The Mechanisms of Optimal Brain Health

Volume 1, Part 1

Introduction

Breakthroughs in brain research have skyrocketed during the past several decades. A new perception of the brain has emerged, which accounts for the interaction between the cranial brain and a «second brain», which resides within the gut. Scientists now explain the brain in terms of the microbiome-Gut Brain Axis (GBA), a bidirectional communication system between the microbiome, the central nervous system (CNS), the autonomic nervous system (ANS), the enteric nervous system (ENS), and the hypothalamus pituitary adrenal (HPA) axis.1

The HPA axis coordinates adaptive responses to all stressors (stress-inducing agents), including those that are physical, mental, and emotional.2 In fact, the HPA axis is part of the limbic system, which is the region of the brain that governs emotion, behavior, motivation, long-term memory, and olfaction.3 When we encounter stress, the hypothalamus secrets corticotropin-releasing factor (CRF), which stimulates adrenocorticotropic hormone (ACTH) secretion from the pituitary gland, which then causes the adrenal glands to produce and release cortisol. Stress hormones like cortisol are one of the primary mechanisms by which the brain and gut communicate with each other.

Neurotransmitters are another major mechanism by which the brain and gut communicate. In fact, the ENS includes between 200 and 600 million neurons, which are embedded in the walls of the alimentary canal from the esophagus to the anus.4 This is more neurons than are contained by either the spinal cord or the peripheral nervous system. The ENS produces over 30 different neurotransmitters, including GABA, serotonin, melatonin, histamine, and acetylcholine. Around 95% of the body’s serotonin is located within the gut.5 Most of these neurotransmitters are produced by or regulated by the gut microbiome, thus demonstrating its profound importance and influence.6

The Gut Microbiome and the Brain

Besides playing a direct and substantial role in digestion, the microbiome also affects the CNS via neural, neuroendocrine, neuroimmune, and humoral links.7 Significantly, our mood and emotions can be regulated, or at least influenced by the microbiome. In 2013, Dr. Ted Dinan and his colleagues at University College Cork coined the term «psychobiotics» to describe an emerging class of probiotics that are capable of altering mood. «Such “mind-altering” probiotics», they explained, «may act via their ability to produce various biologically active compounds, such as peptides and mediators normally associated with mammalian neurotransmission».8

In terms of behavior, the microbiome is also believed to play a critical role in anxiety, motivation, and even socialization. In one study, scientists administered Lactobacillus probiotics to mice, which resulted in the mice behaving less anxiously and being more willing to explore open, exposed areas of their environments. Moreover, the mice exhibited increased levels of GABA, which is associated with decreased anxiety and depression.9 For another study, when scientists transported microbes from the guts of one strain of mice to another, the receiving group began exhibiting behavioral traits of the donating group. For example, the receiving group, which had previously been hesitant to explore unchartered areas, became far less inhibited.10 Regarding socialization, germ-free mice that are raised in sterile environments, thereby preventing the proper development of the microbiome, demonstrate abnormal social behavior and clear autistic-like traits.11

Glutathione and Brain Health

Glutathione, also known as «the master antioxidant», is one of the body’s most important detoxification molecules. Antioxidants are the body’s defense against free radicals (dangerous molecules that cause inflammation and other damage, including accelerated ageing, DNA strand denaturing, and mitochondrial damage).12 Free radicals arise from many external influences, including environmental pollution, emotional stress, physical stress, pharmaceutical drugs, cigarette smoke, electromagnetic pollution, denatured foods, artificial preservatives, herbicides, pesticides, and common household chemicals. On the other hand, free radicals also arise from normal biological processes, particularly the metabolizing of oxygen. Despite only constituting about 2% of body weight, the brain consumes about 20% of the body’s oxygen, which means it generates a considerable amount of reactive oxygen species (free radicals formed the oxygen metabolism).13 The brain’s glutathione needs, therefore are high. Insufficient brain glutathione uptake, over time, can contribute to cognitive decline. For a breakthrough study in 2015, scientists made the novel discovery that glutathione levels constitute a clinically relevant biomarker for both mild cognitive impairment and for Alzheimer’s disease.14

Omega-3 and Brain Health

Omega-3 fatty acids are one of the most widely studied molecules with respect to brain health and are unambiguously one of the most beneficial molecules for preventing inflammation and cognitive decline, while mitigating the consequences of brain ageing.15, 16 As we grow older, the brain becomes increasingly susceptible to inflammation, which underlies declined learning and memory function. One way scientists quantify these declines is by measuring long-term potentiation (LTP) — an electrophysiological property of certain neuronal circuits, which is used as a model to investigate the pathways involving synaptic plasticity, learning, and memory.17 Dietary supplementation of long-chain omega-3 (EPA and DHA) has been shown to reverse age-related impairments in LTP.18

It’s important to clarify that omega-3 fatty acids appear in short-chain, as well as long-chain versions. The short-chain version is alpha-linolenic acid (ALA), whereas the long-chain versions are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA is found in various nuts and seeds, particularly flax seeds and chia seeds. DHA and EPA, on the other hand, can only be obtained from animal-food sources, most notably oily fish. Broadly speaking, the health benefits of omega-3 come from the long-chain molecules, DHA and EPA.19 The body can convert ALA into the beneficial DHA and EPA forms, but this conversion is inefficient.20 Therefore, it’s always preferable to consume omega-3 in its DHA and EPA forms, whether from supplements or food sources. Besides the aforementioned benefits, other brain-related benefits of long-chain omega-3 include:

  • EPA has been shown to be as effective as Prozac in treating depression.21
  • For infants and young children, DHA supplementation is associated with increased IQ, improved communication and social skills, less behavioral problems, decreased risk of developmental delay, and decreased risk of ADHD and autism.22, 23, 24
  • Fish consumption and omega-3 supplementation are linked to decreased age-related mental decline and a reduced risk of Alzheimer’s disease.25, 26
  • DHA supplementation is linked to improved quality of sleep.27, 28

Leaky Brain Syndrome and its Prevention

The blood brain barrier (BBB) is a highly selective, semipermeable membrane barrier that keeps circulating blood from the brain separate from extracellular fluid in the central nervous system (CNS), thereby protecting the brain by denying access to any potentially harmful molecules. «Leaky brain» is a colloquial term for BBB hyper-permeability, a condition whereby the BBB becomes increasingly permeable, thereby setting the stage for various degenerative brain conditions.

A multitude of factors contribute to leaky brain, including inflammation, excessive stress (resulting in an overactive HPA axis), leaky gut, elevated homocystein, and many other factors.29, 30, 31, 32 There are many tests that practitioners utilize to help determine whether or not a patient has or is prone to leaky brain. These tests include the GABA-EEG test, the Evans Blue-dyed albumin test, and the elevated MMP9 test. If allowed to progress, leaky brain can contribute to many serious conditions, including:

  • Brain fog.33
  • Alzheimer’s disease.34
  • Depression.35
  • Cognitive decline.36

Neurogenesis and Brain Plasticity

With age, the brains of most people decline, but this need not be the case. Exciting new research demonstrates that adult brains are capable of neurogenesis (the birth of new neurons) and neuroplasticity (the malleability of neural circuits).37 In early 2017, scientists at the University of Alabama at Birmingham, found that newly born granule cell neurons in the dentate gyrus wire themselves into neural networks by forming synapses via neuroplasticity. The dentate gyrus is the region of the hippocampus that deals with new episodic memories, the spontaneous exploration of novel environments, and various other functions.38 One of the best ways to stimulate neurogenesis is through regular exercise. Exercise directly increases synaptic plasticity by affecting synaptic structure and strength, while simultaneously strengthening the systems that underlie plasticity including neurogenesis, metabolism and vascular function.39

  1. Rhee SH, et al. (2009). Principles and clinical implications of the brain-gut-enteric microbiota axis. Nature Reviews. Gastroenterology & Hepatology, 6(5).
  2. Tsigos C, et al. (Oct 2002). Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res., 53(4).
  3. Kadohisa, M. (2013). Effects of odor on emotion, with implications. Frontiers in Systems Neuroscience, 7, 66.
  4. Furness JB, et al. (2014). The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv Exp Med Biol., 817.
  5. Camilleri, M. (2009). Serotonin in the Gastrointestinal Tract. Current Opinion in Endocrinology, Diabetes, and Obesity, 16(1).
  6. Dinan TG, et al. (Apr 2015). Collective unconscious: How gut microbes shape human behavior. Journal of Psychiatric Research, 63.
  7. Saulnier DM, et al. (2013). The intestinal microbiome, probiotics and prebiotics in neurogastroenterology. Gut Microbes, 4(1).
  8. Wall R, et al. (2014). Bacterial neuroactive compounds produced by psychobiotics. Adv Exp Med Biol., 817.
  9. Bravo JA, et al. (Sep 2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAS, 108(38).
  10. Bercik P, et al. (Aug 2011). The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice. Gastroenterology, 141(2).
  11. Desbonnet L, et al. (2014). Microbiota is essential for social development in the mouse. Molecular Psychiatry, 19.
  12. Floyd RA, et al. (1992). Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann Neurol., 32 (Suppl: S).
  13. Dringen R. (Dec 2000). Metabolism and functions of glutathione in brain. Prog Neurobiol., 62(6).
  14. Mandal PK, et al. (Nov 2015). Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol Psychiatry., 78(10).
  15. Denis I, et al. (Mar 2015). Omega-3 polyunsaturated fatty acids and brain aging. Curr Opin Clin Nutr Metab Care., 18(2).
  16. Dyall SC. (2015). Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Frontiers in Aging Neuroscience, 7(52).
  17. Bliss TV, et al. (Jan 1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 361(6407)
  18. McGahon BM, et al. (1999). Age-related changes in synaptic function: analysis of the effect of dietary supplementation with omega-3 fatty acids. Neuroscience, 94(1).
  19. Turchini GM, et al. (2012). Jumping on the omega-3 bandwagon: distinguishing the role of long-chain and short-chain omega-3 fatty acids. Crit Rev Food Sci Nutr., 52(9).
  20. Goyens PLL, et al. (Jul 2006). Conversion of α-linolenic acid in humans is influenced by the absolute amounts of α-linolenic acid and linoleic acid in the diet and not by their ratio. Am J Clin Nutr., 84(1).
  21. Jazayeri S, et al. (Oct 2007). Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Australian and New Zealand Journal of Psychiatry, 42(3).
  22. Helland IB, et al. (Jan 2003). Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Pediatrics, 111(1).
  23. Judge MP, et al. (Jun 2007). Maternal consumption of a docosahexaenoic acid-containing functional food during pregnancy: benefit for infant performance on problem-solving but not on recognition memory tasks at age 9 mo. Am J Clin Nutr., 85(6).
  24. Strickland AD. (May 2014). Prevention of cerebral palsy, autism spectrum disorder, and attention deficit-hyperactivity disorder. Med Hypotheses., 82(5).
  25. Fotuhi M, et al. (Mar 2009). Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Clin Pract Neurol., 5(3).
  26. Mohajeri MH, et al. (Feb 2015). Inadequate supply of vitamins and DHA in the elderly: implications for brain aging and Alzheimer-type dementia. Nutrition, 31(2).
  27. Ladesich JB, et al. (Aug 2011). Membrane level of omega-3 docosahexaenoic acid is associated with severity of obstructive sleep apnea. J Clin Sleep Med., 7(4).
  28. Hansen AL, et al. (May 2014). Fish Consumption, Sleep, Daily Functioning, and Heart Rate Variability. J Clin Sleep Med., 10(5).
  29. Varatharaj A, et al. (Feb 2017). The blood-brain barrier in systemic inflammation. Brain Behav Immun., 60.
  30. Esposito P, et al. (Jan 2001). Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res., 888(1).
  31. Banks, WA. (2008). The Blood-Brain Barrier: Connecting the Gut and the Brain. Regulatory Peptides, 149(1-3).
  32. Beard RS, et al. (Aug 2011). Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions. Blood, 118(7).
  33. Theoharides TC, et al. (2015). Brain «fog», inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci., 9(225).
  34. Sharma HS, et al. (2012). The blood-brain barrier in Alzheimer’s disease: novel therapeutic targets and nanodrug delivery. Int Rev Neurobiol., 102.
  35. Gudmundsson P, et al. (Oct 2007). The relationship between cerebrospinal fluid biomarkers and depression in elderly women. Am J Geriatr Psychiatry., 15(10).
  36. Iadecola C. (Jan 2015). Dangerous Leaks: Blood-Brain Barrier Woes in the Aging Hippocampus. Neuron., 85(2).
  37. Adlaf EW, et al. (Jan 2017). Adult-born neurons modify excitatory synaptic transmission to existing neurons. eLife, 6:e19886.
  38. Saab BJ, et al. (Sep 2009). NCS-1 in the Dentate Gyrus Promotes Exploration, Synaptic Plasticity, and Rapid Acquisition of Spatial Memory. Neuron, 63(5).
  39. Cotman CW, et al. (Sep 2007). Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci., 30(9).