Mouse gut mic

Mutation in TET methylcytosine dioxygenase 2 (TET2) induces a pre-malignant clonal hematopoiesis of indeterminate potential (CHIP) that increases the risk of developing hematological malignancy. It has previously been shown that hematopoietic Tet2-deficiency in mice triggers a pro-inflammatory state with increased intestinal permeability, gut bacterial translocation, and accelerated clonal expansion. Gut microbes themselves can exert an influence on myeloid leukemia progression through synthesis of compounds including short-chain fatty acids (SCFAs), which promote intestinal barrier integrity. Dietary levels of (1C) metabolites and cofactors have been found to alter gut microbial composition, affecting SCFA production and intestinal permeability, in disease-free adults. Given the connection between diet, SCFAs and gut permeability, we sought to determine the impact of dietary 1C metabolites on gut microbial composition and function in CHIP progression. Here we show that increased supplementation with micronutrients of 1C metabolism in murine models of wild-type and TET2-deficient hematopoiesis promotes gut dysbiosis and a reduction in SCFA-producing bacteria. High B12 supplementation specifically exacerbates Tet2-deficient myelopoiesis and is associated with elevated levels of circulating inflammatory cytokines and an increased pro-inflammatory response to bacterial stimuli. These data suggest that high levels of B12 may cooperate with CHIP progression via its influence on the microbiome.