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Simopoulos  AP (ed): Evolutionary Aspects of Nutrition and Health. Diet, Exercise, Genetics and Chronic  Disease.
World  Rev Nutr  Diet. Basel, Karger,  1999, vol 84, pp 19–73

Cereal Grains:
Humanity’s Double-Edged Sword

Loren Cordain

Department of Exercise and Sport  Science, Colorado State University,  Fort  Collins, Colo.,  USA


Here is bread which stregthenss mans heart,  and therefore  called the staff of life’ (Mathew  Henry:  1662–1714, Commentary on Psalm 104)
‘Man cannot  live on bread  alone’ (Bible, Matthew  4:4)


20    Introduction
22    Archaeological Perspective
24    Dietary  Imbalances  of Cereal Grains
26        Vitamins  A, C and Beta-Carotene
27        B Vitamins
29        Minerals
34        Essential  Fatty  Acids
36        Amino  Acids
41    Antinutrients in Cereal Grains
43        Alkylresorcinols
43        Alpha-Amylase Inhibitors
44        Protease  Inhibitors
45        Lectins
47    Autoimmune Diseases and Cereal Grain  Consumption
48        Autoimmunity
49        Molecular  Mimicry
49        Genetic  and Anthropological Factors
51         Autoimmune Diseases Associated  with Cereal Grain  Consumption
56    Psychological and Neurological Illnesses Associated with Cereal Grain Consumption
58    Conclusions
60    Acknowledgments
60    References




The number  of plant  species which nourish  humanity is remarkably lim- ited.  Most  of the  195,000 species of  flowering  plants  produce  edible  parts which could  be utilized  by man;  however  less than  0.1% or fewer than  300 species are  used  for  food.  Approximately 17 plant  species provide  90% of mankind’s  food supply, of which cereal grains supply far and away the greatest percentage  (tables  1, 2). From  table  1, it can be shown  that  the world’s four major  cereal grains  (wheat,  maize, rice and  barley)  contribute more tonnage

Table 1. The world’s top 30 food crops
(estimated  edible dry matter)                                                                         Million  metric tons

1       Wheat                   468
2       Maize                   429
3       Rice                      330
4       Barley                   160
5       Soybean                  88
6       Cane sugar             67
7       Sorghum                 60
8       Potato                  54
9       Oats                        43
10       Cassava                   41
11       Sweet potato        35
12       Beet sugar              34
13       Rye                         29
14       Millets                    26
15       Rapeseed                19
16       Bean                       14
17       Peanut                     13
18       Pea                          12
19       Musa                       11
20       Grape                      11
21       Sunflower                 9.7
22       Yams                         6.3
23       Apple                        5.5
24       Coconut                   5.3
25       Cottonseed (oil)      4.8
26       Orange                      4.4
27       Tomato                    3.3
28       Cabbage                    3.0
29       Onion                        2.6
30       Mango                      1.8

Adapted from Harlan [3].


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to  humanity’s  food  supply  than  the  next  26 crops  combined.   Eight  cereal grains: wheat,  maize, rice, barley,  sorghum,  oats,  rye, and millet provide  56% of  the  food  energy  and  50% of  the  protein  consumed  on  earth  [1]. Three cereals: wheat,  maize and  rice together  comprise  at least 75% of the world’s grain  production (table  1). It  is clear that  humanity has  become  dependent upon cereal grains for the majority  of its food supply. As Mangelsdorf [2] has pointed  out,  ‘cereal grains  literally  stand  between  mankind and  starvation’; therefore,  it is essential  that  we fully understand the nutritional implications of cereal grain consumption upon  human  health  and  well being.
Modern man  has become so dependent upon  eating  cereal grains  (grass seeds) that it has prompted at least one author [3] to say that we have become ‘canaries’. However,  this has not  always been the case. For  the vast majority of mankind’s  presence on this planet,  he rarely if ever consumed  cereal grains [4]. With  the  exception  of  the  last  10,000  years  following  the  agricultural ‘revolution’,  humans  have existed as non-cereal-eating hunter-gatherers  since the  emergence  of  Homo  erectus  1.7  million  years  ago.  Although the  first anatomically modern  humans  (Homo  sapiens) appeared in Africa  ?90,000 years  ago,  humans  prior  to  the  mesolithic  period  (~15,000 years  ago)  like other primates rarely if ever utilized cereal grains [4]. Post-pleistocene (~10,000 years  ago)  hunter-gatherers  occasionally   consumed   cereal  grains;  however these foods  were apparently not  major  dietary  components for  most  of the year [5]. It is apparent that  there is little or no evolutionary precedent  in our species for  grass  seed consumption [6–8]. Consequently, we have  had  little time  (=500  generations) since  the  inception  of  the  agricultural revolution 10,000 years ago  to  adapt  to  a food  type  which now  represents  humanity’s major  source of both  calories and  protein. The sum of evidence indicates  that  the human  genetic  constitution has changed  little in the past  40,000 years [7]. The foods  which were commonly

Table 2. Food group totals (estimated edible dry matter)

Million  metric tons

1                Cereals                                    1,545
2                Tubers                                        136
3                Pulses                                        127
4                All meats, milk and eggs        119
5                Sugar                                         101
6                Fruits                                           34

Adapted from Harlan [3].


Cereal Grains:  Humanity’s  Double-Edged Sword                                                                               21 

Table 3. Key events in the development of agriculture  and domestication of cereal grains

Event                                                              Time from present       Location years

Development of agriculture                           10,000                         Near  East
8,000                          Greece, West Africa
7–8,000                         Central  and S. America
7,000                          China,  India  and SE Asia
6,500                          Paris basin
6,000                          Central  Africa
5,500                          Scandinavia, England
Domestication of wheat and barley             10,000                         Near  East
Domestication of rice                                      7,000                          China,  India  and SE Asia Domestication of maize                                   7,000                          Central  and S. America Domestication of millets                             5–6,000                         Africa
Domestication of sorghum                          5–6,000                         East Africa Domestication of rye                                       5,000                          SW Asia Domestication of oats                                      3,000                          Europe


available  to preagricultural man  were the foods  which shaped  modern  man’s genetic nutritional requirements. Although our genetically determined nutri- tional needs have changed  little in the past 40,000 years, our diet has changed dramatically since the advent of agriculture 10,000 years ago [7]. Cereal grains as a staple food are a relatively recent addition to the human  diet (table 3) and represent  a dramatic departure from those foods  to which we are genetically adapted.  Discordance between   humanity’s   genetically  determined dietary needs  and  his present  day  diet  is responsible  for  many  of the  degenerative diseases which plague industrial man [9]. Although cereal grains are associated with  virtually  every highly  developed  civilization  in mankind’s  history  and now occupy the base of the present day food selection pyramid  in the United States  [10], there  is a significant  body  of evidence which suggests that  cereal grains  are  less than  optimal  foods  for  humans  and  that  the  human  genetic makeup  and physiology may not be fully adapted to high levels of cereal grain consumption.


Archaeological Perspective

At the close of the paleolithic era and during the mesolithic period (20,000– 10,000 years ago), there was a widescale extinction  of large mammals  through- out Europe, North America and Asia [11] that  coincided with a fundamental


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change in how hunter-gatherer’s made use of their environment and obtained their food sources. People all over the world began to adopt a broader spectrum of hunting  and gathering  which more fully utilized all niches in their environ- ment.  Tools  and  weapons  became  smaller,  more  elegant  and  more  efficient [3]. The  aquatic  environment was  increasingly  exploited  via  boats,  canoes, harpoons, fish nets,  hooks  and  weirs. Birds and  waterfowl  began  to  appear more  frequently  in the  fossil record  associated  with  man’s  food  supply.  For the first time (15,000 years ago) grindstones and  crude  mortars appeared in the archaeological record in the near east [6], thereby heralding  the beginnings of humanity’s  use of cereal grains for food. Since wild cereal grains are small, difficult to harvest and minimally digestible without  processing (grinding) and cooking  [5, 12, 13], the appearance of stone-processing tools  is an essential indication of when and where cultures  began to include cereal grains in their diet.
As human population numbers increased following the pleistocene (10,000 years ago) and  as large grazing  herbivores  became  either  extinct  or severely depleted, humanity became more and more reliant upon small mammals,  fish, fowl and gathered  plant foods to supply his caloric needs. Gradually, as these resources  became depleted,  in the face of increasing  human  population num- bers, agriculture became the dominant way of life, and  cereal grains  became the  dominant caloric  and  protein   source  in  many,  but  not  all  prehistoric cultures [3, 14]. Whereas hunter-gatherers derived most of their calories from a diversity of wild animal  meats, fruits and vegetables encompassing between 100 and 200 or more species [15], agricultural man became primarily dependent upon  a few staple  cereal foods,  3–5 domesticated meats  and  between  20 and 50 other  plant  foods.  In  many  third-world countries  and  in  a  number  of historical  agrarian societies, a single cereal staple could provide up to 80% or more of the daily caloric intake with few or no calories regularly coming from animal  sources  [7, 16].
Generally, in most  parts  of the world,  whenever  cereal-based  diets were first adopted as a staple  food  replacing  the primarily  animal-based diets  of hunter-gatherers, there was a characteristic reduction in stature  [4, 17–19], an increase in infant mortality [19, 20], a reduction in lifespan [19, 20], an increased incidence of infectious diseases [19–22], an increase in iron deficiency anemia [19, 20, 22], an increased  incidence of osteomalacia, porotic  hyperostosis and other  bone mineral  disorders  [4, 19, 20, 22] and an increase in the number  of dental  caries  and  enamel  defects  [19, 20, 23]. In  a review of 51 references examining human  populations from around the earth and from differing chro- nologies, as they made the transition from hunter-gatherers to farmers, Cohen [19] concluded that there was an overall decline in both the quality and quantity of life. There is now substantial empirical and clinical evidence to indicate that


Cereal Grains:  Humanity’s  Double-Edged Sword                                                                               23



many of these deleterious changes may be directly related to the predominantly cereal-based  diet of these early farmers. Cereal grains truly represent  humanity’s  double-edged sword, for without them  we likely would  not  have  had  an  agricultural ‘revolution’.  We surely would  not  be able  to  sustain  the  enormous present-day human  population (?6 billion),  nor  would  there  likely have  been  societal  stratification which ultimately was responsible for the vast technological/industrial culture in which we live [21]. The enormous increase in human knowledge would probably never had taken place had it not been for the widespread  adoption of agriculture by humanity, and  our  understanding of  medicine,  science and  the  universe  is a  direct  outcome   of  the  societal  stratification wrought   by  the  agricultural ‘revolution’ [21]. On  the  other  hand,  agriculture is generally  agreed  to  be responsible  for many of humanity’s  societal ills including whole-scale warfare, starvation, tyranny, epidemic diseases, and class divisions [21]. Cereals provide the  major  caloric  and  protein   source  for  humanity and  therefore   are  the mainstay  of agriculture; they have allowed man’s culture  to grow and  evolve so that man has become earth’s dominant animal species, but this preeminence has not occurred without cost. Because of cereal grains mankind has dramatic- ally altered  his original  culture;  moreover  cereal  grains  have  fundamentally altered  the foods to which our species had been originally  adapted over eons of evolutionary experience. For  better  or for worse, we are no longer hunter- gatherers, however  our  genetic  makeup  is still that  of a paleolithic  hunter- gatherer, a species whose nutritional requirements are optimally  adapted to wild meats, fruits and vegetables, not to cereal grains. We have wandered  down a path  toward  absolute  dependence  upon cereal grains, a path for which there is no return. It is critical that we fully understand the nutritional shortcomings of cereal grains  as we proceed.


Dietary Imbalances of Cereal Grains

All  cereal  grains  have  significant  nutritional  shortcomings which  are apparent upon analysis. From  table 4 it can be seen that  cereal grains contain no vitamin  A and  except for yellow maize,  no cereals contain  its metabolic precursor, beta-carotene. Additionally, they contain  no vitamin  C, or vitamin B12. In  most  western,  industrialized countries,   these  vitamin  shortcomings are  generally   of  little  or  no  consequence,   since  the  average   diet  is  not excessively dependent upon  grains  and  usually  is varied  and  contains  meat (a  good  source  of  vitamin  B12),  dairy  products (a  source  of  vitamins  B12 and  A),  and  fresh  fruits  and  vegetables  (a  good  source  of  vitamin  C  and beta-carotene).


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Table  4. Vitamin  and  mineral  content  of eight  unprocessed  cereal  grains  (100-gram samples)

Wheat   Maize   Rice      Barley    Sorghum   Oats      Rye       Millet

B1, mg                             0.38      0.39      0.40      0.65       0.24          0.76      0.32      0.42 (35%)   (35%)   (36%)   (59%)    (22%)       (69%)   (29%)   (38%)
B2, mg                             0.12      0.20      0.09      0.29       0.14          0.14      0.25      0.29 (9%)     (15%)   (7%)     (22%)    (11%)       (11%)   (19%)   (22%)
B3, mg                             5.47      3.63      5.09      4.60       2.92          0.96      4.27      4.72 (36%)   (24%)   (34%)   (31%)    (20%)       (6%)     (28%)   (31%)
B6, mg                             0.30      0.62      0.51      0.32       n.a.            0.12      0.29      0.38 (21%)   (39%)   (32%)   (20%)    (n.a.)         (7%)     (18%)   (24%)
Folate,  mg                       38.2      19.0      19.5      19.0       n.a.            56.0      59.9      85.0 (21%)   (11%)   (11%)   (11%)    (n.a.)         (31%)   (33%)   (47%)
Pantothenic acid, mg    0.95      0.42      1.49      0.28       n.a.            1.35      1.46      0.85 (17%)   (8%)     (27%)   (5%)      (n.a.)         (24%)   (26%)   (15%)
Biotin                               n.a.        n.a.        n.a.        n.a.         n.a.            n.a.        n.a.        n.a. (n.a.)     (n.a.)     (n.a.)     (n.a.)      (n.a.)         (n.a.)     (n.a.)     (n.a.)
E, mg                              n.a.        0.49      0.68      0.57       n.a.            1.09      1.28      0.05 (n.a.)     (6%)     (9%)     (7%)      (n.a.)         (14%)   (16%)   (1%)

Potassium, mg                363        287        223        452         350            429        264        195 (18%)   (14%)   (11%)   (23%)    (17%)       (21%)   (13%)   (10%)
Sodium,  mg                    2            35          7            12           6                2            6            5 (0%)     (1%)     (0%)     (1%)      (0%)         (0%)     (0%)     (0%)
Calcium,  mg                   29.0      7.0        23.0      33.0       28.0          53.9      33.0      8.0 (4%)     (1%)     (3%)     (4%)      (4%)         (7%)     (4%)     (1%)
Phosphorus, mg             288        210        333        264         287            523        374        285 (36%)   (26%)   (42%)   (33%)    (36%)       (65%)   (47%)   (36%)
Magnesium, mg             126        127        143        133         n.a.            177        121        114 (45%)   (45%)   (51%)   (48%)    (n.a.)         (63%)   (43%)   (41%)
Iron,  mg                          3.19      2.71      1.47      3.60       4.40          4.72      2.67      3.01 (21%)   (18%)   (10%)   (24%)    (29%)       (31%)   (18%)   (20%)
Zinc, mg                         2.65      2.21      2.02      2.77       n.a.            3.97      3.73      1.68 (22%)   (18%)   (17%)   (23%)    (n.a.)         (33%)   (31%)   (14%)
Copper,  mg                     0.43      0.31      0.27      0.50       n.a.            0.63      0.45      0.75 (19%)   (14%)   (12%)   (22%)    (n.a.)         (28%)   (20%)   (33%)
Manganese,  mg              3.98      0.46      3.75      1.95       n.a.            4.92      2.68      1.63 (114%) (14%)   (107%) (56%)    (n.a.)         (140%) (77%)   (47%)
Selenium, mg                 0.043     0.004     n.a.        0.066      n.a.            n.a.        n.a.        n.a. (78%)   (8%)     (n.a.)     (120%)  (n.a.)         (n.a.)     (n.a.)     (n.a.)

Values in (parentheses)  represent  RDA  %. n.a.>Not  available.  No  detectable  amounts of vitamins  A, C, D, B12  in any grain.


Cereal Grains:  Humanity’s  Double-Edged Sword                                                                               25



However,  as more  and  more  cereal grains  are included  in the diet, they tend  to displace  the calories  that  would  be provided  by other  foods  (meats, dairy products, fruits and vegetables), and can consequently disrupt  adequate nutritional balance.  In  some  countries  of Southern Asia,  Central  America, the Far  East  and  Africa  cereal product consumption can comprise  as much as 80% of the total  caloric intake  [16], and in at least half of the countries  of the world,  bread  provides  more  than  50% of the total  caloric  intake  [16]. In countries  where cereal grains comprise the bulk of the dietary intake, vitamin, mineral  and  nutritional deficiencies are commonplace.

Vitamins  A, C and Beta-Carotene
Vitamin  A deficiency remains  one of the major  public health  nutritional problems  in the third  world [24]. Twenty to 40 million children worldwide  are estimated  to have at least mild vitamin A deficiency [25]. Vitamin A deficiency is a leading  cause of xerophthalmia and  blindness  among  children  and  also a major  determinant of childhood morbidity and  mortality [26]. In virtually all  infectious  diseases,  vitamin  A  deficiency  is known  to  result  in  greater frequency,  severity,  or  mortality [27]. A  recent  meta-analysis [28] from  20 randomized controlled trials  of  vitamin  A supplementation in third  world children  has shown  a 30–38% reduction in all cause mortality in vitamin  A- supplemented children.  Analysis  of cause-specific mortality showed  vitamin A supplementation elicited a reduction in deaths  from  diarrheal disease  by
39%, from respiratory disease by 70% and  from all other  causes of death  by 34% [28]. Clearly,  the  displacement of  beta-carotene-containing  fruits  and vegetables  and  vitamin  A-containing foods  (milk  fat,  egg yolks  and  organ meats)  by excessive consumption of cereal  grains  plays  a major  role  in the etiology  of vitamin  A deficiency in third  world children.
In  numerous epidemiologic   studies,  an  increased  intake  of  fruits  and vegetables  has been associated  with a reduced  risk of many  types of cancer [29, 30] and coronary heart  disease (CHD)  [31, 32]. Much of the evidence for the link between fruit, vegetables and cancer and CHD  points  to those foods rich in antioxidants, including  vitamin C, carotenoids and phytochemicals. In the  United  States,  an  estimated  45% of the  population had  no  servings  of fruit  or  juice,  and  22% had  no  servings  of  a  vegetable  on  any  given  day [33]. Further, 91% of the  adult  population did  not  meet  the  United  States Department of Agriculture’s  daily  recommendation of 2–3 servings of fruit and  3–5 servings of vegetables  [33]. Although frank  vitamin  C deficiency is virtually  unknown in the  United  States  and  other  western  countries,  it has been  shown  to  be common  in portions of rural  India  wherein  cereals  and pulses comprise the dietary mainstays, and vitamin C-rich fruits and vegetables are consumed  in low quantities [34]. Again, since cereal grains contain  unde-


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tectable  amounts of vitamin  C and  carotenoids, they tend  to displace  foods rich in these substances;  foods which are associated  with a decreased  risk for many  common  cancers [35] and  heart  disease [31, 32].
Cereal- and pulse-based diets of the third world generally tend to be considerably lower  in both  total  fat,  saturated fat  and  cholesterol  than  the meat-based diets of western countries  [36], yet paradoxically, CHD  mortality is in some cases either higher [36] or similar [36, 37] to that in western countries. Since the antioxidant status of CHD-prone individuals  chronically  consuming cereal- and pulse-based  diets has been shown to be low [36, 38], and increased consumption of fruit  and  vegetables  has  been  shown  to  improve  the  CHD risk profile of this population [39], it is likely that high cereal grain consumption partially  contributes to increased CHD  mortality via its displacement of anti- oxidant  rich fruits  and  vegetables.

B Vitamins
Diets based primarily  or wholly upon plant food sources tend to be either low or deficient in vitamin B12, since this nutrient is found exclusively in animal products [40]. Vitamin  B12  deficiency causes  a megaloblastic anemia  which ultimately  results  in cognitive  dysfunction via its irreversible  impact  on  the neurological system [41]. Additionally, it is known that a chronic B12 deficiency produces  elevated  homocysteine levels [42, 43] which  are  an  important risk factor  for arterial  vascular  disease and thrombosis [43, 44]. Vitamin  B12  defi- ciency is generally assumed to be uncommon because omnivorous diets provide adequate intake,  and the vitamin  is conserved  efficiently by the enterohepatic circulation [40]. However,  in countries  such  as India  in which  the  diets  are mainly cereal and  pulse based,  vitamin  B12  deficiencies are common  [45, 46]. Additionally, even if minimal  amounts of animal-based foods  are consumed along with traditional cereal- and pulse-based  diets, intestinal infection, which is widespread in the third world, has been shown to worsen an already compro- mised  B12  status  and  result  in widespread  B12  deficiencies [47]. The  human nutritional requirement for vitamin  B12  clearly demonstrates that  vegetarian diets based  entirely  upon  cereal grains,  legumes and  other  plant  foods  were not  the sole dietary  components which shaped  the human  genome.
Many  nutritionists consider  cereal grains  to be good  sources  of most of the B vitamins except for vitamin B12. Inspection of table 4 generally is support- ive of this concept, at least in terms of the % RDA  which cereal grains contain. However,  of more importance is the biological  availability  of the B vitamins contained within  cereal  grains  and  their  B  vitamin  content   after  milling, processing and cooking. It is somewhat  ironic that two of the major B vitamin deficiency diseases which have plagued agricultural man (pellagra and beriberi) are almost exclusively associated  with excessive consumption of cereal grains.


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Beriberi occurs from a thiamin deficiency which is associated with polished rice consumption. In  the  late  1800s, with  the  introduction of polished  rice, beriberi reached epidemic proportions in Japan  and other countries  in South- east  Asia [48]. Human crossover  experiments  done  in the  early part  of this century  induced  beriberi  in subjects  fed polished  rice, but  not  in those  fed brown  rice [48]. The removal  of the outer  thiamin-containing coat of the rice kernel during the polishing process was found to be the factor  responsible  for inducing  beriberi  in  rice-eating  populations [48]. Beriberi  has  been  largely eliminated  with the advent  of ‘enriched  rice’ to which thiamin  is added,  but still occurs in some African countries whose populations consume high quanti- ties of polished  rice [49].
Pellagra is thought to be a multiple deficiency disease caused by a lack of niacin and the essential amino acid tryptophan [14], and occurs almost exclus- ively in people eating corn as their staple food.  In the United  States between 1906 and 1940 there was an epidemic of pellagra in the southern states which resulted in approximately 3 million cases with at least 100,000 deaths [50]. Similar epidemics have occurred in Europe and India [51], and pellagra is still widespread in parts of Africa [52, 53]. Although administration of niacin is known to rapidly eliminate all symptoms  of pellagra, there is a continuing suspicion that not all of the precipitating factors which operate  in maize to elicit overt symptoms  of pellagra are understood [54, 55]. Traditional lime-processing techniques of corn (boiling of dried corn flour for 30–50 min in a 5% lime water solution) prevents pellagra, and it is thought to do so by increasing niacin’s availability  [14]. How- ever, a modern  study [55] recently reanalyzed  historical pellagra-inducing diets and  even after correcting  for niacin’s low availability, found  these diets to be adequate in niacin equivalents  (niacin+0.0166¶tryptophan), suggesting that factors in corn other than low niacin and tryptophan were responsible  for the disease. Corn, like all cereal grains, is rich in antinutrients including lectins which are known to decrease intestinal absorption of many key nutrients [56, 57]. Since villous atrophy of the small intestine  has been demonstrated in patients  with pellagra  [58], it is possible that  certain  antinutrients in maize could interfere with intestinal absorption of both niacin and tryptophan or that plasma-borne antinutrients could interfere with the conversion of tryptophan to niacin similar to the effects of isoniazid, an anti-tuberculous drug which is known to produce pellagra-like symptoms  [59].
Although table  4 suggests  that  most  cereal  grains  except  for  oats  are relatively  good  sources  of vitamin  B6, the  bioavailability of B6  from  cereal grains tends to be low, whereas bioavailability of B6  from animal  products is generally  quite  high,  approaching 100% [60]. Vitamin  B6  exists in foods  as three nonphosphorylated forms (pyridoxine, pyridoxal and pyridoxamine) and two  phosphorylated forms  of  pyridoxal   and  pyridoxamine. An  additional


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glycosylated adduct of pyridoxine, pyridoxine glucoside, occurs widely in cereal grains  and  has  been  shown  to  reduce  the  bioavailability of both  nonphos- phorylated and phosphorylated forms of vitamin  B6  by 75–80% [60, 61]. The presence  of  pyridoxine   glucoside  in  cereal  grains  has  an  overall  effect of depressing  the vitamin  B6  nutritional status  [62]. Data  from  Nepalese  vege- tarian  lactating women has shown a low vitamin B6 status for both the mothers and their infants which was partially  attributed to the high levels of pyridoxine glucosides  found  in their  cereal-,  legume- and  plant-based diet [60]. B6  defi- ciencies appear  to be quite common  in populations utilizing cereals and pulses as staples [63, 64]. Low tissue levels of vitamin B6, like vitamin B12 are known to elevate plasma homocysteine levels and increase the risk for arterial vascular disease [43]. To date,  plasma  homocysteine levels have not been evaluated  in cereal- and pulse-eating  populations of the Indian  subcontinent wherein there is a high mortality rate  from CHD  [36].
Perhaps  the  least  studied  of the  B complex  vitamins  is biotin.  Animal studies have shown that  most cereal grains except maize have very low levels of bioavailable biotin  [65, 66], whereas  foods  derived  from  animal  sources have a high biotin  digestibility  [66]. Both  wheat  and  sorghum  not  only have a  low biotin  bioavailability, but  seem to  have  elements  within  them  which seem to elicit a depression  of biotin metabolism [66]. The enzyme, biotinidase, recycles the  biotin  derived  from  the  turnover of  the  biotin-dependent car- boxylases and from exogenous  protein-bound dietary  biotin  (fig. 1). Whether or not  antinutrients present  in cereal grains  interfere  with biotinidase is not known.  However,  the biotin-dependent carboxylases  are important metabolic pathways  of fatty acid synthesis. A biotin deficiency severely inhibits the chain elongation and  desaturation of linoleic acid to  achidonic acid [67] (fig. 2), and biotin-deficient rats are known to exhibit prominent cutaneous symptoms including  scaling,  seborrheic  dermatitis and  alopecia  [68], symptoms  which are identical in humans with biotin and biotinidase deficiencies. Recent human biotin  supplementation trials  have  shown  this  vitamin  to  reduce  fingernail brittleness   [69]. Anecdotal evidence  has  suggested  that   subjects  who  had adopted the Pritikin  diet (a low-fat  diet based  primarily  upon  cereal grains) for periods  of 1–2 years developed  vertical ridges on their fingernails  [70]. It is unclear if these symptoms  are caused by impaired  biotin metabolism; how- ever the available  research  on this poorly  studied  vitamin  suggests that  diets based primarily  upon cereal grains are responsible  for causing biotin deficien- cies in a variety of laboratory animals.

Table 4 displays the mineral content  and the percent of the recommended daily allowance  (RDA)  in a 100-gram  sample of the world’s most commonly


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Fig. 1. Biotin  metabolism. Biotin-dependent carboxylation reactions  can  be divided into step 1 (the formation of carboxyl biotinyl enzyme), and step 2 (carboxyl transfer  to an appropriate acceptor  substrate, dependent  upon  the specific transcarboxylase involved).


consumed  cereal  grains.  Of the  minerals,  cereal  grains  are  poor  sources  of sodium and calcium but are relatively rich sources of phosphorous, potassium and  magnesium.  Not  all of the minerals  are included  in table  4; however  it can be seen that  cereal grains  contain  moderate amounts (10–33%) of zinc, copper  and  iron and  high amounts of manganese.
Calcium. Except  for  calcium  and  sodium,  it  would  appear   that  cereal grains  provide  reasonable amounts  of  most  minerals  needed  for  adequate nutrition. Since  the  western  diet  is already  overburdened by  high  dietary sodium  levels [71], the  low sodium  content  of cereal  grains  is desirable.  In most western populations that consume a mixed diet, the low calcium content of cereal grains  does not  normally  represent  a problem  since dairy  products and  leafy green vegetables  are good  sources  of calcium,  if they are included in the  diet.  However,  as is the  case for  vitamins,  as more  and  more  cereal grains  are  included  in  the  diet,  they  tend  to  displace  dairy  and  vegetable sources  of calcium.  Further, cereal  grains  have  a Ca/P  ratio  which  is quite low (mean from table 4>0.08) and which can negatively impact  bone growth and metabolism. Consumption of a large excess of dietary  phosphorus, when calcium  intake  is adequate or  low, leads  to  secondary  hyperparathyroidism and  progressive  bone  loss [72]. The  recommended, ideal  Ca/P  ratio  is 1:1,


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Fig. 2. The essential fatty acids and their long-chain  polyunsaturated metabolites.


whereas  in the  United  States  it averages  0.64 for  women  and  0.62 for  men [72]. In addition to the unfavorable Ca/P ratio,  cereal grains maintain a quite low  Ca/Mg  ratio  (averaging  0.19  from  table  4)  which  also  favors  net  Ca excretion,  since imbalances  in Mg intake relative to Ca decrease gastrointesti- nal  absorption and  retention of  Ca  [73, 74]. Because  of  the  high  phytate content  of  whole  grain  cereals  much  of  the  calcium  present  is unavailable for  absorption because  the phytate  forms  insoluble  complexes  with calcium [75]. The  net  effect of a low calcium  content,  a low Ca/P  ratio,  a low Ca/ Mg  ratio,   and  low  bioavailability  of  calcium  via  a  high  phytate   content frequently  induces bone mineral  pathologies in populations dependent upon cereal  grains  as  a  staple  food.  In  populations where  cereal  grains  provide the major  source of calories, osteomalacia, rickets and osteoporosis are com- monplace  [76–79]. Cereal grains have been shown to cause their rachitogenic- and osteomalacia-producing effects in spite of the presence of adequate sun- shine [80]. Further, substitution of leavened  white breads  of lower extraction for  unleavened  whole  grain  breads  improved  biochemical  symptoms  in pa- tients  with  rickets  or  osteomalacia [77].


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Consumption of high levels of whole grain cereal products impairs  bone metabolism not  only  by  limiting  calcium  intake,  but  by  indirectly  altering vitamin  D  metabolism. In  animal  studies  it has  been  long  recognized  that excessive consumption of cereal grains  can induce  vitamin  D deficiencies in a wide variety  of animals  [81–83] including  primates  [84]. Epidemiological studies of populations consuming high levels of unleavened  whole grain breads show vitamin D deficiency to be widespread  [85–87]. A study of radiolabelled
25-hydroxyvitamin D3  (25(OH)D3)  in humans  consuming  60 g of wheat bran daily for 30 days clearly demonstrated an enhanced  elimination of 25(OH)D3 in the intestinal lumen [88]. The mechanism by which cereal grain consumption influences vitamin D is unclear.  Some investigators have suggested that  cereal grains  may  interfere  with  the  enterohepatic circulation of vitamin  D  or  its metabolites [84, 88], whereas  others  have  shown  that  calcium  deficiency in- creases the  rate  of inactivation of vitamin  D  in the  liver [89]. This  effect is mediated  by 1,25-dihydroxyvitamin D (1,25(OH)2D) produced in response  to secondary hyperparathyroidism, which promotes hepatic conversion of vitamin D to polar inactivation products which are excreted in bile [89]. Consequently, the low Ca/P  ratio  of cereal  grains  has  the ability  to  elevate  PTH  which in turn  stimulates  increased  production of 1,25(OH)2D  which causes an acceler- ated  loss of 25-hydroxyvitamin D.
Iron. In addition to their deleterious  influence upon calcium metabolism, cereal grains  when consumed  in excessive quantities can adversely  influence iron metabolism. Because of their fiber and phytate  content,  the bioavailability of iron in cereal grains is quite low [75, 90]. Iron deficiency is the most prevalent nutritional problem in the world today affecting 2.15 billion people throughout the  world  and  being  severe  enough  to  cause  anemia  in  1.2 billion  people [91, 92]. The causative  factor  has been clearly demonstrated to be the poor bioavailability of iron  from  cereal-based  diets,  which  are  the  staple  food  in many  developing  countries  [93]. The displacement of iron-rich  animal  foods by cereal grains, legumes and plant-based diets is thus largely indirectly respon- sible for the worldwide  epidemic of iron deficiency. Iron  deficiency is known to reduce work capacity  and productivity in adults,  increase the severity and incidence of infection, and increase maternal, prenatal and perinatal mortality [94]. Perhaps  the most serious effect of iron deficiency is the often irreversible impairment of a child’s learning  ability  [94].
There appear  to be a number  of elements within cereal grains which may inhibit nonheme iron absorption including phytate  [75], tannins  [95], fiber [75], lectins [96], phosphate [97] and perhaps  other unknown factors [98]. However, the primary inhibitor of nonheme iron absorption by cereal grains is its phytate content  [98]. Recent  work  has indicated  that  phytate  must  be almost  totally removed  to  eliminate  its inhibitory effect on  nonheme  iron  absorption [99].


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Consequently, diets  based  upon  whole  grain  maize  [100], rice [101], wheat [102] and oats [103] have been consistently  shown to reduce iron absorption. Nonheme iron absorption can be enhanced  by including  ascorbate-rich fruit and  vegetables  with cereal-based  meals [101]. Further, the addition of yeast fermentation to make leavened breads is known to reduce their phytate content [102]. Additionally, fortification of cereal grains with iron has been shown to be an effective procedure to prevent  iron deficiency anemia  [104, 105].
Other  Minerals.  In  addition to  calcium  and  iron,  the  bioavailability of zinc, copper and magnesium  in cereal grains is generally low [75], whereas the absorption of  manganese,   chromium   and  selenium  does  not  appear   to  be impaired  [90]. Except for zinc, the clinical implications of deficiencies in these minerals relative to cereal grain consumption have been poorly  studied.  Con- sequently, few links have been established  between high cereal grain consump- tion   and   deficiencies  of  copper,   magnesium,   manganese,   chromium   and selenium in human  diets. However, there is substantial evidence which demon- strates that relatively high consumption of cereal grains can have a detrimental influence upon  zinc metabolism and  thus  adversely  affect human  health  and well-being.
Zinc.  Radiolabelled studies  of zinc absorption in rats  [106] and  humans [107] have  clearly  demonstrated that  consumption of  whole  grain  cereals (wheat, rye, barley, oats and triticale) impairs zinc absorption. Similar to iron, it appears  that  phytate  plays a major role in the inhibition of zinc absorption [106, 107]; however,  other  factors  are  likely involved  [106]. In  humans, zinc deficiency results  in a characteristic syndrome  called hypogonadal dwarfism in which there is arrested  growth, hypogonadism and delayed onset of puberty [108]. In rural  Iran  where unleavened, whole grain flat bread  (tanok)  contrib- utes  at  least  50% of the  daily  calories  [106], the  incidence  of hypogonadal dwarfism was estimated  to be nearly 3% in 19-year-old  conscripts  [109]. Since the zinc intake of these populations exceeds the RDA  by a substantial margin [109], it has  been shown  that  the high consumption of tanok  is responsible for inducing negative zinc balances [110]. Recent studies of nonhuman primates moderately deprived  of zinc [111] as well as zinc supplementation trials  in children  [112] have  confirmed  Reinhold’s   earlier  work  [109] showing  how marginal   zinc  nutriture, independent of  other  nutrients, may  limit  skeletal growth. Yeast leavening of whole grain breads can reduce their phytate  content and improve the bioavailability of zinc [106]; however increased  ascorbic acid intake does not enhance the absorption of zinc [103]. Because the bioavailability of zinc from meat is four times greater  than  that  from cereals [113], it is clear that  the displacement of animal-based foods by cereal-grain-  and plant-based diets is not only responsible  for impaired  zinc metabolism in developing coun- tries, but  also in western  populations adopting vegetarian  diets [114, 115].


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Essential Fatty  Acids
Cereal  grains  are quite  low in fats (table  6) averaging  3.6% fat for their total  caloric  content;  even still a predominantly cereal- and  plant-based diet can contribute 5–10 g per person  per day of linoleic acid (LA), the major  X-
6 (n-6)  polyunsatuarated fatty  acid  found  in  grains  [5]. The  linolenic  acid content  of cereals is quite  low, and  they are devoid  of the longer  chain  X-3 (n-3) derivatives  of linolenic acid, including  eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Consequently, cereal-based  diets,  particularly if they are supplemented by vegetable  oils, tend  to have a high n-6/n-3 ratio (table  6) and  are  deficient  in EPA,  DHA  and  long-chain  derivatives  of LA including  arachidonic acid (AA).
In man, the longer chain fatty acids can be synthesized from their shorter chain precursors; however the process is inefficient [117], and because linoleic and  linolenic  acid  must  utilize  the  same  desaturase and  elongase  enzymes, there  is competitive  inhibition of one another, so that  high dietary  levels of linoleic  acid  tends  to  inhibit  the  formation of  EPA  from  linolenic  acid  if preformed EPA is not obtained directly in the diet from fish or meat sources. The importance of certain  long-chain  fatty acids [20:3n-6 (dihomogammalin- olenic acid), 20:4n-6 (AA) and 20:5n-3 (EPA)] is that  they serve as precursors for the synthesis of eicosanoids  (the prostaglandins, prostacyclins, thrombox- anes, and leukotrienes), potent  hormone-like substances  which have a variety of  effects including  regulation of  platelet  aggregation, thrombosis  and  in- flammation [118]. Increased  dietary  consumption of n-3 fatty  acids, particu- larly EPA has been shown to decrease triglycerides, decrease thrombotic tendencies   [119] and  reduce  symptoms   of  many  inflammatory  and  auto- immune  diseases  including  arthritis [120] and  inflammatory bowel  disease [121]. Additionally, epidemiological studies indicate  a reduced mortality from coronary heart  disease  in populations consuming  increased  amounts of n-3 fatty  acids  [122].
Vegetarian diets based primarily upon cereals, legumes and plant products are  known  to  have  a high  n-6/n-3  ratio  because  of their  low levels of both linolenic  acid  and  the absence  of its long-chain  derivatives,  EPA  and  DHA [123]. Studies  of preterm  infants  deprived  of DHA  have shown  both  visual and  cortical  abnormalities [124]. A recent  study  of South  Asian  vegetarian mothers  has indicated  lower plasma  levels of EPA and DHA  when compared to white nonvegetarians [125]. Additionally, cord  DHA  levels were lower in the  vegetarian  mothers,  and  the  duration of gestation  was 5.6 days  shorter than  the meat-eating controls.  In the vegetarian  women  early onset  of labor and emergency cesarean  section were more common,  and birth  weight, head circumference and body length were lower in the infants born to the vegetarian women [125].


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In  the  United  States,  the  US  Department of  Agriculture has  recently adopted a ‘food pyramid’  of nutritional recommendations that  places grains and pasta at the bottom (i.e. to be eaten in the largest amounts; 6–11 servings per day). It has recently been argued that a diet of this nature  likely encourages essential fatty acid (EFA)  deficiencies and may lead to an increased  incidence of atherosclerosis [126]. The recommendation for a low-fat/high-carbohydrate diet,  which  is high  in  trans  fatty  acids  due  to  margarine intake,  leads  to decreases in EFA.  Since the standard American  diet falls considerably short of the 6–11 servings of cereal grains  recommended by the USDA  [127], it is unlikely that cereal grain consumption, by itself, adversely influences the EFA status  of the  average  American  omnivorous diet.  However,  there  are  world populations in which excessive cereal grain consumption clearly has a deleteri- ous impact upon essential fatty acid status. Studies of vegetarian  and nonvege- tarian  populations from the Indian  subcontinent who derive the bulk of their caloric  intake  from  cereals  and  pulses  have  consistently  demonstrated high plasma  n-6/n-3  ratios,  low levels of 20:5n-3 and  22:6n-3 and  high  levels of
18:2n6 when compared to western populations [125, 128–130]. Associated with these altered  fatty acid levels is a mortality rate from CHD  which is equal to [36, 37] or  higher  than  [36, 129,  130] that  found  in  western  populations. Although the precise etiology of high levels of CHD  in Indian  populations is unclear,  reduced  plasma  levels of n-3 fatty  acids  likely increase  the  risk  for CHD  by a variety of mechanisms which influence blood lipids, blood pressure, blood  thrombic tendencies,  and  cardiac  arrhythmias [119]. Since the western diet is already overburdened by an excessively high (n-6/n-3) ratio from vegeta- ble oils, margarine and shortening [131], nutritional recommendations encour- aging increased  cereal grain consumption at the expense of fruits,  vegetables, seafood  and  lean  meats  may  indirectly  contribute to  an  EFA  profile  which promotes CHD.
There is substantial evidence to show that low-density lipoprotein (LDL) oxidation plays an integral role in atherogenesis [132], and that diets enriched in linoleic acid increase the linoleic acid content  of LDL  and therefore  increase its susceptibility  to oxidation [133]. Blankenhorn et al. [134] have found  that increased  intake  of linoleic acid significantly  increased  the risk of developing new atherosclerotic lesions in human coronary arteries. Further, the linoleic acid content of adipose tissue has been positively associated with the degree of CHD in patients  undergoing coronary angiography [135]. Because cereal-grain-  and pulse-based diets are quite high in linoleic acid (table 6), populations consuming these diets have been shown to have elevated plasma levels of linoleic acid when compared to western populations [125, 129]. It is possible that the high mortality rates of these populations [36, 129, 130] may be partially  attributable to a high linoleic acid intake which increases the oxidative susceptibility  of LDL.


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These facts underscore the importance of a proper  dietary balance of not only the short-chain n-3 and n-6 fatty acids, but of the preformed long-chain fatty acids of both  the n-3 and n-6 families which are only found  in foods of animal and marine origin. A diet based primarily  upon cereal grains, legumes and plant foods inevitably leads to a disruption of this delicate balance among the  dietary  fatty  acids,  and  ultimately  may  alter  optimal  health  via  subtle changes in eicosanoid, prostaglandin, prostacyclin, thromboxane and leukotri- ene function  in various tissues. Human dietary lipid requirements were shaped eons ago, long before the agricultural revolution, and long before humanity’s adoption of cereal grains as staple foods. Hence, the lipid composition of diets based upon  cereal grains,  legumes, vegetable  oils and other  plant  products is vastly at odds with that  found in wild game meat and organs [6], the primary, evolutionary source of lipids to which the human  genetic constitution is opti- mally adapted [5].

Amino  Acids
Because human  body proteins  constantly undergo  breakdown and resyn- thesis  during  growth,  development and  aging,  there  is a  dietary  need  for protein.  Human body proteins are composed of 21 separate  amino acids which are divided into three categories:  (1) essential; (2) conditionally essential, and (3) nonessential. The nine essential amino  acids cannot  be synthesized  in the body and consequently must be supplied  by diet. The conditionally essential amino  acids can be endogenously synthesized,  however under  certain  physio- logical and  pathological conditions, endogenous synthesis is inadequate and needs must be met by the diet. The nonessential amino  acids can be endoge- nously synthesized under  all conditions if there is an adequate dietary  source of usable nitrogen. Consequently, in order for normal  human  protein  metabo- lism to take  place, there  must  be an adequate dietary  intake  (qualitative) of all 9 essential  amino  acids  as  well as  an  adequate intake  (quantitative) of protein  for  synthesis  of the  conditionally essential  and  nonessential amino acids.  The  long-term  metabolic  consequences  of imbalanced or  marginally insufficient dietary  amino  acid  intake  in humans  are  not  well documented; however  there  is evidence  which  suggests  these  types  of diets  can  result  in impaired  linear  growth  [136], losses  of  body  mass,  muscular   strength   and impaired immune function [137] as well as impaired recovery from illness [138] and  surgery [139].
Table 7 contrasts the amino  acid contents  of animal  food sources to that in cereal grains and legumes. Inspection of both  tables 5 and 7 show that  the essential amino  acid, lysine, is consistently  lower in cereal proteins  compared to animal proteins.  Also, the essential amino acid, threonine, tends to be lower in cereal-based  proteins  relative to animal protein  sources. The relative protein


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Table 5. Amino acid and nutrient composition of eight unprocessed  cereal grains (100- gram samples)

Wheat   Maize   Rice      Barley   Sorghum   Oats      Rye       Millet

Essential amino acids
Tryptophan, mg                160       67         101       208        124            234       154       119 (64%)   (27%)   (40%)   (83%)    (50%)       (94%)   (62%)   (48%)
Threonine, mg                   366       354       291       424        345            575       532       354 (81%)   (79%)   (65%)   (94%)    (77%)       (128%) (118%) (79%)
Isoleucine,  mg                   458       337       336       456        433            694       550       465 (71%)   (52%)   (52%)   (70%)    (67%)       (107%) (85%)   (72%)
Leucine, mg                       854       1,155    657       848        1,491         1,284    980       1,400 (90%)   (122%) (69%)   (89%)    (157%)     (135%) (103%) (147%)
Lysine, mg                         335       265       303       465        229            701       605       212 (42%)   (33%)   (38%)   (58%)    (29%)       (88%)   (76%)   (26%)
Methionine, mg                201       198       179       240        169            312       248       221 (47%)   (46%)   (42%)   (56%)    (40%)       (73%)   (58%)   (52%)
Cystine*, mg                     322       170       96         276        127            408       329       212 (76%)   (40%)   (23%)   (65%)    (30%)       (96%)   (77%)   (50%)
Phenylaline,  mg                 593       463       410       700        546            894       673       580 (125%) (97%)   (86%)   (147%)  (115%)     (188%) (142%) (122%)
Tyrosine*,  mg                   387       383       298       358        321            573       339       340 (81%)   (81%)   (63%)   (75%)    (68%)       (121%) (71%)   (72%)
Valine, mg                          556       477       466       612        561            937       747       578 (85%)   (73%)   (72%)   (94%)    (86%)       (144%) (115%) (89%)
Histidine,  mg                     285       287       202       281        246            405       367       236 (52%)   (52%)   (37%)   (51%)    (45%)       (74%)   (67%)   (43%)

Nutrient  composition
Kilocalories                        327       365       370       354        339            389       335       378
Protein, % total calories    12.6      9.4        7.9        12.5       11.3           16.9      14.7      11.0
Carbohydrate, % total      71.3      74.1      77.2      73.3       74.4          66.0      69.8      73.0 calories
Fat,  % total  calories         1.5        4.7        2.9        2.3         3.3            6.9        2.5        4.2

Values in (parentheses)  represent RDA  %. No detectable amounts of taurine  in any grain.
* Conditionally essential amino  acids.


content  of cereal grains  averages  12.0% (table 5) whereas that  in lean beef is
22%. Consequently, a higher total intake of cereal products would be required to meet the needs for both total protein  and certain individual  essential amino acids when compared to animal  foods.
Table 8 clearly indicates that cereal grains provide the majority  of protein calories for most countries  of the world. Because cereal-based  diets frequently


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Table 6. Fatty  acid content  of cereal grains  (g fatty  acid/100-gram  sample):  adapted from Weihrauch  et al. [116]

Fatty  acid                         Wheat   Maize   Rice     Barley    Sorghum   Oats      Rye       Millet

Saturated  fats
14:0                                  –            0.00      0.03     0.01       0.01          0.02      –            0.00 (myristic acid)
16:0                                  0.36      0.40      0.54     0.45       0.44          1.21      0.25      0.68 (palmitic  acid)
18:0                                  0.01      0.06      0.04     0.02       0.03          0.10      0.02      0.16 (stearic acid)
20:0                                  –            0.01      0.01     0.00       0.00          0.04      0.00      0.02 (arachidic)

Monounsaturated  fats
16:1                                  0.01      0.01      0.01     0.01       0.04          0.02      0.01      0.02 (palmitoleic)
18:1                                  0.25      0.91      0.54     0.24       1.15          2.60      0.22      0.83 (oleic acid)

Polyunsaturated  fats
18:2n-6                             1.20      2.12      0.78     1.14       1.46          2.87      0.95      1.69 (linoleic acid)
18:3n-3                             0.10      0.03      0.03     0.13       0.09          0.16      0.12      0.13 (linolenic acid)
Ratio  (n-6/n-3)                12.0      70.7      26.0     8.7          16.2          17.9      7.9        13.0
Fat,  % total  calories       2.7        4.1        2.3       2.8          3.3            7.4        2.2        4.1

–>=0.005 g.


include legumes and small amounts of animal protein,  they are almost always adequate in the qualitative aspect of amino  acid nutriture [140]; however the possibility  exists  that  lysine  intake  may  be  marginal   [140], particularly  in children  receiving a single or limited number  of food  protein  choices [141].
Although cereal-  and  legume-based   diets  are  usually  adequate in  the qualitative aspects of amino  acid nutriture, there is evidence that  under  some circumstances they may fall short in quantitative aspects. The current estimated mean  dietary  protein  requirements for healthy  adult  men and  women  of all ages is 0.6 g/kg/day,  with a suggested safe protein  intake  set at 0.75 g/kg/day by the Joint  FAO/WHO/UNU Expert  Consultation [142] and at 0.8 g/kg/day by the Food  and Nutrition Board of the US National Research  Council [143]. There  is now  considerable evidence  to  suggest  that  these  recommendations are  too  low for  both  adults  [144, 145] and  the  elderly  [146] and  that  safe


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Table 7. Amino  acid distribution in cereal, legume and  animal  food sources: adapted from Young  et al. [140]

Food                          Lysine content      Sulfur amino  acids     Threonine            Tryptophan mg/g protein          mg/g protein                mg/g protein        mg/g protein

Cereal grains            31×10                   37×5                            32×4                   12×2
Legumes                   64×10                   25×3                            38×3                   12×4
Animal  foods           85×9                     38                                 44                         12

Table  8. Nutritional contributions of cereal  grains  to  various  regions  of the  world:
adapted from Young  et al. [141]

Region                                      Caloric  intake   Caloric  intake   Protein  intake    Protein  intake g                         from cereals      g                         from cereals
%                                                   %

North America                       3,557                  17                       105.7                  18
Western  Europe                       3,376                  26                         94.8                  29
Eastern  Europe and USSR    3,481                  38                       103.3                  37
Latin  America                         2,557                  39                         65.5                  38
Africa                                       2,205                  47                         55.0                  51
Near  East                                2,620                  61                         73.5                  62
Far  East                                   2,029                  67                         48.7                  63
All developed  countries         3,395                  31                         99.1                  30
All developing countries        2,260                  61                         57.3                  55
World                                       2,571                  50                         68.8                  45

dietary  protein  intakes  may be as high as 1.0–1.25 g/kg/day  [145, 146]. The elderly are particularly vulnerable  to inadequate protein  intakes. A nutritional survey of 946 free-living men and  women  in the United  States  over the age of  60  years  showed  that  approximately half  of  them  consumed   less than
1.0–1.25 g/kg/day of protein  [147]. Because the total  protein  content  of cereal grains  is considerably less than  that  in animal-based foods  (table  7), the dis- placement  of animal  foods by excessive consumption of cereal grains has the potential to compromise  adequate protein  intake.  Indeed,  only 2 of 8 elderly Brazilian  men consuming  their typical rice and bean diet (containing 0.63 g/ kg/day  protein)  were able to achieve positive nitrogen  balance  [148]. Because cereal-grain-based diets  provide  at  least  50% of the  protein  calories  for  the world population, it is quite likely that inadequate protein  intake in the elderly may be quite common  [137, 146, 148].
Although taurine  is considered a conditionally essential amino acid, there is increasing recognition that humans  have limited ability to synthesize taurine


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Table 9. Diseases which may occur
simultaneously with celiac disease                       Addison’s disease
Aphthous ulceration
Atopic  diseases
Autoimmune thyroid  diseases Dental  enamel defects Dermatitis herpetiformis
Epilepsy with cerebral  calcifications Insulin-dependent diabetes  mellitus IgA nephropathy
Liver disease
Chronic  active hepatitis Primary  sclerosing cholangitis Primary  biliary cirrhosis
Rheumatoid arthritis Selective IgA deficiency Sjogren’s syndrome
Systemic lupus erythematosus


from cysteine [149, 150], consequently dietary taurine  plays an important role in maintaining body taurine pools [151, 152]. All plant foods have undetectable amounts of taurine  [153] including  cereal grains  (table  5). Studies  of vegans have shown them to maintain lower levels of both plasma and urinary  taurine [154, 155]. The clinical sequelae of long-term  taurine  deficiency in individuals consuming  cereal- and plant-based diets has not been studied.  However,  tau- rine is known to positively influence cardiovascular disease by reducing platelet aggregation [156], by reducing  reperfusion injury  via free radical  scavenging action  [157], and  by  exhibiting  antiarrhythmic activity  [158]. Furthermore, taurine  appears  to  have  an  essential  role in the  posttrauma state  [159, 160] and  in maintaining normal  retinal  function  [161].
Consistent with populations from the fossil record showing a characteristic reduction in stature  with the adoption of cereal-based  agriculture [4, 17–19], is the observation that  present-day populations depending  upon  cereal grains for  the  bulk  of  their  energy  and  protein   also  tend  to  be  of  short  stature [162–165]. Further, vegan and  vegetarian  children  often  fail to grow as well as their  omnivorous cohorts  despite  apparently adequate intakes  of amino acids and nitrogen  [166]. There are a variety of reasons why cereal-based  diets may impair  linear growth.  These include deficiencies in energy, protein,  zinc, iron, copper,  calcium, vitamin D, vitamin B12 and vitamin A [136, 166]. How- ever, for none of these nutrients is there clear, consistent  evidence that supplementation with the nutrient benefits linear growth [136]. It is likely that


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Fig. 3. Pathogenesis of childhood urinary bladder stones. Adapted from Teotia et al. [174].


growth and hence adult stature is limited by multiple, simultaneous deficiencies [136] in populations dependent upon cereal grains for the bulk of their caloric intake.  Excessive consumption of cereal grains clearly has a deleterious  effect upon  virtually  all of the previously  listed nutrients.
Childhood urinary bladder stones have virtually disappeared from western countries,  however they are still very common  in developing countries  such as Pakistan, India,  Thailand, Sumatra, Taiwan and Iran [167–170]. These stones are composed  primarily  of ammonium acid urate,  and  studies  of children  in these areas have demonstrated increased urinary  excretion of oxalate ammonia and uric acid and decreased urinary  phosphate and pH; factors which strongly favor ammonium urate calculi [168, 171]. It has been shown that an increase in urinary  ammonia occurs in babies whose feeds consisted predominantly of rice [168]. Furthermore, urinary  bladder  stones have been reported to be common in Australian aboriginal children in which breast feeding is supplemented with white flour and little else [172]. Bladder stone disease in children was endemic in 19th-century England, and it has been suggested that the exclusive substitu- tion of breast milk with porridge and bread was a significant factor in the patho- genesis of this disease [173]. Endemic childhood bladder  disease clearly occurs in countries and populations in which cereal grains comprise most of the caloric


Cereal Grains:  Humanity’s  Double-Edged Sword                                                                               41



intake, and cereal grains have been implicated in the etiology of the disease [168,
172]. However, it is likely that other factors, including calorie and protein malnu- trition, infection and starvation operate synergistically with high intake of cereal grains to elicit the disease [174] (fig. 3).


Antinutrients in Cereal Grains

In the evolution  of plant  life history  strategies,  plant  species encounter a basic  dilemma  in the  amount of adaptational energy  they  must  allocate  to growth versus that which they must allocate to defenses necessary for survival in the presence  of pathogens and  herbivores  [175]. Therefore,  plants  face an evolutionary tradeoff;  they must grow fast enough  to compete,  yet they must also divert enough  energy for the synthesis of secondary  metabolites required to ward off pathogens and herbivores.  Defense is not the only role of secondary metabolites, and  other  functions  include attraction of pollinators, protection from ultraviolet light, structural support, temporary nutrient storage,  phyto- hormone regulation, facilitation of nutrient uptake  and  protection of roots from acidic and reducing environments [175]. Quite frequently, plants provision seeds with high concentrations of secondary  metabolites to ensure the survival of the seed and  the rapidly  growing  seedling before it can synthesize its own secondary  compounds.
Cereal grains which are the seeds of grasses (gramineae)  contain  a variety of secondary  metabolites which can be either toxic, antinutritional, benign or somewhere  in between,  dependent upon  the physiology  of the consumer  an- imal. The presence of secondary  metabolites in plants  do not guarantee free- dom from predation by herbivores, and many herbivores have evolved a number of strategies for circumventing the resistance mechanisms  of their hosts [175]. Many  birds, rodents,  insects and ruminants can clearly consume cereal grains in high  quantities with  minimal  undue  effects. Because primates  evolved  in the tropical  forest, all of their potential plant food was derived from dicotyle- donous  species; therefore,  the primate  gut was initially  adapted to  both  the nutritive  and  defensive components of dicotyledons rather  than  the nutritive and  defense  components of  monocotyledonous cereal  grains  [176]. Under certain  conditions a  few species  of  primates   (Papio  species,  Theropithecus gelada) have  been  observed  to  consume  grass  and  grass  seeds; however,  by and large, consumption of monocotyledonous plant foods, particularly cereal grains,  is a notable  departure from  the traditional plant  foods  consumed  by the majority  of primates  [176]. Consequently, humans, like all other  primates have had  little evolutionary experience in developing  resistance  to secondary and  antinutritional compounds which normally  occur in cereal grains.


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Alkylresorcinols are phenolic  compounds which are found  in the highest amounts in rye (97 mg/100 g), in high amounts in wheat  (67 mg/100 g) and in lower amounts in other  cereals such as oats,  barley,  millet and  corn [177]. These compounds are concentrated in the outer  bran  layers of cereal grains and are thought to provide resistance from pathogenic organisms  during dor- mancy and germination [178]. Alkylresorcinols previously were associated only with rye and were thought to be a problem  only in animal  nutrition. Feeding of rye in large  amounts to  cattle,  sheep,  horses,  pigs and  poultry  has  been shown to cause slower growth  than  feeding of other  cereal grains [177]. Sub- sequent studies indicated the growth depressive effects of alkylresorcinols could be attributed to  both  an  appetite  depressive  effect (70%) and  a direct  toxic effect (30%) [179].
Although there  is scant  information upon  the effects of alkylresorcinols in human  nutrition, in animal  models they have been shown to cause red-cell blood  hemolysis,  permeability changes  of erythrocytes and  liposomes,  DNA strand  scission,  and  have  been  shown  to  be involved  in many  pathological conditions including  hepatocyte and  renal  degeneration [177]. An  in  vitro experiment  in humans  has shown that  alkylresorcinols were able to stimulate platelet  thromboxane (TXA2)  production by 30–65% using 0.02–2.0 mmol/l concentrations. To date no human  experiments  have been conducted to deter- mine if these proinflammatory effects can occur in vivo from alkylresorcinols ingested from whole grain wheat products. It should be pointed  out that cereal grain  alkylresorcinols may  have  antimutagenic activity  [181], and  in  lower concentrations may have antioxidant properties [182].

Alpha-Amylase Inhibitors
The  aqueous/saline protein  extract  of wheat  seed is called  the  albumin fraction. Within  the  albumin   fraction   are  a  very  large  number  of  protein components capable  of inhibiting  alpha-amylases from  insect,  mammalian, avian and marine  species. Alpha-amylase inhibitors make up as much as 80% of  the  total  albumin  fraction  and  may  represent  1% of  wheat  flour  [183]. Because  of  their  thermostability,  alpha-amylase inhibitors  persist  through bread baking and are found in large amounts in bread, breakfast cereals, pasta and  other  wheat  products [183]. Alpha-amylase inhibitors are ubiquitous in the cereal family (gramineae)  and in addition to their presence in wheat, they have been found in rye, barley, oats, rice and sorghum. As with alkylresorcinols, alpha-amylase inhibitors are  thought to  have  evolved  in cereal  grains  as a defense mechanism against herbivore predation, primarily against insects [184].
The multiple alpha-amylase inhibitors found in cereal grains have distinc- tive structural properties and show considerable variability  in their inhibitory


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effect upon  human  salivary and pancreatic alpha-amylase [185, 186]. Because salivary and pancreatic amylases catalyze the hydrolysis of glycosidic linkages in starch  and  other  related  polysaccharides, their  inhibition by cereal  grain alpha-amylase inhibitors have  been  theorized  to  have  beneficial  therapeutic effects by reducing carbohydrate-induced hyperglycemia and hyperinsulinemia [187]. Early studies of commercially available alpha-amylase inhibitor prepara- tions failed to decrease starch digestion in humans  [188, 189] perhaps  because of insufficient antiamylase activity [190]. More recent research utilizing purified amylase  inhibitors have  demonstrated that  these  antinutrients can  rapidly inactivate  amylase in human  intestinal  lumen [186, 190] in a dose-dependent manner  [186] and  reduce postprandial rises in glucose and  insulin [191].
Although the  acute  effects of alpha-amylase inhibitors may  appear  to have therapeutic benefit in patients  suffering from  diabetes  mellitus,  obesity and  other  diseases  of  insulin  resistance,  chronic  administration in  animal models has been shown to induce adverse effects including  deleterious  histo- logical changes to the pancreas  and  pancreatic hypertrophy [192]. Because it is unclear  if these dietary  antinutrients can elicit similar deleterious  changes in  the  pancreatic structure and  function  of  humans  [193], the  presence  of alpha-amylase inhibitors in human  foodstuffs  is generally  considered  to  be undesirable [183].
In addition to their influence upon starch digestion, alpha-amylase inhib- itors are known  to be prominent allergens.  The inhalation of cereal flours is the cause of baker’s  asthma, an occupational allergy with a high prevalence in the baking  industry  [194]. Baker’s asthma  is mediated  by IgE antibodies, and until recently the identification of the IgE binding  proteins  (allergens) in the  putative  cereal  flours  was unknown. Over  the  past  decade,  it has  been conclusively  demonstrated that  a variety of alpha-amylase inhibitor proteins are responsible  for bakers’ allergenic reaction  to cereal flours [194, 195]. Fur- ther, alpha-amylase inhibitors recently have been demonstrated to be a relevant allergen  in children  experiencing  hypersensitivity reactions  following  wheat ingestion  [196].

Protease Inhibitors
Protease inhibitors are proteins which have the ability to inhibit the proteo- lytic activity of certain  enzymes and are common  throughout the plant  king- dom, particularly among the legumes. As with alpha-amylase inhibitors, there are  a  muiltiplicity  of plant  proteins  which  have  protease  inhibitor activity. The two best-studied protease  inhibitors, derived from plants,  are the Kunitz inhibitor, which has  a specificity directed  mainly  towards  trypsin  in human gastric  juice, and  the Bowman-Birk inhibitor which is capable  of inhibiting chymotrypsin as well as trypsin. The Bowman-Birk inhibitor is relatively stable


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to both  heat  and  digestion  and  can therefore  survive intact  through cooking and  transit  through the stomach  [197].
Normally, there is a negative feedback loop whereby the secretory activity of the  pancreas  is controlled by the  level of trypsin  in the  intestinal  tract. Intraluminal trypsin  inhibits  pancreatic secretion  by inhibiting  the release of the hormone cholecystokinin from the intestinal  mucosa;  however when die- tary protease  inhibitors bind trypsin, there is an uncontrolled release of chole- cystokinin. This continuous and excessive release of cholecystokinin has been shown  in animal  models to result  in pancreatic hypertrophy and  hyperplasia [198] and  may  eventually  lead  to  cancer  [199]. The  deleterious  influence  of the Bowman-Birk inhibitor upon this negative feedback loop has been demon- strated  in humans  [200].
As with  other  secondary  metabolites, the  primary  function  of protease inhibitors in plants is thought to prevent predation from invading  insects and microbes  [201]. Protease  inhibitors have  been  found  in  virtually  all  of  the cereal grains [201]; however, they apparently have low trypsin inhibitory activ- ity. Wheat  has been shown  to have only 1.5% the trypsin  inhibitory activity of soy beans  [202]. Nonetheless, feedings of raw rice bran  [201] and  raw rye and  barley  [203] have  resulted  in  pancreatic hypertrophy in  broiler  chicks which was attributable to protease  inhibitors. In humans, the dietary  effects of chronic  low level exposure  to plant  protease  inhibitors are unknown, and there  is some  evidence  that  they  may  have  beneficial,  antineoplastic effects [204].

Lectins  are proteins  that  are widespread  in the plant  kingdom  with the unique property of binding to carbohydrate-containing molecules, particularly toward  the sugar  component. They were originally  identified by their  ability to agglutinate (clump)  erythrocytes which occurs  because  of the interaction of multiple  binding  sites on the lectin molecule  with specific glycoconjugate receptors  on the surface  of the erythrocyte cell membranes. Because of this binding  property, lectins can interact  with a variety of other  cells in the body and  are recognized  as the major  antinutrient of food  [205].
Of the eight commonly  consumed  cereal grains,  lectin activity  has been demonstrated in wheat,  rye, barley,  oats,  corn [206], and rice [207] but not in sorghum or millet [208]. The biological activity of lectins found in cereal grains are similar because  they are closely related  to one another both  structurally and immunologically [209]. The best studied of the cereal grain lectins is wheat germ  agglutinin  (WGA),  and  the  in vitro  biological  effects of WGA  upon tissues  and  organs  are  astonishingly widespread.  Virtually  every cell in the body,  and  every extracellular substance  can  be bound  by WGA  because  of


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the ubiquity  of secreted  glycoconjugates [210]. In his comprehensive review, Freed [210] has shown that WGA can bind (in vitro) the following tissues and organs: alimentary tract (mouth, stomach, intestines), pancreas,  musculoskele- tal system, kidney, skin, nervous and myelin tissues, reproductive organs,  and platelets  and  plasma  proteins.
WGA  is heat  stable  and  resistant  to digestive proteolytic breakdown in both rats [211] and humans [212] and has been recovered intact and biologically active in human  feces [212]. WGA  and lectins in general bind surface glycans on gut brush  border  epithelial  cells, and the damage  they cause to these cells interferes with digestive/absorptive activities, stimulates shifts in bacterial flora and  modulates the  immune  state  of the  gut  [213]. In  rats,  WGA  has  been shown  to  cause hyperplastic and  hypertrophic growth  of the small intestine and interfere with normal  gut metabolism and function,  while simultaneously inducing  pancreatic enlargement and thymic atrophy [211]. The dietary  levels of WGA  (7 g/kg body  weight) necessary  to induce  these untoward effects in rats is significantly higher than dietary levels of WGA which would be normally encountered in foods derived from wheat, since the concentration of WGA  is about  2 g/kg in unprocessed wheat  germ [212]. No  long-term  studies  of low level WGA  ingestion  upon  gut structure and  function  have been conducted in humans;  however there is suggestive evidence that  high wheat gluten diets induce jejunal mucosal architectural changes in normal subjects without celiac disease [214].
Most  food  proteins  entering  the small intestine  are  fully degraded  into their  amino  acid components and  therefore  do not  pass intact  into  systemic circulation. However,  it is increasingly  being recognized  that  small quantities of dietary  protein  which escape digestive proteolytic breakdown can be syste- mically absorbed and  presented  by macrophages to competent lymphocytes of  the  immune  system  [215, 216]. Under  normal  circumstances, when  the luminal  concentrations of  intact  dietary  proteins  is low,  absorbed proteins generally  elicit a minimal  allergic response  because  of the limiting  influence of T-suppressor cells. Because of their resistance to digestive, proteolytic break- down,  the luminal  concentrations of lectins can be quite  high, consequently their transport through the gut wall can exceed that  of other  dietary  antigens by several orders  of magnitude [216]. Additionally, WGA  and  other  lectins, may  facilitate  the passage  of undegraded dietary  antigens  into  the systemic circulation by their ability  to increase the permeability of the intestine  [217]. Consequently, dietary  lectins represent  powerful  oral immunogens capable  of eliciting specific and  high antibody responses  [213]. In rats,  dietary  WGA  is rapidly  transported across  the intestinal  wall into  systemic circulation where it is deposited  in blood  and  lymphatic  vessel walls [211]. Although no direct human  experiments  have  been  conducted evaluating  dietary  WGA  passage


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into  systemic  circulation, there  is substantial evidence  to  indicate  that  this event occurs since serum antibodies to WGA  are routinely  found  in normals [218, 219] and  in celiac patients  [219].
Once WGA crosses into systemic circulation, it has the potential to inter- fere with the body’s normal  hormonal balance,  metabolism and  health  [210,
213]. Numerous in  vitro  studies  have  shown  WGA  to  have  insulomimetic effects [220, 221]. Although few animal  and  no  human  studies  have  been designed to evaluate the in vivo influence of dietary WGA upon insulin metabo- lism, experiments utilizing dietary kidney bean lectin (PHA) in rats have demonstrated a depression  in circulating  insulin levels which modulates com- plex change in the body’s hormonal balance  [213]. Numerous in vitro studies suggest that WGA may have the potential to subtly impact health via its ability to inhibit  the mitogenic  actions  of multiple  peptide  growth  factors  including insulin-like  growth  factor  (IGF)  [222], platelet-derived growth  factor  [222], epidermal  growth  factor  [222, 223] and  nerve growth  factor  [224]. Children with  celiac disease  exhibit  short  stature  and  stunted  growth  patterns [225], depressed  levels of IGF-I [226–228], depressed  levels of IGF-binding protein
3 (IGFBP-3) [226, 227] and  lower levels of growth  hormone binding  protein II  (GH-BP   II)  [226]. Administration of  wheat  (gluten)-free  diets  in  celiac children  increases  circulating  levels of IGF-I [226, 227], IGFBP-3 [226, 228] and GH-BP  II [226] while simultaneously improving  height and weight [226]. Presently, there is insufficient data in humans  to determine the health ramifica- tions  of  chronic  low  level  consumption of  WGA,   but  because  detectable amounts of functionally and immunochemically intact  WGA  are transported across the intestinal  wall [211], the potential for this lectin to disrupt  human health  is high.


Autoimmune Diseases and Cereal Grain Consumption

Autoimmune diseases occur when the body loses the ability to discriminate self proteins  from nonself proteins.  This loss of tolerance  ultimately  results in destruction of self tissues by the immune system. Autoimmune diseases occur in a variety  of tissues and  include  such well-known  maladies  as rheumatoid arthritis, multiple  sclerosis, and insulin-dependent diabetes  mellitus (IDDM). Typically, autoimmune diseases are characterized by the presence of autoanti- bodies  against  specific  self  proteins   [229]. Most  autoimmune  diseases  are thought to develop  via an interaction of an environmental factor  or factors in conjunction with a specific hereditary component.
Dietary  cereal grains are the known  environmental causative  agent for at least  two  autoimmune diseases:  celiac disease  [230] and  dermatitis herpeti-


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formis [231]. Withdrawal of gluten-containing cereals from the diet ameliorates all symptoms  of both diseases. Further, evidence from clinical, epidemiological and animal studies implicate cereal grains in the etiology of other autoimmune diseases. The mechanism  or mechanisms  by which cereal grains  may induce autoimmunity  in  genetically  susceptible  individuals   is not  clearly  defined; however  it  is increasingly  being  recognized  that  the  process  of  molecular mimicry, by which a specific foreign antigen may cross react with self antigens, may be involved in a variety of autoimmune diseases [232, 233]. Additionally, cereal grain lectins and proteins may also have involvement  in the development of autoimmunity via their  modulation of immune  system components [234,

The development of autoimmunity is a poorly  understood process; how- ever it is generally agreed that  it occurs as a result of an interaction between environmental and  genetic  components [229]. The  genetic  component most closely associated  with the expression of autoimmune diseases are those genes which code for the human  leukocyte antigens (HLA).  The HLA is subdivided into  class I (HLA-A,  HLA-B,  HLA-C),  class II  (HLA-DR, HLA-DQ and HLA-DP) and  class  III  categories.  Both  class  I  and  class  II  proteins   are transmembrane cell surface glycoproteins which are required  for the recogni- tion of both  self and foreign antigens  by T lymphocytes. Class I proteins  are found  on all nucleated  cells and  platelets,  whereas  class II HLAs  are found on  macrophages, monocytes,   epithelial  dendritic   cells, B lymphocytes   and activated   T  lymphocytes. Class  I  HLA  proteins  present  peptide  fragments from  degraded  intracellular viruses to circulating  CD8+ cytotoxic  lympho- cytes which recognize  and  attack  virus-infected  cells. Class II HLA  proteins present foreign antigens to CD4+ T lymphocytes which results in the induction of T-cell proliferation, lymphokine production, and  subsequent synthesis  of immunoglobulin by B lymphocytes. Except for human  spondyloarthropathies, the preponderance of known or suspected autoimmune diseases are associated with class II haplotypes [229].
Many tissues (thyroid, adrenal, pancreatic islet beta cells, bile ducts, kidney, etc.) that are typically attacked by autoimmune diseases do not normally express class II HLA antigens, consequently, it is paradoxical that autoimmunity should develop in these tissues. The induction of inappropriate class II antigens in nucle- ated cells may be an important preliminary event in the etiology of autoimmune disease [236] and can occur from the stimulatory effect of interferon-c (IFN-c) wrought  by viral infections  [210]. Additionally, lectins are potent  inducers  of HLA class II molecules [237], probably via their ability to stimulate  release of IFN-c [238, 239]. Further, the gliadin fraction  of wheat, which exhibits lectin


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activity [240], has been shown to amplify HLA class II expression in intestinal epithelial cell lines [235]. Ingested WGA from dietary wheat products, crossing the intestinal barrier would also influence the development of autoimmunity by its ability to stimulate  T-lymphocyte proliferation [234, 241].

Molecular  Mimicry
In autoimmune disease, the inability of the immune system to distinguish self antigens  from foreign antigens  ultimately  results in the destruction of self tissues. There is now a substantial body of evidence indicating that the breaking of tolerance  to self antigens can occur when invading  foreign proteins  contain amino acid homologies similar to a protein in the host [233, 242]. This similarity in structure shared by products of dissimilar genes (dubbed molecular mimicry) causes  cross-reactive  immune  responses  which  are  directed  not  only  at  the invading  foreign protein  but also at any cells displaying amino acid sequences similar to those of the foreign protein.  The main body of evidence implicates viral and bacterial pathogens as initiators of cross reactivity and autoimmunity [233, 242]; however  there  is an  emerging  body  of literature supporting the view that  dietary  antigens  [243, 244], including  cereal grains  [245, 246], may also  induce  cross-reactivity  and  hence  autoimmunity by  virtue  of  peptide structures homologous to those  in the host.

Genetic and Anthropological  Factors
Virtually  all autoimmune diseases have a strong  genetic component cate- gorized  by a variety  of HLA  haplotypes [229]. For  instance,  there  is a 73% greater  risk of developing  celiac disease in people  displaying  the HLA-DQ2 antigen  relative  to those  who do not  [229]. It is not  entirely  clear why HLA genes alter  the relative  risk for autoimmune disease; however  it is likely that they influence the binding affinity of the HLA peptide complex with circulating T lymphocytes. Because  the  protein  subunits  comprising  the  HLA  antigen binding  groove  are coded  by highly polymorphic HLA  genes [229], various HLA alleles can subtly alter the structure of the HLA antigenic binding groove [247] and therefore  influence whether  a mimicking  epitope  has a proliferative or anergizing  response  upon  engagement  of the HLA  peptide  complex  with the T-cell receptor. From an evolutionary perspective, the inheritance of specific HLA haplotypes appears  to be primarily  related to infectious disease suscepti- bility, and inheritance of certain HLA haplotypes may have conferred  relative protection from invading  pathogens [248, 249].
In celiac disease, there is a general geographical northwest (NW) to south- east (SE) disease incidence gradient  from the Near  East to Northern Europe [249]. Associated  with this gradient  is a concurrent NW/SE  gradient  for the HLA-B8  antigen  which parallels  the spread  of agriculture and  hence cereal


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Fig. 4. HLA-B8  frequencies  and  the spread  of agriculture  in Europe.  Adapted from
Simoons  [249].


grain  consumption (wheat  and  barley)  from  the Near  East  10,000 years ago (fig. 4). HLA-B8  is not a direct marker  for celiac disease, but because it is in linkage disequilibrium with HLA-DQ2, it is directly implicated  with the dis- ease. Consequently, high frequencies  of HLA-B8  (which are positively associ- ated  with  celiac  disease  via  their  close  linkage  with  HLA-DQ2) occur  in European populations with the least evolutionary exposure  to cereal grains, and  conversely,  those  populations with  the  most  evolutionary exposure  to cereal grains  maintain lower frequencies  of HLA-B8  [249, 250]. It has been suggested that  this gradient  occurs because high frequencies  of HLA-B8  and hence HLA-DQ2 were once typical  of Near  Eastern  peoples;  however  these antigens became a liability with the advent of regular cereal grain consumption


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ushered  in  by  the  agricultural revolution [249, 250]. Because  cereal  grain consumption presumably would have increased mortality (via increased suscep- tibility  to  celiac  disease)  in  populations with  HLA-DQ2, natural  selection would have reduced the frequency of this antigen in populations with the most evolutionary exposure  to wheat  and  barley  [249, 250].
Because of the strong linkage disequilibrium for the genes which code for the  (B8,  DR3,  DQ2)  haplotype, autoimmune disorders   linked  with  DR3, including  IDDM, have been found more often in celiac disease patients  [251]. The incidence  of IDDM is approximately 7–10 times higher  in celiacs than in the normal  population [252, 253], and  the incidence of IDDM, like celiac disease,  is found  in Europe  in a general  NW/SE  gradient  [254]. Both  milk [243, 255] and  wheat  [255], contain  dietary  components which  would  have increased  in European populations adopting agriculture, and  have been sus- pected elements in the pathogenesis of IDDM.

Autoimmune  Diseases Associated  with Cereal Grain Consumption
There are a number  of autoimmune diseases in which cereal grains have been  implicated.   In  a  few of  these  diseases  (celiac  disease  and  dermatitis herpetiformis), there  is a 100% certainty  that  cereal grains  are the causative agent,  whereas  in others  the link is not  so strong.  Because of the increased incidence  [251] of  other,  simultaneously occurring  autoimmune diseases  in celiac patients  (table 9), many of these maladies have been examined to deter- mine, what  role, if any, cereal grains  may play in their etiology.
Celiac Disease. Marsh  [256] stated:  ‘Despite  the  central  importance of wheat  as  a  dietary  staple  throughout the  world,  it  is astounding that  its presumptive role in precipitating celiac sprue disease was discovered  only 40 years ago  by the Dutch  pediatrician W.K.  Dicke.’  Indeed,  it is ‘astounding’ that  humanity was unaware, until  only  relatively  recently,  that  an  ordinary and commonplace food such as cereal grains could be responsible for a disease which afflicts between 1 and 3.5 people per 1,000 in Europe  [257]. The precise mechanism  by which certain peptide sequences in the alcohol-soluble fraction (gliadin) of wheat, rye and barley elicit celiac disease is still poorly understood [258]. However,  there  is an  increasing  consensus  that  celiac  disease  is an autoimmune disease [230, 259], mediated  by T lymphocytes  within the lamina propria which damage  intestinal  villi.
It  is probable that  the  process  of molecular  mimicry  is involved  in the development of celiac disease [232]. Kagnoff et al. [260] have shown that wheat alpha-gliadin shares an amino  acid sequence homology  with the E1B protein of human  adenovirus 12 (Ad-12)  and  that  antibodies directed  against  E1B cross-react  with alpha-gliadin. Since 89% of patients  with celiac disease, versus
17% of controls,  showed evidence of Ad-12 infection  [260], it is possible that


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Ad-12 infection in individuals  genetically predisposed to celiac disease (HLA- DQ2)  may facilitate  development of the disease by virtue  of cross-reactivity, perhaps by three-way mimicry among the two foreign antigens (Ad-12, gliadin), the target  tissue and  even HLA  proteins,  themselves [261].
Celiac disease is typically screened by detection of circulating IgG antibod- ies to reticulin  (ARA),  endomysium (AMA)  or gliadin (AGA).  Endomysium is the connective tissue surrounding smooth  muscle fibers of the gut, whereas reticulin  are fibrils connecting  smooth  muscle cells and  elastic tissue within endomysium. The specific protein  or proteins  (autoantigen) within  reticulin and  endomysium to which ARA  and  AMA  are directed  is unclear;  however recent studies have indicated  both transglutaminase [262] and calreticulin [245] are  likely candidates. It  has  been  shown  that  gliadin  and  calreticulin  share homologous amino acid sequences with one another, and anticalreticulin anti- bodies cross react with gliadin [245], thereby supporting the concept that celiac disease  involves  molecular   mimicry  [263]. Because  gliadins  are  a  complex mixture  of proteins  that  contain  at least 40 different  components in a single variety of wheat [264], it is unlikely that  a single gliadin protein  causes celiac disease, but rather  several prolamines that express similar or identical epitopic domains  [265]. Thus,  it is likely that  multiple  gliadin proteins  can cross react with at least one and probably more autoantigens in celiac disease, similar to that  observed  in other  autoimmune diseases [246]. The self antigen  with the closest  molecular  structure (following  HLA  presentation) to  the  mimicking foreign  peptide  will likely be primarily  responsible  for  the destructive  auto- immune  response  wrought  by T lymphocytes.
A general overview of celiac disease would then suggest that dietary WGA bound   to  enterocytes   increases  the  permeability of  the  gut  [217], thereby allowing  entry  of both  WGA  [211] and  other  gliadin  proteins  into  systemic circulation. WGA or perhaps gliadin, by virtue of their lectin properties, induce the inappropriate expression  of HLA  class II molecules,  which may present a variety of internally processed proteins (including calreticulin), on the surface of intestinal  epithelial cells [235]. In genetically susceptible individuals  (HLA- DQ2),  the molecular  conformation of the HLA  antigenic  binding  groove  is subtly altered [247] so that the presentation of the internally processed, mimick- ing protein  (calreticulin)  causes a proliferative rather  than anergizing response upon  engagement  with  the  T-cell receptor.  Circulating gliadin  proteins  are engulfed  by macrophages which  then  present  the  processed  gliadin  peptide fragments, via HLA molecules, to CD4+ T lymphocytes. Because these gliadin peptide  fragments  presented  by the macrophage have amino  acid sequences homologous to those of the endogenous protein  (calreticulin),  which is artifi- cially expressed  upon  the surface  of intestinal  epithelial  cells by cereal grain lectin  stimulation, cytotoxic  CD4+  T  lymphocytes  initiate  an  immune  re-


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sponse both upon the macrophage expressing fragments  of the foreign peptide (gliadin) as well as upon the intestinal epithelial cell expressing the homologous, endogenous protein  (calreticulin).  Viruses suspected  of causing  autoimmune disease operate  in a likewise manner  to induce  the inappropriate expression of  autoantigens, including  calreticulin  [266] on  the  cell surface,  as  well as maintaining structural homology to a self antigen [233, 242]. Once the mimicry process begins, the destructive  autoimmune response may be further  enhanced by the ability of WGA [234, 241] or viruses [210] to induce T-cell proliferation, mediated  by either lectin [238, 239] or viral [210] IFN-c stimulation.
Dermatitis Herpetiformis.  Dermatitis herpetiformis (DH) is characterized as an intensely itching papulovesicular skin disease diagnosed  by IgA deposits in the basement  membrane [267]. DH can be successfully treated  by a gluten- free diet, although it may take  years before the dermatitis is fully controlled by diet only [231]. DH and celiac disease share a common  genetic basis (HLA- DQ2), and approximately 60% of DH patients  have moderate to severe small- bowel villous atrophy [251]. As with celiac disease, the precise tissue autoan- tigen  in  DH  is unclear.  However,  there  are  similar  structural homologies between  human  elastin  and  high-molecular weight  glutenin  (a wheat  gluten protein)   which  have  been  shown  to  cause  IgA  cross-reactivity  of  the  two proteins  in human  serum  [268]. Bodvarsson et al. [268] have  suggested  that DH  may  be due  in  part  to  this  cross-reactivity (mimicry)  between  dietary glutenin  and  dermal  elastin.
Insulin-Dependent Diabetes mellitus. IDDM is a complex disease involving numerous putative  environmental factors;  however it has been suggested that shared  amino  acid sequences (i.e. molecular  mimicry) between  viral proteins and  pancreatic beta-cell  proteins  (e.g. coxsackie  virus protein  and  glutamate decarboxylase)  represent  a  likely  mechanism   causing  the  disease  [269]. In addition to  viral  proteins,  dietary  proteins  in cow’s milk cross  react  with  a beta-cell  antigen  and  are therefore  suspected  environmental etiologic  agents [243]. However,  as pointed  out by Schatz  and  Maclaren [270], the feeding of wheat  in animal  models  of IDDM elicits a greater  incidence  of the  disease than  does milk. Numerous studies  have demonstrated that  feeding of wheat gluten to rats or mice, which are genetically predisposed to IDDM, increases the  expression  of the  disease  [255, 271, 272]. It  remains  elusive how  wheat proteins  increase the expression of IDDM in genetically predisposed animals. Because Ro/SS-A autoantibodies are found in nonobese  (NOD)  diabetic mice [273] and  in  humans  with  IDDM [274] and  in  humans  with  both  IDDM and  Sjogren’s syndrome  [275], the molecular  mimicry which occurs  between calreticulin  and  wheat  gliadin  peptides  [245] may  be involved  in the  auto- immune  response.  Although there  is conflicting  data  regarding  calreticulin’s role in the Ro/SS-A  complex [276], recent evidence unequivocally shows that


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calreticulin exists in a form directly associated  with all four varieties of human
Ro/SS-A  RNA  molecules [276].
Sjo¨ gren’s Syndrome. Sjo¨ gren’s syndrome is an autoimmune disease charac- terized by lymphocytic infiltration of CD4+ T cells into salivary and lachrymal glands leading to symptomatic dry eyes and mouth  [278]. Circulating antibody levels of gliadin and a reticulin  glycoprotein have been found  to be higher in patients with Sjo¨ gren’s syndrome than in controls [279]. Furthermore, Sjo¨ gren’s syndrome occurs at a level approximately 10 times higher in celiac subjects than in normals  [280]. Ro/SS-A  autoantibodies are typically  elevated  in Sjo¨ gren’s syndrome  [275, 278], and because the four cytoplasmic  RNA  components of Ro/SS-A  (hY RNA  1,3,4,5) exist together  with a form  of calreticulin  [277], the  molecular  mimicry  between  alpha-gliadin and  calreticulin  [245] may  in part  be responsible  for the autoimmune response.  Calreticulin is normally  a cytolsolic protein,  however viral infection has been shown to increase its cell- surface  expression  [266]. In a similar  manner,  lectins (including  gliadin)  are known to induce inappropriate expression of HLA class II molecules at nucle- ated  cell surfaces [235, 237].
In  Sjo¨ gren’s  syndrome   an  additional  suspected   autoantigen,  termed
BM180, has been isolated from basement membrane in the lacrimal and parotid exocrine secretory  glands, and which cross-reacts  with alpha-gliadin proteins [246]. Astonishingly, BM  180 contains  an  N-terminal amino  acid  sequence (VRVPVPQLQPQNP) identical to that found in alpha-gliadin, and mono- and polyclonal  antibody data therefore  suggest that BM 180 is a mammalian form of gliadin [246]. Because BM 180 may be required for stimulus secreting coupling by lacrimal  acinar  cells [246], autoimmune attacks  by CD4+ T cells, primed by previous interaction with macrophages presenting  alpha-gliadin, would be directed,  via molecular  mimicry, at lacrimal  and parotid cells inappropriately presenting  BM  180. Despite  the  suggestive  link  between  celiac disease  and Sjo¨ gren’s syndrome,  as well as the molecular  mimicry evidence, there are scant clinical trials evaluating the effectiveness of gluten-free diets in Sjo¨ gren’s syndrome.
Rheumatoid  Arthritis.  Rheumatoid arthritis is a  complex  autoimmune
disease involving numerous environmental and genetic components, and sim- ilar to a number  of other  autoimmune diseases is found  more often in celiac patients  [251, 281]. Multiple  studies  of arthritic patients  have  demonstrated elevated  antibody levels for  gliadin  [282, 283], and  gluten-freee  diets  have been shown  to be effective in reducing  arthritic symptoms  in celiac patients [283–285]. No large clinical trials have been undertaken to specifically examine the effectiveness of gluten-free diets in the treatment of arthritis; however there are  numerous case studies  reporting alleviation  of arthritis symptoms  with grain-free  diets [286–289]. Additionally, complete  withdrawal of food  during fasting reduces objective and  subjective indices of the disease [290].


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Because serum antibodies in arthritic patients  recognize the antigen,  bo- vine serum albumin  (BSA) from  cow’s milk, and  since BSA contains  homo- logous  amino  acid  sequences  with  human  collagen  type  I, Clq,  it has  been suggested that  molecular  mimicry represents  a potential mechanism  by which milk consumption may trigger arthritis [291]. In addition to milk, glycine-rich cell wall protein  (GRP  1.8), which is ubiquitous in cereal grains and legumes, shares significant amino acid homology  with fibrillar collagen and procollagen and  has been shown  to stimulate  T cells from  the synovial  fluid of juvenile and  adult  rheumatoid arthritis patients  [292]. A third  dietary  antigen  which may  also  induce  rheumatoid arthritis via  molecular  mimicry  is the  alpha- gliadin component of wheat which shares significant amino acid sequences with calreticulin  [245]. Anticalreticulin antibodies have been found  in rheumatoid arthritis patients  [293], and  HLA-DR4 molecules  from  arthritic patients  are known  to present  a peptide  fragment  derived from calreticulin  [294]. Dietary antigens  from three food sources (milk, grains and legumes) contain  multiple peptides  which  mimic  those  found  in  joint  tissue  from  arthritis patients, whereas  grains  and  legumes  additionally contain  lectins  which  can  induce inappropriate presentation of HLA class II molecules [235, 237], consequently, future dietary interventions aimed at reducing arthritis symptoms  would need to consider  these potential confounding effects.
Other Autoimmune  Diseases. IgA nephropathy is the most common  form of  primary  glomerulonephritis worldwide,  and  about   one  quarter of  these patients  progress  to terminal  renal failure 10 years after the apparent clinical onset [295]. IgA nephropathy is characterized by deposition of circulating IgA- containing immune  complexes  (IgAIC)  in the mesangium.  IgA nephropathy patients  maintain increased  intestinal  permeability [296], elevated  circulating antibodies to  gliadin  [296, 297], and  have  serum  that  contains   exogenous lectins which induce  interleukin-6 (IL-6),  a nephritogenic cytokine  [298]. In rodent  models,  IgA nephropathy can be induced  by gliadin-containing diets and  have  been  shown  to  significantly  increase  both  gliadin  antibodies and IgA  mesangial  deposits  compared to  gliadin-free  controls   [299]. Humans following  gluten-free  diets  have  shown  reduced  IgA  antigens  and  reduced levels of IgAIC,  however  these diets  do not  appear  to  alter  the progression towards  renal  failure  [300]. Amore  et al. [240] have  suggested  that  gliadin, because  of  its  lectin  activity  may  favor  the  binding  of  IgA  and  IgAIC  to mesangial  cells, thereby  enhancing  both  IgA mesangial  trapping and  in situ IgA  deposit  formation.
The  cause  of recurrent aphthous stomatitis (canker  sores)  is unknown; however  it is suspected  to be mediated  by immunological mechanisms  inter- acting with an undefined target tissue [301]. O’Farrelly  et al. [302] have shown that  4 of 11 aphthous stomatitis patients  had  raised  levels of antibodies to


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alpha-gliadin, and  in  3  of  these  4  subjects,  the  ulceration  remitted   on  a gluten-free diet and relapsed upon gluten challenge. Other studies of aphthous stomatitis patients   have  shown  favorable   responses  to  gluten-free  diets  in some,  but  not  all  aphthous  stomatitis patients   [303, 304]. The  mechanism by which wheat gluten is associated  with the development of aphthous ulcera- tions  is unclear.
There is increasing  recognition that  molecular  mimicry is a highly likely mechanism  underlying  the  development of  multiple  sclerosis  [305, 306]. A number  of viral and  bacterial  proteins  have been shown  to cross react  with myelin  basic  protein  (MBP)  [305], one  of  the  suspected  target  antigens  in multiple  sclerosis (MS). Because the blood-brain barrier  limits access to the CNS  to activated  T cells, invasion  of the CNS  requires  autoreactive T cells to  be stimulated in the  peripheral immune  system.  Therefore,  it is possible that dietary antigens causing persistent  T-cell stimulation, and bearing similar amino  acid homologies  to the various  myelin and nonmyelin  target  antigens, could cause polyclonal  expansion  of autoreactive T cells in the periphery,  in a manner  similar to that  observed  for bacterial  and viral antigens.  Although no homologous amino acid sequences have yet been identified between dietary antigens and suspected autoantigens in MS patients, there are epidemiological reports  which link both  wheat [307] and  milk [308] consumption to the inci- dence of multiple  sclerosis, consistent  with the observations that  MS is posi- tively correlated to latitude  [309]. There are a number  of case reports  showing remission  of MS on gluten-free  diets [310–312]. Furthermore, some MS pa- tients have altered  intestinal  mucosa  [313, 314], suggestive of increased  intes- tinal permeability to dietary  antigens.  However,  MS patients  generally do not show increased antibodies to gliadin [315], and a number  of case studies have not shown beneficial effects of gluten-free  diets [316, 317]. If dietary  antigens containing amino  acid sequences similar to putative  self antigens,  indeed, do stimulate  peripheral T cells, then interventions evaluating  the influence of diet upon  MS  would  need  to  consider  the  potential  confounding influence  of multiple  dietary  antigens  (dairy products, grains, legumes, and yeast) capable of either molecular  mimicry and/or  T-cell stimulation.


Psychological and Neurological Illnesses Associated with
Cereal Grain Consumption

Neurological complications have long been recognized  in celiac patients and  can  include  epilepsy,  cerebellar  ataxias,  dementia, degenerative  central nervous  system disease, peripheral neuropathies (of axonal  or demyelinating type),  and  myopathies [318]. A  recent  study  showed  that  57% of  patients


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with  neuropathies of unknown cause  (25 ataxia,  20 peripheral neuropathy,
5  mononeuritis multiplex,  4 myopathy, 3 motor   myopathy, 2  myelopathy) demonstrated positive  titres  for  antigliadin antibodies, and  16% (40 times higher  than  the  general  population) of  this  group  also  had  celiac  disease [315]. The cause of neurological dysfunction associated  with celiac disease and antigliadin antibodies is unknown; however  it  has  been  suspected  that  an immunological mechanism  may be involved  [315, 318]. Although no clinical trials have yet been conducted of strict adherence  to a gluten-free  diet, it has been suggested that such a diet may result in stabilization or even improvement of neurological dysfunction [315].
Epilepsy  is observed  in 5.5 of 100 cases of celiac disease,  and  in about half of these patients  bilateral  parietooccipital calcifications  are found  in the cortical or subcortical areas [319]. This triple association has a common  HLA haplotype and is thought to occur via an underlying  immunological disorder [320]. If gluten-free diets are adopted soon after the onset of epilepsy, seizures can be severely reduced  or eliminated  [321, 322].
The behavioral syndrome  of autism  in children  is characterized by few or no  language  and  imaginative  skills, repetitive  and  self-injurious  behavior and  abnormal responses  to human  and  environmental stimuli.  The cause of the syndrome  is poorly  understood, however  it is thought that  both  genetic [323] and immunological factors [324] may be involved. Autistic children main- tain HLA haplotypes [323] that frequently occur in other autoimmune diseases including  rheumatoid arthritis, and  they  display  autoantibodies to  myelin basic protein  [324]. Some autistic  patients  have been shown to have increased antibodies to gluten and casein [325]; however, the amelioration of symptoms in response  to gluten-free  diets has been equivocal  [325, 326].
It has been more than 30 years since Dohan first formulated the hypothesis that  opioid  peptides  found  in the enzymatic  digests of cereal grain gluten are a  potentiating factor  evoking  schizophrenia in  susceptible  genotypes  [327,
328]. In  a meta-analysis of the  more  than  50 articles  regarding  the  role  of cereal  grains  in the  etiology  of schizophrenia published  between  1966 and
1990, Lorenz  [329] concluded:  ‘In populations eating  little or no wheat,  rye and  barley,  the prevalence  of schizophrenia is quite low and  about  the same regardless  of type  of acculturating influence.’ In  support of this  conclusion are multiple  clinical studies  [330–332] which have shown  that  schizophrenic symptoms  improved  on gluten-free  diets and  worsened  upon  reintroduction. Furthermore, the incidence of schizophrenia is about  30 times higher in celiac patients  than in the general population [329], and schizophrenics have elevated circulating  IgA antibodies to gliadin  [333].
There is increasing recognition that  in a subset of schizophrenic patients, autoimmune mechanisms  are  involved  in  the  etiology  of  the  disease  [334,


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335]. Schizophrenics maintain several immunological abnormalities including increased prevalence of autoimmune disease and antinuclear and other autoan- tibodies,   decreased   lymphocyte   interleukin-2  (IL-2)  production,  increased serum IL-2 receptor  concentration, increased  serum IL-6 concentrations and an association with HLA  antigens  [334, 335]. Similar  to other  autoimmune diseases,  cereal  grains  may  potentiate their  putative  autoimmune effects in schizophrenia via molecular  mimicry in which self antigens in brain tissue are recognized  and  destroyed  by  autoaggressive T lymphocytes  because  of the structural similarity  between brain  antigens  and foreign dietary  antigens.  Al- though  this  hypothesis  may  be operative  in some  schizophrenics, the  rapid remission of symptoms by gluten-free diets, observed in clinical trials [330–332], is suggestive that  an acute mechanism  may be additionally responsible,  since it is unlikely  that  damaged  neuronal cells could  regenerate  in such  a short time  frame.  In  this  regard,  it has  been  long  recognized  that  certain  gluten peptides  derived  from  wheat  have  high  opioid-like  activity  that  is naloxone reversible [336, 337]. The structural identity  of these opioid  peptides  derived from the enzymatic digest of wheat gluten have recently been characterized and sequenced  [338–340], and  there  is significant  evidence utilizing  radiolabelled gliadin isotopes to show that these peptides reach opioid receptors in the brain and  peripheral organs  [329]. Thus,  it is possible that  cereal grains  may elicit behavioral changes  via direct  interaction with central  nervous  system opioid receptors  or  perhaps   via  simultaneous  immune-mediated reactions   against central  nervous  system antigens.



From  an  evolutionary perspective,  humanity’s  adoption of agriculture, and hence cereal grain consumption, is a relatively recent phenomenon. Table
3 shows  that  this  event  occurred  in most  parts  of the  world  between  5,500 and  10,000 years  ago.  Cereal  grains  represent  a biologically  novel  food  for mankind [341, 342], consequently there  is considerable genetic  discordance between  this  staple  food,  and  the  foods  to  which  our  species is genetically adapted.
Cereal  grains  lack a number  of nutrients which are essential  for human health and well-being; additionally they contain  numerous vitamins and min- erals with low biological  availability. Furthermore, the inability  of humans  to physiologically  overcome cereal grain antinutrients (phytates, alkylresorcinols, protease  inhibitors, lectins,  etc.) is indicative  of the  evolutionary novelty  of this food for our species. This genetic maladaptation between human  nutrient requirements and  those  nutrients found  in cereal  grains  manifests  itself as


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vitamin  and  mineral  deficiencies  and  other  nutritionally related  disorders, particularly when  cereal  grains  are  consumed   in  excessive quantity. More disturbing is the ability  of cereal grain  proteins  (protease  inhibitors, lectins, opioids  and  storage  peptides)  to  interact  with  and  alter  human  physiology. These interactions likely occur because of physiological  similarities (resultant from  phylogenetic  commonalities) shared  between  humans  and  many  herbi- vores which have traditionally preyed upon the gramineae  family. The second- ary compounds (antinutrients) occurring  in cereal grains (gramineae  family), were shaped  by eons of selective pressure  and  were designed to prevent  pre- dation  from traditional predators (insects, birds and ungulates)  of this family of plants. Because primates and hominids evolved in the tropical forest, wherein dicotyledonous plants prevailed, the human  physiology has virtually no evolu- tionary  experience with monocotyledonous cereal grains, and hence very little adaptive  response  to a food  group  which now represents  the staple  food  for many  of the world’s peoples.
Cereal grains obviously can be included in moderate amounts in the diets of most  people without  any noticeable,  deleterious  health  effects, and  herein lies their strength. When combined  with a variety of both  animal-  and plant- based  foods,  they  provide  a  cheap  and  plentiful  caloric  source,  capable  of sustaining   and   promoting  human   life.  The  ecologic,  energetic   efficiency wrought  by  the  widespread  cultivation and  domestication of  cereal  grains allowed for the dramatic expansion  of worldwide  human  populations, which in  turn,  ultimately  led  to  humanity’s  enormous cultural  and  technological accomplishments. The downside  of cereal grain  consumption is their  ability to  disrupt  health  and  well being  in virtually  all people  when  consumed  in excessive quantity. This information has  only been  empirically  known  since the discovery of vitamins,  minerals  and certain  antinutrients in the early part of this century.
The realization that cereal grain peptides interact  with and induce change in human  physiology and therefore elicit disease and dysfunction is even newer and dates to the early 1950s with the discovery of wheat gluten as the causative agent in celiac disease. In the past 10 years has come the evidence (admittedly incomplete)  that  certain cereal peptides may interact  with the immune system to elicit a variety of autoimmune-related diseases. These two seemingly distinct entities (autoimmune disease and consumption of a staple food) are connected primarily  through an  evolutionary collision  of dissimilar  genes which  bear identical  products (molecular  mimicry). Although, cereal grain consumption may  appear  to  be historically  remote,  it is biologically  recent;  consequently the human immune, digestive and endocrine systems have not yet fully adapted to a food  group  which provides  56% of humanity’s  food  energy and  50% of its protein.


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Cereal grains are truly humanity’s double-edged sword. For without them, our species would likely have never evolved the complex cultural  and techno- logical  innovations which  allowed  our  departure from  the  hunter-gatherer niche. However, because of the dissonance between human  evolutionary nutri- tional  requirements and  the  nutrient content  of these  domesticated grasses, many of the world’s people suffer disease and dysfunction directly attributable to the consumption of these foods.



I wish to thank the following individuals for reviewing this manuscript and their constructive criticisms: Jennie Brand-Miller, S. Boyd Eaton, Staffan Lindeberg, Klaus Lorenz, and  Norman Salem.  A particular debt  of gratitude goes to  R.  Shatin  for  his pioneering thoughts and writings.



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Loren  Cordain,  PhD,  Department of Exercise and Sport  Science, Colorado State University, Fort  Collins, CO 80523 (USA)
Tel. +1 970 491 7436








Cereal Grains:  Humanity’s  Double-Edged Sword                                                                               73