Showing posts with label intestinal permeability. Show all posts
Showing posts with label intestinal permeability. Show all posts

Sunday, July 4, 2010

Type 2 Diabetes and Endotoxemia

by Maelán Fontes

Currently there’s an epidemic of type 2 diabetes (T2D) worldwide, especially in Westernized countries. T2D is characterized by persistent elevated glucose levels due to disrupted insulin action or an alteration in pancreatic insulin production1.

It was estimated that 171 million people were suffering from T2D in 2001, with a total overall population prevalence of 6%. More alarming is the fact that in Caucasian adolescents 4% suffer from T2D and 25% are glucose intolerant1. However, T2D prevalence in hunter-gatherer societies is low2-6, and even nonexistent in the island of Kitava in Trobiand Islands in Papua New Guinea3.

Genetics does not seem to explain the difference, because when these populations are Westernized they suffer even more from diseases of civilization such as T2D, obesity, myocardial infarction and stroke among others7-10 than original Western populations. Furthermore, there’s evidence showing that hunter-gatherer populations can reverse T2D when they are resettled in their ancient habitat8, a fact that has been demonstrated in two recent clinical trials conducted on Western populations11, 12.

Insulin resistance seems to be one of the factors involved in T2D which is caused, by low-grade chronic inflammation13-15 among other factors. Interestingly, low-grade chronic inflammation is a hallmark16-19 in T2D patients.

Considering these factors, it seems plausible that the nutrition introduced with the agricultural revolution 10,000 years ago played an important role in the current diabetes epidemic in Westernized populations. Western foods are overload with antinutrients, namely lectins, saponins and gliadin, which may explain the great disparity between paleolithic and modern Western food when it comes to metabolic syndrome (a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes). There is evidence showing that antinutrients act as endocrine disrupting substances, promoting metabolic syndrome20. On the other hand, antinutrients may elicit their negative health effects through increased intestinal permeability21. However, scant evidence exists regarding the role of antinutrients in the aetiology of Western diseases.

Gliadin and increased intestinal permeability

One of the most studied foods in the recent years is wheat, which contains a protein called gliadin, and is part of the gluten protein family22. Gliadin increases gut permeability by means of Zonulin production (a protein that regulates in tight junctions between cells in the wall of the digestive tract) in the gut enterocytes (epithelial cells found in the small intestines and colon). Zonulin binds the CXCR3 chemokine receptor leading to intracellular signalling cascades, mediated by protein kinase C (PKC), which ultimately causes disruption of the tight junction proteins which maintain the gut barrier function, and lead to increased gut permeability23, 24.

In addition, when intestinal permeability is increased, gliadin - which is resistant to heat and digestive enzymes - is able to interact with gut associated lymphoid tissue (GALT) stimulating the innate immune system, leading to low-grade chronic inflammation22, 24. Several studies have demonstrated that gliadin induces the production of pro-inflammatory cytokines (a small protein released by cells that has a specific effect on the interactions between cells, communications between cells or the behavior of cells), independent of one’s genetic predisposition to celiac disease – which is virtually everyone23, 25, 26.

Lectins and increased gut permeability

Lectins are a family of glycoproteins (a complex protein containing a carbohydrate combined with a simple protein) found in the plant kingdom, including grains, legumes and solanacous plants (tomatoes, potatoes, eggplants and peppers)21, 27. Lectins also have the ability to bind sugar containing molecules. They were first studied for their ability to agglutinate (cause to adhere) red blood cells by binding to their cell membranes. Many lectins present in other foods are harmless, but some lectins found in grains, legumes and solanaceous plants have been shown to be harmful to human physiology28. Lectins are resistant to heat (unless cooked by pressure cooking)29 and digestive enzymes38, and therefore arrive intact when they reach the intestinal epithelium, passing through the intestinal barrier into peripheral circulation. Lectins are able to bind peripheral tissues, producing many deleterious health effects21. Furthermore, lectins disrupt intestinal barrier and immunological function when they bind surface glycans (a carbohydrate polymer containing simple sugars) on gut epithelial cells, causing cellular disruption and increasing gut permeability. Lectins also facilitate the growth of certain bacteria strains, stimulate T-cell proliferation, increase intercellular adhesion molecules (ICAM), stimulate production of pro-inflammatory cytokines (IL-1, TNF-alpha, etc.), and amplify HLA class II molecules expression, among other effects21.

Saponins and increased gut permeability

Saponins are glycoalkaloids (a family of poisons commonly found in the plant species Solanum dulcamara - nightshades) produced by plants, technically known as steroid glycosides or triterpenoids, are formed by a sugar compound (glucuronic acid, glucose or galactose, among others) and aglycone (non-sugar molecule) portion30-32. The aglycone portion binds the cholesterol molecule on gut cell membranes. When certain amounts of saponins bind cell membrane cholesterol molecules of the intestinal epithelial cells at a 1:1 ratio, the sugar portion of the saponins bind together, resulting in a complex molecule consisting of cholesterol and saponins. This new molecule disrupts the gut barrier and increases intestinal permeability. This has been shown in humans who consume a diet rich in alpha-solanine and alpha-chaconine - two of the saponins found in potatoes31.

On the other hand, saponins have adjuvant-like activity, which means that they are able to affect the immune system leading to pro-inflammatory cytokine production33, 34, ultimately inducing insulin resistance.

Intestinal permeability and endotoxemia

Intestinal epithelia act as a physical barrier between the outside and the inside of the body, meaning that the intestinal lumen is technically outside the organism. When the intestinal barrier is disrupted, it allows increased passage of gut luminal antigens derived from food, bacteria and viruses into the organism21. In case of bacteria derived antigens, lipopolysaccharide (LPS) is the most commonly studied and utilized antigen to induce acute immune stimulation, this is known as endotoxemia (the presence of endotoxins - a toxin that forms an integral part of the cell wall of certain bacteria - in the blood which may cause hemorrhages, necrosis of the kidneys, and shock)35. In addition, endotoxemia is associated with low-grade chronic inflammation, insulin resistance and T2D13, 18, 36. In a recent human study it was demonstrated that LPS induced low-grade chronic inflammation in adipose tissue in T2D36 humans.

LPS-TLR4 interaction and low-grade chronic inflammation

The innate immune system is localised in the GALT. When luminal antigens pass through the intestinal barrier, they are phagocited (consumed) by dendritic cells or macrophagues, key components of the innate immune system. Dendritic cells or macrophagues recognize antigens through a family of receptors known as Toll-like receptors (TLR). The best studied and known antigens from gram negative bacteria are LPS which interact with toll-like receptors-4 (TLR4), inducing the production of pro-inflammatory cytokines and ultimately insulin resistance and T2D35. Interestingly, a recently published study demonstrated increased TLR4 expression in T2D humans, contributing to an increased inflammatory state37.

In summary, antinutrients introduced with the agricultural revolution 10,000 years ago may be one of the causal factors in the epidemic of obesity, (as well as T2D) in Western countries. Lectins, saponins and gliadin increase intestinal permeability and allow increased passage of gut bacteria from intestinal lumen to peripheral circulation. LPS - an antigen found in gram-negative bacteria cell membranes - interacts with TLR-4, leading to inflammatory cytokine production and low-grade chronic inflammation, which is at the root of insulin resistance. Insulin resistance is recognised to induce the metabolic syndrome, including T2D. Endotoxemia-induced insulin resistance in T2D patients may be exacerbated, in part, by antinutrients.

References:
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  2. Joffe BI, Jackson WP, Thomas ME, Toyer MG, Keller P, Pimstone BL. Metabolic responses to oral glucose in the Kalahari Bushmen. British medical journal 1971;4(5781):206-8.
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  13. Fernandez-Real JM, Pickup JC. Innate immunity, insulin resistance and type 2 diabetes. Trends in endocrinology and metabolism: TEM 2008;19(1):10-6.
  14. Reyna SM, Ghosh S, Tantiwong P, et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 2008;57(10):2595-602.
  15. Song MJ, Kim KH, Yoon JM, Kim JB. Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochemical and biophysical research communications 2006;346(3):739-45.
  16. Duncan BB, Schmidt MI. The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes. Diabetes technology & therapeutics 2006;8(1):7-17.
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  18. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes care 2004;27(3):813-23.
  19. Spranger J, Kroke A, Mohlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003;52(3):812-7.
  20. Jonsson T, Olsson S, Ahren B, Bog-Hansen TC, Dole A, Lindeberg S. Agrarian diet and diseases of affluence--do evolutionary novel dietary lectins cause leptin resistance? BMC endocrine disorders 2005;5:10.
  21. Cordain L, Toohey L, Smith MJ, Hickey MS. Modulation of immune function by dietary lectins in rheumatoid arthritis. The British journal of nutrition 2000;83(3):207-17.
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  24. Visser J, Rozing J, Sapone A, Lammers K, Fasano A. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Annals of the New York Academy of Sciences 2009;1165:195-205.
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  26. Rakhimova M, Esslinger B, Schulze-Krebs A, Hahn EG, Schuppan D, Dieterich W. In vitro differentiation of human monocytes into dendritic cells by peptic-tryptic digest of gliadin is independent of genetic predisposition and the presence of celiac disease. Journal of clinical immunology 2009;29(1):29-37.
  27. Kilpatrick DC, Pusztai A, Grant G, Graham C, Ewen SW. Tomato lectin resists digestion in the mammalian alimentary canal and binds to intestinal villi without deleterious effects. FEBS letters 1985;185(2):299-305.
  28. Cordain L. Cereal grains: humanity's double-edged sword. World review of nutrition and dietetics 1999;84:19-73.
  29. Grant G, More LJ, McKenzie NH, Pusztai A. The effect of heating on the haemagglutinating activity and nutritional properties of bean (Phaseolus vulgaris) seeds. Journal of the science of food and agriculture 1982;33(12):1324-6.
  30. Francis G, Kerem Z, Makkar HP, Becker K. The biological action of saponins in animal systems: a review. The British journal of nutrition 2002;88(6):587-605.
  31. Patel B, Schutte R, Sporns P, Doyle J, Jewel L, Fedorak RN. Potato glycoalkaloids adversely affect intestinal permeability and aggravate inflammatory bowel disease. Inflammatory bowel diseases 2002;8(5):340-6.
  32. Keukens EA, de Vrije T, van den Boom C, et al. Molecular basis of glycoalkaloid induced membrane disruption. Biochimica et biophysica acta 1995;1240(2):216-28.
  33. Oda K, Matsuda H, Murakami T, Katayama S, Ohgitani T, Yoshikawa M. Adjuvant and haemolytic activities of 47 saponins derived from medicinal and food plants. Biological chemistry 2000;381(1):67-74.
  34. Pickering RJ, Smith SD, Strugnell RA, Wesselingh SL, Webster DE. Crude saponins improve the immune response to an oral plant-made measles vaccine. Vaccine 2006;24(2):144-50.
  35. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57(6):1470-81.
  36. Creely SJ, McTernan PG, Kusminski CM, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. American journal of physiology 2007;292(3):E740-7.
  37. Dasu MR, Devaraj S, Park S, Jialal I. Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes care;33(4):861-8.
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Tuesday, January 19, 2010

Paleo Diet Q & A - 19 January 2010


Dear Readers,

Today's Paleo Diet Q & A on MS.



Q: As a MS patient for 5 years, I have been following the Swank diet (or the Judy Graham's approach to the Swank diet) since the beginning. Meaning that I am in a low fat diet with a high intake of Omega 6 (2-3 gr. of Primrose Oil daily) and Omega 3 (1 gr. of Fish Oil daily). As a Spanish person, I also take lots of Extra Virgin Olive Oil (as salad dressing or cooking oil). I did not take milk or dairy in all these years. I swim half hour every week. The result is that my lesions are inactive, I have had just one MS episode in the last three years but, on the other side, I suffer of great fatigue and I get very tired after walking short distances. And I hardly can stand stressing situations.

Your conference in Youtube made me buy your book and I have started following the Paleo diet. My question is if I am doing the right thing taking that amount of vegetable oils. I understood (in the video part 3) that lots of Omega 6 and few Omega 3 could be inflammatory and is not recommended for autoinmune diseases. But in my case I think that is helping to feel better (I have felt worse when I have stopped taking it for several weeks).

Do you have any recommendation for me?

Cordially,
Andrés

A: Hi Andrés,

Yes, you are right. We think that a high intake of vegetable oils (specially omega-6 linoleic acid), probably, is not the best approach for inflammatory conditions. However, Primrose Oil is a good source of GLA, a precursor of anti-inflammatory substances namely PGE1.

Perhaps 2-3 grams of Primrose Oil is too much and 1 gram of Fish Oil is not enough. For an inflammatory disease we recommend to take 2 grams EPA+DHA/day.

Regarding your fatigue symptoms, you don't necessarily have to stick to a low-fat diet when treating MS, and muscles should be well adapted to burn fat. One of the causes of chronic fatigue is fatty acid deficiency, so we encourage you to eat good fat sources such as oily fish, olive oil, coconut oil (a good source of Medium Chain Triglycerides for your muscles and keeps harmful bacteria under control) and nuts (macadamia and walnuts).

A paleolithic-type diet will provide you the adequate amount and balance between the different fatty acids.

On the other side, you may be aware of the importance of gut permeability on MS patients, so the paleo diet will help you treating this part of the story.

I hope this is helpful,

Best wishes,
Maelán

Tuesday, January 12, 2010

Paleo Diet Q & A - 12 January 2010


Dear Readers,

Here's today's edition of Paleo Diet Q & A.



Q: Have you had any results in curbing the symptoms of Crohn's Disease with the Paleo Diet. As I am a sufferer, I would love to know.

Thank you,
Shannon

A: Dear Shannon,

Indeed, inflammatory bowel disease (Ulcerative Colitis & Crohn's Disease) patients usually do very well with The Paleo Diet, as nutrients are one of the main environmental triggers of this condition.

Crohn's disease is an autoimmune disease where the immune system mounts an attack against its own tissues, in this case the cells lining the intestine.

For an autoimmune disease to occur we need a genetic predisposition and an environmental trigger. The genetic predisposition depends on genes coding for the HLA system. On the other side, one of the environmental triggers may be nutrition, besides infections, geography (vitamin D deficiency), physical trauma or vaccination.

One of the key points in this process is increased intestinal permeability. This means that the gut barrier allows increased passage of bacterial or food proteins (antigens) into peripheral circulation, skipping a process known as oral tolerance. Once antigens get in contact with the immune system located in the gut associated lymphoid tissue, they may elicit a T-cell mediated immune response against those antigens.

If the molecular structure of the dietary or bacterial antigens is similar to that of the HLA system (part of the immune system presenting cells machinery), chances are that a cross reaction between foreign antigens and self antigens (produced by T-cells) occur. This is termed molecular mimicry and leads to self injury by the adaptive immune system.

Hence, decreasing intestinal permeability is one of the treatment targets. There are several nutrients known to increase intestinal permeability that you may want to avoid, at least until symptoms subside. Here you have a list of them and the noxious substance in parentheses:

  • Cereal grains (lectins and gliadin)
  • Legumes, including soya and peanuts (lectins and saponins)
  • Tomato (tomato lectin and alpha-tomatin)
  • Potato (lectins and saponins)
  • Chili (capsaicin)
  • Quillaja (foaming substance)
  • Quinoa (saponins)
  • Egg white (lisozyme)
  • Alfalfa sprouts (saponins)
  • Amaranth (saponins)
  • Alcohol
Moreover, some nutrients exert an adjuvant-like activity (they stimulate the immune system), which is something you don't want to if you are suffering from an autoimmune disease. Nutrients containing adjuvants:
  • Quillaja extract, found in root beer
  • Tomato alpha-tomatine
Dairy products and vegetable oils also have deleterious effects upon your immune system.

I hope this helps.
Maelán



Q: Good Morning,

I've recently started on the Paleo Diet. I've read through your site and others to make sure I'm going about it the right way. What a revelation! It's fantastic in its simplicity.

My concern is that when I was about 18 I developed an allergy to fish. I have no idea how this happened. I ate two or three nights a week growing up at home. Curiously, this allergy seems to only apply to scaled fish, as I can still eat shellfish. I am 23 years old.

When I eat fish I get terrible heartburn/indigestion, and the last time I tried it, about two years ago, my face started swelling and itching. I saw an allergist who told me to avoid fish because of the potential of a very serious reaction.

What do you recommend I do? It seems like eating seafood is a big part of the Paleo Diet. I'm happy to eat shellfish, but aside from shrimp it's often prohibitively expensive. Obviously I'm not going to eat fish unless I can "outgrow" the allergy. I was once allergic to eggs, but I've gotten over that now.

Thanks!
Harrison

A: Dear Harrison,

From an evolutionary standpoint fish allergy is nonsense, as it has been part of the human nutrition since, probably, 2-2.5 million years ago.

Allergy is an exaggerated reaction of the body's immune system against foreign proteins, where the body's common mucosal immune system (located in the gut, nose, eyes, lungs, etc) increases the production of cell (eosinophils) and/or antibody (IgE) mediated immune response. This leads to histamine release throughout the CMIS and signs and symptoms related to allergy, such as inflammation, redness, itching, sneezing, or anaphylactic shock if acute vasodilatation occurs.

But how or why do fish proteins trigger an allergy reaction?
  1. An early exposure to food proteins, lets say before 3-6 months of life, when the gut associated lymphoid tissue is immature increases the risk of allergy later in life.

  2. An increased intestinal permeability allows food proteins to pass through the gut barrier and skip M-cells mediated oral tolerance, inducing hyper-sensitivity to those proteins.

  3. In the last years a wide body of scientific papers has shed light to what is known as the "hygiene hypothesis". A correlative association has been shown between increased use of antibiotics and vaccines and inflammatory conditions such as multiple sclerosis, type 1 diabetes and allergy, during the last 50 years. Human beings are less exposed to microorganisms, such as intestinal bacteria, than they used to. This leads to lack of immune regulation mediated, in part, by gut and environmental microorganisms.
How can the Paleo Diet help you?

Of course we can not address point 1 but we can do something regarding points 2 and 3.

The Paleo Diet is free of some food known to increase intestinal permeability such as cereal grains, legumes (soya and peanuts), alcohol, tomato, potato, quinoa, amaranth, egg white, alfalfa sprouts and root beer (quillaja extract). By eliminating those foods and eating a diet based on lean meats, shellfish, vegetables, fruits and nuts your intestinal permeability will decrease and your immune system will be less challenged by those food proteins (fish) and perhaps we can restore immune tolerance to a normal food as fish. For more information about intestinal permeability and nutrition we recommend you to check out our published newsletters section.

Regarding point 3 we suggest you to take a probiotic supplement (6-9 billion/day) for several months.

Other supplements that can help you improve intestinal permeability:
  • Pre-biotic 2-4grs/day
  • L-glutamine 0.2grs/kg body weight one month, then 0.1gr/kg
  • Zinc 25mg/day
  • Vitamin D 2000 IU
  • Omega-3 fatty acids EPA+DHA=2.6grs/day
I hope this is useful.
Maelán

Monday, November 9, 2009

Paleo Diet Q & A - 11.9.09

Dear Readers,

We hope you're finding our Q&A posts from the Paleo Diet community to be useful and informative. We've received several new questions and comments on previous Q&A posts, and encourage you submit yours.

We receive a great amount of feedback, and we are not able to always answer personally. We do read all questions, and are very interested in hearing your thoughts and learning about your experiences with the Paleo Diet.



Q: Dr. Cordain, I was interested in your Sept. 25th issue because of long standing problems (since the early 1980's) with Chronic Fatigue Syndrome and also various bowel problems. I have been doing quite well for the last seven or so years (thought I am 70 now) thanks to the Paleo Diet, but am not fully recovered. With regard to your list of foods to avoid, I do avoid, completely, all those foods except pepper with capsaisin. Over the course of a week, I consume 2 teaspoons of cayenne pepper. I do this specifically to help with widespread inflammation as capsaisin in known for healing inflammation. I am alarmed now that something I am eating is actually working against my recovery and healing, but I can't understand why a product that reduces the inflammation connected with CFS and bowel disease would be contributing to those diseases. Perhaps you made this obvious in your report, and I simply didn't understand it. But if you could make it more clear to me, in layman's language, I would be very grateful.

Thank you.

A: Yes, capsaicin has anti-inflammatory properties. However, in case of irritable bowel syndrome, capsaicin is able to increase intestinal permeability and this condition can increase the activity of the immune system lining the gut, which means low grade chronic inflammation, despite capsaicin's anti-inflammatory properties. In other words, increased intestinal permeability (and hence inflammation) exceeds the anti-inflammatory capacity of capsaicin. If you didn't have irritable bowel syndrome capsaicin would be an anti-inflammatory nutrient. As you may know, increased intestinal permeability allows increased passage of gut bacteria and nutrient antigens into circulation, and this is associated to CFS (see reference list of the last newsletter).

On the other hand, in the case of intestinal irritability, we recommend the use of several supplements such as Probiotics (6-9 billions/day), Prebiotics (2-4 grams/day, L-glutamine (0,2grs/kg/day), Zinc (25mg/day), vitamin D3 (test your blood levels and be sure to be in the 50-70ng/ml range) and omega-3 fatty acids (4 grams a day at the beginning).

We hope this helps.



Q: I am a personal coach working with some clients on health issues. At a table discussion last week a colleague mentioned that amaranth and quinoa are exceptions in the general GRAIN category and therefore acceptable in the Paleo Diet. I think not, but would like your opinion.

A: You are correct. Quinoa and amaranth are grain-like crops with potential harmful substances namely saponins. Saponins have been demonstrated to increase intestinal permeability which is one of the factors contributing to many autoimmune diseases, as well as irritable bowel syndrome. So, we recommend to avoid quinoa and amaranth, specially if you suffer from an autoimmune disease.



Q: I am not a fan of the taste of shellfish or seafood. Can I still obtain the same benefits of this diet if I only eat the meat and not any of the suggested fish or seafood?

A: There are a lot of crucial substances for optimal health in fish and seafood such as omega-3 fatty acids, zinc, selenium, vitamin E, etc. So, if you can't eat it we suggest you to take some supplements, such as:
  • Omega-3 fatty acids: EPA+DHA 3-4 grams a day
  • Zinc 25mg a day
  • Multivitamin/multimineral supplement
Eat lean meat to ensure an adequate protein balance.