<i>Bacillus velezensis</i> -derived muropeptide promotes growth of zebrafish via NOD2-mediated induction of IGF1 signaling

Abstract The role of gut microbiome in regulating vertebrate metabolism has been well-recognized. However, the effects of gut bacteria on growth have been less studied. Bacillus is a prevalent genus in the gut microbiota of human and animals. In this study, the effect of gut-derived Bacillus velezensis T23 on growth was investigated in zebrafish. B. velezensis T23 improved the growth of zebrafish and promoted IGF1 production in the liver and muscle, with a concomitant activation of the AKT/mTOR signaling pathway. The growth-promoting effect of B. velezensis T23 was not dependent on lipopeptides and polyketides. Cell wall peptidoglycan isolated from B. velezensis T23, as well as muramyl dipeptide (MDP), was sufficient to stimulate IGF1 signaling and growth. Further, the effect of B. velezensis T23 on growth and IGF1 production was abrogated in nod2 -/- zebrafish, confirming that B. velezensis T23 promoted growth via MDP-NOD2 signaling. Gut transcriptomic analysis indicated that B. velezensis T23 promoted renewal and differentiation of intestinal cells, suggesting an involvement of gut-liver axis in the effect of B. velezensis T23 on systemic IGF1 production. Together, our results revealed an effect of gut Bacillus -derived muropeptide on growth via NOD2-IGF1 signaling, and provided novel mechanistic insights in the beneficial effect of Bacillus spp. as probiotics.