Tag Archives: gluten

Gluten Free | The Paleo Diet

Last week, The New York Times published an op-ed by Roger Cohen, its International Affairs and Diplomacy correspondent, regarding…wait for it – gluten!1 Has gluten become the nefarious “sticking point” that underlies our most critical diplomatic issues? Or was this just another of Cohen’s haughty rants against people who purchase organic food, implement health-optimizing diets, and keep abreast of nutrition science research? Spoiler alert – it’s the latter.

The gist of Cohen’s latest article, “This Column is Gluten-Free,” is that wheat has gotten a bad rap, despite graciously feeding the world for the past 12,000 years. Cohen acknowledges that gluten is harmful for the roughly 1% of the population that has celiac disease, but what about the remainder of the estimated 30% of Americans who are cutting back on gluten or going gluten-free?2

Does non-celiac gluten sensitivity (NCGS) exist? Is there evidence that gluten can be harmful for the general population? According to Cohen, people who eschew gluten (celiac patients excluded) are “self-indulgent” narcissists with imaginary food intolerances. “Having a special dietary requirement,” Cohen asserts, “is one way to feel special in the prevailing ‘me’ culture.”

Narcissism seems to be Cohen’s favorite buzzword when describing nutrition-motivated people, particularly those who buy organic food and avoid gluten. In this capacity, he uses the n-word no less than three times in his latest article, and in a previously article, he scolds the “affluent narcissism” of the upper middle class, people who purchase organic food while the poor “get a lot more nutrients from the two regular carrots they can buy for the price of one organic carrot.”3

This gets to the crux of Cohen’s ethos. He takes issue with individualism and self-determination, preferring a social structure whereby the balance of power is significantly tilted toward the state. In yet another recent article, he comments on a Pew Global Attitudes survey for which Americans and Europeans were asked which is more important,

  1. “freedom to pursue life’s goals without state interference,” or
  2. “state guarantees that nobody is in need.”

Much to Cohen’s dismay, 58% of Americans say the former is more important (compared to 62% of Europeans who prefer the latter).4 He then suggests the government should be more empowered to dictate how people eat, starting with a “coordinated policy action” designed to reduce sugar consumption, but where would it end?

What if the government decided that gluten is only dangerous for those with celiac disease? Could it outlaw a generalized form of “gluten-free” labeling? After all, because the US government supports GMO foods and deems them absolutely safe, it has repeatedly thwarted legislative attempts to implement mandatory GMO labeling. Not surprisingly, Cohen also strongly supports GMO foods:

“To feed a planet of 9 billion people,” he insists, “we are going to need high yields not low yields; we are going to need genetically modified crops; we are going to need pesticides and fertilizers and other elements of the industrialized food processes that have led mankind to be better fed and live longer than at any time in history.”5

Feeding the poor is a noble goal, even with subsistence-level nutrition, but so is health optimization for individuals, which is a primary goal of nutrition science research. These goals, however, are not incompatible; they are complementary. Nevertheless, Cohen’s steadfast resolve to restore wheat’s “amber waves” reputation prevents him from critically assessing and/or acknowledging the scientific research on gluten, the dangers of which extend far beyond just celiac patients.

Just last month, for example, researchers at the National Institutes of Health published a randomized, double-blind, placebo-controlled, cross-over trial on people who don’t have celiac disease but believe themselves to be gluten sensitive. The results? “The severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo.”6

For further reading on the science behind how gluten can damage the gut and compromise health, check out Trevor Connor’s excellent 5-article review, “The Wheat Series.” Nutrition is always vulnerable to politicization, but rather than choosing sides, why not seek mutually beneficial solutions to complex, interdependent challenges? Being kind and respectful also helps immensely (leave the diet-shaming for the narcissists).

References

1. Cohen, R. (October 19, 2015). This Column is Gluten-Free. The New York Times. Retrieved from //www.nytimes.com/2015/10/20/opinion/this-column-is-gluten-free.html?_r=0

2. Strom, S. (February 17, 2014). A Big Bet on Gluten-Free. The New York Times. Retrieved from //www.nytimes.com/2014/02/18/business/food-industry-wagers-big-on-gluten-free.html

3. Cohen, R. (September 6, 2012). The Organic Fable. The New York Times. Retrieved from //www.nytimes.com/2012/09/07/opinion/roger-cohen-the-organic-fable.html

4. Cohen, R. (August 5, 2015). Incurable American Excess. The New York Times. Retrieved from //www.nytimes.com/2015/08/07/opinion/roger-cohen-incurable-american-excess.html

5. Cohen, R. (August 5, 2015). Incurable American Excess. The New York Times. Retrieved from //www.nytimes.com/2015/08/07/opinion/roger-cohen-incurable-american-excess.html

6. Di Sabatino, A., et al. (September 2015). Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clin Gastroenterol Hepatol, 13(9). Retrieved from //www.ncbi.nlm.nih.gov/pubmed/25701700

The Wheat Series Part 4: Home Invasion | The Paleo Diet

Did you miss The Wheat Series Part 1: Wheat and the Immune System? Read it HERE.
Did you miss The Wheat Series Part 2: Opening the Barrier to Poor Gut Health? Read it HERE.
Did you miss The Wheat Series Part 3: Setting Off the Bacterial Alarms – With or Without the Bacteria Read it HERE.

Nothing is scarier than someone invading your home. You’re nearly asleep when you hear the sound of something rustling downstairs. Instantly you’re awake and your internal alarm bells go off. You grab the phone. Fortunately the police are nearby and arrive almost instantly. They’ll catch the invader. You have nothing left to fear. Or do you?

The police enter the darkened house to a confusing scene. Your teenage son, sneaking home from the party you told him not to go to, has stumbled into the unknown invader. Meanwhile, your partner has entered the other side of the room carrying a baseball bat. The police can just make out three figures in the dark. Several seem armed and one may be a hostage. An officer draws her gun, but who does she point it at?

Sadly, it’s not always a happy ending. Innocent people are killed in their own homes all too often.

While a home invasion is something most of us will hopefully never experience, dealing with invaders is something our bodies have to handle thousands of times each day. And just like a thief entering your house, it would seem the job of identifying the invader – bacteria and viruses – should be a simple task. But it’s not.

The immune system – the police of our bodies – has to deal with equally dark and confusing scenarios as it tries to differentiate dangerous invaders from our own cells, beneficial microflora, and food.1-3

Fortunately, it has evolved remarkably complex systems that make it very good at determining which is which.

One food however is even better at breaking in, turning out the lights, and making the police point the gun in the wrong direction.  Wheat.

In Parts 1, 2, and 3 of this series on wheat, we talked about how wheat affects the three things that can cause the digestive immune system to dysfunction. The first was increased permeability (Part 2), the second was excess bacterial stress (Part 3). The third is the subject of this post – harmful dietary antigens.

ANTIGENS – IDENTIFYING THE INVADER

Antigens are critically important to our immune defenses. In fact, without them, most of our immune system wouldn’t be able to function. Which begs the question – what exactly are antigens?

They are just molecules. And not really any special type of molecule. Antigens exist in everything – bacteria, viruses, our food, even our own cells. As long as our immune cells can bind to it and identify it, it’s an antigen.4

Certain cells in our immune system, called antigen presenting cells (APCs), travel around our bodies “sampling” everything they encounter. They aren’t particular – they’re just as likely to check out our own cells as a foreign bacterium. They chew everything they sample into small molecules and present these antigens to the brains of our immune system – T Cells.4

T Cells are trained from birth not to respond to our own unique self-antigens which makes them remarkably good at identifying anything foreign. Together, T Cells and APCs determine when an antigen isn’t self and more importantly if it’s something to be worried about.5

Think of an antigen as an ID card. APCs and T Cells are the police hunting through the house for anyone who doesn’t belong. The more hot-headed APC likes to slam anyone it encounter up against the wall and takes their ID. It’s the T Cell who looks over their identification and decides if they belong or not. It’s the misfit buddy cop movie of our bodies.

The problem is, just like in the movies, ID cards are easy to fake. Some viruses have evolved the ability to mimic our own antigens in an attempt evade detection.6, 7

And like your daughter’s boyfriend who tends to sneak through the window at night, not everything from outside is bad (though some fathers reading this may be thinking “shoot him.”) Beneficial bacteria in our gut are foreign, but we’ve learned to live in synergy with them.2, 3, 8 Likewise, all food is technically foreign, but an immune response to we eat would lead to debilitating allergic reactions and worse.9-11
To deal with this extra level of complexity, our immune systems have developed two sophisticated “interogation” techniques – co-stimulation and oral tolerance.

CO-STIMULATION (OR THE SECOND SIGNAL)

Just identifying an antigen as foreign actually isn’t enough for a T Cell to start an immune response. The T Cell must also receive an activating signal from the APC as it presents the antigen. The APC gives this second signal when it has been exposed to a large amount of the antigen or if the body is in an inflamed state.5, 12-15

It’s the equivalent of the T Cell asking the APC “I don’t recognize this guy, should I draw my gun?” Surprisingly, the tough guy APC generally replies “What this wimp? Nah I can take him.”

ORAL TOLERANCE

This is a fancy term for not reacting to food. A special type of APC, called dendritic cells (DCs), specializes in reaching into the gut to sample food particles and microflora. Most of the time it presents the antigens with the message: “This is food. Don’t do anything.”1, 12, 14 DCs work in conjunction with a special T cell called T Regulatory (Treg) cells that respond to self-antigens instead of foreigners. But unlike other T cells, when activated, Tregs supress the immune system.12, 16-18

These two cells are the police movie equivalent of the by-the-books pencil-pushers who constantly tells the loose cannon to holster his gun. Fortunately, in our bodies, the pencil-pushers are in control most of the time.17

The image below shows the antigen identification system in action. Plasma cells, macrophages and DCs are all APCs. As you can see, in the healthy gut, Tregs dominate.19

WHEAT: THE MASTER CRIMINAL

For the rest of this post we’ll talk about how wheat is essentially a “master criminal” able to flip our antigen identification system on its head. But unlike a virus, wheat doesn’t break the system to try to evade detection. Instead it intentionally sets of the alarms and provokes the immune system to draw its guns. Tragically it’s also very good at getting immune cells to fire on the wrong target.20

THE LOCK PICKING PICKPOCKET

Part 2 of this series explained how wheat effectively opens the tight junctions of our gut allowing bacteria, large molecules and gliadin from wheat itself to enter the body.21-24

But that’s not the only way wheat breaks in.

A protein in wheat called Wheat Germ Agglutinin (WGA) is very good at binding to the cells in our digestive tract and passing right through them into our blood stream.13, 25, 26 WGA can also bind other particles. So not only can it gain entry into circulation, but it can carry antigens from the gut with it.27, 28

THE POLICE PROVOKER

Above, we discussed how the immune system doesn’t automatically respond to foreign antigens. It first needs a co-stimulation before drawing its guns. We also covered the two things that cause APCs to provide this second signal.

The first was exposure to a large quantity of antigens. By “picking the locks” to the house, wheat essentially flings open the doors allowing a huge flow of antigens from the gut into the body.

The second thing that gets APCs to provide the co-stimulation is inflammation. In Part 3 of this series, I explained how wheat tricks the body into believing it is under perpetual bacterial stress.29-33 This creates a constant inflammatory state that causes the once suppressive DCs to flip and start activating the immune system.34, 35 Other APCs follow suite.30, 32, 36-39

In other words, the once tolerant “pencil-pusher” cops of the immune system become gun happy in a way that would make Arnold Schwarzenegger cringe.13

In short, wheat ensures there’s a co-stimulation. Wheat also breaks tolerance:

WGA is able to enter the body bypassing all the mechanisms of oral tolerance.25, 28 So, the first time WGA and the food antigens bound to it are exposed to the immune system is in circulation where the response is almost always inflammatory.

Worse, in multiple studies of wheat’s effect on mice and humans, wheat reduced the levels of Treg (the immune-suppressors) in favor of a type of T Cell called Th17.29, 34, 40 We’ll explore this shift in greater detail in Part 5. All you need to know for now is Th17 is the loose cannon cop who shoots first, asks questions later.41-43

THE RED HERRING

This is the definition of an autoimmune disease. It is a condition where the immune system identifies self-antigens as foreign and attacks its own body.44 In other words, the police accidently shoot the residents.

One popular theory of how autoimmune disease comes about is the viral mimicry theory. A virus enters the body that mimics self-antigens.14 In the process of fighting the virus, the immune system ends up identifying the mimicked self-antigens as foreign.6, 7, 45

For this to happen, the body has to be in an inflamed state. That way APCs provide the co-stimulation required and they also suppress Treg cells which would otherwise prevent a reaction to self. This is why the theorists looked at viruses. Not only would they mimic self-antigens, they’d also create the necessary inflammation.7, 45

However, we’ve just seen that wheat does an equally good job of providing the co-stimulation and shutting down Treg’s. And wheat may provide the mimicry as well, so forget the virus.20, 44, 46-48

Of the over 100 autoimmune conditions identified, the trigger has been discovered for only a handful. One of those is celiac disease. In this condition, gliadin from wheat binds a protein in the body called tissue transglutaminase (tTG). The immune system reacts to tTG-gliadin antigens causing it to attack the digestive tract.39, 49, 50

Gliadin may also cross-react with neural components of the brain and contribute to conditions like multiple sclerosis, gluten ataxia, and autism.46, 47, 51 Similarly, WGA is able to bind to many different cells once inside the body.20, 26, 31 While responding to WGA, the immune system will sometimes also react to its binding tissues.20, 52

What all of this amounts to is the ending to that home invasion story none of us want to hear. Wheat and the police end up in a tense standoff and guns are drawn. Tragically your son gets mistaken for one of the invaders and gets killed in the cross-fire.

Fortunately, while wheat can dysregulate the immune system in all of us, not everyone who eats it develops an autoimmune disease. In the final part of this series we’ll talk about how genetic susceptibility is required for disease.

Read The Wheat Series Part 5: Pulling the Trigger on a Loaded Chamber HERE

 

REFERENCES

[1]du Pre, M.F. and J.N. Samsom, Adaptive T-cell responses regulating oral tolerance to protein antigen. Allergy, 2011. 66(4): p. 478-90.

[2]McFall-Ngai, M., Adaptive immunity: care for the community. Nature, 2007. 445(7124): p. 153.

[3]Ohnmacht, C., et al., Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity. Cell Microbiol, 2011. 13(5): p. 653-9.

[4]Murphy, K., et al., Janeway’s immunobiology. 8th ed. 2012, New York: Garland Science. xix, 868 p.

[5]Lenschow, D.J., T.L. Walunas, and J.A. Bluestone, CD28/B7 system of T cell costimulation. Annu Rev Immunol, 1996. 14: p. 233-58.

[6]Oldstone, M.B.A., Molecular mimicry and immune-mediated diseases. Faseb Journal, 1998. 12(13): p. 1255-1265.

[7]Wucherpfennig, K.W. and J.L. Strominger, MOLECULAR MIMICRY IN T-CELL-MEDIATED AUTOIMMUNITY – VIRAL PEPTIDES ACTIVATE HUMAN T-CELL CLONES SPECIFIC FOR MYELIN BASIC-PROTEIN. Cell, 1995. 80(5): p. 695-705.

[8]Smith, P.D., et al.,Intestinal macrophages and response to microbial encroachment. Mucosal Immunol, 2011. 4 (1): p. 31-42.

[9]Ahmed, T., et al., Immune response to food antigens: kinetics of food-specific antibodies in the normal population. Acta Paediatr Jpn, 1997. 39(3): p. 322-8.

[10]Seibold, F., Food-induced immune responses as origin of bowel disease? Digestion, 2005. 71(4): p. 251-260.

[11]Ganeshan, K., et al., Impairing oral tolerance promotes allergy and anaphylaxis: A new murine food allergy model. Journal of Allergy and Clinical Immunology, 2009. 123(1): p. 231-238.

[12]Williamson, E., G.M. Westrich, and J.L. Viney, Modulating dendritic cells to optimize mucosal immunization protocols. J Immunol, 1999. 163(7): p. 3668-75.

[13]de Aizpurua, H.J. and G.J. Russell-Jones, Oral vaccination. Identification of classes of proteins that provoke an immune response upon oral feeding. J Exp Med, 1988. 167(2): p. 440-51.

[14]Stepniak, D. and F. Koning, Celiac disease–sandwiched between innate and adaptive immunity. Hum Immunol, 2006. 67(6): p. 460-8.

[15]Scalapino, K.J. and D.I. Daikh, CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev, 2008. 223: p. 143-55.

[16]Battaglia, M., et al., IL-10-producing T regulatory type 1 cells and oral tolerance. Ann N Y Acad Sci, 2004. 1029: p. 142-53.

[17]Wing, K. and S. Sakaguchi, Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol, 2010. 11(1): p. 7-13.

[18]Veldman, C., A. Nagel, and M. Hertl, Type I regulatory T cells in autoimmunity and inflammatory diseases. International Archives of Allergy and Immunology, 2006. 140(2): p. 174-183.

[19]Macdonald, T.T. and G. Monteleone, Immunity, inflammation, and allergy in the gut. Science, 2005. 307(5717): p. 1920-5.

[20]Vojdani, A., Lectins, agglutinins, and their roles in autoimmune reactivities. Altern Ther Health Med, 2015. 21 Suppl 1: p. 46-51.

[21]Drago, S., et al., Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol, 2006. 41(4): p. 408-19.

[22]Fasano, A., Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation Living Life on the Edge of the Wall. American Journal of Pathology, 2008. 173(5): p. 1243-1252.

[23]Fasano, A., Surprises from celiac disease. Sci Am, 2009. 301(2): p. 54-61.

[24]Lammers, K.M., et al., Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology, 2008. 135(1): p. 194-204 e3.

[25]Lavelle, E.C., et al., Mucosal immunogenicity of plant lectins in mice. Immunology, 2000. 99(1): p. 30-7.

[26]Pusztai, A., et al., Antinutritive effects of wheat-germ agglutinin and other N-acetylglucosamine-specific lectins. Br J Nutr, 1993. 70(1): p. 313-21.

[27]Ertl, B., et al., Lectin-mediated bioadhesion: preparation, stability and caco-2 binding of wheat germ agglutinin-functionalized Poly(D,L-lactic-co-glycolic acid)-microspheres. J Drug Target, 2000. 8(3): p. 173-84.

[28]Gabor, F., M. Stangl, and M. Wirth, Lectin-mediated bioadhesion: binding characteristics of plant lectins on the enterocyte-like cell lines Caco-2, HT-29 and HCT-8. J Control Release, 1998. 55(2-3): p. 131-42.

[29]Antvorskov, J.C., et al., Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice. Immunology, 2013. 138(1): p. 23-33.

[30]Bernardo, D., et al., Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut, 2007. 56(6): p. 889-890.

[31]Dalla Pellegrina, C., et al., Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol, 2009. 237(2): p. 146-53.

[32]Jelinkova, L., et al., Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB. FEBS Lett, 2004. 571(1-3): p. 81-5.

[33]Junker, Y., et al., Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med, 2012. 209(13): p. 2395-408.

[34]Palova-Jelinkova, L., et al., Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol, 2005. 175(10): p. 7038-45.

[35]Nikulina, M., et al., Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol, 2004. 173(3): p. 1925-33.

[36]Harris, K.M., A. Fasano, and D.L. Mann, Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clin Immunol, 2010. 135(3): p. 430-9.

[37]Palova-Jelinkova, L., et al., Pepsin digest of wheat gliadin fraction increases production of IL-1beta via TLR4/MyD88/TRIF/MAPK/NF-kappaB signaling pathway and an NLRP3 inflammasome activation. PLoS One, 2013. 8(4): p. e62426.

[38]Thomas, K.E., et al., Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol, 2006. 176(4): p. 2512-21.

[39]Tuckova, L., et al., Activation of macrophages by gliadin fragments: isolation and characterization of active peptide. J Leukoc Biol, 2002. 71(4): p. 625-31.

[40]Ejsing-Duun, M., et al., Dietary gluten reduces the number of intestinal regulatory T cells in mice. Scandinavian Journal of Immunology, 2008. 67(6): p. 553-559.

[41]Langrish, C.L., et al., IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med, 2005. 201(2): p. 233-40.

[42]Evans, H.G., et al., In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses. Proc Natl Acad Sci U S A, 2009. 106(15): p. 6232-7.

[43]Mesquita Jr, D., et al., Autoimmune diseases in the TH17 era. Braz J Med Biol Res, 2009. 42(6): p. 476-86.

[44]Sollid, L.M. and B. Jabri, Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol, 2013. 13(4): p. 294-302.

[45]Oldstone, M.B.A., MOLECULAR MIMICRY AND AUTOIMMUNE-DISEASE. Cell, 1987. 50(6): p. 819-820.

[46]Hadjivassiliou, M., et al., Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology, 2006. 66(3): p. 373-7.

[47]Vojdani, A., et al., Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci, 2004. 7(3): p. 151-61.

[48]Alaedini, A., et al., Immune cross-reactivity in celiac disease: anti-gliadin antibodies bind to neuronal synapsin I. J Immunol, 2007. 178(10): p. 6590-5.

[49]Dieterich, W., et al., Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine, 1997. 3(7): p. 797-801.

[50]Molberg, O., et al., Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Medicine, 1998. 4(6): p. 713-717.

[51]Vojdani, A., D. Kharrazian, and P.S. Mukherjee, The prevalence of antibodies against wheat and milk proteins in blood donors and their contribution to neuroimmune reactivities. Nutrients, 2014. 6(1): p. 15-36.

[52]Falth-Magnusson, K. and K.E. Magnusson, Elevated levels of serum antibodies to the lectin wheat germ agglutinin in celiac children lend support to the gluten-lectin theory of celiac disease. Pediatr Allergy Immunol, 1995. 6(2): p. 98-102.

Which Diet Best Supports Heart Health? | The Paleo Diet

“A healthy diet and lifestyle,” says the American Heart Association (AHA), “are your best weapons in the fight against heart disease.”1 But does the AHA’s recommended diet protect against heart disease better than other diets, particularly the Paleo diet?

Researchers from Eastern Michigan University (EMU) recently compared these two diets for a study published in Nutrition Research. They found that adherence to the Paleo diet for four months significantly decreases total cholesterol (TC), LDL cholesterol, and triglycerides, while increasing HDL cholesterol, compared to four months on the AHA’s recommended diet.

The AHA’s diet includes large amounts of whole grains and dairy, two food groups the Paleo diet, of course, eliminates. The AHA also discourages saturated fat, claiming, “Eating foods that contain saturated fats raises the level of cholesterol in your blood.”2 The current study, however, adds to a growing body of evidence suggesting saturated fat is heart healthy, whereas high-carbohydrate grain-based diets may worsen cardiovascular disease markers.

The EMU researchers recruited 10 men and 10 women between the ages of 40 and 62. Each had hypercholesterolemia (high cholesterol levels) and none were taking cholesterol-reducing medication. Each participant followed the AHA’s recommend diet for 4 months, followed by 4 months on the Paleo diet. Compared to baseline, TC decreased slightly (3%) following the AHA diet, followed by a “very large” 20% decrease from AHA to Paleo.3 Similarly, LDL reductions were “small” (3%) from baseline to AHA, followed by a “very large” 36% decrease from AHA to Paleo.

Weight loss occurred on both diets but was significantly better on the Paleo diet. For men, the AHA diet reduced mean body weight by 3.3 ± 2.7 kg, relative to baseline (P < .001), with an additional 10.4 ± 4.4 kg reduction following 4 months on the Paleo diet. For women, no significant weight reductions followed the AHA diet, but the Paleo diet resulted in significant 8.1 ± 5.9 kg reductions.

This study follows up on previous studies demonstrating improved lipid profiles based on Paleo diet adherence, including a 2009 study showing significant improvements after just 10 days on Paleo and another 2009 study showing significant improvements for type-2 diabetes patients following 3 months on Paleo. 4, 5 The current study, however, does have some limitations, which the researchers openly acknowledge, including a small sample size (20 participants) and the study’s racial homogeneity (predominantly white). Additionally, the study did not allow for order bias, meaning all participants first cycled through the AHA diet, followed by the Paleo diet.

Additionally, it would have also been interesting to see each diet’s impact on both small-particle and large-particle LDL. Measurements of total LDL can be misleading because small-particle LDL accumulates within the arterial walls, whereas large-particle LDL floats through the bloodstream and is generally considered benign.6 Saturated fat has been shown to change small-particle LDL into large-particle LDL.7 In this study, the Paleo diet decreased LDL cholesterol levels more than the AHA diet, but the study tells us nothing about changes in the small- and large-particle LDL.

The AHA’s recommended diet appears to be relatively ineffective for treating hypercholesterolemia. Besides encouraging an AHA-type diet, typical allopathic treatments for hypercholesterolemia often include statin drugs. Statins may reduce cholesterol favorably, but have numerous potential side effects, including myopathy, nausea, neuropathy, elevated liver enzymes, and increased risk of new-onset diabetes.8,9

With no risks and significant benefits, the Paleo diet seems to be the smartest approach to reversing hypercholesterolemia and generally improving heart health. You have nothing to lose and everything to gain going Paleo.

 

REFERENCES

[1] Healthy Eating. American Heart Association. Retrieved from //www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyEating/Healthy-Eating_UCM_310436_SubHomePage.jsp

[2] Saturated Fats. American Heart Association. Retrieved from //www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyEating/Saturated-Fats_UCM_301110_Article.jsp

[3] Pastore, RL, et al. (June 2015). Paleolithic nutrition improves plasma lipid concentrations of hypercholesterolemic adults to a greater extent than traditional heart-healthy dietary recommendations. Nutrition Research, 35(6). Retrieved from //www.nrjournal.com/article/S0271-5317%2815%2900097-4/abstract

[4] Frassetto, LA, et al. (February 2009). Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. European Journal of Clinical Nutrition, 63. Retrieved from //www.nature.com/ejcn/journal/v63/n8/full/ejcn20094a.html

[5] Jonsson, T, et al. (July 2009). Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovascular Diabetology, 8(35). Retrieved from //www.cardiab.com/content/8/1/35

[6] Tribble, DL, et al. (April 1992). Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. Atherosclerosis, 93(3). Retrieved from //www.ncbi.nlm.nih.gov/pubmed/1590824

[7] Campos, H, et al. (February 1992). Low density lipoprotein particle size and coronary artery disease. Arteriosclerosis and Thrombosis, 12(2). Retrieved from //www.ncbi.nlm.nih.gov/pubmed/1543692#

[8] Zhang, H, et al. (April 2013). Discontinuation of Statins in Routine Care Settings: A Cohort Study. Annals of Internal Medicine, 158(7). Retrieved from //annals.org/article.aspx?articleid=1671715

[9] Carter, AA, et al. (May 2013). Risk of incident diabetes among patients treated with statins: population based study. British Medical Journal, 346. Retrieved from //www.bmj.com/content/346/bmj.f2610

The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria | The Paleo Diet

Did you miss The Wheat Series Part 1: Wheat and the Immune System? Read it HERE.
Did you miss The Wheat Series Part 2: Opening the Barrier to Poor Gut Health? Read it HERE.

It’s a battle that’s been waging for millions of years. Viruses, bacteria, and a variety of pathogens looking for a nice warm home have evolved more and more sophisticated techniques to evade our immune systems. In response, our immune systems developed an array of specialized cells to launch remarkably targeted attacks at these unwanted invaders.

In the face of this cellular army, pathogens discovered one of their best weapons is a microscopic form of hide-and-seek.

Viruses mimic our bodies so immune cells pass them by.1, 2 Meningitis hangs out in the nervous system where immune cells dare not go, and HIV takes up home in immune cells themselves – after, of course, dismantling a few defenses.

These are all ways of telling the immune system “keep moving, nothing to see here.”

But what would happen if instead of looking for a good hiding place, an invader actually tried to set off the immune system alarm bells? More importantly, why would an invader want to do that?

Well, imagine you’re a plant. When some hungry animal looks at you and says “lunch” you can’t really run away. Nor can you fight back. So what do you do?

You make sure that after the animal has its meal, it is sick enough to think twice about ever touching one of your brethren.

Enter wheat.

In Part One of this series on wheat, I talked about how the normally sluggish digestive immune system can become inappropriately inflamed and lead to disease. Three things can cause this: intestinal permeability (leaky gut); chronic or too high a bacterial load; and dietary antigens.

Wheat has the unique distinction of influencing all three.

The first, intestinal permeability, is promoted by wheat through the release of zonulin.3-5 We covered that in Part Two.

Let’s get to Part Three – chronic or too high a bacterial load.

Of course, you’ve probably already realized that wheat is not bacteria. True. But the same way viruses mimic our bodies, wheat has evolved ways to “mimic” bacteria. All with the purpose of setting off the immune system alarm bells – whether the bacteria is there or not.

BACTERIAL ALARM BELLS

Our bodies actually like bacteria.

At least when they stay where they belong – in the gut.6-9 In fact, in Part One, we talked about how much of our digestive immune system evolved to allow us to live with this bacteria.7, 9-11

It’s when the bacteria – especially the less friendly types such as gram negative bacteria – get into our bodies that the immune system takes action. As a result, our immune cells have developed critical tools for the sole purpose of hunting down and identifying bacteria inside the body.

Fortunately, the bad gram negative bacteria has a tell. All over its surface is something called lipopolysaccharide (LPS).12

Antigen presenting cells (APCs) hunt down bacteria using two receptors for LPS called TLR-4 and CD14.12, 13 When LPS binds TLR-4 and CD14, the immune system alarm bells go off.

The diagram below shows the basics of this sophisticated alarm system,14 but the end result is simple. The immune system spins up and inflammation ensues.

The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria | The Paleo Diet

WHEAT – THE GREAT BACTERIAL MIMICKER

That subtitle is actually only partially accurate. A better description might be “wheat – the boy who cried bacterial wolf.”

The problem is our bodies never learn to ignore this particular boy.

Wheat has developed a variety of sophisticated techniques for activating the LPS response. But in some cases, it does it differently from LPS, bypassing key regulatory steps such as CD14 which would otherwise prevent inflammation in places we don’t want it.6, 10

A full description of these mechanisms is beyond the scope of this article and probably your boredom limit. So, the following is only a cursory description, but with lots of journal references that will keep the geekiest of you happy.

MECHANISM 1: LET BACTERIA IN

Part Two gives an in depth description of how wheat opens up the digestive tract barrier and allows things in our gut to get into our bodies. This includes our intestinal bacteria.15

The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria | The Paleo Diet

In other words, wheat actually lets the wolf into the chicken coop and then cries wolf.

MECHANISM 2: HOMEBREW LPS

Wheat contains its own LPS-like molecule, sometimes called LPSw, that has similar effects but admittedly isn’t as potent as the real thing.16, 17 In one study on mice, LPSw was able to promote a bacterial immune response.17

MECHANISM 3: ATI’S

(No It’s Not a Computer Company)

At the barrier of our gut are a special type of immune cell called dendritic cells. Constantly sampling the contents of our digestive tract, tthey are the on/off switch of the immune system.18 Think of them as Paul Revere riding back to the immune system yelling “the bacteria are coming!”

Wheat contains molecules that very potently activates dendritic cells called α-Amylase/Trypsin Inhibitors (ATIs).19 They act through TLR-4 on the dendrites. And sorry to those of you who love to say you’re “gluten-free” – ATIs, which exist in many grains, are found in a different part than gluten.

ATI’s are responsible for a long known condition called Baker’s Asthma named so because it was common among people who worked with flour.20

MECHANISM 4: SKIP THE ALARM BUT GET THE RESPONSE

TLR-4 and CD14 are not strongly expressed in the gut immune system making it hard to sound the bacterial alarm in the gut.21-23 In an area of the body that’s exposed to bacteria thousands of times each day, an inflammatory response isn’t something we want.21, 22

So it should be concerning to hear that wheat has developed ways of causing the inflammatory response without bothering with TLR-4 or CD14.

The ways wheat does it gets complex. We’ll just touch on them.

First, in several studies, small amounts of gluten were able to flip the dendritic cell’s “on switch” in mice and start an inflammatory response without touching TLR-4.24, 25

Another molecule in wheat (there’s a lot) called wheat germ agglutinin (WGA) can bind and pass right through the gut barrier to interact with immune cells on the other side. WGA then promotes a highly inflammatory response26, 27 including turning dendritic cells on.

Finally, remember all those antigen presenting cells in the gut that avoid sounding the bacterial alarm bells by simply not expressing CD14? Gliadin promotes something called IL-15 which is highly effective at activating APCs that don’t express CD14.28-33

And of a variety of foods tested, gliadin was the only one able to so effectively activate these cells.33

WHAT HAPPENS WHEN YOU PREPARE FOR AN INVASION WITHOUT THE INVASION?

That’s a lot of science and frankly we only just skimmed the surface. So here’s the point – wheat is amazingly effective at activating the bacterial defence mechanisms of our immune cells.

More importantly, this response happens in everyone and not just celiac disease (though there’s evidence it’s more pronounced in celiacs).29

So what happens when our bodies mount a defense against bacteria that isn’t there? The answer to that question is the focus of the final part to this series. But the short answer is it creates a constant state of inflammation as long as we continue to eat wheat.34, 35

Recent research is now associating a state of constant inflammation with the onset of nearly all major chronic diseases36 including heart disease,37 Alzheimer’s disease,38 diabetes,39 cancer,40, 41 and overall morbidity.42

But the question remains does the inflammation that results from wheat inappropriately setting off the bacterial alarms also contribute to these conditions?

That’s a question we’ll hope to delve into in the next two parts. But fortunately, by eating a wheat-free Paleo diet, it’s a question you may never have to worry about.

Read The Wheat Series Part 4: Home Invasion HERE

 

REFERENCES

[1]Alcami, A., Viral mimicry of cytokines, chemokines and their receptors. Nat Rev Immunol, 2003. 3(1): p. 36-50.

[2]Amara, A. and J. Mercer, Viral apoptotic mimicry. Nat Rev Microbiol, 2015.

[3]Lammers, K.M., et al., Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology, 2008. 135(1): p. 194-204 e3.

[4]Drago, S., et al., Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol, 2006. 41(4): p. 408-19.

[5]Visser, J., et al., Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci, 2009. 1165: p. 195-205.

[6]Ohnmacht, C., et al., Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity. Cell Microbiol, 2011. 13(5): p. 653-9.

[7]McFall-Ngai, M., Adaptive immunity: care for the community. Nature, 2007. 445(7124): p. 153.

[8]Ivanov, II, et al., Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell, 2009. 139(3): p. 485-98.

[9]Cao, A.T., et al., Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol, 2012. 189(9): p. 4666-73.

[10]Smith, P.D., et al., Intestinal macrophages and response to microbial encroachment. Mucosal Immunol, 2011. 4(1): p. 31-42.

[11]Arrieta, M.-C. and B.B. Finlay, The commensal microbiota drives immune homeostasis. Frontiers in Immunology, 2012. 3.

[12]Kawai, T., et al., Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol, 2001. 167(10): p. 5887-94.

[13]Perera, P.Y., et al., CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol, 2001. 166(1): p. 574-81.

[14]Buer, J. and R. Balling, Mice, microbes and models of infection. Nat Rev Genet, 2003. 4(3): p. 195-205.

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

[16]Yamazaki, K., J.A. Murray, and H. Kita, Innate immunomodulatory effects of cereal grains through induction of IL-10. Journal of Allergy and Clinical Immunology, 2008. 121(1): p. 172-178.

[17]Nishizawa, T., et al., Homeostasis as regulated by activated macrophage. I. Lipopolysaccharide (LPS) from wheat flour: isolation, purification and some biological activities. Chem Pharm Bull (Tokyo), 1992. 40(2): p. 479-83.

[18]Williamson, E., G.M. Westrich, and J.L. Viney, Modulating dendritic cells to optimize mucosal immunization protocols. J Immunol, 1999. 163(7): p. 3668-75.

[19]Junker, Y., et al., Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med, 2012. 209(13): p. 2395-408.

[20]Sapone, A., et al., Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med, 2012. 10: p. 13.

[21]Kamada, N., et al., Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest, 2008. 118(6): p. 2269-80.

[22]Nagler-Anderson, C., Tolerance and immunity in the intestinal immune system. Critical Reviews in Immunology, 2000. 20(2): p. 103-120.

[23]Smythies, L.E., et al., Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest, 2005. 115(1): p. 66-75.

[24]Palova-Jelinkova, L., et al., Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol, 2005. 175(10): p. 7038-45.

[25]Nikulina, M., et al., Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol, 2004. 173(3): p. 1925-33.

[26]Dalla Pellegrina, C., et al., Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol, 2009. 237(2): p. 146-53.

[27]Gabor, F., M. Stangl, and M. Wirth, Lectin-mediated bioadhesion: binding characteristics of plant lectins on the enterocyte-like cell lines Caco-2, HT-29 and HCT-8. J Control Release, 1998. 55(2-3): p. 131-42.

[28]Harris, K.M., A. Fasano, and D.L. Mann, Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clin Immunol, 2010. 135(3): p. 430-9.

[29]Bernardo, D., et al., Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut, 2007. 56(6): p. 889-890.

[30]Jelinkova, L., et al., Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB. FEBS Lett, 2004. 571(1-3): p. 81-5.

[31]Palova-Jelinkova, L., et al., Pepsin digest of wheat gliadin fraction increases production of IL-1beta via TLR4/MyD88/TRIF/MAPK/NF-kappaB signaling pathway and an NLRP3 inflammasome activation. PLoS One, 2013. 8(4): p. e62426.

[32]Thomas, K.E., et al., Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol, 2006. 176(4): p. 2512-21.

[33]Tuckova, L., et al., Activation of macrophages by gliadin fragments: isolation and characterization of active peptide. J Leukoc Biol, 2002. 71(4): p. 625-31.

[34]Nilsen, E.M., et al., Gluten activation of peripheral blood T cells induces a Th0-like cytokine pattern in both coeliac patients and controls. Clin Exp Immunol, 1996. 103(2): p. 295-303.

[35]Antvorskov, J.C., et al., Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice. Immunology, 2013. 138(1): p. 23-33.

[36]Hotamisligil, G.S., Inflammation and metabolic disorders. Nature, 2006. 444(7121): p. 860-867.

[37]Libby, P., P.M. Ridker, and A. Maseri, Inflammation and atherosclerosis. Circulation, 2002. 105(9): p. 1135-1143.

[38]Akiyama, H., et al., Inflammation and Alzheimer’s disease. Neurobiology of Aging, 2000. 21(3): p. 383-421.

[39]Xu, H.Y., et al., Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation, 2003. 112(12): p. 1821-1830.

[40]Grivennikov, S.I., F.R. Greten, and M. Karin, Immunity, Inflammation, and Cancer. Cell, 2010. 140(6): p. 883-899.

[41]Coussens, L.M. and Z. Werb, Inflammation and cancer. Nature, 2002. 420(6917): p. 860-867.

[42]Krabbe, K.S., M. Pedersen, and H. Bruunsgaard, Inflammatory mediators in the elderly. Exp Gerontol, 2004. 39(5): p. 687-99.

Fight Inflammation with a Paleo Diet

Most athletes are well aware of a fun little word called “inflammation”.1 Tough workouts are a common cause of inflammation. Acute inflammation (the only kind most people are aware of) is actually beneficial.2, 3 But – and this is a big BUT – chronic inflammation is a killer. Literally.4, 5, 6 The difference here is important, and very misunderstood. One of the biggest health benefits of consuming a Paleo diet comes from its anti-inflammatory nature.7, 8, 9 By fixing the Standard American Diet (SAD) ratio of high omega-6 to low omega-3, nearly everyone sees improvements.10, 11 But before we proceed further, let’s specify and define acute inflammation and chronic inflammation.

Fight Inflammation with a Paleo Diet

Imai, Yumi, Anca D. Dobrian, Margaret A. Morris, and Jerry L. Nadler. “Islet Inflammation: A Unifying Target for Diabetes Treatment?” Science Direct. Trends in Endocrinology & Metabolism, July 2013. Web. 25 Mar. 2015.

Fight Inflammation with a Paleo Diet

Heneka, Michael T., Markus P. Kummer, and Eicke Latz. “Innate Immune Activation in Neurodegenerative Disease.” Immunology Reviews. Nature, 25 June 2014. Web. 25 Mar. 2015.

Acute inflammation is what occurs when you get a bruise, cut, experience stress, or go through a hard workout.12 I used to practice Brazilian Jiu Jitsu and CrossFit on a near-daily basis, and I became very familiar with inflammation! However, this is the good kind of inflammation, remember. Without acute inflammation, you would never heal. Think about that for a minute. Chronic inflammation, by contrast, is problematic for two reasons. One, it is much less noticeable. You likely won’t have a bruise, cut, or any obvious symptoms. And two, it is the cause behind most serious diseases – whether it be cancer, heart disease or other conditions.13, 14, 15

With regard to diet, inflammation also plays a bigger role than most are aware of. Take acne, for example. This is an inflammatory condition. Some have even surmised that inflammation plays a role in acne at a subclinical level.16 This is one of the many reasons why dairy should be avoided when consuming a Paleo Diet. Perhaps surprisingly to some, coconut oil has been shown to have components which help protect against acne.17 The lauric acid found in coconut oil has anti-bacterial and anti-inflammatory properties, and would therefore also be beneficial after a tough workout.18 Win-win.

Vegetables are another key component of an anti-inflammatory diet, and unsurprisingly, a healthy Paleo diet is largely comprised of vegetables!19, 20 So what should athletes be eating? Coconut oil, protein and vegetables! Of course you’ll also want some anti-inflammatory fats, like the omega-3 fatty acids found in wild-caught seafood.21 From strictly a scientific perspective, it is quite clear athletes should stick to a diet based upon these foods to provide you with the best results.

Fight Inflammation with a Paleo Diet

Dantzer, Robert et al. “From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain.” Nature reviews. Neuroscience 9.1 (2008): 46–56. PMC. Web. 25 Mar. 2015.

Another aspect of inflammation which many are unaware of is that it can occur (and often does occur) in your brain!22 If the brain’s barrier is opened, your glial cells will likely be activated.23 These are the cells that deal with immunity. Once activated, an inflammatory response in your brain occurs.24 This is not good. To add to the fun, your brain now has trouble communicating with your gut, creating more issues, specifically serotonin biosynthesis problems.25 And, the delicate HPA (hypothalamus, pituitary, adrenal) axis will now likely be off-balance, as well.26

So, what is the best way to avoid inflammation, of all kinds (except beneficial, acute inflammation)? Quite simply: eat a Paleo diet. By avoiding gluten (a huge instigator of inflammation throughout the body and brain) you will be doing yourself a huge favor.27, 28 And when we replace problematic proteins like gluten, with nutrient-dense foods rich in protein, antioxidants and anti-inflammatory compounds, we procure better health for ourselves.29 Your mom was right: eat your vegetables for better health and less inflammation.30 Stay the course with a Paleo Diet and optimal health sans inflammation is within reach.

 

REFERENCES

[1] Pinto A, Di raimondo D, Tuttolomondo A, Buttà C, Milio G, Licata G. Effects of physical exercise on inflammatory markers of atherosclerosis. Curr Pharm Des. 2012;18(28):4326-49.

[2] Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays Biochem. 2006;42:105-17.

[3] You T, Arsenis NC, Disanzo BL, Lamonte MJ. Effects of exercise training on chronic inflammation in obesity : current evidence and potential mechanisms. Sports Med. 2013;43(4):243-56.

[4] Osiecki H. The role of chronic inflammation in cardiovascular disease and its regulation by nutrients. Altern Med Rev. 2004;9(1):32-53.

[5] Peev V, Nayer A, Contreras G. Dyslipidemia, malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease. Curr Opin Lipidol. 2014;25(1):54-60.

[6] Kelly E, Owen CA, Pinto-plata V, Celli BR. The role of systemic inflammatory biomarkers to predict mortality in chronic obstructive pulmonary disease. Expert Rev Respir Med. 2013;7(1):57-64.

[7] De punder K, Pruimboom L. The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients. 2013;5(3):771-87.

[8] Soares FL, De oliveira matoso R, Teixeira LG, et al. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem. 2013;24(6):1105-11.

[9] Nowlin SY, Hammer MJ, D’eramo melkus G. Diet, inflammation, and glycemic control in type 2 diabetes: an integrative review of the literature. J Nutr Metab. 2012;2012:542698.

[10] Kowalski LM, Bujko J. [Evaluation of biological and clinical potential of paleolithic diet]. Rocz Panstw Zakl Hig. 2012;63(1):9-15.

[11] Jönsson T, Granfeldt Y, Lindeberg S, Hallberg AC. Subjective satiety and other experiences of a Paleolithic diet compared to a diabetes diet in patients with type 2 diabetes. Nutr J. 2013;12:105.

[12] Ryan GB, Majno G. Acute inflammation. A review. Am J Pathol. 1977;86(1):183-276.

[13] Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73(10):768-74.

[14] Mcmillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone J, Mcardle CS. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer. 2001;41(1-2):64-9.

[15] Gomes de lima KV, Maio R. Nutritional status, systemic inflammation and prognosis of patients with gastrointestinal cancer. Nutr Hosp. 2012;27(3):707-14.

[16] Tanghetti EA. The role of inflammation in the pathology of acne. J Clin Aesthet Dermatol. 2013;6(9):27-35.

[17] Huang WC, Tsai TH, Chuang LT, Li YY, Zouboulis CC, Tsai PJ. Anti-bacterial and anti-inflammatory properties of capric acid against Propionibacterium acnes: a comparative study with lauric acid. J Dermatol Sci. 2014;73(3):232-40.

[18] Huang WC, Tsai TH, Chuang LT, Li YY, Zouboulis CC, Tsai PJ. Anti-bacterial and anti-inflammatory properties of capric acid against Propionibacterium acnes: a comparative study with lauric acid. J Dermatol Sci. 2014;73(3):232-40.

[19] Watzl B. Anti-inflammatory effects of plant-based foods and of their constituents. Int J Vitam Nutr Res. 2008;78(6):293-8.

[20] Galland L. Diet and inflammation. Nutr Clin Pract. 2010;25(6):634-40.

[21] Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68(5):280-9.

[22] Dantzer R, O’connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.

[23] Prat A, Biernacki K, Wosik K, Antel JP. Glial cell influence on the human blood-brain barrier. Glia. 2001;36(2):145-55.

[24] Skaper SD, Facci L, Giusti P. Mast cells, glia and neuroinflammation: partners in crime?. Immunology. 2014;141(3):314-27.

[25] Spiller R. Serotonin, inflammation, and IBS: fitting the jigsaw together?. J Pediatr Gastroenterol Nutr. 2007;45 Suppl 2:S115-9.

[26] Morand EF, Leech M. Hypothalamic-pituitary-adrenal axis regulation of inflammation in rheumatoid arthritis. Immunol Cell Biol. 2001;79(4):395-9.

[27] Hansen CH, Krych L, Buschard K, et al. A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes. 2014;63(8):2821-32.

[28] Antvorskov JC, Fundova P, Buschard K, Funda DP. Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice. Immunology. 2013;138(1):23-33.

[29] Halliwell B. Antioxidants in human health and disease. Annu Rev Nutr. 1996;16:33-50.

[30] Holt EM, Steffen LM, Moran A, et al. Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents. J Am Diet Assoc. 2009;109(3):414-21.

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet

Did you miss The Wheat Series Part 1: Wheat and the Immune System? Read it HERE.

It was a comment I’ve heard too many times. I was watching tennis with a friend who knew me as a cyclist, not as someone who researches nutrition. The commentators were discussing world No. 1 ranked tennis player Novak Djokovic’s newfound success since going on a gluten-free diet. My friend got noticeably irritated and finally blurted “I’m tired of this gluten-free fad! There’s not a scrap of evidence it makes a difference unless you have celiac disease.” As much as I wanted to, I chose not to respond, but thought to myself, “The bottom drawer of my research cabinet is awfully heavy for not having a scrap of anything in it.

This viewpoint that the health benefits of a gluten-free diet are more fad than science is a pervasive one. But what has led so many, including doctors and scientists, to say the research doesn’t exist?

Certainly the science is extensive for celiac disease where the role of gluten is indisputable. Gliadin, a protein in gluten, binds to a molecule in our bodies called tissue transglutaminase. In celiac patients it’s this new, combined molecule that sets off the inappropriate immune response.1, 2, 3

Without gluten, celiac disease couldn’t exist.

Recently other gluten-related disorders like gluten allergies and gluten ataxia have been identified.4, 5  But admittedly, these conditions affect only about 2% – 10% of the population. Outside of these diseases my friend has a point; research showing gluten having a direct pathogenic role, as it does in celiac disease, isn’t there.

But perhaps this is where the disconnect exists.

While a great deal of published research is showing that wheat and gluten can promote a large range of chronic conditions4, 6, 7, 8, gluten’s role is not so direct. Instead, gluten may breakdown the body’s natural defenses, setting up an inflammatory environment. This environment is highly conducive to a variety of chronic diseases in those of us who are unfortunate enough to have the wrong genetics.9, 10 Gluten sets the stage.

Looking at gluten this way, the bottom drawer of my cabinet suddenly gets a lot heavier. I hope to share a few posts on the ways in which wheat can set the stage for unwanted inflammation and disease. Let’s start with a surprising function that came out of celiac research.

LOOSENING OUR BORDERS

One of the most important roles of our gut, beside processing nutrients and hosting a rich microflora, is to provide a barrier blocking the entry of unwanted particles. Fortunately tight junctions (TJ) between the epithelial cells of our intestine carefully regulate entry of all but a few small molecules and essential nutrients.

Over the last 20 years, Dr. Alessio Fasano at the University of Maryland has researched breakdowns in this barrier, ultimately identifying a molecule produced in our guts called zonulin.14 Zonulin has the unique ability to dissolve the occludins, claudins, zonular occluden, and ZO-1 proteins that make up the structural cytoskeletons of our tight junctions.6, 15, 16, 17, 18

Put simply, zonulin can breakdown our barrier and increase intestinal permeability. An effect that’s often referred to around the web as “leaky gut.” It is rapid, reproducible, and fortunately, reversible.16

To date, two powerful triggers for zonulin have been identified.

The first trigger is exposure to bacteria in the intestine. Interestingly, infection by both pathogenic and “healthy” bacteria can have a triggering effect. However, it’s amplified with the “bad guys” as we can see from the chart below on the left.19

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet
Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet
It is believed that zonulin evolved to protect us against bacterial colonization in the gut.6, 17, 19 When there’s an overload of bacteria in an otherwise healthy digestive tract, zonulin opens up the tight junctions allowing fluid to rush into the gut and flush out microorganisms.

The second powerful activator of the zonulin system is gliadin.

Gliadin fragments bind to the CXCR3 receptor on the epithelial cells of the gut. Then through a MyD88 signaling process, these epithelial cells release zonulin and cause an opening of tight junctions.6, 15, 17, 20, 21

It’s a complex process, but all you need to know is that gliadin can do this from inside the gut. It doesn’t have to get into our systems. More importantly, gluten is inappropriately high jacking a powerful defense mechanism designed to handle bacterial contamination.17

In the above right figure, we can see from Dr. Fasano’s research how gliadin’s ability to stimulate zonulin can be as powerful as bacterial triggers.6

Finally, while gliadin’s effect is much stronger in individuals with celiac disease, gliadin does not discriminate, and it happens in all peoples guts.6, 17

PERMEABLE CONSEQUENCES

With a healthy gut barrier, large molecules are degraded before entering the body and are well tolerated by the immune system.12 Intestinal permeability caused by gluten and bacteria allows these large molecules to get into circulation and act as antigens (activators) for the immune system.15, 17, 22

This becomes a real concern considering gluten is normally consumed with a meal. Its rapid effect on gut permeability happens at the same time that the gut is being hit by a large number of foreign antigens.

 

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet

Dr. Fasano and his group proposed that once these antigens gain entry, they can be misinterpreted by the immune system in genetically susceptible individuals. The result is an inappropriate immune response that ultimately leads to chronic illness.6, 12, 15, 23, 24, 25In a healthy gut, these antigens would never gain access to the immune system.

The image above provides a nice representation of how gluten can open tight junctions and lead to diseases such as celiac disease and type 1 diabetes.6

LOSING THE BARRIER TO DISEASE

So, what does this all amount to? Intestinal permeability caused by either bacterial overgrowth or gluten (both of which are heavily influenced by diet) may be a key early step to set the body up for many chronic illness.

But is there any research? Fortunately, this is where I have to start using more drawers in my research cabinet.

Higher zonulin levels and intestinal permeability have been associated with and often precede many autoimmune conditions including type 1 diabetes,16, 30, 3132, 33celiac disease,17, 28, 34 multiple sclerosis,35, 36 rheumatoid arthritis,37, 38ankylosing spondylitis,37, 39 and Crohn’s disease.40, 41Eating wheat has been directly linked to diabetes.31, 42, 43, 44

A popular theory of autoimmune disease – called the molecular mimicry theory – proposed that autoimmune disease is initiated by viruses that mimic our bodies.26, 27 Dr. Fasano and his group suggested instead that dietary antigens passing through a leaky gut may be the environmental trigger. To test their theory, they were able to use a zonulin inhibitor to reduce the severity of celiac disease symptoms in humans 28 and the incidence of type 1 diabetes in mice.29

Intestinal permeability isn’t just associated with autoimmune conditions. Permeability may affect asthmatics by increasing their exposure to allergens.45, 46 Elevated zonulin levels have been found in irritable bowel disease 47, 48 and cancer.4950Even schizophrenia has recently been linked to gluten consumption and zonulin levels.51, 52

But a final question remains.

In a world where most people reach for a bagel and toast as soon as they get out of bed, intestinal permeability may just be a part of western life that gets an unfair rap by association. In other words, is it too easy to just link permeability with chronic disease? Does it really play a role?

In his 2011 review of zonulin and disease, Dr. Fasano addressed this question pointing out a number of studies where symptoms and incidence rates were reduced when gluten was removed from the diet or when zonulin’s effects were blocked.6

Wheat, a no-no for any good Paleo dieter, was clearly opening doors.

Read The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria HERE

REFERENCES

[1]Dieterich, W., et al., Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine, 1997. 3(7): p. 797-801.

[2]Molberg, O., et al., Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Medicine, 1998. 4(6): p. 713-717.

[3]Plenge, R.M., Unlocking the pathogenesis of celiac disease. Nat Genet, 2010. 42(4): p. 281-2.

[4]Sapone, A., et al., Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med, 2012. 10: p. 13.

[5]Hadjivassiliou, M., et al., Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain, 2003. 126(Pt 3): p. 685-91.

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

[7]Biesiekierski, J.R., et al., Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol, 2011. 106(3): p. 508-14; quiz 515.

[8]Bernardo, D., et al., Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut, 2007. 56(6): p. 889-890.

[9]Palova-Jelinkova, L., et al., Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol, 2005. 175(10): p. 7038-45.

[10]De Palma, G., et al., Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br J Nutr, 2009. 102(8): p. 1154-60.

[11]Yu, Q.H. and Q. Yang, Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biol Int, 2009. 33(1): p. 78-82.

[12]Fasano, A., Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation Living Life on the Edge of the Wall. American Journal of Pathology, 2008. 173(5): p. 1243-1252.

[13]Shen, L. and J.R. Turner, Role of epithelial cells in initiation and propagation of intestinal inflammation. Eliminating the static: tight junction dynamics exposed. Am J Physiol Gastrointest Liver Physiol, 2006. 290(4): p. G577-82.

[14]Di Pierro, M., et al., Zonula occludens toxin structure-function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain. J Biol Chem, 2001. 276(22): p. 19160-5.

[15]Sander, G.R., et al., Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett, 2005. 579(21): p. 4851-5.

[16]Visser, J., et al., Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci, 2009. 1165: p. 195-205.

[17]Drago, S., et al., Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol, 2006. 41(4): p. 408-19.

[18]Fasano, A., et al., Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Invest, 1995. 96(2): p. 710-20.

[19]El Asmar, R., et al., Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology, 2002. 123(5): p. 1607-15.

[20]Lammers, K.M., et al., Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology, 2008. 135(1): p. 194-204 e3.

[21]Clemente, M.G., et al., Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut, 2003. 52(2): p. 218-23.

[22]Fasano, A., Intestinal zonulin: open sesame! Gut, 2001. 49(2): p. 159-62.

[23]Cereijido, M., et al., New diseases derived or associated with the tight junction. Arch Med Res, 2007. 38(5): p. 465-78.

[23]Fasano, A., Surprises from celiac disease. Sci Am, 2009. 301(2): p. 54-61.

[24]Mowat, A.M., Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol, 2003. 3(4): p. 331-41.

[25]Oldstone, M.B.A., MOLECULAR MIMICRY AND AUTOIMMUNE-DISEASE. Cell, 1987. 50(6): p. 819-820.

[26]Wucherpfennig, K.W. and J.L. Strominger, MOLECULAR MIMICRY IN T-CELL-MEDIATED AUTOIMMUNITY – VIRAL PEPTIDES ACTIVATE HUMAN T-CELL CLONES SPECIFIC FOR MYELIN BASIC-PROTEIN. Cell, 1995. 80(5): p. 695-705.

[27]Paterson, B.M., et al., The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther, 2007. 26(5): p. 757-66.

[28]Watts, T., et al., Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci U S A, 2005. 102(8): p. 2916-21.

[29]Bosi, E., et al., Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia, 2006. 49(12): p. 2824-7.

[30]Mojibian, M., et al., Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes. Diabetes, 2009. 58(8): p. 1789-96.

[31]Sapone, A., et al., Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes, 2006. 55(5): p. 1443-1449.

[32]De Magistris, L., et al., Altered mannitol absorption in diabetic children. Ital J Gastroenterol, 1996. 28(6): p. 367.

[33]De Palma, G., et al., Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol, 2010. 10: p. 63.

[34]Westall, F.C., Abnormal hormonal control of gut hydrolytic enzymes causes autoimmune attack on the CNS by production of immune-mimic and adjuvant molecules: A comprehensive explanation for the induction of multiple sclerosis. Med Hypotheses, 2007. 68(2): p. 364-9.

[35]Yacyshyn, B., et al., Multiple sclerosis patients have peripheral blood CD45RO+ B cells and increased intestinal permeability. Dig Dis Sci, 1996. 41(12): p. 2493-8.

[36]Smith, M.D., R.A. Gibson, and P.M. Brooks, Abnormal bowel permeability in ankylosing spondylitis and rheumatoid arthritis. J Rheumatol, 1985. 12(2): p. 299-305.

[37]Edwards, C.J., Commensal gut bacteria and the etiopathogenesis of rheumatoid arthritis. J Rheumatol, 2008. 35(8): p. 1477-14797.

[38]Liu, J., et al., Identification of disease-associated proteins by proteomic approach in ankylosing spondylitis. Biochem Biophys Res Commun, 2007. 357(2): p. 531-6.

[39]D’Inca, R., et al., Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn’s disease. Aliment Pharmacol Ther, 2006. 23(10): p. 1455-61.

[40]Irvine, E.J. and J.K. Marshall, Increased intestinal permeability precedes the onset of Crohn’s disease in a subject with familial risk. Gastroenterology, 2000. 119(6): p. 1740-4.

[41]Maurano, F., et al., Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia, 2005. 48(5): p. 931-7.

[42]Ziegler, A.G., et al., Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA, 2003. 290(13): p. 1721-8.

[43]Funda, D.P., et al., Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes. Diabetes-Metabolism Research and Reviews, 2008. 24(1): p. 59-63.

[44]Knutson, T.W., et al., Effects of luminal antigen on intestinal albumin and hyaluronan permeability and ion transport in atopic patients. J Allergy Clin Immunol, 1996. 97(6): p. 1225-32.

[45]Hijazi, Z., et al., Intestinal permeability is increased in bronchial asthma. Arch Dis Child, 2004. 89(3): p. 227-9.

[46]Arrieta, M.C., et al., Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse. Gut, 2009. 58(1): p. 41-8.

[47]Weber, C.R. and J.R. Turner, Inflammatory bowel disease: is it really just another break in the wall? Gut, 2007. 56(1): p. 6-8.

[48]Lai, C.H., et al., Proteomics-based identification of haptoglobin as a novel plasma biomarker in oral squamous cell carcinoma. Clin Chim Acta, 2010. 411(13-14): p. 984-91.

[50]Dowling, P., et al., 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins. Electrophoresis, 2007. 28(23): p. 4302-10.

[51]Wan, C., et al., Abnormal changes of plasma acute phase proteins in schizophrenia and the relation between schizophrenia and haptoglobin (Hp) gene. Amino Acids, 2007. 32(1): p. 101-8.

[52]Kalaydjian, A.E., et al., The gluten connection: the association between schizophrenia and celiac disease. Acta Psychiatr Scand, 2006. 113(2): p. 82-90.

Millet | The Paleo Diet

Over the past 5-7 years, more and more people worldwide have become aware of the Paleo Diet, which really is not a diet at all, but rather a lifelong way of eating to reduce the risk of chronic disease and maximize health and wellbeing. One of the fundamental principles of The Paleo Diet is to eliminate or drastically reduce consumption of cereal grains, whether they are refined or whole. Currently, 8 cereal grains (wheat, corn, rice, barley, sorghum, oats, rye, and millet) provide 56% of the food energy and 50% of the protein consumed on earth.3 However, from an evolutionary perspective, these foods were rarely or never consumed by our hunter gatherer ancestors.3

When I first made the suggestion that as a species we would be a lot healthier if we reduced or eliminated cereal consumption in 1999,3 I received, and still receive, criticism by some professionals in the nutritional community because they believe that the elimination of an entire food group (cereals) is nutritionally unsound and “will produce numerous dietary deficiencies.” This statement is not supported by any experimental evidence. In fact, the contrary is true. As I have previously pointed out, elimination of cereal grains actually increases the nutrient density of the 13 vitamins and minerals most lacking in the U.S. diet4, 5 – providing cereals are replaced by fresh fruits, vegetables, meats, poultry, fish, seafood and eggs.

Besides this fundamental lack of knowledge concerning the nutrient density of cereal grains, nearly all classically trained nutritionists have little or no appreciation for the antinutrients present in grains. As the name implies, antinutrients are dietary substances which interfere with our normal metabolism and physiology. Cereal grains are generally concentrated sources of numerous antinutrients and may produce undesirable health effects,3 particularly when consumed as daily staples.

In the U.S. “gluten free” foods have become incredibly popular in recent years as many people recognize that they simply feel better by eliminating the 3 gluten containing grains (wheat, rye and barley). Gluten conscious consumers frequently replace wheat, rye and barley with non-gluten containing grains (rice, corn, oats, sorghum and millet) in the mistaken belief that these 5 non-gluten grains are harmless. However, as I have previously pointed out, even the 5 non-gluten containing grains should be avoided for a variety of reasons.3 Specifically, I’ll detail below how millet adversely affects iodine metabolism and may cause goiter (swelling of the neck) when eaten regularly.

The Culprit: Millet

Unless you are a vegan, a vegetarian or are in search of gluten-free grains, most Americans and westerners have never tasted millet. Nevertheless, you don’t have to look very far to find this cereal grain (grass seed) at most health food stores. If you only dine upon millet dishes once in a blue moon, it will have zero repercussions upon your health, but be aware that millet is a nutrient poor, antinutrient laden food – the regular consumption of which may cause multiple dietary deficiencies and nutrient related diseases,3 including impairment of iodine metabolism and risk for goiter.

Millet is not a single plant species (as are most other cereal grains), but rather interpreted broadly may comprise about 500 species of grass seeds worldwide.13 Only a few species of millet are commonly cultivated as food crops. Worldwide, pearl millet (Pennisetum glaucum) is the most widely produced millet15 and is cultivated extensively in Africa and India. Finger millet (Eleusine coracana, proso millet (Panicum miliaceum), fonio millet (Digitaria exilis), and foxtail millet (Setaria italic) are also important crop species in developing countries.13, 15 Nevertheless millet is a minor cereal grain in terms of global economic importance. Worldwide production of millet is about 1% of either wheat or rice.13

Because millets require little water and are highly drought resistant, they grow well in arid and semi arid regions of the world such as in countries surrounding the Sahara desert in Africa and in dry areas in India and Asia. Further, millet is an attractive agricultural crop for farmers in these regions because under good conditions, it can yield two harvests per year13 and is resistant to pests and pathogens.

In the Sudan region (Darfur Province) of Africa, dietary surveys show that millet consumption in three communities (Kas, Tawaila and Nyala) was the primary source of food calories, respectively yielding 73.6%, 66.7%, and 37.1% of total daily energy.20 In this study, the occurrence of goiter was outrageously high – greater than almost anywhere else in the world. The incidence of goiter for girls in these three communities was 75%, 55%, and 13%, respectively; for boys it was 46%, 35%, and 10%, respectively. Similar high rates of goiter and thyroid disorders have been reported for school children in the Gujarat district of Western India where millet is a staple food.2

Millet Consumption, Iodine Deficiency and Goiter

Wherever and whenever millet becomes a staple food worldwide, the incidence of goiter increases and abnormalities of thyroid function and iodine metabolism occur2,7,16-20 Further, animal studies in rats, pet birds, and goats and tissue (in vitro) studies demonstrate unequivocally that this cereal plays a major role in causing goiter, thyroid abnormalities and impairment of iodine metabolism.1, 8, 10-12, 22

Iodine is an essential nutrient for humans, without which we most conspicuously develop goiter (an enlargement of the thyroid gland about the neck). Additionally, lack of iodine in the diet impairs cognitive development in growing infants and children, miscarriage in pregnant women and brain and nervous system dysfunction in adults.24, 25

Originally, it was thought that goiter occurred primarily from a deficiency of iodine in our food supply and water. Accordingly, in the U.S. and elsewhere most dietary salt (NaCl) has been fortified with iodine. An unappreciated aspect of iodine metabolism is that metabolic deficiencies of this nutrient can still occur even when dietary intake of iodine appears to be sufficient.7 Although virtually unknown to most nutritionists, elements found in millet represent powerful antinutrients that impair iodine metabolism and frequently cause goiter and symptoms of iodine deficiency.

Goitrogens in Millet

Goitrogens are dietary substances which impair thyroid and iodine metabolism and may ultimately cause the development of goiter. As I have previously alluded, a few scientists in the nutritional community early on appreciated that high millet diets promoted goiter. However, it was not completely understood how millet produced its goitrogenic effect. Subsequent discoveries and experiments over the past 35 years now show that compounds known as flavonoids in millets are responsible for causing iodine dysfunction and may in turn produce goiter when consumed as staples.6, 7, 21, 23

All millets are concentrated sources of compounds known as polyphenolics, some of which are referred to as flavonoids. Numerous flavonoids have been found in millets including apigenin, luteolin , kaempferol and vitexin; all of which severely impair thyroid function and iodine metabolism6, 10-12, 21, 23 and cause goiter in animal and tissue models.1, 8, 10-12, 22 Although it is not completely understood, flavonoids from millets appear to inhibit iodine uptake by most cells in the body, impair secretion of thyroid hormones, and reduce organification of Iodine by the enzyme thyroperoxidase.6, 7, 10, 23

Additional Antinutrients in Millets

Although a few scientific articles suggest that millets may possess positive health effects,26, 27 these papers and authors seem to be completely unaware of the numerous antinutrients found in millets and their potential for disrupting nutrition and health.

Let’s begin with the mistaken notion that millets are good sources of calcium.26, 27 Upon chemical analysis on paper, this statement may be true, but in the body (in vivo), nothing could be further from the truth. Calcium, along with iron and zinc that may be present in millets are actually poorly absorbed in our bodies because phytates, tannins and other compounds prevent their assimilation.28-32 Accordingly, high cereal grain diets whether millet derived or not, frequently result in multiple nutrient deficiencies including calcium, iron and zinc.3

In addition to their high phytate, flavonoid and polyphenolic contents, millets are also concentrated sources of other antinutrients including protease inhibitors (trypsin, chymotrypsin, alpha amylase and cysteine)33-35 and steroidal saponins.36, 37 Cereal grain protease inhibitors likely elicit adverse effects upon the pancreas when consumed as staple foods,3 and saponins are known to increase intestinal permeability and may contribute to chronic low level systemic inflammation.

Taken in its entirety, an overwhelming scientific literature demonstrates that millets are second rate foods that when consumed regularly may adversely affect iodine metabolism and elicit goiter. I’m not completely sure where the USDA dietitians derived their recommendations for whole grain consumption, but it certainly could not have come from their familiarity with the millet literature.

Cordially,

Loren Cordain, Ph.D., Professor Emeritus

 

References

1. Abel Gadir WS, Adam SE. Development of goitre and enterohepatonephropathy in Nubian Goats fed with pearl millet (Pennisetum typhoides). Vet J. 1999 Mar;157(2):178-85.

2. Brahmbhatt S, Brahmbhatt RM, Boyages SC. Thyroid ultrasound is the best prevalence indicator for assessment of iodine deficiency disorders: a study in rural/tribal schoolchildren from Gujarat (Western India). Eur J Endocrinol. 2000 Jul;143(1):37-46.

3. Cordain L. (1999). Cereal grains: humanity’s double edged sword. World Review of Nutrition and Dietetics, 84: 19-73.

4. Cordain L. The nutritional characteristics of a contemporary diet based upon Paleolithic food groups. J Am Neutraceut Assoc 2002; 5:15-24.

5. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH, Brand-Miller J. Origins and evolution of the western diet: Health implications for the 21st century. Am J Clin Nutr 2005;81:341-54.

6. de Souza Dos Santos MC, Gonçalves CF, Vaisman M, Ferreira AC, de Carvalho DP. Impact of flavonoids on thyroid function. Food Chem Toxicol. 2011 Oct;49(10):2495-502

7. Elnour A, Hambraeus L, Eltom M, Dramaix M, Bourdoux P. Endemic goiter with iodine sufficiency: a possible role for the consumption of pearl millet in the etiology of endemic goiter. Am J Clin Nutr. 2000 Jan;71(1):59-66.

8. Elnour A, Liedén S, Bourdoux P, Eltom M, Khalid SA, Hambraeus L. Traditional fermentation increases goitrogenic activity in pearl millet. Ann Nutr Metab. 1998;42(6):341-9.

9. Elnour A, Liedén S, Bourdoux P, Eltom M, Khalid SA, Hambraeus L. The goitrogenic effect of two Sudanese pearl millet cultivars in rats. Nutr Res 1997; Mar (17): 533–546.

10. Gaitan E, Cooksey RC, Legan J, Lindsay RH. Antithyroid effects in vivo and in vitro of vitexin: a C-glucosylflavone in millet. J Clin Endocrinol Metab. 1995 Apr;80(4):1144-7.

11. Gaitan E, Lindsay RH, Reichert RD, Ingbar SH, Cooksey RC, Legan J, Meydrech EF, Hill J, Kubota K. Antithyroid and goitrogenic effects of millet: role of C-glycosylflavones. J Clin Endocrinol Metab. 1989 Apr;68(4):707-14.

12. Gaitan E, Lindsay RH, Cooksey RC, Hill J, Reichert RD, Ingbar SH. The thyroid effects of C-glycosylflavonoids in millet. Prog Clin Biol Res. 1988;280:349-63

13. Hunt HV, Badakshi F, Romanova O, Howe CJ, Jones MK, Heslop-Harrison JS. Reticulate evolution in Panicum (Poaceae): the origin of tetraploid broomcorn millet, P. miliaceum. J Exp Bot. 2014 Jul;65(12):3165-75.

14. Lu H, Zhang J, Liu KB, Wu N, Li Y, Zhou K, Ye M, Zhang T, Zhang H, Yang X, Shen L, Xu D, Li Q. Earliest domestication of common millet (Panicum miliaceum) in East Asia extended to 10,000 years ago. Proc Natl Acad Sci U S A. 2009 May 5;106(18):7367-72

15. McDonough CM, Rooney LW, Serna-Saldivar SO. (2000). “The Millets”. Food Science and Technology: Handbook of Cereal Science and Technology (CRC Press). 99 2nd ed: 177–210.

16. Medani AM1, Elnour AA, Saeed AM. Endemic goitre in the Sudan despite long-standing programmes for the control of iodine deficiency disorders. Bull World Health Organ. 2011 Feb 1;89(2):121-6.

17. Moreno-Reyes R1, Boelaert M, el Badawi S, Eltom M, Vanderpas JB. Endemic juvenile hypothyroidism in a severe endemic goitre area of Sudan. Clin Endocrinol (Oxf). 1993 Jan;38(1):19-24.

18. [No authors listed] Millet–a possibly goitrogenic cereal. Nutr Rev. 1983 Apr;41(4):113-6.

19. Osman AK, Basu TK, Dickerson JW. A goitrogenic agent from millet (Pennisetum typhoides) in Darfur Province, Western Sudan. Ann Nutr Metab. 1983;27(1):14-8.

20. Osman AK, Fatah AA. Factors other than iodine deficiency contributing to the endemicity of goitre in Darfur Province (Sudan). J Hum Nutr. 1981 Aug;35(4):302-9.

21. Sartelet H, Serghat S, Lobstein A, Ingenbleek Y, Anton R, Petitfrère E, Aguie-Aguie G, Martiny L, Haye B. Flavonoids extracted from fonio millet (Digitaria exilis) reveal potent antithyroid properties. Nutrition. 1996 Feb;12(2):100-6.

22. Schoemaker NJ, Lumeij JT, Dorrestein GM, Beynen AC. Nutrition-related problems in pet birds]. Tijdschr Diergeneeskd. 1999 Jan 15;124(2):39-43.

23. Schröder-van der Elst JP1, Smit JW, Romijn HA, van der Heide D. Dietary flavonoids and iodine metabolism. Biofactors. 2003;19(3-4):171-6.

24. Zimmermann MB.The role of iodine in human growth and development. Semin Cell Dev Biol. 2011 Aug;22(6):645-52.
25. Taylor PN1, Okosieme OE, Dayan CM, Lazarus JH. Therapy of endocrine disease: Impact of iodine supplementation in mild-to-moderate iodine deficiency: systematic review and meta-analysis. Eur J Endocrinol. 2013 Nov 22;170(1):R1-R15. doi: 10.1530/EJE-13-0651. Print 2014 Jan.

26. Devi PB, Vijayabharathi R, Sathyabama S, Malleshi NG, Priyadarisini VB. Health benefits of finger millet (Eleusine coracana L.) polyphenols and dietary fiber: a review. J Food Sci Technol. 2014 Jun;51(6):1021-40.

27. Shobana S, Krishnaswamy K, Sudha V, Malleshi NG, Anjana RM, Palaniappan L, Mohan V. Finger millet (Ragi, Eleusine coracana L.): a review of its nutritional properties, processing, and plausible health benefits. Adv Food Nutr Res. 2013;69:1-39.

28. Lestienne I, Besançon P, Caporiccio B, Lullien-Péllerin V, Tréche S. Iron and zinc in vitro availability in pearl millet flours (Pennisetum glaucum) with varying phytate, tannin, and fiber contents. J Agric Food Chem. 2005 Apr 20;53(8):3240-7.

29. Lestienne I, Caporiccio B, Besançon P, Rochette I, Trèche S. Relative contribution of phytates, fibers, and tannins to low iron and zinc in vitro solubility in pearl millet (Pennisetum glaucum) flour and grain fractions. J Agric Food Chem. 2005 Oct 19;53(21):8342-8.

30 Udayasekhara Rao P, Deosthale YG. In vitro availability of iron and zinc in white and coloured ragi (Eleusine coracana): role of tannin and phytate. Plant Foods Hum Nutr. 1988;38(1):35-41.

31. Suma PF, Urooj A. Nutrients, antinutrients & bioaccessible mineral content (invitro) of pearl millet as influenced by milling. J Food Sci Technol. 2014 Apr;51(4):756-61.

32. Archana, Sehgal S, Kawatra A. Reduction of polyphenol and phytic acid content of pearl millet grains by malting and blanching. Plant Foods Hum Nutr. 1999;53(2):93-8.

33. Pattabiraman TN. Trypsin/chymotrypsin inhibitors from millets. Adv Exp Med Biol. 1986;199:439-48.

34. Shivaraj B, Pattabiraman TN. Natural plant enzyme inhibitors. Characterization of an unusual alpha-amylase/trypsin inhibitor from ragi (Eleusine coracana Geartn.). Biochem J. 1981 Jan 1;193(1):29-36.

35. Joshi BN, Sainani MN, Bastawade KB, Deshpande VV, Gupta VS, Ranjekar PK.
Pearl millet cysteine protease inhibitor. Evidence for the presence of two distinct sites responsible for anti-fungal and anti-feedent activities. Eur J Biochem. 1999 Oct;265(2):556-63.

36. Lee ST, Mitchell RB, Wang Z, Heiss C, Gardner DR, Azadi P. Isolation, characterization, and quantification of steroidal saponins in switchgrass (Panicum virgatum L.). J Agric Food Chem. 2009 Mar 25;57(6):2599-604.

37. Patamalai B, Hejtmancik E, Bridges CH, Hill DW, Camp BJ. The isolation and identification of steroidal sapogenins in Kleingrass. Vet Hum Toxicol. 1990 Aug;32(4):314-8.

Celiac Disease, Gluten, and Children

Researchers posit introducing gluten at specific points of time during infancy development might be the key to celiac disease prevention. A few recent studies tested the hypothesis on an infant population who were genetically at risk for developing the disease.1

Celiac Disease - Diagram 1

Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009;373:1480–1493.

For those unfamiliar, celiac disease is (very simply) defined as an autoimmune disorder, which is caused by a reaction to gliadin.2 Gliadin is a prolamine protein, which is found in wheat.3 Those with celiac disease are usually also sensitive to other proteins, which are chemically similar in structure.4, 5

Celiac Disease - Diagram 2

World J Gastroenterol. Nov 14, 2012; 18(42): 6036–6059.

Surprisingly, the researchers’ hypothesis was disproved.6 The studies exhibited that children developed the disease equally, regardless of the time frame of gluten introduction. Perhaps most surprisingly, breastfeeding didn’t seem to provide any protective benefits either, which is seemingly contradictory to earlier scientific findings.7

Celiac Disease - Diagram 3

BMC Pediatr. 2011; 11: 46.

Children with chronic illnesses are known to be more predisposed to emotional and behavioral problems.8 The above chart (MASC Tscore Mean) shows the increased rate of emotional and behavioral problems in children with celiac disease.9 Since the topic of gluten, celiac disease and children is a somewhat sensitive one, it is important for us to look at the likely cause of the disease.10 Causative, not correlative, mechanisms and reasons are, at the end of the day, what’s really important about scientific findings.11 What we seem to have learned from these very well conducted studies, is that celiac disease may be caused almost entirely by genetics.12

Celiac Disease Table 1

World J Gastroenterol. 2012 November 14; 18(42): 6036–6059.

Almost all people with celiac disease have one of 2 genes, DQ2 or DQ8.13 The above table shows the worldwide frequency and distribution of the genes.14 However, interestingly, about 33% of the population also has one of these genes – but they never develop the disease.15 This leads researchers to think that perhaps there are lifestyle and/or epigenetic factors at play, as well.16

Celiac Disease Diagram 3

J Clin Invest. 2011;121(6):2126-2132. doi:10.1172/JCI58109.

Genetic and diet-induced obesity are associated with alterations of (i) the composition and (ii) the functional properties of the gut microbiota. (A) Leptin-deficient ob/ob mice rapidly gain weight. Development of obesity correlates with a shift in the abundance of the 2 dominating divisions, the Bacteroidetes and the Firmicutes. Compared to lean ob/+ or +/+ littermates, obesity was associated with a 50% reduction in Bacteroidetes and a proportional division-wide increase in Firmicutes. Moreover, ob/ob mice showed an increase in environmental gene tags that matched Archaea, methanogenic microorganisms that might promote bacterial fermentation by removing one of its end products, namely hydrogen (H2). The metagenomic analysis of the obese gut microbiome revealed an increase in glycoside hydrolases, capable of breaking down otherwise indigestible alimentary polysaccharides. Furthermore, the obese microbiome showed enrichment for transport proteins and fermentation enzymes further processing breakdown products. As a consequence, ob/ob mice have an increased capacity to harvest energy from their diet. (B) The interrelationship between diet, intestinal microbial ecology, and energy homeostasis was investigated in a mouse model of diet-induced obesity.28 The microbiota of mice fed a high-fat/high-sugar prototypic Western diet was compared with the microbiota of mice receiving a low-fat/high-polysaccharide diet. Again, as in the ob/ob model, the Western diet was associated with an increased body weight, a lower relative abundance of Bacteroidetes, and a higher relative abundance of Firmicutes. However, unlike in the ob/ob model this shift was not division-wide. The overall diversity of the Western diet-associated gut microbiota dropped dramatically. The reason was a bloom in a single class of the Firmicutes—the Mollicutes. The Western diet gut microbiome was enriched for genes involved in import and fermentation of simple sugars and host glycans, enriched for genes for beta-fructosidases, and depleted for genes involved in motility. Gastroenterology Volume 136, Issue 5, Pages 1476–1483, May 2009 .

Tilg, Herbert et al. Gastroenterology. Volume 136 , Issue 5 , 1476 – 1483

One hypothesis is that changes may occur, in gut bacteria, before the disease develops.17 This means that things such as antibiotics, refined sugar, artificial colors, gluten and other artificial food elements may be causing detrimental changes in the microbiome.18 This would also mean that intervening with a probiotic might be one possible “fix.”19, 20 Above, we can see how changes in microbiota, sometimes brought upon by diet, affect many changes and processes in the body.21, 22

Prevalence of celiac disease worldwide. N/A: Not available.   World J Gastroenterol. Nov 14, 2012; 18(42): 6036–6059.

World J Gastroenterol. Nov 14, 2012; 18(42): 6036–6059.

Hypothetically, it would make sense that the recent rise in celiac disease could be due to our massive shift in diet.23 We have changed our diet, almost totally and completely, since the 1970s.24, 25 Obviously, our genome has not really had much time to adapt to these changes.26

Another interesting factor that has also changed since the 1970s is that children are exposed to fewer germs – and parents are much more vigilant about cleanliness.27 This theory of disease is nicknamed the “hygiene hypothesis.”28 With decreased exposure to harmful environmental elements, which our body then learns to defend itself against, children’s immune systems may be turning inward – attacking the body’s own tissue, instead.29, 30

Though the cause of celiac disease may be genetic, the only cure, as has long been known, is a gluten-free diet.31 On the diet, the small intestinal mucosal injury heals and gluten-induced symptoms and signs disappear.32 If you have children, the best course of action is a screening, to see if they may be at risk for celiac disease.33 This goes doubly if any family members have the disease, as the genetic risk factor makes the likelihood increase.34

However, regardless of your children’s potential risk for developing celiac disease, it is not a good idea to be eat gluten.35, 36 There are many downsides to gluten, and it has many negative effects on the body and mind.37, 38, 39, 40 In fact, one study showed that removing gluten from the diet reduced adiposity, inflammation and insulin resistance.41

Other studies have shown that in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction, though this point is somewhat debatable.42, 43, 44 What is interesting, however we previously detailed, is that schizophrenics among others with mental disorders, seem to respond positively to the removal of gluten from the diet.45

As should be obvious by now, you can see the benefits in removing gluten and gluten-like compounds from your children’s diet. Therefore, a Paleo Diet, which is rich in nutrients and avoids problematic proteins like gluten, is the best course of action to take – for both children and adults. You will likely see a decrease in your blood pressure, improve your glucose tolerance and your lipid profile.46 These are all healthy, positive changes – whether you’re young or old.

REFERENCES

1. Lionetti E, Castellaneta S, Francavilla R, et al. Introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med. 2014;371(14):1295-303.

2. Rubio-tapia A, Murray JA. Celiac disease. Curr Opin Gastroenterol. 2010;26(2):116-22.

3. Thompson T. Wheat starch, gliadin, and the gluten-free diet. J Am Diet Assoc. 2001;101(12):1456-9.

4. Troncone R, Auricchio S, De vincenzi M, Donatiello A, Farris E, Silano V. An analysis of cereals that react with serum antibodies in patients with coeliac disease. J Pediatr Gastroenterol Nutr. 1987;6(3):346-50.

5. Hollén E, Högberg L, Stenhammar L, Fälth-magnusson K, Magnusson KE. Antibodies to oat prolamines (avenins) in children with coeliac disease. Scand J Gastroenterol. 2003;38(7):742-6.

6. Available at: //www.bostonglobe.com/lifestyle/health-wellness/2014/10/05/studies-find-tactics-prevent-celiac-disease-newborns-don-work/zsbjwMAjdYOPFzRsDhriuO/story.html. Accessed October 12, 2014.

7. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005;293(19):2343-51.

8. Hysing M, Elgen I, Gillberg C, Lundervold AJ. Emotional and behavioural problems in subgroups of children with chronic illness: results from a large-scale population study. Child Care Health Dev. 2009;35(4):527-33.

9. Mazzone L, Reale L, Spina M, et al. Compliant gluten-free children with celiac disease: an evaluation of psychological distress. BMC Pediatr. 2011;11:46.

10. Niewinski MM. Advances in celiac disease and gluten-free diet. J Am Diet Assoc. 2008;108(4):661-72.

11. Verhulst B, Eaves LJ, Hatemi PK. Correlation not causation: the relationship between personality traits and political ideologies. Am J Pol Sci. 2012;56(1):34-51.

12. Monsuur AJ, Wijmenga C. Understanding the molecular basis of celiac disease: what genetic studies reveal. Ann Med. 2006;38(8):578-91.

13. Castro-antunes MM, Crovella S, Brandão LA, Guimaraes RL, Motta ME, Silva GA. Frequency distribution of HLA DQ2 and DQ8 in celiac patients and first-degree relatives in Recife, northeastern Brazil. Clinics (Sao Paulo). 2011;66(2):227-31.

14. Gujral N, Freeman HJ, Thomson AB. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol. 2012;18(42):6036-59.

15. Szałowska-woźniak DA, Bąk-romaniszyn L, Cywińska-bernas A, Zeman K. Evaluation of HLA-DQ2/DQ8 genotype in patients with celiac disease hospitalised in 2012 at the Department of Paediatrics. Prz Gastroenterol. 2014;9(1):32-7.

16. Alegría-torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics. 2011;3(3):267-77.

17. Nistal E, Caminero A, Herrán AR, et al. Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. Inflamm Bowel Dis. 2012;18(4):649-56.

18. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327-36.

19. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-401, 1401.e1-4.

20. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-12.

21. Tilg H, Moschen AR, Kaser A. Obesity and the microbiota. Gastroenterology. 2009;136(5):1476-83.

22. Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011;121(6):2126-32.

23. Brown K, Decoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095-119.

24. Hurt RT, Kulisek C, Buchanan LA, Mcclave SA. The obesity epidemic: challenges, health initiatives, and implications for gastroenterologists. Gastroenterol Hepatol (N Y). 2010;6(12):780-92.

25. Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341-54.

26. Tännsjö T. Should we change the human genome?. Theor Med. 1993;14(3):231-47.

27. Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1-9.

28. Rook GA. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology. 2009;126(1):3-11.

29. Bloomfield SF, Stanwell-smith R, Crevel RW, Pickup J. Too clean, or not too clean: the hygiene hypothesis and home hygiene. Clin Exp Allergy. 2006;36(4):402-25.

30. Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both?. Immunology. 2004;112(3):352-63.

31. See J, Murray JA. Gluten-free diet: the medical and nutrition management of celiac disease. Nutr Clin Pract. 2006;21(1):1-15.

32. Mäki M. Celiac disease treatment: gluten-free diet and beyond. J Pediatr Gastroenterol Nutr. 2014;59 Suppl 1:S15-7.

33. Aggarwal S, Lebwohl B, Green PH. Screening for celiac disease in average-risk and high-risk populations. Therap Adv Gastroenterol. 2012;5(1):37-47.

34. Rubio-tapia A, Van dyke CT, Lahr BD, et al. Predictors of family risk for celiac disease: a population-based study. Clin Gastroenterol Hepatol. 2008;6(9):983-7.

35. Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106(3):508-14.

36. Marziali M, Venza M, Lazzaro S, Lazzaro A, Micossi C, Stolfi VM. Gluten-free diet: a new strategy for management of painful endometriosis related symptoms?. Minerva Chir. 2012;67(6):499-504.

37. Drago S, El asmar R, Di pierro M, et al. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41(4):408-19.

38. Gluten sensitivity as a neurological illness. Journal of Neurology, Neurosurgery & Psychiatry. 2002;72(5):560.

39. Hadjivassiliou M, Grünewald RA, Kandler RH, et al. Neuropathy associated with gluten sensitivity. J Neurol Neurosurg Psychiatr. 2006;77(11):1262-6.

40. Hadjivassiliou M, Grünewald RA, Lawden M, Davies-jones GA, Powell T, Smith CM. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology. 2001;56(3):385-8.

41. Soares FL, De oliveira matoso R, Teixeira LG, et al. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem. 2013;24(6):1105-11.

42. Hadjivassiliou M, Sanders DS, Grünewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010;9(3):318-30.

43. Nijeboer P, Mulder C, Bouma G. [Non-coeliac gluten sensitivity: hype, or new epidemic?]. Ned Tijdschr Geneeskd. 2013;157(21):A6168.

44. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145(2):320-8.e1-3.

45. Kraft BD, Westman EC. Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature. Nutr Metab (Lond). 2009;6(1):10.

46. Frassetto LA, Schloetter M, Mietus-synder M, Morris RC, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr. 2009;63(8):947-55.

Gluten & the Brain | The Paleo Diet

With the plethora of benefits supported by scientific evidence,1 Gluten-free diets have been gaining in popularity in recent years.2 Studies range from gastrointestinal symptom improvement,3 to possible correlations with autism,4 and diabetes.5 However, there may not be a more fascinating area of gluten study than how the protein composite can be related to cognitive function.6 One study shows large changes in brain tissue, specifically, white matter, in those who are sensitive to gluten.7

Gluten MRI

Gluten and White Matter in the Brain

Why is this an important discovery? White matter is actively involved in neurogenesis, or “the growth of new neurons.”8, 9, 10 If gluten is possibly disrupting this process, like chemotherapy has been studied to do,11 then its effects may not be just temporary and transient. Instead they may be both long lasting and potentially damaging.12

Stress, sleep disruption, exercise and inflammation have all been linked with regulating hippocampal neurogenesis and implicated in the pathophysiology of mood disorders.13 But can gluten be linked to mood disorders? The science says yes.14

Many reports evidence unexpected resolution of long-term schizophrenic symptoms, when eliminating gluten from the diet.15 Interestingly, one study of Pacific Islanders who consumed almost no grains (or dairy) showed that only 2 in 65,000 subjects presented with overtly psychotic cases of schizophrenia.16, 17 However, since there are oftentimes confounding variables in these studies, it is not yet mechanistically clear on what may be causing remission of symptoms.18

In regards to cognitive function, as far back as 2004, scientists have shown improvements in the frontal region of the brain, in subjects consuming a gluten-free diet.19 Other research shows gluten’s effects are clearly not limited to gastrointestinal issues alone.20

Mapping of α-gliadin motifs

 

Gluten-Related Algorithm

Proposed algorithm for the differential diagnosis of gluten-related disorders, including celiac disease, gluten sensitivity and wheat allergy.

To whom does this apply21 and how exactly does gluten cause cognitive impairment? Definitively, we can seem to say that removing gluten from the diet improves cognitive functioning in many individuals.22, 23 Gluten elicits an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 genes.24

The “foggy brain” symptoms, as reported by non-celiac disease subjects, are intriguing. In these subjects, we see an up-regulation of claudin-4, which is associated with an increased expression of toll-like receptor-2 and a significant reduction of the T-regulatory cell marker FoxP3.25 This is part of why an innate immune system response seems to be involved in these subjects, rather than an adaptive immune system response.

Gluten sensitivity as a neurological illness

However, individuals diagnosed with celiac disease, α-amylase/trypsin inhibitors (ATIs) are strong activators of innate immune system responses in macrophages, monocytes and dendritic cells, via toll-like receptor-4.26 Despite these details, however, we cannot yet definitively say that gluten causes cognitive impairment,27, 28 no matter how likely it may seem in the scientific literature.

Brain MRI: Gluten Ataxia

Brain MRI of a patient with gluten ataxia showing rapid onset of cerebellar atrophy over a period of 15 months before the diagnosis of gluten ataxia.

The distinction is very important. A much-publicized study29 from early 2014 suggested it might not be gluten itself that causes issues, but instead it may agglutinins, FODMAPs, prodynorphins, deamidated gliadin and/or gliadorphins.

These findings illustrate more studies need to be done in order to show, mechanistically, what is causing physiologic disruptions, changes in white matter. Furthermore, research may determine distinct populations that should avoid gluten, if indeed the protein composite is causing these issues.

“Early diagnosis and removal of the trigger factor, by the introduction of a gluten-free diet, is a promising therapeutic intervention,” said researchers in a study published in the Journal of Neurology.30 A promising intervention – that needs much more research.31

I do not dismiss anecdotal improvements seen in individuals adopting gluten-free diets, such as the Paleo Diet. And with that said, we need instead maintain scientific rigor and provide the best, most accurate, recommendations possible.

The negative effects of gluten and other gluten-like compounds have been well-documented for many years.32, 33, 34, 35 Just because a specific mechanism for neurologic dysfunction hasn’t yet been identified – doesn’t mean gluten is doing anyone any favors.36, 37

We must also remember that although the human genome has remained primarily unchanged since the agricultural revolution 10,000 years ago, our diet and lifestyle have become progressively more divergent from those of our ancient ancestors.38, 39 A Paleo Diet still provides the best defense against neurologic impairment, as well as providing favorable changes in risk factors, such as weight, waist circumference, C-reactive protein, glycated haemoglobin (HbAlc), blood pressure, glucose tolerance, insulin secretion, insulin sensitivity and lipid profiles.40



References

1. Soares FL, De oliveira matoso R, Teixeira LG, et al. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem. 2013;24(6):1105-11.

2. Available at: //www.cbsnews.com/news/gluten-free-diet-more-popular-than-ever-but-who-really-needs-it/. Accessed August 3, 2014.

3. Murray JA, Watson T, Clearman B, Mitros F. Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease. Am J Clin Nutr. 2004;79(4):669-73.

4. Buie T. The relationship of autism and gluten. Clin Ther. 2013;35(5):578-83.

5. Sildorf SM, Fredheim S, Svensson J, Buschard K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012;2012

6. Hu WT, Murray JA, Greenaway MC, Parisi JE, Josephs KA. Cognitive impairment and celiac disease. Arch Neurol. 2006;63(10):1440-6.

7. Hadjivassiliou M, Grünewald RA, Lawden M, Davies-jones GA, Powell T, Smith CM. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology. 2001;56(3):385-8.

8. Liu XS, Chopp M, Kassis H, et al. Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience. 2012;220:313-21.

9. Takemura NU. Evidence for neurogenesis within the white matter beneath the temporal neocortex of the adult rat brain. Neuroscience. 2005;134(1):121-32.

10. Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science. 1999;286(5439):548-52.

11. Nokia MS, Anderson ML, Shors TJ. Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. Eur J Neurosci. 2012;36(11):3521-30.

12. Lichtwark IT, Newnham ED, Robinson SR, et al. Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Aliment Pharmacol Ther. 2014;40(2):160-70.

13. Lucassen PJ, Meerlo P, Naylor AS, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur Neuropsychopharmacol. 2010;20(1):1-17.

14. Dickerson F, Stallings C, Origoni A, et al. Markers of gluten sensitivity and celiac disease in bipolar disorder. Bipolar Disord. 2011;13(1):52-8.

15. Kraft BD, Westman EC. Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature. Nutr Metab (Lond). 2009;6:10.

16. Dohan FC, Harper EH, Clark MH, Rodrigue RB, Zigas V. Is schizophrenia rare if grain is rare?. Biol Psychiatry. 1984;19(3):385-99.

17. Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull. 1988;14(4):489-94.

18. Di sabatino A, Corazza GR. Nonceliac gluten sensitivity: sense or sensibility?. Ann Intern Med. 2012;156(4):309-11.

19. Usai P, Serra A, Marini B, et al. Frontal cortical perfusion abnormalities related to gluten intake and associated autoimmune disease in adult coeliac disease: 99mTc-ECD brain SPECT study. Dig Liver Dis. 2004;36(8):513-8.

20. Hadjivassiliou M, Grünewald RA, Davies-jones GA. Gluten sensitivity: a many headed hydra. BMJ. 1999;318(7200):1710-1.

21. Troncone R, Jabri B. Coeliac disease and gluten sensitivity. J Intern Med. 2011;269(6):582-90.

22. Genuis SJ, Lobo RA. Gluten sensitivity presenting as a neuropsychiatric disorder. Gastroenterol Res Pract. 2014;2014:293206.

23. Bürk K, Bösch S, Müller CA, et al. Sporadic cerebellar ataxia associated with gluten sensitivity. Brain. 2001;124(Pt 5):1013-9.

24. Junker Y, Zeissig S, Kim SJ, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012;209(13):2395-408.

25. Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10:13.

26. Laparra, M., Zevallos, V. and Schuppan, D. (n.d.). Influence of faecal contents from a gluten-free vs. gluten-containing diet on alpha-amylase/trypsin inhibitor-mediated inflammation. Zeitschrift fur Gastroenterologie, 50(08), p.174.

27 Poloni N, Vender S, Bolla E, Bortolaso P, Costantini C, Callegari C. Gluten encephalopathy with psychiatric onset: case report. Clin Pract Epidemiol Ment Health. 2009;5:16.

28 Gluten sensitivity as a neurological illness. Journal of Neurology, Neurosurgery & Psychiatry. 2002;72(5):560.

29. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145(2):320-8.e1-3.

30. Gluten sensitivity as a neurological illness. Journal of Neurology, Neurosurgery & Psychiatry. 2002;72(5):560.

31. Biesiekierski JR, Muir JG, Gibson PR. Is gluten a cause of gastrointestinal symptoms in people without celiac disease?. Curr Allergy Asthma Rep. 2013;13(6):631-8.

32. Norström F, Sandström O, Lindholm L, Ivarsson A. A gluten-free diet effectively reduces symptoms and health care consumption in a Swedish celiac disease population. BMC Gastroenterol. 2012;12:125.

33. Gasbarrini G, Mangiola F. Wheat-related disorders: A broad spectrum of ‘evolving’ diseases. United European Gastroenterol J. 2014;2(4):254-62.

34. Paoloni M, Tavernese E, Ioppolo F, Fini M, Santilli V. Complete remission of plantar fasciitis with a gluten-free diet: Relationship or just coincidence?. Foot (Edinb). 2014;

35. Cordain L. Cereal grains: humanity’s double-edged sword. World Rev Nutr Diet. 1999;84:19-73.

36. Lachance LR, Mckenzie K. Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis. Schizophr Res. 2014;152(2-3):521-7.

37. Catassi C, Bai JC, Bonaz B, et al. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013;5(10):3839-53.

38. O’keefe JH, Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. Mayo Clin Proc. 2004;79(1):101-8.

39. Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341-54.

40. Kowalski LM, Bujko J. [Evaluation of biological and clinical potential of paleolithic diet]. Rocz Panstw Zakl Hig. 2012;63(1):9-15.

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