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Cordain Newsletter - Nightshades part 2
« on: June 12, 2010, 04:33:19 PM »
Consumption of Nightshade Plants (Part 2) - by Loren Cordain, Ph.D., Professor

Editor's note: Dr. Cordain latest paper on paleo nutrition discusses the consumption of the nightshade family of plants (potatoes, tomatoes, and chili peppers). We will publish this paper in three parts in the free weekly edition of The Paleo Diet Update, in addition to making the newsletters available for purchase in our web store the following week for a limited time. Afterwards, this paper will be available in its entirety from our web store. If you were not a subscriber for last week’s installment of the paper you may purchase last week’s edition from our web store. Note that the numbering of figures, tables and references in this week's installment reflect the paper in its entirety.

Consumption of Nightshade Plants, Human Health and Autoimmune Disease
Part 2: Tomatoes

In addition to potatoes, tomatoes represent another nightshade which increases intestinal permeability25. The primary tomato saponin which causes a leaky gut is the glycoalkaloid, ?-tomatine. Table 4 below shows the concentration of ?-tomatine in a variety of tomatoes and tomato food products. Note that smaller and unripe tomatoes have noticeably increased concentrations of ?-tomatine, whereas this compound is barely detectable in a standard ripe, red tomato. In contrast, ketchup, green salsa, pickled green tomatoes and cherry tomatoes are all concentrated sources of ?-tomatine. Although tomatoes typically maintain lower concentrations of glycoalkaloids than potatoes, they are more potent than potatoes in disrupting the intestinal membrane and promoting a "leaky gut"27.

Table 4. ?-tomatine concentrations (mg/kg) in tomatoes and tomato food products. Adapted from reference 26.
Type of Tomato or Tomato Product    ?-tomatine concentration (mg/kg)
1. Unripe, small immature green    548.0    
2. Unripe medium immature green    169.0    
3. Pickled green tomatoes (Brand A)    71.5    
4. Unripe pickled green    28.0    
5. Pickled green tomatoes (Brand B)    28.0    
6. Green salsa    27.5    
7. Sundried red tomatoes    21.0    
8. Unripe green large    16.0    
9. Unripe large immature green    10.0    
10. Sungold cherry tomatoes    11.0    
11. Fried Green tomatoes    11.0    
12. Microwaved green tomatoes    11.0    
13. Yellow cherry tomatoes    9.7    
14. Ketchup    8.6    
15. Red Sauce    5.7    
16. Yellow pear cherry tomatoes    4.5    
17. Tomato juice    2.8    
18. Red cherry tomatoes    2.7    
19. Condensed tomato soup    2.2    
20. Red pear cherry tomatoes    1.3    
21. Medium yellow tomatoes    1.3    
22. Large yellow tomatoes    1.1    
23. Stewed canned tomatoes    1.1    
24. Ripe red beefsteak tomato    0.9    
25. Green zebra tomatoes    0.6    
26. Roma    0.4    
27. Standard red ripe tomato    0.3    

In addition to ?-tomatine, tomatoes contain another anti-nutrient called tomato lectin (TL) which rapidly crosses the gut barrier and enters into the bloodstream in humans28. The concentration of TL in tomatoes and tomato products is between 3.0 – 6.0 mg/kg29. More recently, TL has been employed by the pharmaceutical industry to experimentally deliver large molecular weight drugs across the gut barrier30, 31. The simultaneous presence of a saponin and a lectin capable of binding gut tissue has an additive effect upon intestinal permeability32. Hence, certain tomatoes and tomato food products contain both saponins and a lectin which compromise intestinal function and promote a "leaky gut." No dietary interventions have ever been carried out in living humans to determine if tomato or potato consumption may adversely affect the immune system and promote inflammation, autoimmune disease and other chronic inflammatory diseases.

Tomatoes and Autoimmune Diseases

Having said this, a convincing body of literature from animal studies shows that ?-tomatine is a powerful stimulator of the immune response – so much so that it is employed in vaccines as an adjuvant. Any substance which increases the potency of a vaccine is called an adjuvant. Autoimmune diseases and vaccines have numerous immunological similarities: vaccines "pre-program" the immune system using elements within the vaccine to attack a foreign invader; whereas autoimmune diseases result in the immune system attacking one or more of the body’s own tissues.

Before I can address how tomatoes may be involved with autoimmune diseases, I’ve got to briefly explain how vaccines and adjuvants work. The immune response is normally a healthy reaction because it allows our bodies to detect foreign antigens (proteins) derived from invading microbes and take appropriate steps via the immune system to destroy these organisms. Medicine has taken advantage of this naturally occurring response and has utilized it to prevent diseases in the form of vaccines. With a typical vaccine, dead or weakened microorganisms are injected into the body with a hypodermic needle and syringe. The immune system then recognizes the vaccine antigens as foreign and destroys them, and in the process learns to "remember" them. When the "real" (virulent) version of the vaccine antigen appears, the immune system recognizes the invading microbe and destroys it thereby preventing the disease. With an autoimmune disease, it is as if this very same process occurs, except that the immune response is directed at one or more of the body’s own tissues or organs.

When immunologists first began to manufacture vaccines they realized that many vaccines simply didn’t work with weakened viruses or bacteria alone. They simply didn’t "rev" up the immune system sufficiently to result in a full blown immune response. It was eventually discovered that by mixing weakened or dead microbes with another compound called an adjuvant the effectiveness of the vaccine was increased and full immunity could be established. The three most commonly used adjuvants are 1) alum (aluminum hydroxide), 2) Freund’s adjuvant (an antigen solution emulsified in mineral oil, used as an immunopotentiator or compound that boosts the immune system) and 3) Incomplete Freund’s adjuvant (the same adjuvant, but without the mycobacterial components). Of these three, only alum is licensed for human use; the other two are used primarily in animals.

So from what I’ve explained, you might expect it possible for scientists to cause autoimmune diseases by creating vaccines containing some of the body’s own tissues (antigens). Clearly, it would be unethical to deliberately cause an autoimmune disease in humans, but experiments in animals confirm that organ specific autoimmune diseases can be caused by injecting a self-antigen with a powerful adjuvant such as Freund’s33, 34. Neither the adjuvant alone nor the self-antigen typically results in autoimmunity in animals33-35. Now the question arises, is it possible that we can unknowingly be exposed to "natural" vaccines (containing pathogens plus adjuvants) that trick our immune systems into developing immunity against our own tissues?

As immunologists further developed vaccines, instead of injecting the foreign antigen with a hypodermic needle through the skin, they attempted to initiate an immune response by having subjects swallow a capsule containing the foreign antigen. Invariably, these experiments failed because dendritic cells in the gut which normally process foreign antigens did not elicit an immune response, but rather were nonreactive. This nonreactive state by dendritic cells is actually the normal or default response called oral tolerance, and prevents immune responses to non-harmful dietary and microbial antigens. Immunologists discovered that if they administered the foreign antigen containing capsule along with an adjuvant, they could now prevent oral tolerance by dendritic cells and cause a full blown immune response36-38. So if a gut borne antigen is simultaneously present with a gut borne adjuvant, the stage is set for promoting an immune response that may lead to an autoimmune disease if molecular mimicry exists between the gut borne antigen and one of the body’s own tissues.

Of the common autoimmune diseases (Table 5), infectious agents such as viruses and bacteria are thought to be the most likely environmental trigger39. How viruses and bacteria ultimately set off an autoimmune response is not completely understood, but many scientists40-42 (including me15) believe it is through a process called molecular mimicry whereby amino acid sequences from viruses and bacteria resemble amino acid sequences in our body’s organs and tissues (see Figure 2 below). This similarity in molecular structure between infectious agents and our body’s own tissues sometimes confuses certain components of the immune system causing "self tolerance" to break down, thereby resulting in the destruction of tissues and organs by the immune system.

Table 5. Common autoimmune diseases.
Disease    Tissue/Organ Affected    Prevalence
Alopecia areata    Hair follicle    170 per 100,000
Ankylosing spondylitis    Spine and sacroiliac joints    129 per 100,000
Autoimmune urticaria    Skin    330 per 100,000
Celiac disease    Small intestine    400 per 100,000
Crohn's disease    Gastrointestinal tract    184 per 100,000
Diabetes (type 1)    Pancreas    120 per 100,000
Graves' disease    Thyroid gland    1,120 per 100,000
Hashimoto's thyroiditis    Thyroid gland    9,460 per 100,000
Lupus erythematosis    Any tissue in the body    510 per 100,000
Multiple sclerosis    Central nervous system    140 per 100,000
Psoriasis    Skin    2,020 per 100,000
Rheumatoid arthritis    Joints    920 per 100,000
Scleroderma    Skin, many other organs    110 per 100,000
Sjögren's syndrome    Salivary and tear glands    370 per 100,000
Ulcerative colitis    Colon    35-100 per 100,000
Uveitis    Anterior eye    850 per 100,000
Vitiligo    Skin    740 per 100,000

Exposure to viruses, bacteria and other microbes most typically occurs in a number of ways: 1) the microbe may enter your body through mucous membranes in your nose, mouth or gastrointestinal or genitourinary tracts, or 2) it enters your body through a break in your skin caused by a wound or insect/vector bite. On a daily basis, we are regularly exposed to microbes via all of these pathways, however far and away the greatest regular exposure to microbes comes from viruses and bacteria that reside in our intestines43. In healthy people the gut tissue represents a powerful barrier that prevents microorganisms within the gut from entering the bloodstream. Additionally, certain components of the immune system and the liver act to prevent proteins (antigens) from gut microbes from entering circulation. However, under certain circumstances gut permeability may increase thereby facilitating the first step for entry of microbe antigens and food antigens into circulation14, 15.

Figure 2. Schematic representation of the molecular mimicry process.

An emerging consensus among scientists who study autoimmune disease is that a number of autoimmune diseases (including type 1 diabetes, Crohn’s disease, dermatitis herpetiformis, rheumatoid arthritis, celiac disease, and ankylosing spondylitis) have an environmental trigger that originates from a leaky gut, thereby allowing microbe and food antigens continual access to the immune system14, 15, 44, 45.

As I have previously outlined, tomatoes contain two antinutrients (tomato lectin and ?-tomatine) which increase intestinal permeability. Additionally, both of these compounds may simultaneously bind the cell walls of various gut bacteria, viruses and partially digested bacteria/viruses thereby forming complexes containing: 1. tomato lectin + viral or bacterial antigen46, 47 and/or 2. ?-tomatine + viral or bacterial antigen. In other words, both tomato lectin and ?-tomatine may act as a "Trojan Horse," thereby causing the intestines to become leaky while simultaneously binding to and pulling bacterial and viral antigens past the gut barrier. A healthy immune system response to these foreign antigens is "oral tolerance" (ignoring) of these gut borne invaders. However if an adjuvant is simultaneously present with these bacterial or viral antigens, then a full blown immune response can occur. Well you guessed it, ?-tomatine not only increases intestinal permeability but also is a powerful immunological adjuvant48-54 used in the manufacture of vaccines. Similarly, tomato lectin acts as a potent adjuvant46.

In the wild world of the internet and elsewhere, urban legend has it that consumption of nightshade (tomato, potato, eggplant, bell peppers, hot peppers, and paprika) free diets may improve symptoms in some rheumatoid arthritis patients55, 56. Is there any scientific basis for these alleged anecdotal observations? Indeed, in theory a growing body of scientific studies points toward the use of nightshade-free diets in the treatment of rheumatoid arthritis and other autoimmune diseases. To date, no animal or human experiments have been conducted that confirm or deny this hypothetical evidence. As has been my policy in the past, I believe that anyone suffering from an autoimmune disease should remove suspect foods from the diet for an extended period and then monitor symptoms. If conditions get worse after you re-introduce the food, then this particular food may be problematic for you and should not be part of your lifelong diet.

Because the effects of saponins on membrane function and intestinal permeability are dose dependent25, 27, then the more saponins you consume the greater the potential for your gut to become leaky. To date, little is known about the dietary threshold concentrations of saponins required to elicit a leaky gut in humans and its associated adverse health effects. My recommendation for healthy people would be to avoid potatoes for all of the reasons I have previously listed (see last week’s newsletter for part 1 of this paper and the discussion of potatoes). However, because ripe red tomatoes have such low concentrations of ?-tomatine, and because they are rich sources of vitamins, minerals and other healthful nutrients, only people with an autoimmune disease or allergies should consider limiting their fresh ripe tomato intake.

Next week we will publish part 3 of this article: Chili Peppers.

References:

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  29. Nachbar MS, Oppenheim JD, Thomas JO. Lectins in the U.S. Diet. Isolation and characterization of a lectin from the tomoto (Lycopersicon esculentum). J Biol Chem 1980;2056-2061.
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  32. Alvarez JR, Torres-Pinedo R. Interactions of soybean lectin, soyasaponins, and glycinin with rabbit jejunal mucosa in vitro. Pediatr Res 1982;16:728-31.
  33. Fairweather D, Kaya Z, Shellam GR, Lawson CM, Rose NR. From infection to autoimmunity. J Autoimmun. 2001 May;16(3):175-86.
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  35. Fairweather D, Rose NR. Women and autoimmune disease. Emerg Infect Dis 2004;10:2005-2011.
  36. Mcl Mowat A. Dendritic cells and immune responses to orally administered antigens. Vaccine 2005;23:1797-99.
  37. Strobel S, Mowat MA. Oral tolerance and allergic responses to food proteins. Curr Opin Allergy Clin Immunol. 2006 Jun;6(3):207-13.
  38. Benko S, Magyarics Z, Szabó A, Rajnavölgyi E. Dendritic cell subtypes as primary targets of vaccines: the emerging role and cross-talk of pattern recognition receptors. Biol Chem. 2008 May;389(5):469-85.
  39. Progress in Autoimmune Disease Research. The Autoimmune Disease Coordinating Committee Report to Congress. U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases. Bethesda (MD), 2005. http://www3.niaid.nih.gov/topics/autoimmune/PDF/ADCCFinal.pdf
  40. Lee S, Levin MC. Molecular mimicry in neurological disease: what is the evidence? Cell Mol Life Sci. 2008 Apr;65(7-8):1161-75.
  41. Blank, M., Barzilai, O. and Shoenfeld, Y. (2007) Molecular mimicry and auto-immunity. Clin. Rev. Allergy Immunol. 32, 111–118.
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  47. De Aizpurua HJ, Russell-Jones GJ. Oral vaccination. Identification of classes of proteins that provoke an immune response upon oral feeding. J Exp Med 1988;167:440-451.
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  51. Heal KG, Sheikh NA, Hollingdale MR, Morrow WJ, Taylor-Robinson AW. Potentiation by a novel alkaloid glycoside adjuvant of a protective cytotoxic T cell immune response specific for a preerythrocytic malaria vaccine candidate antigen.Vaccine. 2001 Jul 20;19(30):4153-61.
  52. Rajananthanan P, Attard GS, Sheikh NA, Morrow WJ.Novel aggregate structure adjuvants modulate lymphocyte proliferation and Th1 and Th2 cytokine profiles in ovalbumin immunized mice.Vaccine. 1999 Aug 20;18(1-2):140-52.
  53. Sheikh NA, Rajananthanan P, Attard GS, Morrow WJ.Generation of antigen specific CD8+ cytotoxic T cells following immunization with soluble protein formulated with novel glycoside adjuvants. Vaccine. 1999 Aug 6;17(23-24):2974-82.
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  55. http://noarthritis.com/research.htm
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Re: Cordain Newsletter - Nightshades part 2
« Reply #1 on: June 14, 2010, 12:06:27 AM »
Quote
only people with an autoimmune disease or allergies should consider limiting their fresh ripe tomato intake.
I understand that Dr. Cordain has to err on the side of caution, to avoid being attacked by the scientific community, but I would go one step further. I would recommend that everyone try eliminating all night shades for 2-4 weeks to see what effects, if any, it has, because autoimmune disease is not black and white. It's not an on/off switch that you either have or don't. I see it as more of a spectrum of illness from very little to severe, and even people who don't have full-blown clinical autoimmune disease have reported benefits from eliminating various nightshades. I didn't think nightshades were much of a problem for me (other than maybe green peppers and tomato sauce) until I eliminated them and experienced significant benefits. There are other foods that are better sources of the nutrients they provide.
>"When some one eats an Epi paleo Rx template and follows the rules of circadian biology they get plenty of starches when they are available three out of the four seasons." -Jack Kruse, MD
>"I recommend 20 percent of calories from carbs, depending on the size of the person" -Ron Rosedale, MD (in other words, NOT zero carbs) http://preview.tinyurl.com/6ogtan
>Finding a diet you can tolerate is not the same as fixing what's wrong. -Tim Steele
Beware of problems from chronic Very Low Carb

Offline lorenmark

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Re: Cordain Newsletter - Nightshades part 2
« Reply #2 on: May 09, 2013, 05:09:22 AM »
This makes perfect sense to me, what this is saying is that autoimmune issues have two parts:

1. An adjuvant must be present in the body to "prime" the immune system
2. A separate dietary trigger must be consumed to "set it off"

This is extremely interesting to me because most people are walking around with adjuvants in their mouths, in the form of amalgam fillings. Combine this with a dietary allergen (gluten, dairy, ect..) and the body goes autoimmune.


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Re: Cordain Newsletter - Nightshades part 2
« Reply #3 on: May 09, 2013, 06:27:25 AM »
And don't forget the Old Friends Hypothesis and insufficient hormesis.
>"When some one eats an Epi paleo Rx template and follows the rules of circadian biology they get plenty of starches when they are available three out of the four seasons." -Jack Kruse, MD
>"I recommend 20 percent of calories from carbs, depending on the size of the person" -Ron Rosedale, MD (in other words, NOT zero carbs) http://preview.tinyurl.com/6ogtan
>Finding a diet you can tolerate is not the same as fixing what's wrong. -Tim Steele
Beware of problems from chronic Very Low Carb