Georg Ivanovas From Autism to Humanism - systems theory in medicine
Closely connected to nutrition is the gut flora which came into the centre of scientific interest lately. The gut flora contributes to the host’s nutrition by providing carbohydrates, amino acids and vitamins (Gilmore/Ferretti 2003). By that it regulates fat storage and even might be connected to obesity (Bäckhed et al 2004). Every kind of nutrition has its own flora with its own characteristics. The intestinal flora consists of about 1,2 kg bacteria and is so complex that not two people have the same complement of bacteria (Abott 2004). These micro-organisms adapt to each other and to the host even by exchanging genetical material (Xu et al 2007).
To really judge the importance of the gut flora, its organizational purpose has to be understood. The intestines are the most pervious part of the body. In the guts the distinction between me and other is problematic. Food has to be reduced to a size that the autopoietic unit ‘human’ (chap. 4.8) is able to absorb it and to maintain simultaneously its autonomy.
This happens in cooperation and in a symbiotic exchange relation with many bacteria. That is, the human is here in a very close contact with a multitude of bacteria that are potentially harmful. The mechanisms how this shifting balance between helpful and harmful bacteria is performed are slowly investigated (Xavier/Podolsky 2000; Neish et al 2000; Podolsky 2002; Ganz 2003; Coye et al 2005).
Immune regulation and inflammation processes are closely involved in this process. Thus, the gut flora plays an important role for the immunological balance (Podolsky 2000), might influence allergic disposition (Noverr et al 2005), is the first line of defence against pathogenic bacteria (LeBlanc et al 2008) and even might prevent kidney stones (Kaufman et al 2008). It is an ecological system with all characteristics of complexity.
When Helicobacter pylori infection was found to be related to stomach ulcer, this lead to a shift of paradigm in the treatment of the disease. Till then stomach ulcer was a typical ‘psychosomatic’ disease. Today Helicobacter is seen as the leading cause even of gastric malignancies (Kawakubo et al 2004), although it is inadequate as a monocausal explanation. Only a fraction of the ‘infected’ patients develop peptic ulcer, gastric cancer, or malignant lymphoma (Kawakubo et al 2004). The lifetime risk for persons with Helicobacter pylori to suffer peptic ulcer ranges from 3 percent in the US to 25 percent in Japan. Life style factors are still as good to predict peptic ulcer and the best results are attained, if the two (life-style and bacterium) are combined (Levenstein 1998). Nevertheless, Helicobacter is present in most cases of peptic ulcer (Suerbaum/Michetti 2002) and the typical linear strategy of medicine is the eradication of the bacterium understood as ‘causing’ the disease.
Such an intervention into an ecological context changes its balance. Therefore, some scientists expected an altered immune response with unpredictable consequences after Helicobacter eradication (Whitfield 2003). There is, indeed, some evidence that the eradication of Helicobacter contributes to cancers of the upper stomach (cardia) (Kamangar et al 2006), to asthma (Chen/Blaser 2007), to oesophageal disease and infant diarrhoea (Whitfield 2003).
Applying a linear logic to such relations is somehow confusing. When Helicobacter is defined as the ‘cause’ of stomach ulcer, then the eradication of Helicobacter is the ‘cause’ of oesophagitis, diarrhoea, cardia cancer and asthma. But such statements do not really make sense as systems like the gut are necessarily nonlinear. For example, in mice the prognosis in the case of a re-infection with Helicobacter is worse than in the infected and untreated animals (Mueller et al 2005). This finding makes only sense, when principles of adaptation are introduced.
In any case, it would be more appropriate to talk about the ‘presence’ of Helicobacter facilitating gastric ulcer and not of ‘causes’ or of H. pylori ‘infection’. This becomes even more obvious when different contexts are taken into account.
The stomach is normally protected against bacterial damage through gastric mucin (Kawakubo et al 2004). The reduced defence mechanism could be seen as cause of the disease on a different level. This is, indeed, the old paradigm of stress theory. But also nutrition plays a role. It not only influences the gut population, in general. Exogenous cholesterol enhances the growth of H. pylori populations directly (Kawakubo et al 2004). That is, a nutrition rich in cholesterol (the minor part) or inducing the own production of cholesterol (the major part) contributes to the increase of Helicobacter.
A ‘causal chain’ (chap 2.1.d) wisely knowing that such a chain has no other meaning than to exhibit the theory and interest of the observer would be
nutrition ► cholesterol ► Helicobacter ► stomach ulcer
Every intervention, every drug changes the gut flora contributing to many diseases (Stockert 2001). The effects of iron, antibiotics and systemic cortisone can be judged in middle and long term only, when their effects on the gut are considered. For example, the higher incidence of breast cancer through antibiotics has been attributed to the damage they do to the gut flora (Velicer et al 2003).
Another disease attributed to the damage of the gut flora through antibiotics and bad diet is eosinophilic oesophagitis which showed a sharp rise in the last years (Noel et al 2004). Its eosinophilic character is of special interest. Eosinophilic reaction is normally seen in helminth infection or in allergic disease. The two are somehow interconnected as the reduction of helminth infections leads to a rise of allergic disease (Wickelgren 2004). One proposed explanation for this finding is that worm infections occupy certain receptors which might provoke allergic disease when not used. This theory, as such, is surely too simplistic as receptors change according to a certain situation and IgE is part of a wider network (Gould/Sutton 2008). However, it provides a first rough model of how the body can be triggered by different germs, or, if these are lacking, by other substances.
The theory says, more generally spoken and probably much nearer to the truth, that the immune system has to be occupied with a certain amount of germs, otherwise it occupies itself with substances normally not acting as an antigen. This is also the core of the so-called hygiene hypothesis (Watts 2004). It says that the reduced contact with bugs leads to allergic disease. The theory is based on the observation that a reduced exposition to bacterial and helminth diseases is related to atopic disease. For example, children with many brothers and sister and/or with animals, and/or children living on farms have an impressingly lower incidence of allergic disease (Braun-Fahrländer et al 2002).
The hypothesis is supported by animal studies (King et al 2004). “Autoimmune diseases in susceptible strains of mice or rats develop earlier and at a higher rate among animals bred in a specific pathogen-free environment than among animals bred in a conventional environment.” (Bach 2002). Even lymphoma (Becker et al 2004) and multiple sclerosis (Ponsonby et al 2005) are connected to the lack of exposition to bugs. Some attribute the protective effect of bacterial infection to T cell differentiation and to the level of cytokines (Weiss 2002).
The ‘hygiene’ problem starts already with birth. The gut flora develops within the first 2-3 days. The first colonisation is extremely important. Colosturm, the first milk in breast feeding, plays a major role. But the bacteria of the environment as well. It has been shown that infants born in a modern hospital are exposed to fewer bacteria and develop a less rich flora than children under ‘normal’ hygienic conditions (Stockert 2001). As in hospitals patients acquire multiple antibiotic-resistant enterococcal strains within days of admission (Gilmore/Ferretti 2003) hospital birth might contribute to allergic disease in two ways. It leads to a reduced flora and it provides highly selected, often pathogen bacteria.
Therefore, the hygiene hypothesis has to be seen in a wider sense. It is not only the confrontation of the immune system with certain bacteria that matters. It is also the question which bacteria persist in the human under which circumstances. This wider concept explains why infectious diseases during the first 6 months of life are associated with an increased risk of atopic dermatitis (Benn et al 2004). The more inadequate the gut flora is, the more probable are infections and the more probable is the persistence of pathogenic germs.
Antibiotics play a role. “By altering the balance of gut microbes, antibiotics can disrupt the immune system's ability to distinguish between innocuous substances and harmful microbes. This finding, from experiments on mice, adds weight to the notion that antibiotics could be at least partly responsible for the rise in allergies and asthma in children” (Randerson 2004). This connection between the use of antibiotics and allergic disease has been maintained by many researchers (Bach 2002; Randerson 2004, Noverr et al 2005). But it is no surprise that other studies do not confirm these findings (Benn et al 2004).
As the gut is a nonlinear system, interventions into its ecology through nutrition or in eradicating certain bacteria will not reveal predictable results. Nothing might happen, consequences might occur only very slow, or other co-factors are needed to produce symptoms.
Therefore it is also doubtful whether the administer of worms in patients with bowel inflammation or allergic disease is really as useful as first results suggest (Coghlan 1999, Kolfs 2004, Summers 2005). Although the eradication of the helminths gives rise to allergic reactions, this does not mean that the administration of helminths will have the opposite effect. This linear exchange value is not true in polyvalent situations (chap 3.5). This does not mean that the application of worms is generally useless. It only means that the whole concept has to be considered cautiously, especially all generalizing statements.
The administration of living organisms, so-called probiotics, has a long tradition, but was seen as “folk medicine” (Tamboli et al 2003) used only by different methods of complementary and alternative medicine (CAM) in the treatment of atopic diseases, in all kind of bowel disturbances and in people with a tendency for infections. Only lately its positive effects became accepted by orthodox medicine (Bach 2002; Shanahan 2003) and had been proved to be effective in respected trials (Tubelius et al 2005). Thus the positive effect of germ administration became more widely accepted.
B. thetaiotaomicron is helpful to prevent bowel inflammation (Gilmore/Ferretti 2003) and E coli nissle 1917 is as effective in the treatment of colitis ulcerosa as mesalazine (Rembacken et al 1999). The protective effect of the E. coli nissle 1917 was detected (by observation) in WW I, when the bacterium was isolated in a soldier who was spared of a severe gastroenteritis. The bacterium became the main substance of a probiotic remedy (Mutaflor®), and was used since for many purposes.
In the now flowering research on probiotics it has been found that already the DNA of probiotic bacteria has an immunstimulatory effect (Rachmilewitz et al 2004). But even this has been known by CAM for decades. Refined parts of bacteria (for example Prosymbioflor®) is used at the beginning of a probiotic therapy, in small children and/or in sensible persons.
The orthodox proposition to add the immunstimulating DNA to nutrition in order to avoid allergic diseases (Rachmilewitz et al 2004) springs from the linear thinking that so often leads into trouble. The therapy with refined bacterial parts has sometimes no effect, but not so rarely it leads to an overstimulation with all kind of inflammatory reactions. Therefore it is no surprise that a trial showed that the general administration of certain probiotics is correlated with an increased mortality in acute pancreatitis (Besselink et al 2008). Probiotics have to be dosed carefully and the regimen has to be altered according to the observed effects. There is no simple dose-effect relation.
But the gut flora is only one part of human symbiosis, although the most prominent one. The flora of the mouth, the ears, the vagina, the skin, they all play a role in the adaptation of humans to their environment and in the competence of the immune system. Actually, the human organism consists of 90% non-human cells (Nicholoson et al 2004).
Thus, all kinds of diseases might be influenced with probiotics. It is a quite common strategy in vaginosis. Also HIV-infections seem to be to some extend preventable through lactobacillus (Tao 2005). As this germ is often present, especially in the milk and the mouth, this might explain why the transmission of HIV through breastfeeding is rarely observed. It was also proposed to use probiotics in recurrent otitis media (All-Sttodley et al 2006).
The understanding of the bacterial biotope ‘human’ is essential for any concept of chronic diseases.
For example, it is futile to ask which germ is causing bacterial vaginosis. Until now 35 bacteria have been found (Fredericks et al 2005) and may be Helicobacter will have soon some companions as the cause of peptic ulcer. However, these germs might often be more an indicator of an imbalance and less a causal agent.
Although the bacterial flora is quite complex it is not such a great methodological challenge. With some concepts of adaptation, symbiosis, cooperation and competition it should not be too difficult to model clinical observations.