As many holistic practitioners who work with chronic disease will tell you, if you don’t consider and address gut function, the body will struggle to get well. This concept has long been emphasized regarding conditions as diverse as chronic infections, autoimmune disease, skin conditions, allergies, mental health, neurodegenerative conditions, autism, metabolic syndrome, and so much more. And now, with the onslaught of research on the health and microbiota of the gut, we have many new insights into the gut’s connection to these medical conditions.1,2,3 Probiotics, micro-organisms that have been shown to exert a beneficial impact on health, are big business, for food and supplement companies alike.
But gut health goes beyond a balanced flora, and most people with even a passing interest in holistic health are familiar with the phrase “leaky gut.” Leaky gut, which in medical research settings is called “increased intestinal permeability,” also is making its mark in medical publications and supplement development. Just as gut dysbiosis affects health, so does increased intestinal permeability, which has shown associations with autism, mood, immune system activation, cognitive health, and many more conditions.4,5,6,7 Increased gut permeability usually comes hand-in-hand with intestinal inflammation, and can be caused by infection, food sensitivities or allergies, alcohol intake, heavy metal or toxin exposure, intense exercise, and even stress. 8,9,10,11 With increased gut permeability, bacterial components from the gut lumen, including the immune response-triggering portion known as endotoxin, or lipopolysaccharide (LPS), are able to enter into systemic circulation. Because of this, inflammation does not just stop at the gut, and affects the body systemically.
Endotoxin-associated inflammation has a negative effect on detoxification by multiple mechanisms. Exposure to endotoxin, and related inflammatory cytokines, downregulates expression of some of the important components of detoxification known as Phase I cytochrome P450 enzymes and Phase III transporters.12,13 Endotoxin also inhibits the kidney elimination of mercury, and further contributes to renal damage.14 Last, but not least, endotoxin has a dramatic negative effect on bile flow.15 Because many of the toxins, particularly heavy metal-glutathione conjugates, are removed from circulation via the bile,16 when bile flow is impeded, elimination is impaired at the level of the kidneys as well. The body then has difficulty overcoming the situation. The toxic metals become stuck in circulation, and seep back into tissues, including the brain, where they cause inflammation and damage.17
Gut health is important for detoxification from heavy metals, as high levels of the proteins necessary for all phases of detoxification are expressed here.18,19 Unfortunately, with exposure to heavy metals such as mercury, gut mucosa inflammation and increased intestinal permeability occur, associated with oxidative stress and glutathione depletion.20 Although a probiotic can help mitigate these issues, it often is not enough, and a more strategic approach to treatment is necessary. In addition to bitter compounds which promote the movement of bile out through the liver and gallbladder, as well as a healthy gut flora balance, support for intestinal mucosa health and function in detoxification also is important.
Clearing the Way for Effective Detoxification
One thing which has a negative impact on detoxification is biofilm. Biofilms can occur with colonization of dysbiotic or pathogenic gastrointestinal flora.21 A biofilm is a matrix of extracellular polymeric substances (also known as exopolysaccharides) that vary greatly depending on the organism by which they were created, and the environment in which they develop.22 In addition to facilitating a communication network and serving as protection for the community which created them, biofilms can further contribute to heavy metal accumulation and retention, as heavy metals are also trapped here.23,24 Nattokinase, a fibrinolytic enzyme, has been shown to disrupt biofilms.25
The interactions of selenium with mercury in the body have long been recognized. Mercury binds to selenium with a very high affinity, and it has a specific and irreversible effect of inhibiting selenium-dependent enzymes.26, 27 Selenium-dependent enzymes, also known as selenoproteins, act to repair oxidative damage in the body, particularly in the brain, and include glutathione peroxidase.28 Because of the strong interactions with mercury, selenium is sequestered and depleted with mercury exposure. Studies in fish, our main source of dietary mercury, have shown that selenium interacts with methylmercury in the gut, reducing methylmercury accumulation.29 Selenium also induces the Nrf2 pathways, which promotes cellular products of antioxidants and antioxidant enzymes.30 The protective role of selenium has not only been shown with mercury, but other damaging metals such as cadmium and aluminum.31,32
Terminalia chebula, also known as Haritaki, is widely used in Ayurvedic medicine and is part of the famous blend of three herbs known as Triphala, having a long history of use for a variety of digestive complaints.33 Haritaki, as a part of this combination, has been shown to play a role in healing the brush border membrane of intestine, as well as restoring phospholipid and glutathione content after damage.34 Haritaki also has been shown to have a protective effect on the gastrointestinal mucosa, reducing the formation of gastric ulcers in addition to demonstrating potent systemic inflammatory activity.35,36 It supports the reduction of constipation, and the movement of digestive waste and toxins from the gastrointestinal tract as well.37
Although liposomal formats are ideal for nutritional supplements which are directed at supporting the body systemically, non-liposomal formats are appropriate for delivering nutrients intended for local action in the gut. Because each of the phases of detoxification occur at high levels locally in the gut, supporting the antioxidant systems of the cells of the small intestinal mucosa also is important. Polyphenolic antioxidants such as epicatechin (found in pine bark extract) and lipoic acid have demonstrated tremendous efficacy in doing this by "turning on" Nrf2, the master intracellular antioxidant switch that promotes transcription of antioxidants and enzymes necessary for detoxification. 38,39,40 Pomegranate, well known for its antioxidant effects, not only supports glutathione and glutathione peroxidase levels in the cells lining the gastrointestinal tract, but by doing so also has been shown to protect the gastrointestinal mucosa from aspirin and alcohol-induced inflammation and injury. 41
5 Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008 Feb;29(1):117-24. View Abstract
6 Daulatzai MA. Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia. Neurochem Res. 2014 Apr;39(4):624-44. View Abstract
7 Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013 Mar;80(3):264-70. View Abstract
8 Lindén SK, et al. Mucin dynamics in intestinal bacterial infection. PLoS One. 2008;3(12):e3952.
9 Purohit V, Bode JC, Bode C, et al. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium. Alcohol. 2008 Aug;42(5):349-61. View Abstract
11 Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 2011 Dec;62(6):591-9. View Abstract
12 Tang W, Yi C, Kalitsky J, Piquette-Miller M. Endotoxin downregulates hepatic expression of P-glycoprotein and MRP2 in 2-acetylaminofluorene-treated rats. Mol Cell Biol Res Commun. 2000 Aug;4(2):90-7. View Abstract
13 Kalitsky-Szirtes J, Shayeganpour A, Brocks DR, Piquette-Miller M. Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats. Drug Metab Dispos. 2004 Jan;32(1):20-7. View Abstract
17 Monnet-Tschudi F, Zurich MG, Boschat C, et al. Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases. Rev Environ Health. 2006 Apr-Jun;21(2):105-17. View Abstract
23 Dominique Y, Maury-Brachet R, Muresan B, et al. Biofilm and mercury availability as key factors for mercury accumulation in fish (Curimata cyprinoides) from a disturbed Amazonian freshwater system. Environ Toxicol Chem. 2007 Jan;26(1):45-52. View Abstract
25 Zapotoczna M, et al. An Essential Role for Coagulase in Staphylococcus aureus Biofilm Development Reveals New Therapeutic Possibilities for Device-Related Infections. J Infect Dis. 2015;212(12):1883–93. View Abstract
31 Liu L, Yang B, Cheng Y, Lin H. Ameliorative Effects of Selenium on Cadmium-Induced Oxidative Stress and Endoplasmic Reticulum Stress in the Chicken Kidney. Biol Trace Elem Res. 2015 Oct;167(2):308-19. View Abstract
32 Viezeliene D, Jansen E, Rodovicius H, et al. Protective effect of selenium on aluminium-induced oxidative stress in mouse liver in vivo. Environ Toxicol Pharmacol. 2011 Mar;31(2):302-6. View Abstract
34 Nariya M, et al. Comparison of enteroprotective efficacy of triphala formulations (Indian Herbal Drug) on methotrexate-induced small intestinal damage in rats. Phytother Res. 2009 Aug;23(8):1092-8. View Abstract
36 Pampattiwar SP, Adwani NV, Sitaram B, Rao PM. Pharmacological study of anti-inflammatory action of haritaki preparations on wistar rats in hemorrhoids (piles). Global J Res Med Plants Indig Med. 2013 Mar 1;2(3):178. View Abstract
38 Rohdewald P, et al. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther. 2002 Apr;40(4):158-68. View Abstract
40 Suh JH, et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3381-6. View Abstract
41 Ajaikumar KB, Asheef M, Babu BH, Padikkala J. The inhibition of gastric mucosal injury by Punicagranatum L. (pomegranate) methanolic extract. J Ethnopharmacol. 2005 Jan 4;96(1-2):171-6. View Abstract