Early life microbiota skew long-term gene expression and epigenome of bone marrow hematopoietic precursors

Asthma is the most prevalent chronic childhood disease in developed nations, yet its etiology remains incompletely understood. Emerging evidence suggest a crucial role for the gut microbiota in shaping immune development and future susceptibility to atopic disease. We previously demonstrated that short-chain fatty acids (SCFAs) as fermentation products of normal gut bacteria, regulate an innate type 2 immune axis that serves to dampen susceptibility to allergic lung inflammation. Here, we show that neonatal depletion of SCFA-producing gut bacteria via antibiotics robustly alters Lin⁻Sca-1⁺c-Kit⁺ (LSK) hematopoietic stem and progenitor cell (HSPC) output, resulting in a transplantable atopic immune phenotype: bone marrow (BM) transplants from these mice generates recipients with increased lung B cell IgE expression, elevated serum levels of IgE, dowstream increased IgE bound to basophils and exacerbated allergic lung inflammation following papain challenge. Notably, neonatal depletion of SCFA bacteria also enhanced susceptibility to chemotherapy (5-fluorocuracil) -induced myelosuppression, marked by impaired neutrophil recovery and increased DNA damage in long-term HSCs. Importantly, these antibiotic effects were reversed by supplementation of antibiotic-treated mice with exogenous SCFA. Single-cell RNA sequencing (scRNA-seq) of LSK HSPCs revealed distinct shifts in gene expression following vancomycin treatment, including increased proliferation-associated signatures with stress-adaptive features. Epigenetic profiling further revealed differential histone acetylation in HSPCs, consistent with an SCFA-mediated epigenetic regulatory mechanism. Collectively, these findings establish an epigenetic link between gut microbiota composition, hematopoiesis, and long-term immune function, providing a mechanistic basis for microbiota-driven atopic disease susceptibility and hematopoietic dysfunction.