Arizona Advanced Medicine Clinic

Leaky Gut - Real or Imaginary?

Shelly, 52 years old, developed indigestion and multiple chemical sensitivities 12 years ago. Her symptoms progressed to severe fatigue, and she had constant diarrhea and joint pains. She was then diagnosed with rheumatoid arthritis. She was treated with pharmaceutical medication. Two years later she had developed high cholesterol, had gained 30 pounds, and was diagnosed with diabetes . Recently she has also been diagnosed with psoriasis and she believes she is not as sharp in her thought processes as she used to be. She was on 16 different pharmaceutical medications when she first came to see us.

Does this sound familiar? Why do we see so many conditions developing in one person? Is there any connection?

This patient is not unique.

One of the common links among all these conditions is the continuous chemical insults to which our bodies are exposed.

You could have leaky gut syndrome without even realizing it.

Leaky gut Syndrome contributes to many seemingly unrelated conditions. Leaky gut syndrome is one of the diagnoses in medicine that, if properly understood, cuts across the boundary lines of specific organ systems and medical specialties.

As we understand from the paradigm of functional medicine, distress in one organ may cause disease in another seemingly unrelated organ. Oriental Medicine had discovered this concept centuries ago. It took Western medicine some time to catch up.

Thus it is vital to look beyond the symptoms and discover the root cause of illness.

Conditions that may signal the necessity of looking for leaky gut syndrome:

– Arthritis[1],[2]

– fatigue, malaise, muscle pain[3]

– Fibromyalgia, chronic fatigue syndrome[4]

– depression4,[5]

– Poor exercise tolerance[6], [7], [8]

– Skin conditions like dermatitis, eczema, hives, psoriasis[9], [10]

– Allergies[11], [12]

– Inflammatory bowel conditions - Crohn's disease, Ulcerative colitis[13], liver cirrhosis[14], diarrhea, pancreatic insufficiency, celiac disease[15]

– Cancer treatment with cytotoxic drugs[16]

– Metabolic syndrome, hyperlipidemia, diabetes[17], [18], [19]

– Cognitive and memory deficiencies[20]

– Some heart conditions[21]

– Some cases of autism[22]

Thus a better understanding of leaky gut syndrome helps us find a more definitive solution for treatment of multiple different conditions. LGS is often undiagnosed or misdiagnosed. Diagnosing it correctly is the key to recovering from many illnesses.

The gut lining is covered by single columnar (column-shaped) cells, connected to one another by tight junctions. The tips of these cells are covered with microvilli, tiny projections which hugely increase the surface area. These microvilli absorb properly digested nutrients and transport them through the columnar cells into intestinal wall and finally to the bloodstream.

Downloaded with permission from the GI Tract Histology page of Dr. Michael Hortsch http://histology.med.umich.edu/medical/small-and-large-intestine

The tight junctions only allow fully digested particles and nutrients through the intestinal wall into the blood stream.[23], [24] This barrier mechanism is how the body regulates the trafficking of macromolecules, toxins, parasites, chemicals etc. between itself and its environment.

Underneath the single layer of cells and tight junction lies the intestinal wall, which contains 75% of our immune system (the gut associated lymphocytes, or GALT). The GALT is continuously activated by sampling the molecules that pass through the intestinal lining. Thus the GALT starts a chain of controlled and appropriate defense mechanisms consisting of antibodies and cytokines, to keep body's immune systems in normal balance.[25]

By enlisting the assistance of the GALT, the neuroendocrine network of hormones and chemical messengers, the intestinal epithelial barrier cells, intestinal cell tight junctions, and healthy intestinal microbiota (bacteria, yeasts and other micro-organisms), the human body is able to control the equilibrium between tolerance and immunity to non-self antigens.

When this finely tuned trafficking of macronutrients becomes dysregulated - because of poor food choices, antibiotic treatment, excessive worry or stress - in genetically susceptible individuals, then both intestinal and extra-intestinal immune and inflammation-related disorders can occur.

Compromised intestinal barrier function - intestinal permeability or Leaky Gut - allows macromolecules (larger molecules of food or chemicals) to pass through the first line of defense, that is intestinal lining. These macromolecules are presented to the lymphocytes of the GALT, the immune system of the intestinal wall, which then primes the immune system for action in entire body.[26], [27], [28], [29]

Increased permeability stimulates the classic hypersensitivity response to foods, and unfortunately also sometimes to normal components the gut. Especially active primers include bacterial endotoxins (from dead bacterial cell walls) and dietary gluten (wheat, barley, rye, spelt, kamut) which cause nonspecific activation of inflammatory pathways mediated by complement and cytokines.[30] Many of these components look remarkably like our own body tissues, and thus are also attacked by the activated immune system, under the mistaken impression that our own body tissues are foreign invaders. In experimental animals, chronic low-grade endotoxemia causes the appearance of autoimmune disorders.[31],[32],[33]

One prime and frequent example of such interaction involves Hashimoto's thyroiditis, an auto-immune thyroid inflammation often related to gluten intolerance.[34]

As the macromolecules pass the intestinal wall and enter the bloodstream, the second line of defense is activated, the liver.[35] The liver cells remove macromolecules and oxidize the endotoxins, resulting in generation of free radicals. These free radicals damage liver cells and reduce its ability to metabolize toxins and synthesize nutrients. Free radical rich bile is excreted into the intestine, damaging the intestinal epithelium and adding to the already existing insult, resulting in leakier gut. Thus it becomes a vicious cycle.

Fassano's work clearly connects antibodies to one of the tight junction proteins called Zonulin to inflammation, autoimmunity, and cancer.[36]

Leaky GutOur gut is essentially outside the body (kind of like the inside ring of a donut), and comes in contact with tons of food, bacteria and chemicals over the course of a lifetime. It is exposed to an enormous toxic and antigenic load pretty much day in and day out. From the functional point of view, our gut protects our internal organs from this constant insult. It has very complex and multilevel mechanisms that support one another.

Diet – When we are exposed to pesticides, GMO (genetically modified, bioengineered) foods, sugary drinks, poor quality fats, phytonutrient-poor fast foods, all these factors affect our mitochondria (cellular energy factories) and the walls of our intestinal lining cells themselves. This huge load of antigenic material causes the tight junctions to become more permeable to macromolecules and overloads our body's filtering mechanism (our liver) and our immune system.

The use of endocrine-disrupting plastics like BPA (bisphenol A), and our constant exposure to electromagnetic fields (cell phone towers, microwave towers, cell phones themselves, wireless networks) causes distortion of our human body field. Our stressful lives affect our mitochondrial membranes and cell walls, including the mitochondrial of the intestinal lining and thus the tight junctions between the lining cells, making them more permeable to whatever comes down the intestinal pipe.

Inflammation - any type of inflammation in the gut causes the intestinal barrier to be compromised. This can be secondary to excessive stomach acid, yeast (Candida albicans and other species), bacterial overgrowth, dysbiosis (abnormal micro-organisms in the gut), environmental toxins, parasites.

Medications - nonsteroidal anti-inflammatory drugs (Ibuprofen, aspirin), Tylenol, pain-killers, steroids, antibiotics, chemotherapy agents etc. can all affect the intestinal lining in various ways, altering the tight junctions and allowing macromolecules to have easy access to the immune system and blood stream.

Chronic stress - chronic increased secretion of cortisol by the adrenal glands causes our immune system to lower its guard, thus in turn reducing our ability to handle ongoing further stressful insults to the GI tract, and eventually leading to increased intestinal permeability.[37]

Other diseases - sometimes leaky gut occurs as a result of other diseases, for example celiac disease, in which patients are gluten intolerant. Celiac disease itself (diagnosed only by intestinal biopsy) affects about one person in hundred in North America and is often undiagnosed. Gluten sensitivity affects as many as 60% of our population, and causes the same symptomatology as celiac disease. The high incidence may baffle the experts[38], but it certainly is no secret to food manufacturers and grocery stores - just look at all the gluten free products available in your average grocery store now. Gluten sensitivity is not just an intestinal disease; it causes a generalized break-down of information transfer, leading to systemic disease because the inflammation caused by the gluten molecule or its break-down products leads to leaky gut.

Pharmaceutical medications – Sometimes leaky gut can be result of treatment for diseases like rheumatoid arthritis, cancer chemotherapy, antibiotics given for infection, etc. These pharmaceuticals damage the intestinal lining and cause significant changes in the balance of intestinal micro-organisms, resulting in a compromised intestinal barrier.

Chronic fatigue syndrome and major depressive disorders are associated with leaky gut. Here the activation of immune system produces chemicals called cytokines, which spread throughout the body causing inflammation and changes in neurotransmitter balance.

Altered intestinal permeability is the key element in the pathogenesis (physical changes resulting in disease) of many different diseases. Hyper-permeability initiates a vicious cycle in which allergic sensitization, immune system activation, dysbiosis and bacterial overgrowth[39], liver dysfunction, and pancreatic insufficiency and malnutrition occurs. Each of these factors increases the permeability of the small bowel.

Effective treatment of leaky gut syndrome requires several components, which in Functional Medicine we call the Five Rs.

Remove - any stressors that may be affecting your life - bad relationships, bad energy at work, foods to which you are allergic or sensitive, parasites or abnormal bacteria or yeasts, acid-blocking drugs, antibiotics or other drugs which damage the gut microflora.

Replace - unhealthy fast foods and chemicals with healthy whole foods. Replace missing digestive enzymes and hydrochloric acid.

Re-inoculate - simply overwhelm the abnormal bacteria with healthy bacteria, using large doses of probiotics and fermented foods.[40] Sustain the health of the new bacteria with the right kinds of prebiotics - high soluble fiber foods like artichokes, garlic, leeks, onion, chicory, tofu, and other organic soy products.

Repair - the inflamed gut with healing nutrients such as glycine and butyrate, zinc, antioxidant vitamins and fish oils.

Re-balance - pay attention to lifestyle, and make a good balance between things that stress you and things that relax you. Do not skip meals, or eat a candy bar because you don't have time to eat a meal.

Clues pointing to leaky gut are everywhere. If we keep our eyes and minds open to consider the body as one integrated system, then the leaky gut syndrome does not become a mysterious condition or something about which to scoff because we do not understand it. We as treating practitioners simply have to dig back into what we learned in school about basic science and pathophysiology. That information is fundamentally and scientifically sound, and gives us a real head start in the understanding of disease processes and the correction of dysfunctions.

So what happened to our patient Shelley?

Shelley had moved from New York to her mother's farm in Wisconsin to care for her mother. Her mother died about a year later, and Shelley's symptoms began. She did some testing - for nutritional imbalances and deficiencies, as well as testing for gut bacteria - type and relative amounts. We also did standard blood work, and found that her blood counts were normal, her liver enzymes were slightly elevated over the reference range, and her kidneys were functioning properly. Her fasting blood sugar was on the high side - 115 - and her cholesterol and triglycerides were high.

She was placed on a gluten free casein free elimination diet. We gave her probiotics and a comprehensive multivitamin. Within one week her diarrhea went away, and her fatigue and brain fog began to improve. Over the next two months she began to incorporate some exercise (walking) into her daily routine. After six months she had lost almost 20 pounds without dieting. The blood sugar and cholesterol both came down to normal limits, so she lost the diagnosis of diabetes. She still needed steroid creams for the psoriasis, but was able to go out in public without embarrassment. Life began to be worth living again.

[1] Clin Exp Rheumatol, 1990. 8(1): p. 75-83. A short review of the relationship between intestinal permeability and inflammatory joint disease. Rooney, P.J., R.T. Jenkins, and W.W. Buchanan

[2] Sköldstam L, Magnusson KE. Fasting, intestinal permeability, and rheumatoid arthritis. Rheum Dis Clin North Am, 1991. 17(2): p. 363-71.

[3] Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. 2007 Apr;99(1-3):237-40.

[4] Maes M, Mihaylova I, Kubera M, Leunis JC. An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CFS. Neuro Endocrinol Lett. 2008 Jun;29(3):313-9.

[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.

[6] Yeh YJ, Law LY, Lim CL. Gastrointestinal response and endotoxemia during intense exercise in hot and cool environments. Eur J Appl Physiol. 2013 Jun;113(6):1575-83. doi: 10.1007/s00421-013-2587-x.

[7] Zuhl M, Schneider S, Lanphere K, Conn C, Dokladny K, Moseley P. Exercise regulation of intestinal tight junction proteins. Br J Sports Med. 2012 Nov 7.

[8] Lamprecht M, Frauwallner A. Exercise, intestinal barrier dysfunction and probiotic supplementation. Med Sport Sci. 2012;59:47-56. doi: 10.1159/000342169.

[9] Humbert P, Bidet A, Treffel P, Drobacheff C, Agache P. Intestinal permeability in patients with psoriasis. J Dermatol Sci. 1991 Jul;2(4):324-6.

[10] Michaëlsson G, Gerdén B, Hagforsen E, Nilsson B, Pihl-Lundin I, Kraaz W, Hjelmquist G, Lööf L. Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet. Br J Dermatol. 2000 Jan;142(1):44-51.

[11] Zuberbier T, Pfrommer C, Specht K, Vieths S, Bastl-Borrmann R, Worm M, Henz BM. Aromatic components of food as novel eliciting factors of pseudoallergic reactions in chronic urticaria. J Allergy Clin Immunol. 2002 Feb;109(2):343-8.

[12] Jacobson, P., R. Baker, and M. Lessof “Intestinal permeability in patients with eczema and food allergy.” Lancet, 1981. i: p. 1285-1286.

[13] Sung MK, Park MY. Nutritional modulators of ulcerative colitis: clinical efficacies and mechanistic view. World J Gastroenterol. 2013 Feb 21;19(7):994-1004. doi: 10.3748/wjg.v19.i7.994.

[14] Pijls KE, Jonkers DM, Elamin EE, Masclee AA, Koek GH. Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature. Liver Int. 2013 Jul 3. doi: 10.1111/liv.12271.

[15] Paganelli, R., et al. Intestinal permeability in irritable bowel syndrome. Effect of diet and sodium cromoglycate administration. Ann Allergy, 1990. 64(4): p. 377-80.

[16] Melichar B, Dvorák J, Hyspler R, Zadák Z. Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents.Chemotherapy. 2005 Oct;51(6):336-8. Epub 2005 Oct 13.

[17] Sandek A, Rauchhaus M, Anker SD, von Haehling S (September 2008). The emerging role of the gut in chronic heart failure. Curr Opin Clin Nutr Metab Care 11 (5): 632-9

[18] Krack A, Sharma R, Figulla HR, Anker SD (November 2005). The importance of the gastrointestinal system in the pathogenesis of heart failure. Eur. Heart J. 26 (22): 2368-74

[19] Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes. 2008 Oct;57(10):2555-62. doi: 10.2337/db08-0331.

[20] Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, Pollmächer T. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001 May;58(5):445-52.

[21] Rogler G, Rosano G. The heart and gut. Eur Heart J. 2013 Jul 17. [Epub ahead of print]

[22] de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, Bravaccio C. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24. doi: 10.1097/MPG.0b013e3181dcc4a5.

[23] Berkes J, Viswanathan VK, Savkovic SD, Hecht G (March 2003). “Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation”. Gut 52 (3): 439-51.

[24] Fasano A. Zonulin and its regulation of intestinal barrier function the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011 Jan;91(1):151-75.

[25] Fasano A, Shea-Donohue T (September 2005). Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2 (9): 416-22.

[26] Jacobson, P., R. Baker, and M. Lessof “Intestinal permeability in patients with eczema and food allergy.” Lancet, 1981. i: p. 1285-1286.

[27] Paganelli, R., et al. Intestinal permeability in irritable bowel syndrome. Effect of diet and sodium cromoglycate administration. Ann Allergy, 1990. 64(4): p. 377-80

[28] Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009 Aug;58(8):1091-103.

[29] Sandek A, Rauchhaus M, Anker SD, von Haehling S (September 2008). “The emerging role of the gut in chronic heart failure“. Curr Opin Clin Nutr Metab Care 11 (5): 632-9.

[30] Bose S, Kim H. Evaluation of In Vitro Anti-Inflammatory Activities and Protective Effect of Fermented Preparations of Rhizoma Atractylodis Macrocephalae on Intestinal Barrier Function against Lipopolysaccharide Insult. Evid Based Complement Alternat Med. 2013;2013:363076. doi: 10.1155/2013/363076.

[31] Vaarala O, Atkinson MA, Neu J (October 2008). “The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity”. Diabetes 57 (10): 2555-62

[32] Fasano A, Shea-Donohue T (September 2005). Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2 (9): 416-22.

[33] Humbert, P.; Bidet, A.; Treffel, P.; Drobacheff, C.; Agache, P. (1991). Intestinal permeability in patients with psoriasis. Journal of dermatological science 2 (4): 324-326

[34] Virili C, Bassotti G, Santaguida MG, Iuorio R, Del Duca SC, Mercuri V, Picarelli A, Gargiulo P, Gargano L, Centanni M. Atypical celiac disease as cause of increased need for thyroxine: a systematic study. J Clin Endocrinol Metab. 2012 Mar;97(3):E419-22. doi: 10.1210/jc.2011-1851.

[35] Schnabl B. Linking intestinal homeostasis and liver disease.Curr Opin Gastroenterol. 2013 May;29(3):264-70. doi: 10.1097/MOG.0b013e32835ff948.

[36] Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, ,autoimmunity,,and cancer Physiol Rev. 2011 Jan;91(1):151-75.

[37] Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L, Houdeau E, Fioramonti J, Bueno L, Theodorou V. Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats.Psychoneuroendocrinology. 2012 Nov;37(11):1885-95. doi: 10.1016/j.psyneuen.2012.03.024

[38] Christina Frangou. Gluten Sensitivity Baffles Celiac Disease Specialists. Gastroenterology and Endoscopy News ISSUE: OCTOBER 2010 | VOLUME: 61:10

[39] Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009 Aug;58(8):1091-103.

[40] Lamprecht M, Frauwallner A. Exercise, intestinal barrier dysfunction and probiotic supplementation. Med Sport Sci. 2012;59:47-56.

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