FX Medicine

Home of integrative and complementary medicine

State of mind: how gut health affects the brain

belinda_reynolds's picture

Historically, the standard approach to addressing mental health and cognitive decline has focused directly on brain neurotransmitter production, function and re-uptake. This treatment method has yielded beneficial outcomes in some sufferers, however for many it falls short. One such example are anti-depressants, with studies suggesting that in up to 60% of cases, they are ineffective. This highlights the need to explore options that represent an effective treatment alternative or that may be a safe and effective adjunct.

Some interesting discoveries include the revelation that many mood and neurodegenerative disorders are conditions of inflammation,[1oxidative stress and/or mitochondrial dysfunction.[2] This tells us that these imbalances warrant treatment in many brain/mood disorder patients. 

Secondly, mood disorders such as depression have been associated with reductions in the expression of specific neurotrophic factors (e.g. brain derived neurotrophic factor (BDNF)) in areas of the brain responsible for controlling emotion, learning and memory (e.g. the hippocampus).[3] These neurotrophic factors promote neuronal cell survival, growth of new nerve cells and synaptic plasticity in the brain. Depletions in them thus leads to a local loss of structure and subsequent function.[3] As a result, even if neurotransmitter availability is up-regulated (e.g. by medication), in a BDNF-depleted individual the expected benefits are significantly diminished. However, an interesting finding has been that where antidepressant medications (e.g. selective serotonin re-uptake inhibitors (SSRIs)) have been effective in the long term, it is via their ability to up-regulate BDNF expression.[3,4]

Fortunately, it appears that through promoted expression of factors, such as BDNF, we can protect the brain from stress, begin the process of “neurological healing”, and thus improve mood states associated with low levels. 

Could inflammation exert its effects on depression through reduced brain nerve cell health? Quite possibly. Pro-inflammatory cytokines can interact directly with the brain, altering behaviour and cognition, plus they cause oxidative stress, excitotoxicity, mitochondrial dysfunction and reduced BDNF.[5] Once again, mood therapies that fail to address this aspect of brain illness may be inadequate for achieving the desired outcomes. It is no surprise that studies have identified individuals with elevated inflammatory cytokines to also be at greater risk of not responding to conventional antidepressant medication.[6]

So where do we start?

First of all, we know nutritional sufficiency is essential for neurological and mood health (e.g. B vitamins, amino acids, zinc, magnesium, iron, essential fatty acids etc.). Secondly, one’s body must have the ability to cope with, and recovery from, emotional and physical (e.g. inflammatory, toxic and oxidative) stress. One key factor that plays a fundamental role in achieving these goals is overall gut health (including good microbial diversity and intestinal integrity). This is because local gastrointestinal inflammation will negatively influence nutrient uptake, and will contribute to systemic inflammation. Restoration of the gastrointestinal tract (GIT) and its microflora will thus aid in healing sickness in the “gut brain connection”, improving outcomes in patients seeking mood disorder and cognitive therapy.

One such example are anti-depressants, with studies suggesting that in up to 60% of cases, they are ineffective. This highlights the need to explore options that represent an effective treatment alternative or that may be a safe and effective adjunct.

Features of the gut-brain axis

The gastrointestinal tract and brain have a profound ability to influence each other. This bi-directional interaction occurs via multiple mechanisms including neurotransmission along the vagus nerve, neuroendocrine and immune influences, plus the delivery of signalling molecules in the blood. Addressing any dysregulation in these communications will provide beneficial health outcomes.

When considering the aforementioned role a pro-inflammatory state can play in undermining neurological health, it becomes clear that the intestinal barrier has a significant impact on modulating the wellbeing of the gut-brain axis. This is because a leaky gut leads to systemic and neurological inflammation.

In the presence of intestinal hyperpermeability or “leaky gut”, there is often an increased passage of lipopolysccharides (LPS), toxins and other potentially harmful molecules into the body. These elicit an inflammatory immune response, contributing to oxidative stress and neuroendocrine imbalances. If not rectified, leaky gut results in chronic activation of the inflammatory response. As mentioned earlier, inflammatory cytokines themselves can access the brain and exert multiple negative influences on brain and mood health. 

These levels of inflammation will also contribute to oxidative stress and mitochondrial dysfunction, further exacerbating oxidative stress and reducing energy production and brain cell function. This compromises the expression of nerve growth factors such as BDNF, resulting in accelerated nerve cell death and shrinkage. When these reductions occur in areas of the brain like the hippocampus it can contribute to low mood and compromised cognitive function. Studies support this hypothesis with low levels of BDNF identified in individuals suffering depression.[7]

Leaky gut and inflammation leads to leaky brain

Inflammatory, toxic and oxidative stressors that arise from leaky gut can deteriorate blood brain barrier integrity. This allows the passage of unwanted compounds into the CNS, ultimately setting off a cascade of damaging reactions.

One hypothesis for this link is the increased expression of matrix metalloproteinase-9 (MMP-9) that occurs in certain deficiency and inflammatory states. It is believed excessive MMP-9 is an aetiologic factor in blood brain barrier dysfunction. High levels are identified in patients with schizophrenia,[8] depressive symptoms (increasing with depression severity)[9] and also in the amniotic fluid of mother’s whose children go on to develop autism spectrum disorders.[10] Anti-inflammatory compounds and specific nutrients are able to modulate MMP-9 levels. These include (but are not limited to) quercetin,[11] resveratrol,[12] epigallocatechin-3-0-gallate (EGCG) from green tea[13], curcumin,[14] and vitamin D.[15

Melatonin has also recently demonstrated impressive antioxidant and anti-inflammatory benefits,[16] plus via MMP-9 suppression (and attenuated levels of additional pro-inflammatory cytokines) it is able to protect healthy gut and blood brain barrier function.[16,17] Melatonin is produced from serotonin and this reaction requires S-adenosyl methionine (SAMe), making it a useful supplement in depressive illnesses. Tart or sour cherry is also a natural source of melatonin, plus it provides beneficial anti-inflammatory and antioxidant benefits. Worth noting is that obesity, inflammation and subsequent insulin and leptin resistance can contribute to suppressed melatonin synthesis. Working to achieve a healthy weight should therefore also be high on the agenda.

Furthermore, toxic substances such as mercury, see increased undesirable MMP-9 expression,[18] whilst elevations in blood homocysteine have been shown to promote the expression of a range of inflammatory cytokines and MMP-9, increasing intestinal permeability.[19] This reinforces the widespread importance of detoxification and methylation support nutrients, e.g. folate, vitamin B6, B12, B2, serine and choline.

The microbiome-gut-brain axis

Thanks to an explosion of research on the microbiome we now understand its diverse roles in digestive and immune health. A lesser known function of the microbes in our body, however, is that which they play in maintaining a healthy mood and influencing behaviour. As discussed earlier, gut barrier integrity is important for preventing the central nervous system (CNS) complications of an inflammatory state. It is important to recognise the role the microbiome plays in maintenance of gut barrier integrity. Multiple nutrients are crucial in fuelling the protection and cell renewal processes of the GIT lining (e.g. L-glutamine, quercetin, zinc, essential fatty acids (EFAs), vitamin D3, selenium, vitamin A), however short chain fatty acids (SCFAs) synthesised by friendly microbes are equally essential. These SCFAs are produced during the process where microbes ferment prebiotic fibres meaning both healthy microbial diversity and prebiotic intake are equally important for gut-brain health. 

Moreso, specific bacterial species have the ability to synthesise, or catalyse the synthesis, of a range of neurotransmitters, e.g. Gamma-aminobutyric acid (GABA) and serotonin).[20,21] Research has also shown that specific bacterial species can have short term influences on anxiety behaviour and increase the expression of certain neurotransmitter receptors (e.g. GABA),[20] thus helping to calm the stress response. A healthy balance of microbes in the gut has also been shown to beneficially influence the expression of neurotrophic factors, thus supporting brain health. On the flip side, local infection due to GIT pathogen overgrowth is shown to contribute to anxiety-like and depressive symptoms. Plus, emotional stress can alter microbial colonies, contribute to irritable bowel syndrom (IBS) -type symptoms and result in loss of intestinal integrity, demonstrating that gut-brain influences are a two-way street.[21] Therefore, regardless of which came first, the dysbiosis or the anxiety/depression, re-establishing a healthy microbial may play an integral part in helping the mood long term.

Friendly gut microbes are also shown to support local detoxification processes,[22] preventing the uptake and aiding the excretion of toxins such as heavy metals. Minimising the exposure to toxins helps to protect against the neurological and widespread damage these substances may cause.

On the subject of toxin exposure

Not only do microbial colonies in the gut work to reduce internal toxin exposure, so too do the local cells of GIT wall. These cells carry out detoxification processes and attempt to pump toxins back into the intestinal lumen to prevent their uptake.[23] Understanding this, a leaky barrier (attributed to poor nutrition, dysbiosis, inflammation, high homocysteine) will result in a compounded increase in systemic and subsequent CNS exposure to toxins. Supporting healthy glutathione and glutathione peroxidase synthesis and function (e.g. with selenium, L-glycine, L-glutamine and N-acetyl cysteine, alpha lipoic acid, broccoli sprout extract and milk thistle) will aid in protecting against the damaging effect of toxins. Methylation nutrients, vitamin C and zinc can also support specific liver detoxification pathways and protect against certain heavy metal exposures (e.g. copper) respectively.

Malabsorption issues

In patients presenting with gastrointestinal upset and mood changes, it is worth considering malabsorption issues. It has been identified that those individuals with fructose malabsorption (often associated with IBS-type symptoms), who continue to consume high fructose and sorbitol foods, experience compromised tryptophan uptake. As tryptophan is the precursor to serotonin synthesis, this may result in depressive symptoms. One study found that removing high fructose and sorbitol foods reduced depressive scores in these individuals by an astounding 65.2%.[24]

Treat the Individual

It is important to note also that as we increase our understanding of epigenetics and single nucleotide polymorphisms (SNPs), attention should be paid to recognising the unique genetic features of an individual. Only then can we design a suitable treatment protocol for neurological health. SNPs on genes encoding for enzymes involved in methylation (e.g. 5,10-methylene-tetrahydrofolate reductase (MTHFR)), plus blood levels of homocysteine and histamine, urinary hydroxyhempyrolin (often referred to as pyrroles or the Mauve Factor), and measures that look to identify an individual sensitivity to “sick building syndrome” (mould/biotoxin exposure), are just some of the considerations that can go a long way toward achieving sound mental health, and a new life for your patients.

REFERENCES

  1. Allison DJ, Ditor DS. The common inflammatory etiology of depression and cognitive impairment: a therapeutic target. J Neuroinflammation. 2014;11(1):151. [Full text]

  2. de Sousa RT, Machado-Vieira R, Zarate CA Jr, et al. Targeting mitochondrially mediated plasticity to develop improved therapeutics for bipolar disorder. Expert Opin Ther Targets. 2014;24:1-17. [Abstract]

  3. Castrén E. Neurotrophins and psychiatric disorders. Handb Exp Pharmacol. 2014;220:461-479. [Abstract]

  4. Kim HJ, Kim W, Kong SY. Antidepressants for neuro-regeneration: from depression to Alzheimer's disease. Arch Pharm Res. 2013;36(11):1279-1290. [Abstract]

  5. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-41. [Full text]

  6. Carvalho LA, Torre JP, Papadopoulos AS, et al. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord. 2013;148(1):136-140. [Abstract]

  7. Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223-150. [Abstract]

  8. Yamamori H, Hashimoto R, Ishima T, et al. Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine. Neurosci Lett. 2013;556:37-41. [Full text]

  9. Yoshida T, Ishikawa M, Niitsu T, et al. Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One 2012;7(8):e42676. [Full text]

  10. Abdallah MW, Pearce BD, Larsen N, et al. Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res. 2012;5(6):428-433. [Abstract]

  11. Lee JK, Kwak HJ, Piao MS, et al. Quercetin reduces the elevated matrix metalloproteinases-9 level and improves functional outcome after cerebral focal ischemia in rats. Acta Neurochir (Wien). 2011;153(6):1321-1329. [Abstract]

  12. Gweon EJ, Kim SJ. Resveratrol attenuates matrix metalloproteinase-9 and -2-regulated differentiation of HTB94 chondrosarcoma cells through the p38 kinase and JNK pathways. Oncol Rep. 2014;32(1):71-78. [Abstract]

  13. Khoi PN, Park JS, Kim JH, et al.(-)-Epigallocatechin-3-gallate blocks nicotine-induced matrix metalloproteinase-9 expression and invasiveness via suppression of NF-κB and AP-1 in endothelial cells. Int J Oncol. 2013;43(3):868-876. [Abstract]

  14. Cao J, Han Z, Tian L, et al. Curcumin inhibits EMMPRIN and MMP-9 expression through AMPK-MAPK and PKC signaling in PMA induced macrophages. J Transl Med. 2014;12(1):266. [Full text]

  15. Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002;95(12):787-796. [Full text]

  16. Trivedi PP, Jena GB. Melatonin reduces ulcerative colitis-associated local and systemic damage in mice: investigation on possible mechanisms. Dig Dis Sci. 2013;58(12):3460-3474. [Abstract]

  17. Chen J, Chen G, Li J, et al. Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: a possible role for the regulation of proinflammatory cytokines. J Pineal Res. 2014;57(3):340-347. [Abstract]

  18. Jacob-Ferreira AL, Passos CJ, Jordão AA, et al. Mercury exposure increases circulating net matrix metalloproteinase (MMP)-2 and MMP-9 activities. Basic Clin Pharmacol Toxicol. 2009;105(4):281-288. [Abstract]

  19. Ding H, Mei Q, Gan HZ, et al. Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism. Gastroenterol Rep (Oxf). 2014;2(3):215-220. [Full text]

  20. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA. 2011;108(38):16050-16055. [Full text]

  21. Borre YE, Moloney RD, Clarke G, et al The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. Adv Exp Med Biol. 2014;817:373-403. [Abstract]

  22. Monachese M, Burton JP, Reid G. Bioremediation and tolerance of humans to heavy metals through microbial processes: a potential role for probiotics? Appl Environ Microbiol. 2012;78(18):6397-6404. [Full text]

  23. Liska DJ. The detoxification enzyme systems. Altern Med Rev. 1998;3(3):187-198. [Full text]

  24. Ledochowski M, Widner B, Bair H, et al. Fructose- and sorbitol-reduced diet improves mood and gastrointestinal disturbances in fructose malabsorbers. Scand J Gastroenterol 2000;35:1048–1052. [Abstract]

  25. Tillisch K. The effects of gut microbiota on CNS function in humans.  Gut Microbes. 2014;5(3):404-410. [Full text]

  26. Wall R, Cryan JF, Ross RP, et al. Bacterial neuroactive compounds produced by psychobiotics. Adv Exp Med Biol. 2014;817:221-239. [Abstract]


DISCLAIMER: 

The information provided on FX Medicine is for educational and informational purposes only. The information provided on this site is not, nor is it intended to be, a substitute for professional advice or care. Please seek the advice of a qualified health care professional in the event something you have read here raises questions or concerns regarding your health. 

Share Article: 

SIGN UP TO OUR FREE eNEWS

belinda_reynolds's picture
Belinda Reynolds

Belinda is a dietitian and Senior Educator at one of Australia's leading nutraceutical companies. She graduated with an Honours Degree in Nutrition and Dietetics, and has been involved in the complementary medicine industry for over 15 years. Her key interests are immune modulation, the human microbiome and the impact they have on overall health.