The intestinal microflora, the immune system and probiotics.
The Swedish Medical Journal 50-2001
Lennart Cedgård, MD, GM Wasa Medicals, Gothenburg
Anna Widell BSc in Bioscience, Wasa Medicals, Gothenburg.
In science of today, there is a great interest in the function of the intestine and the intestinal microflora. Research is ongoing all over the world. One of the main issues is how the intestinal microflora influences the immune system and what effect supplementation of probiotics might have on the immune system.
The intestinal microflora and the immune system
There is an enormous amount of bacteria colonising our intestine. The bacteria are referred to as ” the normal intestinal microflora”. The total amounts of bacteria colonising our body and above all the intestine is ten times higher the amount of the cells of the body. Thus, regarding number of cells, 90 % of our body is microorganisms!
The major part of the bacteria are found in the large intestine, approximately 10 11-12 bacteria/g. The bacterial counts of the small intestine are considerably lower, approximately
10 4-7 bacteria/ ml. The dominating species in the large intestine are bifidobacteria and bacteroides whereas lactobacilli and streptococci dominate the small intestinal flora.
The intestinal microflora has numerous functions of which the major parts probably still are unknown. It is known today that the intestinal micro-flora influences the digestion and absorption, the function of the immune system, the peristalsis, production of vitamins such as B-vitamins and influences the turnover of the intestinal epithelial cells. Additionally the metabolism of the microflora influences the secretion of hormones.
One of the most interesting issues regarding the intestinal microflora is the interaction with the immune system. The mucosal membrane of the intestines, with an area of approximately 200 m2 is constantly challenged by the enormous amount of antigens from food and the intestinal micro-flora. Inhaled particles may also reach the intestines. It is therefore not surprising that approximately 80 % of the immune system are found in the area of the intestinal tract especially related to the small intestine. The immune system of the intestine is referred to as GALT ( gut-associated-lymphoid tissue). It consists of the Peyer’s patches, which are units of lymphoid cells; single lymphocytes scattered in the lamina propria and so called intraepithelial lymphocytes spread in the epithelia.
The immune system of infants is not fully developed. Bacterial colonisation of the intestine is important for the development of the immune system. The immune system has two equally important main functions that are either to react to antigens that are harmful or not to react to harmless antigens like nutrients and the tissues of the body. Research show that these functions are interconnected.
Microbial stimulation of the immune system decreases the reactivity against harmless antigens (9)(14)(20). This is one of the reasons why scientists are interested in the relationship between the composition and activity of the intestinal micro-flora and the development of allergies. Research shows that the composition of the intestinal micro-flora in populations of the western world has changed during the past decades and differs from the flora of people in developing countries both in adults (13) and in children (1)(2). The intestinal flora of Swedish children consists of fewer strains and has a slower turnover than that of the children from Pakistan. This may be the cause of a decreased bacterial stimulation of the immune system.
The intestine has an important function in working as a barrier against the surrounding world. This barrier is maintained by tight-junctions between the epithelial cells, by production of IgA antibodies and by influencing the normal microbial flora.
It is of great importance that only harmless substances are absorbed while the harmful substances are secreted via the faeces.
Studies show that individuals allergic to cows milk have defective IgA production (7) and an increased permeability of the intestinal mucosa (8), which results in an increased absorption of macromolecules by the intestinal mucosa (6). The increased permeability is probably caused by local inflammations due to immunological reactions against the allergen, which damages the intestinal mucosa (11).
What may cause changes in the composition of the intestinal microflora?
During the past century our lifestyle has changed dramatically regarding hygienic measures, diet, life standards and usage of medical drugs. Today we eat mostly industrially produced, sterilised food and use different kinds of preservatives, refrigerator and freezers instead of fermenting the food. This has lead to a decreased intake of bacteria including lactic acid producing bacteria (3).
The usage of antibiotics in healthcare and agriculture, antibacterial substances in toothpaste, deodorants, food etc. are also something new for humanity. We have in many ways sterilised our environment, which is detrimental to the micro-flora.
Probiotics are referred to as microorganisms that positively influence health by improving the intestinal microbial balance. The most commonly used probiotics are Lactobacillus spp, Bifidobacterium spp. and Streptococcus spp. In the beginning of the 20th century the scientist Elie Metchnikoff postulated his hypothesis about the influence of the intestinal micro-flora on the human ageing. He claimed that putrefactive processes in the intestine lead to the formation of toxins that contributed to the degeneration of the body. He proposed that supplementation with lactic acid producing bacteria, so called probiotic bacteria in the form of yoghurt, decreased the negative effects of putrefactive bacteria and thus reduced the degenerative processes in the body (12).
Today a lot of research is done to reveal the effects of probiotics. Intake of probiotic bacteria seems to have many positive effects on the body. In an article in Trends of Immunology Today, September -99 about the effects of probiotics on the immune system (4) it was listed suggested beneficial effects of probiotic supplementation, such as improved digestion and absorption, prevention of cancer, prevention of infections in the gastrointestinal channel, regulation of the peristalsis, prevention of degenerative processes such as osteoporosis and arteriosclerosis etc. It seems that Metchnicoff might have been right!
Regarding the immune system it seems as if the intake of probiotics has various effects such as increased production of IgA antibodies (17), increased macrophage activity (15)(16) and increased phagocytosis (19). Supplementation of certain bacteria also decreases the number of inflammatory mediators like TNF-alfa and alfa-1-antitrypsin, which may indicate that probiotic bacteria have a healing effect on the intestinal mucosal membrane. Lactic acid producing bacteria inhibit growth of putrefactive bacteria due to the production of organic acids, which lowers the intestinal pH. The activity of putrefactive bacteria decreases with a lower pH.
Prebiotics are complex carbohydrates such as oligo- and polysaccharides, which are not digested by the enzymes of the small intestine thus reaches the large intestine in a viable form. They are the nutrients for certain bacteria like bifidobacteria. Intake of different kinds of prebiotics reduces the counts of putrefactive bacteria and influences the body beneficially in many different ways. It seems if it decreases the risk of cancer (18). Prebiotics improve the stability of probiotic cultures both in the food and the intestinal tract. This improves the effect of the probiotic bacteria. Products with a combination of probiotics and prebiotics seem to be more favourable. They are referred to as symbiotics.
Choice of probiotics and bacterial logistics.
Bacterial logistics can be defined as stability of probiotic cultures and transport of bacteria from the mouth to the desired region in the stomach or intestines. There are various kinds of probiotic formulations. They may be in the form of liquids like yoghurt, with or without the addition of bacterial cultures of intestinal origin. To improve the stability, the bacterial cultures should be freeze-dried. This makes it possible to use them in powder, capsules or tablets, which improves the chances for the bacteria to survive the passage through the gastrointestinal tract, where they are exposed to gastric acids and bile acids. Normally a major part of the bacteria is killed during this passage.
Most of the pharmaceutically distributed probiotic products are in the form of capsules. The problem with gelatine capsules is that they tend to consist of 10-15% water! This causes decreased stability and viability in the cultures (10). Regarding stability and distribution, the best way to pack probiotic bacteria would be in a tablet that is produced with a low compression force. A tablet with regulated disintegration in the gastrointestinal tract will expose the intestinal system continuously with viable bacteria. Traditional methods of manufacturing tablets are not usable when the contents are living bacterial cultures.
The disintegration of a tablet/capsule most often would take place in the small intestine. Depending on the choice of probiotic strain the optimal time of disintegration may vary. The advantage with probiotics in the form of tablets is the opportunity to regulate the time of disintegration, which makes it possible to apply a slow release process such as in a low compression tablet. The exposure of fresh and viable bacteria is thus optimised.
Capsules will disintegrate quickly in the stomach or if entero-coated in the small intestine. The exposure of fresh and viable bacteria is thus minimised.
It is easier to influence the micro-flora of the small intestine with supplementation of probiotics since the bacterial counts in the small intestine are considerably lower than in the large intestine. Prebiotics like inulin (fructooligo- or polysaccharides) have a greater impact on the large intestine.
There are different ideas which bacterial strains that are the most effective. The original theory about probiotics according to Metchnicoff referred to the use of cultures with food origin like yoghurt and sauerkraut (12).
Today the general idea in science is that bacteria with intestinal origins are preferable, which relates to the idea that supplemented probiotic bacteria must be able to colonise the intestinal mucosa if to be effective.
The composition of the intestinal micro-flora of most individuals is quite stable, especially in the large intestine and it is hard to find studies proving the “colonisation theory”.
It is easier though to influence the metabolic activity of the micro-flora. According to several studies probiotics have several effects on the micro-flora regarding enzyme activity, influence on the endocrine system (5) and immunological activity (15)(16)(17). These effects have been seen when using both “food derived bacteria” and ” intestinal derived bacteria”. Additionally there is a bit of confusion about the definition of these groups since the same bacterial species can be found in both groups!
From a historical/ecological point of view supplementation with probiotics replaces the lack of lactic acid producing bacteria in the food, due to the change of preservation methods (3). Since the loss of probiotic bacteria in food doesn’t refer to a particular strain but rather many different kinds of strains, the probiotic supplements with a mixture of strains would be preferable. Studies also show that different bacteria have different niches in relation to the immune system. A complex micro-flora is important for the immune system. However it is important to notice that supplementation with single strain products also have various beneficial affects. This is documented and patented by different producers of probiotic products.
The effect of probiotic supplementation is probably influenced by the choice of bacteria, the counts of bacteria, the quality, the viability and the stability of the bacteria and how the bacteria is distributed from the mouth to the intestine. The way of distributing bacteria certainly influences the dose required to obtain desired effects. Due to this the variation in dose may be as big as E4-5= 10.000-100.000 per day or per time of dosage. It probably requires higher dosages to influence the micro-flora of the large intestine, than that of the small intestine regarding the bacterial counts in these different areas.
As most studies on the effects of probiotic supplementation have not considered bacterial logistics, it is very difficult to compare them. This probably explains the different results presented.
The role of bacterial logistics is one of the biggest challenges for future studies. Waiting for more clinical studies, we should maybe be careful to claim that probiotics are effective against specific diseases but rather emphasise, that probiotics have a beneficial effect on the health as a whole.
Abstract in English: There is a need for probiotics. Modern life style implies a reduced intake of beneficial bacteria. There is a relationship between health problems of today and microbial ecology. In this relation the micro-flora interacts with the immune system. The concern of bacterial logistics is important when choosing probiotic products.
Keywords: probiotics-ecology-health-immune-prevention-therapy-life style-logistics
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Tel: +46-35-12 05 80
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