Intestinal flora plays a key role in the development of Crohn’s disease or ulcerative colitis. Dr. Julia-Stefanie Frick, a microbiologist from Tübingen, is investigating why some of these usually harmless bacteria suddenly lead to severe inflammation. Her research, which has recently been awarded a research prize, might now pave the way to preventive therapy.
The intestines of embryos in the placenta have not yet been colonised with bacteria. The first bacteria enter the digestive tract at birth. In adults, several billion bacteria colonise the intestine. “We live with intestinal microorganisms in a wonderful symbiosis,” said Dr. Julia-Stefanie Frick (MD) from the Institute of Medical Microbiology and Hygiene at the University Hospital in Tübingen explaining that “these microorganisms help us digest food, produce vitamins and degrade a large number of toxins.” The human intestinal immune system also tolerates the busy helpers well.However, in sufferers of chronic inflammatory intestinal diseases such as Crohn’s disease or ulcerative colitis, the peaceful cooperation is severely impaired. “We know that certain bacteria of the human intestinal flora, which are normally harmless, lead to inflammation of the intestinal mucosa in people with a specific genetic make-up,” said Frick. Such people suffer repeated episodes of painful diarrhoea that can also be associated with life-threatening complications.
On the other hand, intestinal flora harbours a large number of bacteria which have the capacity to prolong the pain-free intervals between two attacks. Some of these microorganisms, which are referred to as probiotic bacteria, are already known and have been approved as drugs for human treatment. "We are interested in how the "good" and "bad" bacteria differ in their composition and mode of action," said Frick describing the research being carried out by her group of researchers. Frick's group is concentrating mainly on immunological processes occurring in the intestinal mucosa.
The scientist from Tübingen is using an established animal model for her groundbreaking research, i.e. genetically modified mice in which interleukin-2 (IL-2), which is a cytokine that is important for T-cell differentiation, has been inactivated. These mice will develop colitis if they come into contact with bacteria. "If bred in specific, pathogen-free isolators, these IL-2 deficient mice will remain healthy," said Frick. This observation clearly highlights the central role of microorganisms in the development of chronic inflammatory intestinal diseases.
These sterile, IL-2-deficient mice are well suited to the specific investigation of the effect of individual bacterial strains. “In the animals’ intestines, the pathogens, which are taken up with drinking water, encounter the dendritic cells, which are part of the human innate immune defence system."
The dendritic cells are located in the upper layer of the intestinal mucosa. They have different receptors on their surface, including the so-called Toll-like and NOD receptors which recognise pathogen-associated molecular patterns. They trigger mechanisms that lead to the secretion of cytokines. Different combinations of cytokines are secreted, depending on whether the receptors are activated by bacteria that trigger an inflammatory reaction or by bacteria that suppress inflammatory reactions.
However, the membrane-bound endotoxins of gram-negative bacteria have considerable differences. If the endotoxin, which acts as antigen, originates from pro-inflammatory bacteria, then it results in an up to 10,000 times stronger stimulation of the receptor. "It is assumed that the combination of several factors leads to the development of chronic inflammatory diseases," said Frick. "These factors might be genetic predisposition, the bacteria of the intestinal flora and the dysregulation of the immune system which can lead to excessive reactions."
The researchers in Frick’s group have recently come up with some very interesting issues: “We have been able to show that dendritic cells, which were stimulated with a very low quantity of endotoxin, only produce IL-6 and no other cytokine.” This substance was previously only attributed pro-inflammatory properties. However, in the absence of other immunological modulators such as TNF-alpha and IL-12, quite the contrary is the case. “IL-6 alone makes dendritic cells insensitive. When stimulated again after 24 hours, the dendritic cells emit no signal, no matter which receptor is activated and how high the endotoxin concentration is,” said Frick. This suggests that the dendritic cells have become tolerant to the bacterial antigens.Frick’s scientific findings, for which she was awarded a research prize at the recent annual meeting of the German Society for Hygiene and Microbiology (DGHM), are now opening up completely new perspectives. “Maybe we will succeed in targeting this mechanism in people who are genetically predisposed to develop a chronic inflammatory intestinal disease and maybe we will be able to induce a preventive protection against the disease,” said Frick. Frick is optimistic, but warns against being too hopeful. “At the moment we are exclusively focusing on basic research – and we know from experience that it is a long road from the mouse model to the application of the findings in people.”
Further information:University Hospital TübingenInstitute of Medical Microbiology and HygieneDr. med. Julia-Stefanie FrickElfriede-Aulhorn-Str. 672076 TübingenTel.: +49 (0)7071 29-81528Fax: +49 (7)071 29-54 40E-mail: julia-stefanie.frick(at)med.uni-tuebingen.de