Genus unclassified_Muribaculaceae and microbiota-derived butyrate and indole-3-propionic acid are involved in benzene-induced hematopoietic injury in mice

Benzene is a group I carcinogen determined by IARC. The prevalence of benzene in occupational and general environments increases the risk of acute myeloid leukemia (AML) among workers and childhood leukemia. However, the mechanism of hematotoxicity induced by benzene remains unclear. Recently, the gut microbiota has been regarded as a pivotal part of normal and malignant hematopoiesis. Therefore, in this study, we explored the function of gut microbiota in hematopoietic injury induced by benzene by 16S rRNA sequencing. We found that benzene exposure caused bone marrow damage, hematopoietic stem and progenitor cells (HSPCs) dysfunction, and peripheral blood cell reduction. Moreover, intestinal barrier damage and gut microbiota dysbiosis were also observed in benzene-exposed mice. Interestingly, two gut flora, Lachnospiraceae_NK4A136_group and unclassified_Muribaculaceae, were significantly up-regulated and associated with hematopoietic indicators, suggesting that gut-host crosstalk might mediate benzene hematotoxicity. Microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites, are the primary mediators of the gut-host crosstalk. Therefore, we conducted absolute quantitative metabolomics to investigate the impact of benzene exposure on these metabolites in mice. The results showed that the concentration of SCFA butyrate, tryptophan metabolites kynurenine, and Indole-3-propionic acid (IPA) were significantly altered after benzene exposure. However, no difference was found in bile acids. Significant correlations were found between altered metabolites and hematopoietic indicators. We then investigated the flora that derived these metabolites. Lachnospiraceae_NK4A136_group and unclassified_Muribaculaceae were enriched in the butyrate metabolism and tryptophan metabolism pathways. Correlation analysis further suggested that unclassified_Muribaculaceae was positively associated with butyrate (r = 0.588, P < 0.05) and IPA (r = 0.59, P < 0.05). The above results demonstrated that unclassified_Muribaculaceae and microbiota-derived butyrate and IPA were involved in hematopoietic toxicity caused by benzene. This study provides insight into gut microbiota-derived metabolites-host crosstalk in benzene hematopoietic toxicity.