Department of Pediatrics, Division of Neonatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Nutrients. 2022 Apr 24;14(9):1779. doi: 10.3390/nu14091779.
Necrotizing enterocolitis (NEC), an inflammatory disease of the intestine, is a common gastrointestinal emergency among preterm infants. Intestinal barrier dysfunction, hyperactivation of the premature immune system, and dysbiosis are thought to play major roles in the disease. Human milk (HM) is protective, but the mechanisms underpinning formula feeding as a risk factor in the development of NEC are incompletely understood. Hyaluronic acid 35 kDa (HA35), a bioactive glycosaminoglycan of HM, accelerates intestinal development in murine pups during homeostasis. In addition, HA35 prevents inflammation-induced tissue damage in pups subjected to murine NEC, incorporating Paneth cell dysfunction and dysbiosis. We hypothesized HA35 treatment would reduce histological injury and mortality in a secondary mouse model of NEC incorporating formula feeding. NEC-like injury was induced in 14-day mice by dithizone-induced disruption of Paneth cells and oral gavage of rodent milk substitute. Mortality and histological injury, serum and tissue cytokine levels, stool bacterial sequencing, and bulk RNA-Seq comparisons were analyzed. HA35 significantly reduced the severity of illness in this model, with a trend toward reduced mortality, while RNA-Seq analysis demonstrated HA35 upregulated genes associated with goblet cell function and innate immunity. Activation of these critical protective and reparative mechanisms of the small intestine likely play a role in the reduced pathology and enhanced survival trends of HA-treated pups subjected to intestinal inflammation in this secondary model of NEC, providing potentially interesting translational targets for the human preterm disease.
坏死性小肠结肠炎（NEC）是一种肠道炎症性疾病，是早产儿常见的胃肠道急症。肠道屏障功能障碍、早产儿免疫系统过度激活和菌群失调被认为在该疾病中起主要作用。人乳（HM）具有保护作用，但配方奶作为 NEC 发展风险因素的作用机制尚不完全清楚。透明质酸 35 kDa（HA35）是 HM 中的一种生物活性糖胺聚糖，可在肠道发育过程中加速鼠仔的肠道发育。此外，HA35 可预防接受鼠 NEC 的幼仔中炎症诱导的组织损伤，包括潘氏细胞功能障碍和菌群失调。我们假设 HA35 治疗会减少包含配方喂养的 NEC 二次小鼠模型中的组织损伤和死亡率。通过二硫代氨基甲酸盐诱导的潘氏细胞破坏和啮齿动物代乳品的口服灌胃，在 14 天大的小鼠中诱导类似 NEC 的损伤。分析死亡率和组织学损伤、血清和组织细胞因子水平、粪便细菌测序和批量 RNA-Seq 比较。HA35 显著减轻了该模型中疾病的严重程度，死亡率呈下降趋势，而 RNA-Seq 分析表明 HA35 上调了与杯状细胞功能和先天免疫相关的基因。这些小肠关键保护和修复机制的激活可能在这种 NEC 的二次模型中肠道炎症导致的 HA 处理幼仔的病理减轻和存活趋势增强中发挥作用，为人类早产儿疾病提供了潜在有趣的转化靶点。
