A team of Swedish and American researchers has discovered the complex defense system against bacteria found in the human gut. It is based on two layers of mucus – the first completely separates the intestine from the bacteria, and the second, on the first layer, contains bacteria that are essential for health (eg Lactobacillus) and produce vitamins.
From Paris for MedOnet Marek Mejssner
An international research team led by prof. Gunnar Hansson from the Göteborgs Universitet presented the Underestimated Role of Eptithelium In Inflammation in Paris in mid-April, organized by the Pasteur Institute and the GREMI research panel, significant discoveries about human immunity, resulting from several years of research on the mechanism of deposition and elimination of bacteria in the human intestines and animals.
Hansson’s team showed that the gut is part of the body’s defense system against infection. These are two layers of mucus with a complex structure, impermeable to bacteria and hindering their metabolism. Disturbances in the production of this mucus can mean serious diseases – from inflammation to cancer.
Mucus shield
The immune system in the gut is very complex and even now difficult to study. The underlying cause is precisely its complexity. The availability of water, mineral salts and food causes the intestine to be colonized by 1013-1014 bacteria – far more than the total number of cells in the human body. They also weigh a total of about 2 kilograms. Some of these bacteria have been known for a long time for the production of vitamins, the breakdown of complex sugars, but so far there has been no research into their colonization and how they interact with the human immune system. It was not known how beneficial bacteria are tolerated, how the microbial environment in the human intestine, which is constantly in dynamic equilibrium, can change and what effects such a change can cause.
Such studies have proved to be very difficult – the mucus produced in the intestine, which consists mainly of water, is transparent, also for analytical devices. The breakthrough was the work of Swedish scientists who decided to color the mucus with marked carbon. In the course of experiments carried out on a rat model, which is as close as possible to the human body, it turned out that there are two layers of mucus with different properties in the intestine. The first, located close to the intestinal epithelial cells, is hard, about 50 micrometers thick, virtually impermeable and free of harmful substances. It’s a shield – it’s a complete barrier to bacteria. The second, located directly on top of the first, has a variable thickness – up to 100 micrometers – is loose and is where bacteria live.
The team of prof. Hansson found that this mucus, produced in the large and small intestine, is produced by MUC2 mucins – proteins of high molecular weight, produced by the epithelium of most animals, including humans. They have the ability to produce gels. MUC2 mucins form three-dimensional networks of the so-called domains – bizarre-shaped structures containing up to 5200 amino acids, resembling, according to Hansson, a bottle brush. Such a network is the backbone of both mucus layers. The inner layer of mucus is produced in the so-called goblet cells in the intestine, and the outer, loose mucus, through mucin granules – also in the intestinal epithelium. The density of the MUC2 structure in the upper mucus layer is thinner and in the lower mucus it is denser. The greater density of the lower layer makes the pores in it so small that no bacteria can enter them. This gives the layer stability and at the same time protects the intestinal epithelium from contact with bacteria.
If the shield disappears….
But what happens when these layers become unstable or even disappear altogether? Working with Hansson, Dr. Anna Velcich from Yeshiva University in New York obtained by mutation selection transgenic mice devoid of goblet cells that produce the inner layer of mucus. The practical absence of MUC2 meant that in mice these bacteria were observed in the diverticula of the intestine, on its surface, and even deep in the intestinal cells. Bacteria in intestinal cells have never been observed in wild animals. Mice lacking goblet cells became seriously ill. They were not developing properly, and had frequent loose stools and bloody diarrhea, proving that the bacteria were damaging the intestines. Colon cancer very often developed in older mice of this type. Interestingly, almost all of the symptoms in these rodents were the same as in humans with ulcerative colitis.
The lower density of the upper mucus layer allowed the bacteria of the intestinal flora to settle there. Some of them used mucin molecules as a source of energy. However, not all bacteria could settle in the intestine – according to the researchers, there is also a MUC2-based selection mechanism in the upper mucus layer, which prevents the accumulation of bacteria that do not match the human intestinal flora or are clearly harmful.
However, there is a large group of bacteria and protozoa that can cope with the intestinal immune system. Some bacteria of the genus Bacteriodes most abundant in the intestines, e.g. Bacteriodes fragilis, contain the so-called BFT toxin digesting the structure of MUC2 proteins. An enzyme similar in action – a cysteine prosthesis – contains a dangerous protozoan – amoebiasis. This protease breaks down the mucin chains. This allows bacteria and protozoa to penetrate through the inner protective layer into the intestinal cells and cause serious infection and inflammation.
According to prof. Hansson, both layers of mucus are the most important element of the system that ensures a balance between the huge habitat of bacteria and the delicate cells of the intestine. Therefore, they are part of the immune system and their proper functioning is essential for human health.
According to prof. Hansson, despite the very important discoveries already made, research into the mechanism of immunity in the gut is only in its early stages. The exact genes responsible for mucin coding are not known. It is not known whether the thickness of the lower mucus layer is species dependent – in rats the layer is thicker than in mice. It is also not known how exactly the mechanism of selecting bacteria in the upper mucus layer works. There is currently no solution to inactivate the enzymes and bacterial toxins that digest the mucin structure. These problems by the team of prof. Hansson intends to resolve during further research.