According to a new study in Nature by Meisel and Hinterleitner et al, signals from the gut microbiota may help induce a pre-leukemic state in individuals with genetic predisposition. Mutations, or deficiency in the gene tet methylcytosine dioxygenase 2 (TET2), occur with advancing age and are often present in patients with leukemia. However, only a proportion of individuals with this mutation, or mice that lack TET2, progress to a pre-leukemic state, suggesting that additional environmental factors are needed to drive disease. Using mice that lack the TET2 gene, researchers at the University of Chicago show that increased small intestinal permeability was present in mice that developed pre-leukemic changes. This “leaky gut” allowed the translocation of microbes, normally residing happily in the lumen of the small intestine, to tissues beyond the gut. Increased IL-6, a molecule that promotes inflammation and that is released following systemic bacterial dissemination, was critical for the development of the pre-leukemic state in TET2 deficient mice. However, antibiotic treatment aborted the pre-leukemic changes. “Interestingly, once the TET2 deficient mice were derived and bred in germ-free conditions at the Axenic Gnotobiotic Unit in McMaster University, no changes in IL-6 were observed, and the pre-leukemic state failed to develop”, said Dr. Heather Galipeau, research associate in Dr. Verdu’s lab. “Maintaining intestinal barrier function could be critical for preventing a pre-leukemic state in genetically susceptible people, in order to restrict intestinal microbes to the gut. The study opens the way to potential new strategies aimed at strengthening the intestinal barrier or preventing systemic infections to reduce the progression to leukemia in individuals that have a genetic predisposition”, said Dr. Verdu, co-author of the study and Canada Research Chair in Diet, Microbiota and Intestinal Inflammation.