<i>Lactiplantibacillus plantarum</i> JY039 Ameliorates Necrotizing Enterocolitis via Intestinal Stem Cell Regeneration

Necrotizing enterocolitis (NEC) is a serious condition in premature infants, driven by dysbiosis-induced inflammation and barrier damage. This study screened probiotics for efficient 2'-fucosyllactose (2'-FL) utilization and intestinal repair potential. <i>Lactiplantibacillus plantarum</i> JY039 (<i>L. plantarum</i> JY039, JY039) was selected from 25 strains (<i>p</i> < 0.05) based on 2'-FL metabolism, intestinal adhesion, and <i>Lgr5</i> induction in TNF-α-damaged organoids. JY039 showed versatile carbon metabolism and sensitivity to 11 antibiotics, indicating its clinical safety. In TNF-α-injured organoids, it elevated intestinal stem cell (ISC) markers (Olfm4 and Ascl2, 4-fold) and proliferation markers (c-Myc, Ki67, and cyclins, 3-fold), with EdU intensity increasing 4-fold versus NEC models. In NEC rats, JY039 (10⁹ CFU/mL) reduced pathology scores and permeability, restored tight junctions, modulated cytokines (TNF-α, IL-6, myeloperoxidase decreased; and IL-10 increased, <i>p</i> < 0.05), activated ISC regeneration, and enriched <i>Lactococcus</i> and <i>Akkermansia</i>. JY039 effectively maintained epithelial regeneration and improved the microbial imbalance, representing a safe NEC candidate. It also offers guidance for producing a functional infant formula.