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Defense against infections

Last update 1-11-2008

Detailed description of the innate defense model

The specific model shows the context of colonization resistance. This page uses the specific model (shown below) to explain how colonization resistance works. First the model is explained. How colonization resistance fits in is described below that.

Specific model of the defense against infections

Detailed description of the specific model

This edition of the specific model is slightly enhanced in that it shows the inter-microorganism chemical warfare in an enlarged detail view.

The specific model shows a detailed view of a tiny part of the gut wall in the small intestines with the immediate surroundings. This area of the gut was chosen as an example because the existence of defensin producing Paneth cells that only occur here. Other parts of the gut have a similar defense mechanism although without the Paneth cells.
Shown are three gut villi with the mucus layer and the microorganisms in the gut lumen on one side and the epithelial cells lining the gut wall, the basal membrane and some white blood cells (macrophages, B-lymphocytes and T-lymphocytes) in the submucosa at the host side. At the deepest part of the space between the villi - the crypts - paneth cells are shown to produce massive amounts of defensins, which most epithelial cells also produce although to a lesser degree.
The B-lymphocytes are shown to produce immunoglobulins (IgA and IgM, kept generic here on purpose) that are expelled into the submucosa and beyond into the gut lumen. If they attach to a microorganism before being inactivated, they will coat it for and enhanced cleanup if the microorganism ever penetrates beyond the basal membrane.

The most striking part of the specific model is that the mucus (slime layer) covering the gut wall (shown as epithelial cells) is home to predominantly indigenous microorganisms only. Our model is a simplification of the reality. Nevertheless it is shown here to make a point. The point we we want to maken is that this way the composition of the indigenous micro flora is maintained rather stable in the mucus layer. This stay in direct proximitty to host cells is permitted by the host as this microflora:

  1. is resistant to the defensins produced by the epithelial cells
  2. finds enough nutrients for growth and reproduction

In the small intestines, the Paneth cells produce a defensin(s) that may differ from the product of the epithelial cells. This could be responsible for the fact that the crypt lumen is normally free of microbes. The result is a mucus layer that is full with the resistant indigenous microflora and it is therefore more difficult to colonize by 'foreign' microorganisms, such as potential pathogens and intestinal pathogens.These newly arriving microbes get starved as available nutrients are used by indigenous microflora and the are either killed by defensins of host origin or are produced by the indigenous bacteria (see hereafter).

Chemical warfare

Since very early in the evolution of life (micro)organisms have used chemicals to enhance their position:

  1. Chemicals to attack other microorganisms - assorted poisons on microorganism scale
  2. Chemicals to counter these attacs by destroying or neutralizing these poisons - by inacivating them
  3. Chemicals to mark microorganisms for destruction, the so-called binding molecules (immunoglobulins - came much later in evolution)

Defensins typically have a broad spectrum activity. The term 'defensins' is used by us in a generic way here to hide complexity that would confuse the issue more than clarify it.
There are three sources of defensins:

  1. Defensins of host origin, produced by epithelial cells and Paneth cells
  2. Defensins of microflora origin, including indigenous microflora origin
  3. Artificially produced defensins for treatment (antibiotics)

All defensins, as well as immunoglobulins, are inactivated within seconds of being released thereby limiting their effect to very short range from their source.

The indiginous microflora is persistent (rather than constant in composition) in the gut for a very long time, can make use of host-provided nutrients and is resistant or can inactivate the host originated defensins.
The indiginous microflora is likely to continue a steady-state chemical warfare among eachother as well as with transient microorganisms. This implies that the indiginous microorganisms are part of the defense against infections, by competition for nutrients as well as playing their part in the chemical war, thereby making life more difficult for potential pathogenic microorganisms.

All epithelial cells produce defensins and probably many if not most body cells - in direct or indirect contact with the outside world - produce them; some may need a trigger to start producing them. Not a lot is known about this mechanism.
There are indications that defensin production is reduced if the organism health / resistance is reduced, such as during serious illness as well as after accidents or major surgery.

Inactivation of defensins and antibiotics

There are two ways defensins (and antibiotics) are inactivated:

  1. Aspecific: inactivation by binding to " Large Molecular Substances" (LMS) - inactivation within seconds, reversible, dependent on concentration of the LMS
  2. Specific: inactivation by enzymes - irreversible, slower than through inactivation by LMS; the enzymes are produced by microorganisms

It is unknown where the Large Molecular Substances are produced. It is likely that they are produced in part by the microorganisms themselves to counter attack by defensins. It is also likely that the eukaryote body cells (epithelial cells for example) also produce LMS. It is known that not every individual has LMS in the gut content. This observation may exclude production by microorganisms or may point at yet to be discovered anti-LMS components that are varying in effectiveness per individual.

Being diffused in the mucus of the mucus layer makes defensins less susceptible for inactivation. As the source of the defensins - epithelial cells and Paneth cells if available - are very close by, the defensin concentration is extremely high as compared to the concentration in the gut lumen.

Antibiotics applied orally for treatment) reach the intestinal tract and are for the part that is not absorbed readily inactivated. The small fraction that is not absorbed and not inactivated will:

  1. kill the sensitive part of the microflora (and thereby reduce the colonization resistance
  2. provide the opportunity to resistant microorganisms to reach high numbers in the gut - as most other microorganisms are eliminated, colonize and - if opportunistic - translocate

As an example quinolones (norfloxacin, ciprofloxacin, etc.) are excreted with the gut mucus and are active while inside the mucus layer. As soon as they leave the mucus layer to reach the intestinal contents, they are fully inactivated by attachment to Large Molecular Substances.
As a consequence in man with normal peristalsis, after 4-5 days of taking these antibiotics all non-resistant gram-negative microorganisms are eliminated in the gut (selective decontamination).

Another example is Polymixin. This antibiotic is not absorbed and is rapidly inactivated by LMS. So very high doses of Polymixin are needed to make it effective for use in selective decontamination.

How colonization resistance works

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

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

Most of the elements of 'colonization resistance' are present in the specific model, so a more detailed analysis of how this idea works can be presented. The key elements of colonization resistance are:

  1. Secretion of saliva - including all defensins and immunoglobulins it contains and swallowing - not shown in the model
  2. Rapid elmination of newly ingested microorganisms by gut peristalsis (and diarrhoea in severe trauma patients and other serious bad clinical conditions) - not shown in the model
  3. Inter-microorganism chemical warfare
  4. Inter-microorganism competition for food, both in the gut lumen and in the submucosa
  5. Inter-microorganism competition for space in the mucus layer; here the indigenous (permanent) microflora play an important role
  6. Secretion of mucus and the host generated defensins it contains
  7. Epithelial cell desquamation - very high rate of epithelial replacement; production of epithelial cell occurs in the crypts and epithelial cells move from there to the tips of the villi. There they are disloged there including any microorganisms that have attached themselves to them
  8. Host produced nonspecific blocking factors for bacterial adherence
  9. Immunoglobulins that mark microorganisms as 'dangerous - to be disposed'

In order to cause an infection microorganisms need to colonize the gut, attach to and penetrate the gut wall and bypass or overwhelm the defense mechanisms inside the body.
The question remains: How microorganisms overcome al these defense mechanisms that make up the colonization resistance, colonize the gut and reach the basal membrane?

In part the ability of potential pathogens to survive, colonize and ultimately cause an infection has to do with their own abilities:

Below a scenario is worked out based on a cutout of the specific model that shows a small part of one villi. In order to show multiple aspects of colonization resistance, a scenario is shown where a large number of potential pathogens is ingested.

Colonization resistance in action
Legend to the specific model
The normal situation in the gut Spoiled food with a lot of potential pathogens is ingested The potential pathogens dominate the gut limen and penetrate the submucosa
In the normal situation a few potential pathogens are easily kept in low numbers and in the gut lumen by the first 6 factors that make up the colonization resistance. If spoiled food is ingested, containing a large number of potential ' pathogens, they will play a majority role in the gut lumen. This allows them to overwhelm the indiginous microflora in the submucosa and attach to the epithelial cells
Some microorganisms manage to penetrate between or through the epithelial cells The normal situation in the gut
Some microorganisms manage to penetrate between or through the epithelial cells Some microorganisms manage to penetrate between or through the epithelial cells and penetrate beyond the basal membrane. Some of these are caught by white blood cells

The scenario shown - spoiled food with large numbers of potential pathogen microorganisms - is one situation where the colonization resistance part of the defence against infections can fail.
Others are: