Mitchell, A. L., Boland, M., Forster, S. C., Gloor, G. B., Tarkowska, A., Lawley, T. D., & Finn, R. D. (2019). A new genomic blueprint of the human gut microbiota. Nature, 568(7753), 499–504.
3. Bailey, M. T., Dowd, S. E., Galley, J. D., Hufnagle, A. R., Allen, R. G., & Lyte, M. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain, behavior, and immunity, 25(3), 397–407.
4. Bercik, P., Park, A. J., Sinclair, D., Khoshdel, A., Lu, J., Huang, X., Deng, Y., Blennerhassett, P. A., Fahnestock, M., Moine, D., Berger, B., Huizinga, J. D., Kunze, W., McLean, P. G., Bergonzelli, G. E., Collins, S. M., & Verdu, E. F. (2011). The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 23(12), 1132–1139.
5. Breit, S., Kupferberg, A., Rogler, G., & Hasler, G. (2018). Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. Frontiers in psychiatry, 9, 44.
6. Carabotti, M., Scirocco, A., Maselli, M. A., & Severi, C. (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of gastroenterology, 28(2), 203–209.
7. Clemente, M. G., De Virgiliis, S., Kang, J. S., Macatagney, R., Musu, M. P., Di Pierro, M. R., Drago, S., Congia, M., & Fasano, A. (2003). Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut, 52(2), 218–223.
8. Costantini, L., Molinari, R., Farinon, B., & Merendino, N. (2017). Impact of Omega-3 Fatty Acids on the Gut Microbiota. International journal of molecular sciences, 18(12), 2645.
9. Dash, S., Clarke, G., Berk, M., & Jacka, F. N. (2015). The gut microbiome and diet in psychiatry: focus on depression. Current opinion in psychiatry, 28(1), 1–6.
10. DeMartino, P., & Cockburn, D. W. (2020). Resistant starch: impact on the gut microbiome and health. Current opinion in biotechnology, 61, 66–71.
11. de Punder, K., & Pruimboom, L. (2013). The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients, 5(3), 771–787.
12. Dimidi, E., Cox, S. R., Rossi, M., & Whelan, K. (2019). Fermented Foods: Definitions and Characteristics, Impact on the Gut Microbiota and Effects on Gastrointestinal Health and Disease. Nutrients, 11(8), 1806.
13. Dinan, T. G., & Cryan, J. F. (2012). Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology, 37(9), 1369–1378.
14. Foster, J. A., & McVey Neufeld, K. A. (2013). Gut-brain axis: how the microbiome influences anxiety and depression. Trends in neurosciences, 36(5), 305–312.
15. Foster, L. M., Tompkins, T. A., & Dahl, W. J. (2011). A comprehensive post-market review of studies on a probiotic product containing Lactobacillus helveticus R0052 and Lactobacillus rhamnosus R0011. Beneficial microbes, 2(4), 319–334.
16. Gareau, M. G., Silva, M. A., & Perdue, M. H. (2008). Pathophysiological mechanisms of stress-induced intestinal damage. Current molecular medicine, 8(4), 274–281.
17. Hufeldt, M. R., Nielsen, D. S., Vogensen, F. K., Midtvedt, T., & Hansen, A. K. (2010). Family relationship of female breeders reduce the systematic inter-individual variation in the gut microbiota of inbred laboratory mice. Laboratory animals, 44(4), 283–289.
18. Human Microbiome Project Consortium (2012). Structure, function and diversity of the healthy human microbiome. Nature, 486(7402), 207–214.
19. Jung, C., Hugot, J. P., & Barreau, F. (2010). Peyer’s Patches: The Immune Sensors of the Intestine. International journal of inflammation, 2010, 823710.
20. Kelly, D., King, T., & Aminov, R. (2007). Importance of microbial colonization of the gut in early life to the development of immunity. Mutation research, 622(1-2), 58–69.
21. Kobayashi, N., Takahashi, D., Takano, S., Kimura, S., & Hase, K. (2019). The Roles of Peyer’s Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases. Frontiers in immunology, 10, 2345.
22. Lauritsen, L., Hufeldt, M. R., Aasted, B., Hansen, C. H. F., Midtvedt, T., Buschard, K., & Hansen, A. K. (2010). The Impact of a Germ Free Perinatal Period on the Variation in Animal Models of Human Inflammatory Diseases – A Review. Scandinavian Journal of Laboratory Animal Science, 37(1).
23. Mackie, A., Rigby, N., Harvey, P., & Bajka, B. (2016). Increasing dietary oat fibre decreases the permeability of intestinal mucus. Journal of functional foods, 26, 418–427.
24. Mayer E. A. (2011). Gut feelings: the emerging biology of gut-brain communication. Nature reviews. Neuroscience, 12(8), 453–466.
25. Mayer, E. A., Knight, R., Mazmanian, S. K., Cryan, J. F., & Tillisch, K. (2014). Gut microbes and the brain: paradigm shift in neuroscience. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(46), 15490–15496.
26. Melini, F., Melini, V., Luziatelli, F., Ficca, A. G., & Ruzzi, M. (2019). Health-Promoting Components in Fermented Foods: An Up-to-Date Systematic Review. Nutrients, 11(5), 1189.
27. Mueller, N. T., Bakacs, E., Combellick, J., Grigoryan, Z., & Dominguez-Bello, M. G. (2015). The infant microbiome development: mom matters. Trends in molecular medicine, 21(2), 109–117.
28. O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural brain research, 277, 32–48.
29. Pereira, M. T., Malik, M., Nostro, J. A., Mahler, G. J., & Musselman, L. P. (2018). Effect of dietary additives on intestinal permeability in both Drosophila and a human cell co-culture. Disease models & mechanisms, 11(12), dmm034520.
30. Reboldi, A., & Cyster, J. G. (2016). Peyer’s patches: organizing B-cell responses at the intestinal frontier. Immunological reviews, 271(1), 230–245.
31. Rhee, S. H., Pothoulakis, C., & Mayer, E. A. (2009). Principles and clinical implications of the brain-gut-enteric microbiota axis. Nature reviews. Gastroenterology & hepatology, 6(5), 306–314.
32. Şanlier, N., Gökcen, B. B., & Sezgin, A. C. (2019). Health benefits of fermented foods. Critical reviews in food science and nutrition, 59(3), 506–527.
33. Sarkar, A., Lehto, S. M., Harty, S., Dinan, T. G., Cryan, J. F., & Burnet, P. (2016). Psychobiotics and the Manipulation of Bacteria-Gut-Brain Signals. Trends in neurosciences, 39(11), 763–781.
34. Sartor RB. Role of commensal enteric bacteria in the pathogenesis of immune-mediated intestinal inflammation: lessons from animal models and implications for translational research. J Pediatr Gastroenterol Nutr. 2005 Apr;40 Suppl 1:S30-1.
35. Śliżewska, K., & Chlebicz-Wójcik, A. (2020). The In Vitro Analysis of Prebiotics to Be Used as a Component of a Synbiotic Preparation. Nutrients, 12(5), 1272.
36. Teitelbaum AA, Gareau MG, Jury J, Yang PC, Perdue MH. Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress. Am J Physiol Gastrointest Liver Physiol. 2008 Sep;295(3):G452-9.
37. Tlaskalová-Hogenová, H., Stepánková, R., Hudcovic, T., Tucková, L., Cukrowska, B., Lodinová-Zádníková, R., Kozáková, H., Rossmann, P., Bártová, J., Sokol, D., Funda, D. P., Borovská, D., Reháková, Z., Sinkora, J., Hofman, J., Drastich, P., & Kokesová, A. (2004). Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunology letters, 93(2-3), 97–108.
38. Vaarala, O., Atkinson, M. A., & Neu, J. (2008). The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes, 57(10), 2555–2562.
39. Vandeputte, D., Falony, G., Vieira-Silva, S., Wang, J., Sailer, M., Theis, S., Verbeke, K., & Raes, J. (2017). Prebiotic inulin-type fructans induce specific changes in the human gut microbiota. Gut, 66(11), 1968–1974.
40. Wang, B., Wu, G., Zhou, Z., Dai, Z., Sun, Y., Ji, Y., Li, W., Wang, W., Liu, C., Han, F., & Wu, Z. (2015). Glutamine and intestinal barrier function. Amino acids, 47(10), 2143–2154.
41. Zhu, A., Patel, I., Hidalgo, M. P., & Gandhi, V. (2015). N-Acetylglucosamine for Treatment of Inflammatory Bowel Disease. Natural Medicine Journal, 7(4).
42. Zhu, B., Wang, X., & Li, L. (2010). Human gut microbiome: the second genome of human body. Protein & cell, 1(8), 718–725.