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Defense against infections

Last update 19-7-2009

On Colonization Resistance

What is Colonization Resistance?

The Colonization Resistance (CR) of the digestive tract is defined as:

"the resistance to colonization of the alimentary canal by newly ingested microorganisms".

The Colonization Resistance determs whether or not an ingested microorganism to survive and multiply in the gut lumen for more than a few days. A few days is the normal interval for microorganisms that do not attach to the gut wall and/or grow to high numbers but cannot stay as they get washed out i.e. get expelled with the intestinal contents as faeces.

The CR is different between microbial species (bacteria as well as fungi) and may even differ between strains of the same species.
The mechanisms involved in CR are multiple and of both microbial and host origin:

  1. Transient microorganisms
    These are microorganisms that live in the gut lumen for a few days or weeks. These microorganisms are likely to play a minor but still valid role by competing for nutrients and participating in chemical warfare with other microorganisms through production of defensins, short chain fatty acids and extracellular enzymes.
  2. Autochtonous microorganisms
    These are non pathogenous microorganisms that have colonized the gut very sucessfully i.e. more or less permanently.
    The autochtonous microflora plays a major role in the functioning of the CR. However, it still is not yet clear which microorganism groups of the indigenous flora are involved although it is certain that they belong to the stricy anarobic fraction. Furthermore, most biochemical mechanism(s) causing CR are still uncertain.
    Microbial products such as defensins, short chain fatty acids, extracellular enzymes, competition for nutrients, etc, all appear to be of importance.
    Also in order to survive long term in the gut lumen it is mandatory to adhere to the mucosa layer that covers the gut wall. This implies that in the CR mechanism there is also a competition for space in the mucosa layer involved.
  3. Host factors
    Host factors contributing to CR involve secretion of saliva, swallowing, peristaltic movement, secretion of mucus (feeder layer), epithelial cell desquamation, defensin production and excretion by Paneth cells, the "Gut Associated Lymphoid Tissue" (GALT) producing sIgA, as well as nonspecific blocking factors for bacterial adherence that limit the microorganisms' ability to adhere to the mucosa.
    There is also a microorganism modulation mechanism through oxygen as some microorganisms need oxygen to survive, some can do without and for yet others oxygen is toxic. The oxygen is ingested with food and drink and possibly excreted with the mucus and used by those microorganisms that can use it.
    Several of these host factors are modulated by his/her autochtonous microflora and vice versa.

The Colonization Resistance is not a 'defense mechanism' in a strict sense. Rather it is an emergent effect of all factors involved.
Here another view is given of Colonization Resistance.

Where does Colonization Resistance come from?

What we call Colonization Resistance is the result of 2 billion years of evolution. The basis was formed when the first microorganisms started competing based on chemical warfare (defensin and counter defensin production). When eukaryote cells first formed they lived in a hostile environment with heavy chemical warfare so they had to be able, and probably were able genetically, to survive. Once multi celled organisms folded i and developed a gut they enclosed the microorganisms and provided a wonderful habitat. Several microorganisms found a new food source and started attacking their host in new ways. So the host was forced to develop new defence mechanisms. In part this was done using already existing mechanisms. Later newer and more advanced mechanisms evolved. CR is a term we use to describe a set of the evolutionary old mechanisms that today still do a large part of the defence against infections.

Why is Colonization Resistance important?

Colonization Resistance is a major element in the defense against infections. It is far easier to eliminate a few microorganisms in the gut lumen than it is to eliminate billions that have entered the body.
Also if the potential pathogenic microorganisms produce toxins (poisons) that makes the host organism ill, the concentration of these toxins is likely to be far lower, if the number of microorganisms that produce them is low. Seen from another angle: if pathogenic microorganisms have entered the body, after some time the last line of defense - the adaptive defense system - kicks in, That can create an inflammatory response, t.e. fever, pain and other unwanted side effects. This can be prevented by early elimination of the potential pathogenic microorganisms.

How does the Colonization Resistance work?

The following overview provides the elements that act in concert, make it difficult for new microorganisms to colonize the gut. The summary of the approach is: prevent them from growing out to large quantities as fast as possible and therewith prevent them from attaching and entering and mark them as dangerous for the next defense layer.

  1. Mechanisms involved in the CR:
  2. Secretion of saliva - including all defensins and immunoglobulins it contains and swallowing (prevent settlement in the mouth and esophagus by rapid transport to the stomach)
  3. Rapid elmination of newly ingested microorganisms by gut peristalsis (and diarrhoea in severe trauma patients and other serious clinical conditions)
  4. Inter-microorganismal chemical warfare through production of defensins, short chain fatty acids and extracellular enzymes
  5. Inter-microorganismal competition for food, both in the gut lumen and in the submucosa
  6. Inter-microorganismal competition for space in the mucus layer and along the epithelial cells; here the indigenous (autochtonous or permanent) microflora plays an important role
  7. Secretion of mucus including nutrients, antibodies (IgA) and the host generated defensins it contains to rapidly shed all microorganisms in to the gut lumen and to restrict the food available to microganisms
  8. Epithelial cell desquamation - very high rate of epithelial cell replacement;
    production of epithelial cell occurs in the crypts and epithelial cells move from there to the tips of the villi. There they are dislodged there including any microorganisms that have attached themselves to them
  9. Host produced nonspecific blocking factors for bacterial adherence that make attachment to the epithelial cells more difficult
  10. Immunoglobulins that mark microorganisms as 'dangerous, to be disposed' and to hinder attachment to the epithelial cells

How does the normal defense against infections work (summary)?

The main components of the defense against infections

As can be read extensively elsewhere in this site, the defense against infections is built in four layers of defense:

  1. Microflora dynamics and inter microorganism chemical warfare
  2. The Innate defense system
  3. The Ideotype defense system
  4. The Adaptive defense system

The Colonization Resistance is largely due to the first defense layer of defense: microflora dynamics and inter microorganism chemical warfare and host activities such as defensin and IgA secretion into the mucous layer.

Is colonization resistance identical in everybody?

The microflora of different individuals (even if they belong to the same species) differs so that the CR may also differ between these individuals. The daily oral intake of bacteria with food and beverages (the changing or 'transient' part of the microflora) may occasionally and temporarily influence the CR and therewith, the colonization pattern
In the intestines the autochtonous microflora is formed beginning shortly after birth. As microorganism intake largely depends on the direct surroundings of the newborn, most importantly the mother, significant variation can be expected in this CR component.
Please note that thousands of micro organism species are involved and billions of microorganisms most of which are harmless to beneficial.

How does age influence the Colonization Resistance?

The microbial part of the CR in particular, evolves soon after birth. At birth, the CR consists of factors of host origin such as defensins, peristalsis etc. In man, in the first four months, a more or less complete microflora develops including an autochthonous part and there with the mcorobial part of the CR establishes. It takes however several years for a mature autochthonous microflora for a to get this status; it may take as long as 4 to 5 years. During senences the composition of the CR involved microflora simplifies so that the CR decreases.

NOOT VOOR DICK: EN HOE ZIT DAT BIJ HET OUDER WORDEN, VERANDERT DE CR DAN OOK?? IK BEDOEL OP HOGERE LEEFTIJD

How does our diet influence our Colonization Resitance?

The diet can decrease but also increase the CR. High carbonhydrate food for example will benefit some microorganisms more than others which may decrease the CR. Eating high fibre foods will have a different effect on the microflora. Ingesting probiotics, which are high in one or two non-harmfull microorganisms may enhance the CR.
In all cases the effect is temporary and will vanish shortly after the diet changes. This is why probiotics need to be continously ingested to keep having some effect.
There is no known way to use a diet to permanently alter the CR, unless it is done in the first few days of a newborn's life.

What happens if the Colonization Resistance is weakened?

There are several reasons why the Colonization Resistance can be weakened:

  1. Irradiation or chemo-therapy that seriously damages the gut epithelial cell layer
  2. Total Intestinal Decontamination - use of broad spectrum antibiotics that kill many benign microorganisms
  3. Severe reduction of host defensin production through for example severe prolonged stress
  4. Malnutrition

Damaged epithelial cell layer and mucosa

If the epithelial cell layer in the gut is damaged - like by chemotherapy or irradiation -, the Colonization Resistance is weakened. This has several effects:

  1. A reduced effluence of mucosa, reducing the rate microorganisms are eliminated by shedding the mucosa
  2. A reduced epithelial cell production and desquamation, reducing the rate microorganisms are eliminated by shedding the epithelial cell layer
  3. A reduced production of defensins by the Paneth cells
  4. Possibly, if the epithelial cell layer becomes damaged, an open contact between the gut lumen and the body internals, eliminating most of the Colonization Resistance

Reduction of the gut microflora

If the microflora in the gut is reduced, the Colonziation Resistance is weakened. This has two effects:

  1. A reduced competition for food and reduced chemical warfare so it is easier for potential pathogens to grow in to high numbers
  2. A reduced competition for space along the gut wall, so adherence to the gut wall is easier

Reduction of the defensin production

If the host decreases the defensin production, the Colonziation Resistance is changed as the hosts' influence on the microorganisms that live in the mucosa layer is weakened, possibly enabling other microorganisms to also take up residence.

Malnutrition

The effect of malnutrition ...

GRAAG AANVULLEN. Wat gebeurt er precies en waarom?

Consequences

Consequently the risk of rampant growth and penetration of potential pathogens is significantly increased, making penetration and infection much more likely.

Specific model

specific model

The specific model provides another angle at explaining Colonization Resitance. It provides a model of a small part of the gut and shows what the key components are and how they interrelate and interact.

GRAAG AANVULLEN.

How to strengthen the colonization resistance?

Several study centers investigate whether probiotics do enhance the CR. There is strong evidence that some probiotics indeed promote the activity of the CR.
Diet may also influence the CR, both in a positive but also in a negative way. Malnutrition obviously has a negative influence. Malnutrition can be both absolute (too low food intake) but also relative (diet lacking sufficient proteins, vitamins and minerals).
Hygienic conditions may also play a role, however, circumstances must rather extreme in well fed individuals before the normal CR fails and let a sufficient number of pathogens surviving in the gut contents to flourish and colonize the mucosal lining for a while; long enough to translocate and cause damage in tissues of the host.

WELKE ELEMENTEN IN HET DIEET VERSTERKEN DE CR??

Hygiene heeft geen invloed op de CR, maar wel op de influx van potentieel pathogenen? Hoort hier eigenlijk niet?

Leiden van een stress arm leven is ook goed voor de CR??

Literature