Mechanistic insights into postbiotic-induced myelopoiesis and immune recovery after chemotherapy.

Many attempts have been made to identify safer immunomodulatory agents that enhance the immune response and reduce the frequency and severity of infections in at-risk populations. Our previous studies have shown that Lacticaseibacillus rhamnosus CRL1505 and its postbiotics, peptidoglycan (PG1505) and cell wall (CW1505), can improve bone marrow myelopoiesis and protect mice undergoing chemotherapy against respiratory pathogens. However, the underlying mechanisms remain poorly understood. In this study, we explored both direct and indirect mechanisms using ex vivo and in vitro approaches. Oral administration of the CRL1505 strain or its cell wall significantly increased bone marrow clonogenic activity and serum G-CSF levels, as well as the percentages of myeloid progenitors (MPP and GMP) and mature cells (neutrophils and monocytes). In vitro, conditioned media from macrophages and fibroblasts stimulated with postbiotics enhanced hematopoietic activity, whereas splenocyte-conditioned media exhibited inhibitory effects on clonogenicity. Direct stimulation of bone marrow cells with the CRL1505 strain increased LSK, MPP, and GMP populations and upregulated TLR2 expression, although clonogenic activity was reduced. Interestingly, CW1505 showed a strong stimulatory effect while PG1505 elicited immune effects more closely resembling those induced by Lacticaseibacillus rhamnosus CRL1505. These findings provide new insight into the cellular and molecular mechanisms underlying the myelopoiesis-enhancing effects of novel, safe postbiotic products. They also support the therapeutic potential of these compounds for promoting immune recovery in immunocompromised patients, such as those undergoing chemotherapy. SIGNIFICANCE STATEMENT: This study demonstrates that Lacticaseibacillus rhamnosus CRL1505 and its postbiotics enhance bone marrow myelopoiesis and G-CSF production in chemotherapy-treated mice. By revealing both direct and macrophage-mediated mechanisms that regulate hematopoiesis, our findings provide new insights into how postbiotics promote immune reconstitution. The strong myelopoiesis-stimulating activity of CW1505 further supports the potential of safe, postbiotic-based immunomodulators to improve immune recovery and reduce the infection risk during chemotherapy.