The contribution of molecular biology in the last few years to our understanding of the complex situation of the genetic of human mucins. Complex certainly... but also an extraordinary capacity to adapt to the different physiological conditions or various pathologies. We must no longer accept the composition of mucins as immutable and stereotyped for an organ and/or a given animal species. Even if the the mechanism modulating the expression of the MUC genes coding for the synthesis of the mucins are not known, they do not permit less to the organism for the fabrication of glycoproteins which the molecular weight and the physicochemical characteristics are best adapted to the circumstances : the large heterogeneity of the messenger RNA is a strong argument in favor of the adaptive phenomenon.
WHAT ARE THE PARTICULARITIES OF THE
BIOLOGY OF THE MUCINS IN THE DIGESTIVE TRACT IN CHILDREN AND MORE GENERALLY
IN IMMATURE ANIMALS?
The obvious difficulties to sample digestive mucus from children, even in the form of perendoscopic intestinal biopsies, contributes to our lack of understanding of the characteristics of the mucins at this age.
In man, the cells of the gastric and intestinal mucosa differentiate during the first trimester of fetal life; the information gathered from rodents suggest that these cells are capable of synthesizing mucins very rapidly after their morphological identification. The meconium is rich in mucus glycoproteins synthesized in utero by the mucus cells. The quantity of mucus found in the intestine of germ free animals is much more elevated when compared with controls, this suggests that the microbial flora can play an important role in the degradation of the glycoproteins of colon mucus. In man, the installation of this bacterial flora capable of degrading the mucins evolves progressively during the first year of life and begins in certain neonates at the age of 3 months. Only some species (Ruminococcus bifidobacterium) in the 500 isolated in the human digestive tube possess the betaglycosidases which, in synergism with the bacterian or engogenous proteases of the host, (leukocytes, epithelial cells, pancreatic enzymes), ensure the degradation of mucins in the intestinal lumen.
It is probable that the variation in the expression of the different mucin genes are reflection of the influence of age and nutrition on the composition of mucins. The mucins in the small intestine of the neonatal rat contain a higher level of proteins than that found in adult rats (27 versus 18%). The sulfate content is also higher in the neonates (5.5 versus 0.9%). The reduction in the sulfate content with age is compatible with the hypothesis that an elevated sulfate content is characteristic of the glycoproteins secreted by the mucous cells from the immature animal. The total carbohydrate content as well as the respective contribution of the fucose and galactosamine residues are markedly less in the immature animals. In the porcine, which exhibits a development and physiology of the digestive tube similar to man, a significant increase in fucose and glucosamine content is observed between birth and 21 days of age (+165% and +37%, respectively). Similar to the rat, the sulfate content and the proteins are more elevated in the immature animals. Nutrition equally influences the composition of colon mucins in the porcine : young animals raised by maternal feeding have a composition closer to those of the adult when compared with animals artificially nourished, specifically in the fucose, galactosamine or sulfate content.
In the rat, the influence of development of the animal on the level of expression of the mucins in the intestine has recently been evoked. The expression of messenger RNA of the MUC 2 gene is very weak at birth and during the period of weening, before the increase at the moment of separation, and attains progressively the level of expression observed in the adult rat.
The modifications of the composition of mucins associated with development and nutrition play a role in
the largest frequency of gastro-intestinal infections observed in the immature and/or breast fed newborns.
The mucins serve in fact as a defense mechanism against infection by presenting a binding site for the
lectins of bacterial or viral origin, preventing the fixation of these lectins on the intestinal
epithelium.
The fucose inhibits the adhesion of Shigella flexneri to the colon in the guinea pig; it equally reduces
the mobility of Entamoeba histolytica in the colon of rat and man. Also a lowering of the rate of fucose
in the saccharide moieties of mucins as that already observed in the most immature porcine and those
nourished artificially, can compromise the capacity of mucins to protect the digestive tube against
infection.
It is also similar during malnutrition, associated with a much greater frequence of gastro-intestinal
infections, not in light of the modifications in the biochemical composition of mucins but a significant
reduction of the quantity of secreted mucins by the mucous cells in the small intestine.
CLINICAL IMPLICATIONS
The clinical projections of molecular biology of gastro-intestinal mucus on pediatric gastro-enterology concern 3 principal themes: Cryptogenetic intestinal inflammatory disease (CIID), gastric infection by Helicobacter pylori and acute diarrhoea.
The CIID are not found only in the adult since they begin in 10 -15% of cases before the age of 15
years. Their principal complications at this age are represented by small stature and late puberty.
The etiology of CIID is not known; the only factor favoring, identified with certitude is smoking.
Active smokers have a more elevated risk of Crohn's disease but appear "protected" against the appearance
of Ulcerative Colitis (UC). The same tendencies have been observed in children exposed passively
to tobacco smoke. One explanation may be due to the action of nicotine on the intestinal mucus. In the
rabbit, high doses of nicotine increase the thickness of colonic mucus which is significantly reduced
during UC disease and the low doses have an inverse effect. This effect on the mucus is not found at the
level of the rectum. However, it is too early to propose nicotine as a new therapy for UC.
The significant reduction of the fraction IV of colonic mucins separated by anion exchange chromatography
appears specific for UC, even if several investigators question this observation. This anomaly has equally
been found in patients without UC, in monozygotic twins born of parents with UC. These observations
suggest that mucin abnormalities are not simply due to the inflammatory process but indeed are composed of
a predisposing cofactor for this abnormality which is genetically determined.
These intestinal mucus abnomalities occur probably early during UC; it remains to be determine whether
they play a role in the age of appearance of the disease and/or the intensity of its clinical expression.
Helicobacter pylori (H. pylori) colonizes the gastric mucus in a specific manner.
It is a bacteria of spiral form. Its mobility due to the presence of a flagella. This bacteria is
microaerobic, specific for man and other higher primates. H. pylori possesses the particularity of
adhering to the mucus cells of the stomach which are the only ones to have a specific glycolipid receptor
for the adhesion of bacteria. The colonization of the stomach by H. pylori produced a reduction in the
thickness of the mucus layer and an alteration in the hydrophobicity.
Ever since its discovery in 1982, H. pylori has been associated with certitude in the different grades of
gastroduodenal pathology.
H. pylori is the most frequent cause of type B gastritis.
It is not exact to consider duodenal ulcers as a pure infectious disease. It is not certain that H. Pylori
plays a central role in the recurrence in ulcerative disease. In this situation, the frequency drops to 5%
one year after elimination of H. pylori as compared with approximately 80% in the case of persistent
infection. Several studies have shown a higher prevalence of infection to H. pylori in gastric cancer
patients as compared with normal individuals of the same age. These arguments suggest that gastritis can
progress to cancer following several intermediary stages: intestinal atrophy, metaplasia and dysplasia.
A number of epidemiological studies have shown an increase of H. pylori infection with age in unfavorable
socio-economic conditions. The prevalence of infection, practically non-existant in young children,
increased from 1% by year of age; practically half of the general population is infected by H. pylori
after the age of 50-60 years. It appears that the greatest prevalence in elderly people may be due to old
infections which were acquired during infancy when the hygenic condition were not as good as now.
The infection by H. pylori presents 2 phases: a high rate of acquisition in children with the risk related
to the infectious pressure of the surroundings and a stationary period in adults where, in spite of the
elevated level of prevalence, the new cases of infection remain rare. The reduction of infection by H.
pylori in childhood can be related to the significant lowering of the frequency of ulcerative disease in
the industrial countries. The unfavorable socio-economic conditions may explain the most elevated
prevalence of infection to H. pylori in developing countries, even if one formally excludes the
possibility of an acquired infection in certain ethnic groups and therefore the eventual influence of
the genetic factors concerning especially the expression of gastric mucins.
Yet acute diarrhoea represents a major problem in public health at the world scale. Nearly 5 million infant deaths each year are attributed to this disorder. In France, it is the 2nd reason for pediatric medical consultations. In the United States, 250,000 infants are hospitalized each year due to the consequences of acute diarrhoea inducing most frequently a dehydration. Independent of the specific cause, alterations in mucus are constantly observed during acute diarrhoea which participate in a rupturing of the mucosal barrier: alterations in the mucus adherent layer-IgA favoring a perturbation of the saprophyte flora in invasive diarrhoea, reactionary hypersecretion and loss of mucus in the intestinal lumen during the enterotoxinogenic and viral diarrhoea.
In this context, the consequences of malnutrition and weening on the intestinal mucin composition (already indicated above) may increase the deliterious effects of the infectious agents on the intestinal mucosa. The hypothesis of a genetic susceptibility to infectious agents in intestinal tropism rests on one or several elements of the mucosal barrier therefore on the mucus itself, is certainly plausible but for the present moment remains purely speculative. The reinforcement of the mucosal barrier during acute diarrhoea is a potentially useful arm in addition with the corner-stone which represents the rehydration by ingestion.