| Summary: | Exposure to probiotics in early life contributes to host intestinal development and prevention of necrotizing enterocolitis (NEC). <i>Cronobacter sakazakii</i> (<i>C. sakazakii</i>), an opportunistic pathogen, can cause NEC, bacteremia, and meningitis in neonates, but the research of probiotics against <i>C. sakazakii</i> is limited relative to other enteropathogens. Here, the protective effect and mechanism of a novel probiotic <i>Ligilactobacillus salivarius</i> (<i>L</i><i>. salivarius</i>) YL20 isolated from breast milk on <i>C. sakazakii</i>-induced intestinal injury were explored by using two in vitro models, including an <i>C. sakazakii</i>-infected intestinal organoid model and intestinal barrier model, as well as an in vivo experimental animal model. Our results revealed that <i>L</i><i>. salivarius</i> YL20 could promote epithelial cell proliferation in intestinal organoids, rescue budding-impaired organoids, prevent the decrease of mRNA levels of leucine-rich repeat containing G protein-coupled receptor 5 (<i>Lgr5</i>), zonula occludens-1 (<i>Zo-1</i>) and <i>Occludin</i>, and reverse <i>C. sakazakii</i>-induced low level of Mucin 2 (MUC2) in intestinal organoids. Additionally, YL20 could inhibit <i>C. sakazakii</i> invasion, increase the expression of ZO-1 and occludin in <i>C. sakazakii</i>-infected HT-29 cells, and reverse TEER decrease and corresponding permeability increase across <i>C. sakazakii</i>-infected Caco-2 monolayers. Furthermore, YL20 administration could alleviate NEC in <i>C. sakazakii</i>-infected neonatal mice by increasing the mice survival ratio, decreasing pathology scores, and downregulating pro-inflammatory cytokines. Meanwhile, YL20 could also enhance intestinal barrier function in vivo by increasing the number of goblet cells, the level of <i>MUC-2</i> and the expression of ZO-1. Our overall findings demonstrated for the first time the beneficial effects of <i>L</i><i>. salivarius</i> YL20 against <i>C. sakazakii</i>-induced NEC by improving intestinal stem cell function and enhancing intestinal barrier integrity.
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