CATEGORY: diseases/allergy
TECHNICAL: **
SUMMARY:
This document was one of the reasons I gave up most
grain completely, and only consume rice and oats (whole grains)
only once a week. Pay careful attention to some of the diseases
being attributed to gluten intolerance (something all humans have
to one degree or another). It's scary. I also liked the way
this paper puts forth the paleo-neo-timeline so easily. I'll
forward other documents in the future that detail the shift of
humans from hunter-gatherer to agrarian. Also take note of the
B8 gene - this mutation, along with blood type differences, can
be attributed to agrarianism and grain consumption.
The most important part of the document, though, is the
part that discusses the genetic singularity in today's grain. Many
people believe that older grains (like spelt) are better than wheat,
but in fact, they are just as "man-made" (in the sense that man
genetically altered them by cross breeding). The note even mentions
lactose intolerance and the fact that, genetically, we are not
well adept at consuming the milk of other animals.
There really is so much info here. One thing I often tell
people is that expectant mothers, and infants should avoid these
foods as well too. Take a look below at the discussion of infant
mortality rates and you'll probably agree. The note even briefly
discusses the importance of breast feeding, but I have more complete
info on this subject that I will send later.

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From the Neolithic Revolution to Gluten Intolerance
_________________________________________________________________

Table Of Contents

* Why So Many Intolerant To Gluten ? by Luigi Greco, D.C.H.,
M.Sc.(MCH), M.D., Department of Pediatrics, University of Naples
30.06.1995
+ Hunters, Fishers and Gatherers
+ The Great Revolution: The First Farmers
+ The Expansion Of The Farmers
+ The Evolution Of Cereals
+ The Rise Of The Intolerance To Gluten
+ Hints On The Epidemiology Of Gluten Intolerance
+ Gluten Sensitive Versus Gluten Intolerant
+ References
_________________________________________________________________

Why So Many Intolerant To Gluten ?

We have recently reported on Lancet (1) a consistent cohort of
patients affected by drug-resistant epilepsy with cerebral
calcifications, half of which were cured by a gluten-free diet. All had an
atrophic jejunal mucosa, which recovered on a gluten free diet. Gluten
intolerance is now a recognized cause of brain calcifications and
epilepsy, of dementia, of psychiatric disturbances: many researchers
believe that, in genetically predisposed subjects, gluten is not healthy
for the brain function (2).

This is just too much.

Having had over 25 years of variegated experience with gluten
intolerance I find hard to imagine that the single most common food
intolerance to the single most diffuse staple food in our environment
might provoke such a complexity of severe adverse immunemediated
reactions in any part of the human body and function. The list is
endless, but malignancies, adverse pregnancy outcome and impaired brain
function are indeed complications above the tolerable threshold of this
food intolerance.

On the other end today we know very well that the majority (as many
as 9 to 1) of gluten intolerant subjects, identified by familial or
population screening, do not manifest any complaint, although they do have
a flat intestinal mucosa (3).

In conclusion a sizable proportion of our population (from 0.3 to 1%)
is gluten intolerant and reacts with a wide spectrum of symptoms from no
apparent reaction to severe life-threatening diseases.

This intolerance is strongly linked to specific genetic markers
which have indeed required thousands years to develop and be selected: the
'population genetic' time is of this dimension, while the changes in the
environment and in the food we eat, require centuries or less.

Where did they come from?
_________________________________________________________________

Hunters, Fishers and Gatherers

Human beings have been on Earth for over 3 millions year, but Homo
Sapiens Sapiens, our nearest parent, is only 100,000 years old. For ninety
thousand years he conducted a nomadic life getting food by hunting,
fishing and collecting fruits, seeds, herbs and vegetables from nature.
Only quite recently (about 10.000 years ago) did some nomadic tribes start
to have stable settlements because they developed the ability to gather
enough food to be stored. The cultivation of wild seeds begun.

Ten thousand years ago the last glaciation came to an end: a
Neo-thermal period ensued which marked the passage from the Paleolithic to
the Neolithic age. Ices melted gradually from the equator to the poles
over several thousands years when new fertile and humid lands were
uncovered in South East Asia all of Europe was still covered with ice and
Northern Countries had to wait up to 4000 years more to get out from a
frozen environment.
_________________________________________________________________

The Great Revolution: The First Farmers

The discovery in the Neolithic age of ways to produce and store food
has been the greatest revolution mankind ever experienced. Passage from
collection to production originates the first system in which human labor
is transferred onto activities which produced income for long periods of
time. The principle of property was consolidated and fortifications to
protect the land and food stores were developed.

Archeological findings suggest that this revolution was not initiated
by the man hunter and warrior, but by the intelligent observations made
by the woman. The woman carried the daily burden of collecting seeds,
herbs, roots and tubers. Most probably she used a stick to excavate roots
and tubers: during this activity she observed the fall of grain seeds on
the ground and their penetration into the soil with rain. She may have
been surprised to find new plants in the places which she herself dug with
a stick, and made the final connection between fallen seeds and new
'cultivated' plants.

She was, for thousands years, the sole leader of the farming
practices and provided a more and more consistent integration to the
scanty products of the man hunter (6).

To our actual knowledge, the origin of farming practices should be
located in the 'Fertile Crescent': the wide belt of South East Asia which
includes Southern Turkey, Palestine, Lebanon and North Iraq. In the
highlands of this area abundant rainfall was caused by the neo-thermal
switch. In all of this area existed, and still exists, a wide variety of
wild cereals, sometimes in natural extended fields, induced by the
rainfalls. Triticum Dicoccoides (wheat) and Hordeum Spontaneum (barley)
were common and routinely collected by the local dwellers. The wild
cereals had very few seeds (2-4) which fell easily on the ground on
maturation.

The people from the Uadi el-Natuf Tell of South East Asia (7800 B.C.)
provided the first traces of the gradual shift from hunters to grain
cultivators. Their economy was based on the hunt of the gazelle, but
their diet also included collected grain seeds. These gradually came to
form a substantial proportion of their energy input, as cultivation
practices ensued. There were no grinding stones or mills and it was most
probable that gathering prevailed on cultivation. But during the
Proto-Neolithic superior a cuneiform mortar appeared. 1000-2000 years
later (5000 B.C.) wild animals, more rare due to incoming drought, formed
only 5% of the daily diet, while cereals and farmed animals become a
sizable part of it (4).

Stable settlements were founded: the village of CatalHuyuk in
Southern Turkey had a population of 5000 inhabitants 9000 years B.C. In
that area a collection of sickles was found with inserted oxidian blades,
smoothed by the routine contact with the siliceous stalk of cereals. The
sickles indicate that it was possible to collect seeds not only by picking
on the ground, but also by cutting stems of plants which were capable of
retaining the seed in an ear (5). 'Mesopotamic' populations, originated in
the first farmers, developed a great civilization with large cities and
powerful armies to defend their land property and food stores. In Egypt a
civilization based on farming practices developed in the 5th millennium:
they became specialists in the cultivation of wheat, barley (to produce
beer) and flax.
_________________________________________________________________

The Expansion Of The Farmers

While in South East Asia the progressive drought made hunting
difficult and encouraged farming, in Europe the Paleolithic culture of
hunters and gatherers persisted for 5000 years more, gradually
transforming into the Mesolithic age.

In the 'Fertile Crescent' the availability of food stores and the
gradual development of animal farming stimulated an unprecedented
demographic explosion. The nuclear family had had a small dimension for
hundreds thousands of years: the birth rate had been limited by nomadic
life. In transmigrations the mother had been able to carry one infant,
while the others had been obliged to walk and move on their own. Small
babies in between had less chances of surviving. Thus mankind remained of
approximately the same size during entire ages.

Farmers, on the contrary, were settlers, possessed food stores and
most probably took advantages in the farming practices of more hands in
the family. In this manner the family size exploded and, as a result, a
progressive continuous need to gain more lands ensued.

The farmer's expansion lasted from 9000 B.C. up to the 4000 B.C. when
they reached Ireland, Denmark and Sweden covering most cultivable lands
in Europe. The expansions followed the waterways of Mediterranean and of
Danube across the time of Egyptians, Phoenicians, Greeks and Romans (7).

The farmers' expansion was not limited to the diffusion of the
agricultural practices, but was a 'demic' expansion: that is a
substantial replacement of the local dwellers, the Mesolithic populations
of Europe, by the Neolithic from South East Asia. More than 2/3 of our
actual genetic inheritance originated in this new population, while the
native genetic background has been progressively lost or confined to
isolated geographical areas.

The genetic replacement of the native European population is marked
by the B8 specificity of the HLA system. Cavalli Sforza and coworkers
showed that the migration of farmers is paralleled by the diffusion of
B8. The frequency of B8 is inversely proportional to the time length of
wheat cultivation. In practice B8 appears to be less frequent in
populations which have lived on wheat for a longer time, as it is caused
by a negative genetic selection in wheat cultivators (7). We are aware
that in Ireland, where the wheat cultivation came only 3000 years B.C., a
very high frequency of gluten intolerance has been reported.
_________________________________________________________________

The Evolution Of Cereals

The early wild cereals, of the Triticum (wheat) and Hordeum (barley)
species were genetically diploid and carried few seeds, which usually fell
on the ground at maturation, making any harvest very difficult. A
chromosomes in ingle couples (diploidicity) allowed for a wide genetic and
phenotypic heterogeneity with remarkable variations in the content of
protein and starches. Poliploid plants occasionally originated in
nature, but they had few chances to survive, without artificial
(cultivation) practices and were usually lost (8).

The beginning of farming, with the use of irrigation, allowed the
survival, and the expansion, of poliploid grains. But the new poliploid
grains had substantially reduced genetic variations (since each gene is
represented in several copies) and more frequently autoimpollinate
themselves, causing remarkable increase of the genetic uniformity.

The first stable formation of poliploid grains is dated around 6000
years B.C.: the genetic uniformity caused a considerable rise in stability
and yield, convincing the early farmer to nduce a progressive and rapid
replacement of the wild species.

Genetic variability of grains was essential in order to adapt the
plant to the very different environmental conditions of different areas,
but the yield was generally low (9).

Triticum Turgide Dicoccoides was crossed with Triticum Fanschii to
originate the Triticum Aestivum, which is the progenitor of all our actual
wheat. The Aestivum is an esaploid wheat with 42 chromosomes, versus the
14 of the T. Monococcum. Such powerful grain replaced all existing
varieties to the point where genetic variability nowadays is lost: over
the world we have 20,000 cultivated species of the same unique T.
Aestivum wheat. The Triticum Turgidum Dicoccoides, progenitor of the
actual 'durum' wheat with which pasta is made, had just few seeds
encapsulated into a pointed and twilled kernel: at maturation the seeds
fell on the soil and penetrated into it with rain, eased by the
arrow-shaped structure of the kernel.

Ten thousand years ago it was difficult to pick them up: hence the
attempt, made by the Neolithics, to select varieties which could retain
the seed longer, in order to allow for an harvest.

Genetic variability was already substantially reduced in Roman times:
'farrum', i.e. spelt, (T. Dicoccoides) and 'Siligo' (T. Vulgaris) were
the common grains. Siligo was used for bread making and contained a
certain amount of gluten, while spelt, used mainly for soups, was poorer
in gluten content (10).

But cultivation of wheat and barley was not started or diffused in
the whole world: only a small geographic area (South East Asia) developed
gluten-containing cereals. In Asia rice was the cultivated species, while
in America maize prevailed and in Africa sorghum and millet. All these
plants were present in nature and were gradually cultivated in the
places of origin (7).

In our part of the world grains had for centuries been selected in
order to improve their homogeneity and productivity, but soon (Roman times
or before?) another desirable quality was preferred: the ability to stick,
to glue up a dough to improve bread making. Early bread making activities
pushed towards grains that contained greater amounts of a structural
protein which greatly facilitated the bread making: the gluten. Gluten was
not chosen because of its, at the time unknown, nutritional value (which
is not absolutely special, since it is a protein with relatively low
nutritional value), but for its commercial qualities.

Rice, maize, sorghum, millet do not contain gluten: no leavened
bread was prepared with them: the majority of mankind never lived on
bread, as we do know it.

Over the last 200 years of our modern age active genetic selection,
and actual genetic manipulation, have changed the aspect of the original
Triticacee enormously: from few grains and little gluten to great wheat
harvests very enriched in gluten (50% of the protein content), well
adapted to cultivation practices and ready to be handled by monstrous
machinery.
_________________________________________________________________

The Rise Of The Intolerance To Gluten

Did everybody adapt to such profound changes in the basic nutrition
over such a short period of time? South Eastern populations, presumably
well adapted to the new foods, grossly replaced the existing Mesolithic
European dwellers who still lived on hunting and gathering. But a
proportion of the local populations (or, rather, of their inheritance )
persisted beside the invaders. The feeding changes were not well tolerated
by everybody.

The best similar example is lactose intolerance: populations that
have more recently adapted to milk consumption, still lack the genetic
ability to digest lactose over the infancy period. Environment has
changed centuries before any change in the inheritance may have been
possible.

Similarly a considerable proportion of the hunters and gatherers of
the pre-Neolithic ages have not fully adapted to the great feed changes
induced by the cultivation of wheat. These people could not recognize
gluten as a 'tolerable' protein available for digestion and absorption:
they may have not have any problem or complaint for centuries, since the
content of gluten in the grains was very low, but when 'industrial'
quantities of gluten were induced by selection of wheat in order to
improve bread making, they were exposed to unbearable quantities of an
'intolerable' protein or peptide.

This population, genetically identifiable today by their specific
HLA pattern, did not recognized, through their HLA system, the gluten
peptide as a tolerable item, but, because of the similarity of some
sequences of gliadin peptides with several pathogenic viruses, they
generate a complex defense mechanism (an immune response) which does not
eventually find the pathogen to destroy, and most probably activate an
auto-immune response which ultimately is the origin of the damage to
their intestine and other organs.

These fierce descendants of hunters and fishers, exposed to this
subtle enemy, could not develop the defense of tolerance and, in the
attempt to fight the unknown, they ultimately develop a disease due to
excess defense. For centuries they underwent a negative selective
pressure, with less chances to survive, and then to be manifest (11).

In the last millennium gluten-intolerant children mostly had a harsh
time behind them: after weaning, malabsorption and malnutrition were the
underlying causes of poor defense to infections during infancy and early
childhood. Acute infectious diarrhea was the main killer of infants up to
50 years ago in Europe and up to 15 babies every thousand died for this
condition. In the suburbs of Naples, only 25 years ago, infectious
diarrhea was the main killer (25% on an infant mortality rate of 100 per
thousands live births) (12).

The vast majority of gluten intolerance occurred among these poor
infants. In my own clinical experience 25 years ago I observed several
fatal gastrointestinal infections in babies with the 'celiac crisis',
which has now disappeared from our wards.

Few chances to survive, few intolerant children that reached the
reproductive age, and become capable of transmitting the intolerance, few
adult cases. Then gluten intolerance may have become extinct, as was in
fact the case with several other pathogenic conditions? Not at all.

The intolerance most probably had some selective advantage which
counterbalanced the gluten intolerance: it is possible to suggest that
it was their very effective HLA Class II system that gave them a selective
advantage against infections, which compensated the disadvantage due to
gluten intolerance.

When, in the last 50 years, infantile infections greatly diminished,
the descendants of the hunters and gatherers with very active
immune-defense, 'over reacted' more frequently to the gluten than to their
ordinary enemy. Hence the rise of the cohort that now appears to manifest,
in different manners, a gluten intolerance.

However, not all populations of the world were ever exposed to such a
nasty protein: the vast majority of mankind, after the development of
agriculture, lived on maize, rice, sorghum and millet, tubers: all gluten
free. All of them did not underwent the selective pressure of gluten
intolerance and they may in fact have been the reservoir of wild genes.

Finally, breast feeding most probably played a major role in
preserving some children from the fatal infection of infancy (13). The
capacities of breast milk to protect against viral and bacterial attack,
the protection given by maternal antibodies and the delaying effect on the
manifestation of symptoms of gluten intolerance (in the predisposed
subjects) may all have protected the hunters and gatherers, who in this
manner avoided to develop fatal symptoms and managed to survive and
transmit their genes to our population.
_________________________________________________________________

Hints On The Epidemiology Of Gluten Intolerance

The epidemiology of gluten intolerance, as we know it today, is the
complex result of the apparition of the population of hunters and
gatherers in our modern world.

As the cohort of those born before the World War II had few chances
to survive infancy, we nowadays have few adult cases and few long term
complications. Where the intolerance is still manifested mainly in the
classical way (infants and small children, malabsorption, diarrhea, often
switched on by an infection) we do not frequent encounter 'atypical'
presentations and adult cases or long term complications. In this case
the epidemiological calculations on observed cases made by
gastroenterologist may be in great contrast with those made by
pediatricians. On the contrary the rarity of 'classical' cases, which has
been used as the proof of the 'disappearance' of gluten intolerance, is
counterbalanced by the presence of atypical and late diagnosis, where
actively searched for.

Finally nutritional attitudes have played a major role with regard to
the chances for hunters to manifest themselves in different age groups:
the example of Sweden as compared to the nearest Denmark or Finland is
paradigmatic (14).

As shown by Maki et al, the ability to identify atypical cases may
completely change the observed epidemiological pattern in a given region.
Hence the reason for the 'iceberg': most cases still to be discovered
(15). Similarly, population-based screening programs uncover more
'silent' than overt cases (3).

Nevertheless, the 'cohort effect', regional differences and so on,
have up to now failed to overcome the limits of numbers: when local
incidence rates are compared with other regions' rates, the 95% Confidence
Intervals of the rates are very often so wide to contain the all lot of
observed rates. No clear-cut statistical difference has really been
shown in the incidence of gluten intolerance in Europe (16).

Wherever extensive studies on symptomatic cases have been run an
incidence of 1 case per each 1000 live births has been reached, but very
often the incidence has been much lower: up to 1 cases every 250 live
births. Population screening studies invariably come to an incidence rate
of 1 every 250. This is very close to the rate predicted by age-adjusted
incidence density studies (17). Recent reports indicate an incidence close
to 1 case per every 100 live births, but this finding needs confirmation.
_________________________________________________________________

Gluten Sensitive Versus Gluten Intolerant

But the epidemiology of gluten intolerance, which entails the tracing
of a group of our ancestors, may completely change once we consider the
increasing knowledge about the 'gluten-sensitive' individuals. 6 to 10%
of first degree relatives of known cases themselves are gluten intolerant
and have a flat intestinal mucosa (these are silent cases), but up to 30%
of sibs of cases, when challenged with a dose of gluten (or its digest)
activates a specific mucosal immune-response (with increase in
intraepithelial infiltration and activation of TCells), without having
any sign of mucosal damage (potential cases?) (18).

We may, in the near future, have a substantial group of individuals
who do not activate, in presence of gluten, a 'pathogenic' immune response
(auto-immunity), but who recognize gluten as a 'suspect' protein in the
same way as their peers really intolerant.

Finally gluten intolerance is indeed linked to a specific genetic
predisposition: most probably at least two genetic loci are involved in
running the risk of intolerance.

How many possess these specific genetic risk at a 'carrier' state?
Certainly more than 5% of the actual population. In conclusion we have a
wide population of 'gluten-reactants' in Europe (EC): at least 1 million
cases of total intolerance to gluten an estimated similar amount of
'gluten sensitive' people 10-15 times more 'carriers' of the risk of
becoming gluten intolerant.

So we have found our ancestral hunters and gatherers: they are a
substantial proportion of our actual community and do deserve a
'gluten-free' alternative not only as a therapeutic mean, but as an option
of our daily life.

References

1. Gobbi G, Bouquet F, Greco L, Lambertini A, Tassinari CA, Ventura A,
Zaniboni MG: "Coeliac Disease, epilepsy and cerebral calcifications"
Lancet, 340, Nx 8817, 439-443, 1992

2. Epilepsy and other neurological disorders in Coeliac Disease. Republic
of S. Marino Meeting, April 10-12 1995, G. Gobbi edt., Raven Press, in
preparation.

3. Catassi C, Ratsch IM, Fabiani E, Rossini M, Bordicchia F, Candela F,
Coppa GV, Giorgi PL: Coeliac Disease in the year 2000: exploring the
iceberg. Lancet, 1994, 343: 200-203.

4. Furon R. Manuel de Prehistorie Generale., 1958, Payor, Paris.

5. Cambel H, Braidwood RJ. An old farmer's village in Turkey. Le Scienze,
1970, 22: 96-103.

6. Heichelheim F. An Ancient Economic History. A.W. Sijthoff edt., Leiden,
1970.

7. Cavalli-Sforza L. Chi Siamo (Who are we). 1993 Mondadori, Milano.

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Inc, New York, 1986.

9. Feldman M, Sears ER The wild gene resources of wheat. Scientific
American, 1981: 98-109.

10. Lucio Giunio Moderato Columella " Libri rei rusticae" Anni 60-65 dopo
Cristo. Ed. Einaudi,1977.

11. Simoons FJ: Coeliac Disease as a Geographic Problem. Food, Nutrition
and Evolution, 1982, 179-199.

12. Greco,L.: " Malnutrizione di classe a Napoli" Inchiesta, 24, 53-63,
1976.

13. Greco,L., Mayer,M., Grimaldi,M., Follo,D., De Ritis,G., Auric-
chio,S.: "The effect of Early Feeding on the onset of Sympthoms in Coeliac
Disease" J.Pediat. Gastroenterology Nutrition, 4:52-55, 1985.

14. Maki M, Holm K, Ascher H, Greco L.: Factors affecting clinical
presentation of coeliac disease: role of type and amount of gluten
containing cereals in the diet. In "Common Food Intolerances 1:
Epidemiology of Coeliac Disease", Auricchio S, Visakorpi JK, editors,
Karger, Basel, 1992, pp 76-83.

15. Maki M, Kallonen K, Landeaho ML, Visakorpi JK.:Changing pattern of
childhood coeliac disease in Finland. Acta Paediatr Scand 1988;
77:408-412.

16. Greco L, Maki M, Di Donato F, Visakorpi JK. Epidemiology of Coeliac
Disease in Europe and the Mediterranean area. A summary report on the
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troenterology and Nutrition. In "Common Food Intolerances 1: Epidemiology
of Coeliac Disease", Auricchio S, Visakorpi JK, editors, Karger, Basel,
1992, pp 14-24.

17. Magazzu, Bottaro G, Cataldo F, Iacono G, Di Donato F, Patane R,
Cavataio F, Maltese I, Romano C, Arco A, Totolo N, Bragion E, Traverso G,
and Greco L: "Increasing Incidence of childhood celiac disease in Sicily:
results of a multicentric study" Acta Paediatr, 83:1065-1069, 1994.

18. Troncone R, Greco L, Mayer M, Mazzarella G, Maiuri L, Congia M, Frau
F, De Virgiliis S, Auricchio S.: "In half of Siblings of Coeliac Chil-
dren rectal gluten challenge reveals gluten sensitivity not restricted to
coeliac HLA."

:cool: TJ :cool: