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An increasing number of studies have confirmed the role of intestinal microbiota in early life maturation including maturation of intestinal immune function. The interaction of the TLR4 with colonizing bacteria in intestinal development is incompletely understood. Thisstudy investigates the mechanism (s) by which TLR4 interacts with metabolites (postbiotics) of the colonizing bacterium, <i>Bifidobacteria Longum </i>subsp. <i>Infantis (B. Infantis) </i>to determine its effect on intestinal development. By using a fetal human small intestinal cell line, authenticatedby human fetal intestinal organoids, we found that TLR4-mediated postbiotics induced immature enterocyte proliferation and filamentous actin (F-actin) maturation both at the mRNA and protein levels. Oral feeding of wild-type (WT) and TLR4 gene knockout (TLR4 ^-/-) neonatal mice of<i>B.Infantis</i> postbiotics increased proliferation of mRNA levels in wild-type mice but not in TLR4^-/- mice, both in the ileum and colon. Postbioticscan also change tight junction distribution in WT neonatal mouse colon but not in TLR4 ^-/-mice. Our data suggest a novel regulation of intestinal development by a synergistic role of the innate immune receptor TLR4 and early life colonizing bacteria, such as <i>B. Infantis,</i> in both the fetal human and immature mouse intestine. This study should provide new insights into the mechanisms of intestinal maturation as well as opportunities to target novel approaches to NEC prevention and treatment.

已有大量研究证实，肠道菌群在生命早期机体发育进程中发挥关键作用，其中涵盖肠道免疫功能的成熟过程。目前关于Toll样受体4（TLR4）与肠道定植菌在肠道发育过程中的相互作用机制尚未完全阐明。本研究旨在探究TLR4与定植菌——长双歧杆菌婴儿亚种（Bifidobacterium longum subsp. infantis, B. Infantis）的代谢产物（后生元，postbiotics）之间的相互作用机制，以明确其对肠道发育的影响。本研究采用经人胎儿肠道类器官验证的人胎儿小肠细胞系，发现TLR4介导的后生元可在mRNA与蛋白水平上诱导未成熟肠上皮细胞增殖，同时促进丝状肌动蛋白（F-actin）的成熟。本研究对野生型（WT）及TLR4基因敲除（TLR4^-/-）新生小鼠灌服B. Infantis来源的后生元后，回肠与结肠组织中野生型小鼠的肠上皮细胞增殖相关mRNA水平显著升高，而TLR4^-/-小鼠则无此变化。此外，后生元可改变野生型新生小鼠结肠的紧密连接蛋白分布模式，但对TLR4^-/-小鼠无此调控作用。本研究数据表明，天然免疫受体TLR4与生命早期定植菌（如B. Infantis）的协同作用，可通过全新的调控机制影响人胎儿及未成熟小鼠的肠道发育。本研究可为肠道成熟的分子机制研究提供新的见解，同时也为坏死性小肠结肠炎（Necrotizing Enterocolitis, NEC）的新型防治策略开发提供潜在方向。