We recently reported that aged humans, primates, and mice accumulate a unique type of activated B cells, termed 4BL cells (Lee-Chang et al., Blood, 2014). Contrary to widely believed assumption that innate B cells do not change upon aging, we showed that these cells are derived from innate B1a cells (Lee-Chang et al., J. Immunol., 2016). Mechanistically, aging activates myeloid cells, such as upregulated 4-1BB and CD40L, to convert B1a cells into 4BL cells expressing 4-1BBL, HLA-I, IFNR1, CD86 and membrane TNF. Functionally, this enables 4BL cells to induce expression of granzyme B in CD8+T cells. Here, we explored the mechanism/cause of activation of myeloid cells and their cell subset which convert 4BL cells; and the clinical consequence of the accumulation of 4BL cells in aging. We report that the main cause of aging-associated activation of myeloid cells is gut microbiome. We found that aging changes their composition, such as accumulates potentially pro-inflammatory microbes while decreases beneficial commensal bacteria. Aging gut was markedly decreased in Akkermansia muciniphila, an anaerobic bacterium which protects epithelial integrity of the gut and supports growth of butyrate-producing beneficial commensals. Mechanistically, the loss of A. muciniphila increased leakage of bacterial products such as endotoxin into the circulation and decreased levels of butyrate, an inhibitor of TLR signaling. Thus, the leakage of endotoxin activates CCR2+ monocytes (MO) when butyrate is decreased. Then, activated MO convert innate B1a cells into 4BL cells in the omentum. The clinical consequence of this pathway is that 4BL cells increase hyperglycemia, insulin resistance (IR) in aged hosts via 4-1BBL axis. We show also that this pathway and IR are reversible, as supplementation with A. muciniphila alone or antibiotic enrofloxacin, which increases its abundance, restores normal insulin response in aged mice and macaques. Additionally, treatment with butyrate or antibodies that eliminate CCR2+ MO or 4BL cells have the same effect on IR. These results underscore the previously unknown pathological function of B1a cells, suggesting that the microbiome-MO-4BL cell axis can be targeted to reverse IR and possibly other age-associated pathologies. The results of this study we recently published in high-impact scientific journal (Bodogai et al., Science Transl. Med., 2018). Overall, the project is progressing well as planned. It continues generating novel insights with significant scientific and clinical implications.
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