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At the interface between the external environment and the body proper, the intestine is a boundary inside the body. Consequently it fulfils two opposing roles: to allow the passage of nutrients and to repel toxic substances.
Every day, billions of molecules pass through the intestinal mucosa. Some of them originate from the external environment (500 g of nutrients per day). Others arise from exocrine digestive secretions recovered by the intestine, involving mainly proteins, lipids and mineral salts. Finally, some are exudated through the intestinal epithelium, in particular plasma proteins and mineral salts.
To repel toxic substances, to recognize potentially harmful substances and to block the passage of pollutants such as heavy metals, bacterial toxins, pathogenic bacteria and viruses, etc. Over the course of thousands of years, the intestine has evolved into a complex functional system based on a key link: the intestinal bacterial flora.
STRUCTURES
- The intestinal flora
Digestive flora is derived from the diet. Ingested food and saliva are not sterile. Some foods even contain living micro-organisms. Every day, thousands of bacteria belonging to various different families penetrate into the intestine. Thus the intestine must defend and protect the body from invasion by bacteria. The gastric acid secretion destroys the majority of penetrating bacteria and toxins. Bacterial proliferation is then slowed down by bile salts and pancreatic proteolytic enzymes. The density of the intestinal flora increases along the digestive tractus: the density of bacterial and yeast populations, low at the exit of the stomach, increase dramatically in the ileum and the colon. Their density peaks in the transverse and left colon (109 to 1011 bacteria/ml).
The type of micro-organisms in the intestinal lumen and in contact with the mucosa depends mainly on the anatomical site and diet. The further one goes from the mouth, the more oxygen is lacking: thus micro-organism development occurs mainly under anaerobic conditions. The higher the diet is rich in complex carbohydrates, which are low or non-digestible by salivary and pancreatic amylases, the more the carbohydrate-consuming flora develops. Thus newborn infants who are breast-fed do not have the same flora as those fed with infant formulas; in adults a high fibre diet promotes the proliferation of certain bacteria populations. Two types of flora exist: the endogenous flora (dominant and subdominant populations), and the transient flora, which only passes through the gastrointestinal tract. The colon contains 300 to 400 different microbial species. Ten to twenty of them are in contact with each other within the adult's colon lumen at high concentrations (109 to 1011 bacteria/ml) . This is the dominant flora.
The subdominant endogenous flora (106 to 108 bacteria/ml) is comprised of bacteria, some of which become pathogenic (acute diarrhea) when they multiply in certain disease situations.
The transient bacterial flora (104 to 106 bacteria/ml) do not implant themselves. Potentially pathogenic, the organisms comprising the transient flora (Citrobacter, Klebsiella, Proteus, Pseudomonas, Staphylococci) are prevented from expressing this toxicity because of the presence of the dominant flora.
- The intestinal mucosa
It is characterised by a large number of cells and their rapid renewal. The small intestine is anatomically organized to multiply the useful surface area. Thus the mucosa has an area of 250 m2 and contains nearly 300 million enterocytes which are totally renewed within four to six days in humans.
In its luminal aspect, the mucusa contains a layer of enterocytes (or colonocytes) and few mucus-secreting cells. Below this layer, interstitial fluid interspersed with blood vessels and immune cells ("inflammatory infiltrate"). The Lamina muscularis mucosae, between the mucosa and the sub-mucosa, enable the mucosal pattern.
- The GI defense system
The immune system, known as the GALT (pour "Gut Associated Lymphoid Tissue"), is organized into sentries and patrol militia. The intestine is one of the organs containing the highest numbers of lymphocyte cells.
Such sentries are found from place to place: lymphoid follicles and Peyer's patches, with distinct B cell follicles and T cell areas. Wherever these patches are located, the mucosa is "thinner" (see diagram). Events occur as if the intestine "gave preference to passive entry" of these substances, to better examine them and take them into consideration. Leaving from or arriving at these Peyer's patches, lymphocytes (especially T lymphocytes) travel through the mucosa (lamina propria) and then reach the mesenteric lymph nodes and the general circulation. Then, mature, they will return into the gastrointestinal tract: they then display memory for antigens which have bound to their receptors, and capacities for proliferation and secretion of cytokines and IgAs. The aim of these shuttles is to keep the two systems, general and intestinal, in phase.
Intestinal B lymphocytes synthesise a specific IgA, secretory IgA. IgAs play a key role in the fight against invasive bacteria and yeasts as well as in "immune tolerance" with respect to the dominant flora.
The intestine also has non-specific defenses: the intestinal flow (30 minutes to travel the 4-meter length of the small intestine); the surface mucous cells; desquamation of enterocytes (60 million a day); polymorphonuclear neutrophils, etc.
FUNCTIONS
- The intestinal flora
It has countless functions (Table I). Three of these are of major importance: the flora participates in the processes of digestion-absorption of nutrients; it cooperates in the process of defense against microbial invasion: it is the barrier-like effect produced by certain micro-organisms, including the probiotics. Lastly, the flora produces derivative products which play a beneficial metabolic role (volatile fatty acids and metabolism of cholesterol; folic acid).
- The intestinal mucosa
The mucosa has remarkable capacities for digestion and absorption, but also adaptation thanks to its ultrafast renewal. At the top of villi, all "active" absorption occurs (energy-dependent (ATP) active transport); at the base of villi, "passive" absorption, particularly that of large molecules (antibodies, large "antigenic" proteins). It is here that Peyer's patches are located.
Two systems allow the passage of large molecules and thus provide information to the immune system: protected transfer of molecules via the enterocytes and transfer of molecules between two enterocytes.
- The immune system
The bacterial flora in the newborn gives the signal for the development and the maturation of the immune system. Its optimum functioning is between infections and allergies. When insufficient, it does not effectively enough oppose the penetration of micro-organisms and their toxins; in case of excessive functioning, it induces hypersensitivity reactions: either allergic reactions (digestive allergies), or digestive intolerance (celiac disease), or over-reaction of the immune system (Crohn's disease, auto-immune enterocolitis, collagen colitis, microscopic colitis, eosinophilic enteritis).
A BALANCE TO BE MAINTAINED AND OPTIMIZED
Many examples demonstrate the usefulness and sometimes the fragility of this functional "flora-mucosa immune system" unit. In order to optimize the flora, it is possible to modulate the defense system.
A new-born infant who is breast-fed for six months will be less subject to allergies (digestive and non-digestive) during weaning and during the following two or three years than a new-born infant who is bottle-fed. This may be related to the fact that repeated exposure to a given bacterial environment affects the flora and thus the immune system: thus allergic events are less frequent during the first two to three years of life.
Antibiotic therapy, if it seriously impairs the dominant flora, may result in the proliferation of a strain of the sub-dominant bacterial flora (Pseudomonas, Klebsiella oxytoca, etc.) or indeed in a serious gastro-intestinal infection (salmonella, enteropathogenic E coli), or candidiasis, mutation in certain strains (toxin-secreting Clostridium difficile, involved in pseudomembranous rectocolitis).
Minor uncomplicated antibiotic-related diarrhea generally is not associated with the proliferation of pathogenic strains of organisms, but with metabolic changes related to the alteration of the dominant flora. For example, the significant reduction in digestion of complex carbohydrates by the flora results in the continued presence of osmotic carbohydrates in the intestinal lumen, which induce diarrhea due to fluid and electrolyte Ingestion of a high population of certain bacterial strains (i.e., Bifidobacteria, Lactobacillus), which however are only passing through, hinders the undesirable effects of antibiotics (in particular, broad spectrum antibiotics). Such probiotics may act directly or their effect may be based on the action of substances, the prebiotics, which they transform. The effect of probiotics may be especially useful in certain populations with a high risk of intestinal infections, such as children and the elderly. However, what is true for one strain of probiotics is not necessarily so for another: the results of a study demonstrating a beneficial effect of a given strain of lactobacillus in a given yoghurt cannot be extrapolated. Lastly, as it is always observed in nutrition, a dose-effect exists. What is true for one lactobacillus at a certain dose will not be so for half the dose or another lactobacillus. The concept that "little is always better than nothing" is not correct in science.
Lastly, what has been demonstrated in some sub-populations is not always applicable to others. Alterations in the bacterial flora and the usefulness of probiotics are found especially in at-risk populations, i.e., children, the elderly, or in physically frail subjects.
Many examples demonstrate the usefulness and sometimes the fragility of this functional "flora-mucosa immune system" unit. In order to optimize the flora, it is possible to modulate the defense system.
A new-born infant who is breast-fed for six months will be less subject to allergies (digestive and non-digestive) during weaning and during the following two or three years than a new-born infant who is bottle-fed. This may be related to the fact that repeated exposure to a given bacterial environment affects the flora and thus the immune system: thus allergic events are less frequent during the first two to three years of life.
Antibiotic therapy, if it seriously impairs the dominant flora, may result in the proliferation of a strain of the sub-dominant bacterial flora (Pseudomonas, Klebsiella oxytoca, etc.) or indeed in a serious gastro-intestinal infection (salmonella, enteropathogenic E coli), or candidiasis, mutation in certain strains (toxin-secreting Clostridium difficile, involved in pseudomembranous rectocolitis).
Minor uncomplicated antibiotic-related diarrhea generally is not associated with the proliferation of pathogenic strains of organisms, but with metabolic changes related to the alteration of the dominant flora. For example, the significant reduction in digestion of complex carbohydrates by the flora results in the continued presence of osmotic carbohydrates in the intestinal lumen, which induce diarrhea due to fluid and electrolyte Ingestion of a high population of certain bacterial strains (i.e., Bifidobacteria, Lactobacillus), which however are only passing through, hinders the undesirable effects of antibiotics (in particular, broad spectrum antibiotics). Such probiotics may act directly or their effect may be based on the action of substances, the prebiotics, which they transform. The effect of probiotics may be especially useful in certain populations with a high risk of intestinal infections, such as children and the elderly. However, what is true for one strain of probiotics is not necessarily so for another: the results of a study demonstrating a beneficial effect of a given strain of lactobacillus in a given yoghurt cannot be extrapolated. Lastly, as it is always observed in nutrition, a dose-effect exists. What is true for one lactobacillus at a certain dose will not be so for half the dose or another lactobacillus. The concept that "little is always better than nothing" is not correct in science.
Lastly, what has been demonstrated in some sub-populations is not always applicable to others. Alterations in the bacterial flora and the usefulness of probiotics are found especially in at-risk populations, i.e., children, the elderly, or in physically frail subjects.
Prof. Daniel RIGAUD
CHU Le Bocage, Dijon
CHU Le Bocage, Dijon
REFERENCES
Hagiage Muriel. La flore intestinale. De l’équilibre au déséquilibre. Ed. Vigot (Paris)1994 : 120 p.
Corthier G, Raibaud P. Ecologie intestinale et flore. In « Les diarrhées aiguës infectieuses », ed. Rambaud JC, Rampal P. In « Progrès en hépato-gastroentérologie » ; Doin Ed 1993 : 1-8.
Hagiage Muriel. La flore intestinale. De l’équilibre au déséquilibre. Ed. Vigot (Paris)1994 : 120 p.
Corthier G, Raibaud P. Ecologie intestinale et flore. In « Les diarrhées aiguës infectieuses », ed. Rambaud JC, Rampal P. In « Progrès en hépato-gastroentérologie » ; Doin Ed 1993 : 1-8.
| Table 1: The different roles and effects of intestinal flora | |
| FUNCTIONS AND EFFECTS | PREFERENTIAL SITE |
| Modification of content
- Alcalinization of the luminal content - Lowering of the oxydation-reduction potential |
Small intestine, colon Colon |
| Modification of colonic functions
- An increase in salt and water absorption - Stimulation of intestinal motility |
Ascending colon |
| Digestion - absorption of nutrients
- Hydrolysis of complex starches and dietary fibers - Hydrolysis of low-digestible proteins - Hydrolysis of lipids |
Ascending and transverse colon Descending colon Descending colon |
| Production
- Volatile fatty acids: acetic acid, butyric acid, propionic acid - Gases : CO2, H2, methane, ammonia - Folic acid and vitamin K |
Ascending colon Ascending and descending colon Small intestine and ascending colon |
| Chemical conversion
- Deconjugation of bile salts - Dehydroxylation of bile salts |
Small intestine and ascending colon Small intestine and ascending colon |
| Actions on xenobiotics
Cardiac glucosides, imipramide, certain antibiotics |
Colon |
Diagram of a Peyer's patch
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