Regulation of coagulation by the bacteria of the gut microbiota

• Applicant: Professor Dr. Christoph Ralf Reinhardt
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 237692519

Little is known on the impact of the intestinal microbiota on the host s coagulation system. Besides hemostasis this fibrin forming enzyme system serves to efficiently prevent the invasion of microorganisms and to combat infections. The human fetus is born into an environment that is dominated by microbes it is colonized by feeding and the commensal intestinal microbiota is formed. Infections with gut bacteria, neonatal sepsis and disseminated intravascular coagulation still represent a major cause of infant mortality. The components of bacterial cell membranes (e.g. lipopolysaccharide) are well known activators of the coagulation system. Microbial-induced procoagulant mechanisms are not only involved in sepsis, but they also play a major role in the pathogenesis of Crohn s disease and ulcerative colitis. In these disease states a reduced intestinal microbial diversity was observed and the pathogenesis is often accompanied by gastrointestinal infarction and an up to four-fold increased thrombotic risk. Our preliminary work suggests that the intestinal microbiota can cause severe functional effects in the regulation of coagulation activation. The impact of the gut microbiota on the ectopic synthesis of coagulation factors in the intestinal epithelium and its functional importance for hemostasis remains unexplored. Interestingly, we could show in preliminary work with germfree and conventionally-raised mice that colonization with a gut microbiota results in systemic alterations in the ex-vivo whole blood clotting time. In the outlined project we will use germfree mice that were reared in sterile plastic isolators. We have recently established a germfree mouse colony at the University of Mainz. These animals have never encountered microorganisms and therefore they are an ideal model system to investigate host-microbial interactions. We will compare the coagulation system of germfree mice with the coagulation system of conventionally-raised mice and with ex-germfree mice that were colonized with a gut microbiota. Furhtermore, we will compare coagulation parameters of germfree mice with ex-germfree mice that were colonized with single bacterial species (with Staphylococcus aureus, Escherichia coli and Bacteroides thetaioatomicron). Thus we will reveal differences in coagulation factor expression that are caused by gut microbes and we can identify the functional impact of the gut microbiota on the host s coagulation system. Colonization experiments with germfree mice will contribute to a better insight of the coagulation activation that is observed in inflammatory bowel disease. Our approach will contribute to the development of new intervention strategies for inflammatory bowel disease and mesenterial infarction.

• DFG Programme: Research Grants