Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
PLoS One. 2020 Aug 7;15(8):e0237182. doi: 10.1371/journal.pone.0237182. eCollection 2020.
Necrotizing enterocolitis is the most common gastrointestinal disorder in premature neonates. This disease is characterized by massive epithelial necrosis, gut barrier dysfunction and improper mucosal defense development. Studies have shown that probiotic administration can decrease NEC incidence and mortality. The proposed mechanisms of probiotics for the prevention of NEC are: promotion of intestinal development; improved barrier function through decreased apoptosis and improved mucin production; decreased expression of proinflammatory cytokines IL6, IL8, and TNFα, and modulation of microbiota dysbiosis in preterm infants. However, reported sepsis in the immunocompromised preterm host has deterred routine prophylactic administration of probiotics in the neonatal intensive care unit. We hypothesize that maternal administration of probiotics to pregnant mouse dams can recapitulate the beneficial effects observed in neonates fed with probiotics directly. We exposed pregnant mice to the probiotics and monitored the changes in the developing intestines of the offspring. Pregnant mice were fed daily with the probiotics Lactobacillus acidophilus and Bifidobacterium infantis (LB) from embryonic day15 to 2-week-old postnatally. Intraperitoneal administration of IL-1β in the pups was used to model proinflammatory insults. Sera were collected at 2 weeks of age and evaluated for inflammatory cytokines by enzyme-linked-immunosorbent-assay and gut permeability by Fluorescein isothiocyanate-dextran tracer assay. Ileal tissues were collected for the evaluation of apoptosis and proliferation of the intestinal epithelium; as well as mucin and tight junction integrity at mucosal surface by immunofluorescent staining. We find that maternal LB exposure facilitated intestinal epithelial cell differentiation, prevented loss of mucin and preserved the intestinal integrity and barrier function and decreased serum levels of IL-1β, TNF-α and IL-6 in the preweaned offsprings. in LB exposed pups. We demonstrate that maternal probiotic supplementation promotes gut maturation in developing offspring. This is potentially a safe alternative therapy to induce intestinal maturation and prevent prematurity-associated neonatal disorders.
坏死性小肠结肠炎是早产儿最常见的胃肠道疾病。这种疾病的特征是大量上皮细胞坏死、肠道屏障功能障碍和黏膜防御不当。研究表明，益生菌的应用可以降低 NEC 的发病率和死亡率。益生菌预防 NEC 的机制有：促进肠道发育；通过减少细胞凋亡和改善黏蛋白生成来改善屏障功能；降低促炎细胞因子 IL6、IL8 和 TNFα 的表达，调节早产儿肠道菌群失调。然而，在免疫功能低下的早产儿中报道的败血症阻止了在新生儿重症监护病房常规预防性应用益生菌。我们假设，向怀孕的母鼠施用益生菌可以重现直接用益生菌喂养的新生儿观察到的有益效果。我们使怀孕的老鼠接触益生菌，并监测后代发育中肠道的变化。从胚胎第 15 天到出生后 2 周，每天给怀孕的老鼠喂食益生菌嗜酸乳杆菌和双歧杆菌（LB）。给幼鼠腹腔内注射白细胞介素 1β（IL-1β）以模拟促炎刺激。在 2 周龄时收集血清，通过酶联免疫吸附试验（ELISA）评估炎症细胞因子，通过荧光素异硫氰酸酯-葡聚糖示踪试验评估肠道通透性。收集回肠组织评估肠道上皮细胞的凋亡和增殖；通过免疫荧光染色评估黏膜表面的黏蛋白和紧密连接完整性。我们发现，母鼠 LB 暴露促进了肠上皮细胞的分化，防止了黏蛋白的丢失，并维持了肠道的完整性和屏障功能，降低了未断奶幼鼠血清中 IL-1β、TNF-α 和 IL-6 的水平。在 LB 暴露的幼鼠中。我们证明了母体益生菌补充剂可促进发育中后代的肠道成熟。这可能是一种安全的替代疗法，可诱导肠道成熟并预防与早产相关的新生儿疾病。
