Glutathione for inflammatory disease

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Reduced glutathione (GSH) is well recognised for its role as a key antioxidant in the body and for its function as an endogenous detoxifier, helping remove toxins and potential carcinogens.

An additional factor, that is often overlooked, is the degree to which inflammation can deplete glutathione (GSH), which in turn contributes to the persistence of an inflammatory state. Research shows that reductions in GSH lead to increased levels of pro-inflammatory mediators and inflammatory potential.[1] Consequently, GSH levels and function should be considered when addressing chronic inflammatory disease states.

Oxidative stress is a driver of inflammation. Increases in reactive oxygen species (ROS) and reactive nitrogen species (RNS) activate transcription factors (e.g. NFkB) and the release of pro-inflammatory cytokines, e.g. tumour necrosis factor (TNF) -alpha.[2,3] The subsequent initiation of inflammatory processes sees the development of further oxidative stress. If unresolved, GSH is depleted, worsening the oxidative and inflammatory environment. As a result a destructive, self-sustaining and auto-amplifying disease state develops. 

GSH and Inflammatory Bowel Disease (IBD)

The cellular damage that leads to chronic intestinal inflammation is not completely understood, however oxidative stress is believed to be a potential triggering factor.[3,4] This may be provoked by a range of insults including bacterial antigens, environmental factors and/or chemical agents.[5] 

As the vicious cycle of inflammation and oxidative stress persists, gut barrier function is impaired contributing to systemic inflammatory stress and more widespread symptoms. More so, GSH depletion is noted in IBD and should be considered when designing a treatment protocol for these patients. 

N-acetyl-cysteine (NAC), once deacetylated, becomes cysteine which is a cellular precursor of GSH. Preliminary evidence has shown NAC supplementation reduces inflammation, alleviates oxidative stress, improves energy status and ameliorates tissue damage in the intestines. These benefits are believed to be achieved through NAC helping to maintain intracellular concentrations of GSH.[6]

GSH and Lung Health

Alterations in alveolar and lung GSH metabolism are widely recognised as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma.[7] Preliminary research investigating the influence of local oxidative stress in pulmonary disease found that by increasing intracellular GSH in lung cells, the release of pro-inflammatory cytokines and chemokines is attenuated via decreased NGkB activation.[2]

In these airway diseases it is believed that an altered ratio of GSH to oxidised Glutathione (GSSG) in the epithelial lining fluid and airway cells is what leads to the release of pro-inflammatory cytokines, e.g. interleukin (IL) -8. These imbalances are also possibly implicated in airway hyper-responsiveness and dysfunction in asthma.[8]

Oral use of NAC may be implicated in chronic lung conditions as not only does it contribute antioxidant benefits but is also used as a mucolytic agent, reducing mucous viscosity and mucociliary clearance.[7]

GSH and Neurological Health

GSH in the brain is a known neuromodulator, neurotransmitter and enabler of neuron survival.[1]

Recently, many neurodegenerative and psychological (e.g. major depression, bipolar disorder and schizophrenia)[9] conditions have been associated with inflammation, oxidative stress, mitochondrial dysfunction, toxicity and compromised integrity at both the gastrointestinal tract and blood brain barrier, all of which can be linked to GSH depletion.

Depression,[10] anxiety disorders[11] and cognitive decline[12] have all been linked with decreases in expression of certain nerve growth factors, e.g. brain derived neurotropic factor (BDNF). BDNF promoted neuronal survival and regeneration in areas of the brain such as those involved in emotion, behaviour, learning and memory.[13] A loss of BDNF therefore results in reduced activity in such areas of the brain and subsequent mood and cognitive symptoms. 

Key factors linked to reduced BDNF expression include inflammation and oxidative stress from ROS and RNS, each associated with GSH depletion.[14]

Not surprisingly, interventions which aim to increase intracellular GSH concentrations (e.g. NAC[1,9,15] and curcumin,[1,16]) and reduce oxidative stress and/or inflammation (e.g. omega-3 from fish [9]) have shown benefit in addressing the symptoms of specific mood disorders.

Glutathione Function

To function as an antioxidant, GSH requires a group of enzymes known as the glutathione peroxidases. These are selenoproteins, meaning they are selenium-dependent. Once GSH functions as an antioxidant, it becomes GSSG; it requires reduction by glutathione reductase, which is riboflavin (Vitamin B2) dependent and NADP (derived from Vitamin B3) is also required. 

The glutathione molecule is a tripeptide consisting of three amino acids, glutamine, cysteine and glycine. Cysteine is the limiting factor for glutathione synthesis. Cysteine acts as an antioxidant in its own right, being converted to cystine in this process. Cystine then requires reduction back into cysteine in order to continue its antioxidant function and/or to be involved in the synthesis of glutathione. Alpha-lipioc acid is known to increase intracellular glutathione through its role in assisting the reduction of cystine to cysteine, thus enhancing its availability for glutathione manufacture within the cells. 

Vitamin D status should also be considered where oxidative stress and inflammation are present. Not only does Vitamin D play a direct role in immune modulation, but a study on healthy adults showed serum 25(OH)D concentrations to be independently associated with major plasma redox systems (measured by reduced and oxidised glutathione and cysteine levels). This suggests that Vitamin D status may be involved in oxidative stress-related pathophysiology.[17]

Glutathione and the Diet

Certain foods contains levels of the actual glutathione tripeptide, whilst others are rich in the amino acid building blocks (e.g. cysteine) and/or antioxidants (e.g. alpha-lipioc acid) which facilitate the maintenance of intracellular GSH levels. Specific foods and herbs will also increase the activity of specific enzymes (e.g. glutathione s-transferase) that support glutathione's detoxification functions. The below listed foods provide one or a combination of these benefits and are thus highly recommended as part of an anti-inflammatory diet (assuming there are no identified intolerances). 

  • Vegetables (e.g. asparagus, capsicum, carrot, onion, broccoli/broccoli sprout, cabbage, avocado, spinach, garlic)
  • Fruits (e.g. apples, oranges, peaches, bananas, melon)
  • Whey Powder (manufacturing processes must ensure retention of intact proteins)
  • Eggs
  • Turmeric (containing curcumin)

Glutathione Bioavailibility

In the past, glutathione bioavailibility has been questioned. More recent research however has demonstrated that orally ingested GSH does in fact achieve significant increases in intracellular GSH levels. 

One recent trial of 54 people administered doses of 250mg or 1000mg or placebo to human subjects for a 6 month period. GSH levels were measured at 1, 3 and 6 months. Both GSH groups achieved dose-dependent increases in GSH at various sites including the blood, erythrocytes, lymphocytes and buccal cells. Both groups were also observed to have reductions in oxidative stress, as indicated by decreases in the oxidised to reduced glutathione ratio in whole blood. After just 3 months natural killer cell cytotoxicity was increased more and two-fold in the higher dose group.[18]

This research suggests that oral glutathione supplementation can be a useful adjunct to treatment protocols for patients presenting with disease states associated with GSH depletion.

Management of illnesses associated with chronic inflammation may benefit from dietary and supplemental approaches that address oxidative stress and mitigate GSH depletions. Reduced glutathione itself is a useful supplement at doses between 250mg and 1000mg, whilst N-acetyl-cysteine, curcumin, alpha-lipoic acid, fish oil, selenium, B vitamins and vitamin D can also be considered.

REFERENCES

  1. Morris G, Anderson G, Dean O, et al. The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol 2014;50(3):1059-1084. [Abstract]
     
  2. Biswas SK, Rahman I. Environmental toxicity, redox signaling and lung inflammation: the role of glutathione. Mol Aspects Med 2009;30(1-2):60-76. [Full text]
     
  3. Sido B, Hack V, Hochlehnert A, et al. Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease. Gut 1998;42(4):485-492. [PDF]
     
  4. Latorre E, Matheus N, Layunta E, et al. IL-10 counteracts proinflammatory mediator evoked oxidative stress in Caco-2 cells. Mediators Inflamm. 2014;2014:982639. [Full text]
     
  5. Zhu H, Li YR. Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence. Exp Biol Med (Maywood) 2012;237(5):474-480. [Abstract]
     
  6. Hou Y, Wang L, Yi D, et al. N-acetylcysteine and intestinal health: a focus on its mechanism of action. Front Biosci 2015;20:872-891. [Abstract]
     
  7. Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000;16(3):534-554. [PDF]
     
  8. Fitzpatrick AM, Teague WG, Burwell L,  et al. Glutathione oxidation is associated with airway macrophage functional impairment in children with severe asthma. Pediatr Res 2011;69(2):154-159. [Full text]
     
  9. Pandya CD, Howell KR, Pillai A. Antioxidants as potential therapeutics for neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2013;46:214-223. [Full text]
     
  10. Yoshimura R, Kishi T, Hori H, et al. Serum proBDNF/BDNF and response to fluvoxamine in drug-naïve first-episode major depressive disorder patients. Ann Gen Psychiatry 2014;13:19. [Full text]
     
  11. Suliman S, Hemmings SM, Seedat S. Brain-derived neurotrophic Factor (BDNF) protein levels in anxiety disorders: systematic review and meta-regression analysis. Front Integr Neurosci. 2013;7:55. [Full text]
     
  12. Shimada H, Makizako H, Doi T. A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front Aging Neurosci 2014;6:69. [Full text]
     
  13. Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2008;33(1):73-83. [Full text]
     
  14. Anderson G, Maes M. Oxidative/nitrosative stress and immuno-inflammatory pathways in depression: treatment implications. Curr Pharm De. 2014;20(23):3812-3847. [Abstract]
     
  15. Sarris J, Mischoulon D, Schweitzer I. Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials. Bipolar Disord 2011;13(5-6):454-465. [Abstract]
     
  16. Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res 2014;28(4):579-585. [PDF]
     
  17. Alvarez JA, Chowdhury R, Jones DP, et al. Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. Clin Endocrinol (Oxf) 2014;81(3):458-646. [Full text
     
  18. Richie JP Jr, Nichenametla S, Neidig W, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2014 May 5. [Epub ahead of print] [Abstract
     
  19. Singh K, Connors SL, Macklin EA, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci USA 2014 Oct 28;111(43):15550-15555. [Full text

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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.