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 immuno-mediated 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 sizeable 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 then 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 nine thousands 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 fertiles and humide 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 digged 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 sizeable part of it (4).
Stable settlements were founded: the village of Catal-Huyuk 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 EXPANSIONS 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 co-workers 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 phenotipic 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 induce 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, mais, 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 machineries.
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 immuno 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 diarrhoea 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 diarrhoea was the main killer (25% on an infant mortality rate of 100 per thousands live births) (12).
The vast majority of gluten intolerants occurred among these poor infants. In my own clinical experience 25 years ago I observed several fatal gastrointestinal infections in babies with the 'coeliac 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 intolerants 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 immunodefense, '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 mais, 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, diarrhoea, 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 programmes 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 clearcut 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 immuno-response (with increase in intraepithelial infiltration and activation of T-Cells), 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' immuno 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):
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