“Acquisition of somatic mutations coupled with multiple environmental factors contribute to the expansion of the CHIP clones. Higher levels of CHIP are observed in autoimmune, inflammatory, and in some instances of chronic intestinal inflammatory disorders. However, the precise underlying cellular and molecular mechanism remains elusive. Disruption of gut homeostasis, a hallmark of aging, is marked by increased intestinal permeability and microbial dysbiosis; and recent work has shown expansion of mutant HSCs in aged human and mice. Therefore, we investigated the effects of aging-associated intestinal-barrier dysfunction on the expansion of mutant HSCs,” explains Daniel T. Starczynowski, the corresponding author of this study.
Agarwal et al. first analyzed the competitive advantage of DNMT3A-deficient HSCs in mice exposed to radiation levels that damaged the intestinal epithelial barrier. They found that high-dose radiation, which injures the intestinal epithelium, promoted the expansion of DNMT3A-deficient HSCs. To mimic human inflammatory bowel disorders, mice were treated with dextran sulfate sodium (DSS), which further induced significant expansion of DNMT3A-deficient HSCs. Aged mice also showed increased intestinal permeability and bacterial disequilibrium that correlated with the expansion of the mutant HSCs, which was not observed in young mice. This expansion was reduced when broad-spectrum antibiotics were administered, which suggests that microbial dysbiosis contributes to the process. Fecal microbiota transplantation experiments confirmed that DSS-induced or age-related microbial dysbiosis drives the expansion of DNMT3A-deficient HSCs, highlighting the role of the microbiome on expansion of mutant HSCs.
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