If you were to compare inflammatory bowel disease with a jigsaw puzzle, it would be anything but complete today. After all, researchers were now able to use another suitable part. Nevertheless, the completed puzzle fragment does not yet offer a definitive overall picture.
"I don't think my life is worth living anymore, I shut myself off more and more from everyone. I used to be a total nonsense and now I only talk about what is necessary," writes a person affected in the forum for German Crohn's disease/ulcerative colitis Union. An illness makes your life hell, from which around 300,000 people in Germany suffer. However, she says nothing to the general public.
These patients are plagued by chronic inflammatory bowel disease (IBD). The two most common forms are Crohn's disease, which usually affects the small intestine, and ulcerative colitis, which causes inflammation of the large intestine. IBD occurs in episodes, during which patients experience severe abdominal pain, often lose a lot of weight and are plagued by diarrhea, which in ulcerative colitis is often bloody. Most of those affected contract the disease between the ages of 20 and 40 and once you have it, you will never get rid of Crohn's disease and co for the rest of your life.
What is relatively certain is that the patient's immune system is somehow going haywire. Bacteria from the stool probably penetrate the intestinal wall and the body does not know how to defend itself other than with an inflammatory reaction. In the worst case, the intestinal wall even becomes full of holes.
The causes are still largely unknown, but "there is definitely a genetic component," says one of the German IBD experts, Susanna Nikolaus from the Schleswig Holstein University Hospital in Kiel."But the environment may also play a major role. With increasing industrialization, such diseases increased," she adds.
A complicated scenario - at the genetic level alone, defects in a wide variety of genes are certainly involved, many of which are still unknown. So far, most is known about the CARD15(NOD2) gene. It contains the building instructions for the NOD2 protein, which stimulates other proteins, the antimicrobial defensins. These destroy the bacteria in the intestinal wall. However, about one fifth of Crohn's disease patients carry a mutation in the NOD2 gene, which means that their intestinal wall is no longer properly protected.
But what about the remaining four-fifths of those infected? In the search for other genes, researchers from different universities have now joined forces and combed the entire human genome for abnormalities. They compared 300,000 variations in the genetic code, so-called SNPs (single nucleotide polymorphisms), from around 540 sick people and just as many he althy people. Their goal was to find variants that are more common in patients and are therefore likely to be related to the predisposition to inflammatory diseases.
They expected, among other things, defects in genes associated with the so-called interleukins, since they play an important role in the immune system. Interleukins (IL) are messenger substances through which the different cell types of the body's defenses communicate with each other. If a cell has the right receptor for the respective interleukin, the substance can bind and stimulate it to take action. In fact, the researchers identified "several genetic signals in the gene for the interleukin-23 receptor that are strongly associated with Crohn's disease," says Richard Duerr of the University of Pittsburgh.
"We know that the IL-23 receptor is important in activating inflammation, including in organs of the digestive tract," continues Judy Cho of Yale University in New Haven. IL-23 boosts an important cell type in the body's defenses, the T-helper cells. In various autoimmune diseases, these cells attack the body's own tissue, which manifests itself in inflammation, among other things. So it could well be that IL-23 incites the T helper cells to do the same in Crohn's disease.
One of their discoveries, however, surprised the researchers quite a bit: They not only found IL-23 receptor variants that appeared specifically in the sick, but also one in the he althy that they seemed to protect against IBD in some way. Can this variant bind the messenger substance more poorly, which means that there is no inflammation?
Interfering with IL and blocking IL-23 seems like a good idea anyway, according to initial clinical testing by Peter Mannon of the National Institute of Allergy and Infectious Diseases in Bethesda and colleagues in 2004. The scientists showed that patients' symptoms improved when they were given a monoclonal antibody against a subunit of IL-23. Cho and colleagues hope that this therapy can now be improved thanks to their new findings. But caution is advised, because there is also a study in which the disease got worse in mice without IL-23. But one of the therapies that are already in common use today has a similar effect. The drug infliximab blocks another important inflammatory messenger called TNF-alpha.
Lately, however, more and more alternative approaches have been developed. One such is worm therapy. It sounds pretty gross, but it also seems to work. Nikolaus explains: "The patients swallow the eggs of the pig whipworm (Trichuris suis) and then the worms hatch in the small intestine. Since humans are false hosts, they cannot reproduce. That means they live their lives in the intestines and then die off normally." These little animals stimulate the immune system, which then releases various messenger substances.
The successes of worm therapy and the knowledge about NOD2 suggest that the immune system in those affected is too lax, while those about IL-23 and TNF-alpha mean that the immune system is overreacting. A paradox that can be explained in part by the complex way in which our body's defenses work. It all depends on which component of the immune system is going haywire - one that supports it or one that inhibits it. The development of IBD is therefore probably extremely heterogeneous. Nikolaus sums it up like this: "In all probability there is not one, but several truths."