Regulation of Intestinal Immunity by Aryl Hydrocarbon Receptor Signaling in Necrotizing Enterocolitis

坏死性小肠结肠炎中芳基烃受体信号传导对肠道免疫的调节

• 批准号: 10421050
• 负责人: Lila Nolan
• 金额: $ 7.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421050
• 关键词: Adaptive Immune System; Address; Adult; Affect; Anti-Inflammatory Agents; Architecture; Aryl Hydrocarbon Receptor; Attenuated; Catabolism; Cells; Colitis; Complex; Cytometry; Data; Dendritic Cells; Dendritic cell activation; Development; Diet; Dioxygenases; Disease; Distal part of ileum; Enteral; Enzymes; Epithelial; Epithelial Cells; Excision; Flow Cytometry; Functional disorder; Gastrointestinal Diseases; Genes; Homeostasis; Human; ITGAX gene; Immune; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Indole-3-Carbinol; Infant; Inflammation; Inflammatory; Inflammatory Response; Intake; Interleukin-1 beta; Intestines; Knock-out; Knowledge; Kynurenine; Lamina Propria; Ligands; Mediating; Morbidity - disease rate; Mucous Membrane; Mus; Necrosis; Necrotizing Enterocolitis; Neonatal Intensive Care Units; Nutritional; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Physiological; Pomegranate; Population; Premature Infant; Prevention strategy; Proteins; Receptor Activation; Receptor Cell; Receptor Signaling; Regulation; Research; Resected; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Small Intestines; Supplementation; Testing; Therapeutic; Tight Junctions; Tissues; Tryptophan; Tumor-infiltrating immune cells; Wild Type Mouse; Work; aryl hydrocarbon receptor ligand; attenuation; cell type; chemokine; cruciferous vegetable; cytokine; dietary; dysbiosis; experience; gut inflammation; gut microbiota; indoleamine; insight; intestinal barrier; intestinal epithelium; intestinal homeostasis; mRNA Expression; macrophage; microbial; microbial community; monocyte; mortality; mouse model; murine colitis; neonatal mice; neonatal period; next generation sequencing; novel; nuclear factor-erythroid 2; pathogenic bacteria; preservation; prevent; protective effect; pup; receptor expression; scavenger receptor; single cell analysis; single-cell RNA sequencing; therapeutic development; therapeutically effective; tool

PROJECT SUMMARY/ABSTRACT Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in preterm infants in the neonatal intensive care unit (NICU). The discovery of effective therapeutic and preventative strategies against NEC remains an ongoing priority. Although the multiple components of the innate and adaptive immune system have a described role in the pathogenesis of NEC, the overall immune cell signature during NEC compared to intestinal homeostasis has not been described. Preliminary data has shown the important anti-inflammatory role of the aryl hydrocarbon receptor and its dietary ligand, indole-3-carbinol, in attenuating inflammation during NEC and preserving intestinal architecture. The preliminary data further shows that mice lacking AhR in CD11c+ cells (AhR∆CD11c) have an increased expression of pro-inflammatory IL-1β during NEC, whereas mice lacking AhR in the intestinal epithelial cells (IEC) (AhR∆IEC) experience no difference in the severity of NEC. The anti- inflammatory functions of some dietary AhR ligands have been described in adult experimental colitis, but their role in NEC is unknown. Therefore, this proposal tests the central hypothesis that the inflammation in the small intestine of infants with NEC contains a distinct immune cell infiltrate and that dietary AhR ligands activate signaling pathways during NEC to attenuate the inflammatory response. This proposal will use next generation sequencing tools to evaluate the immune cell infiltrate of the small intestine during our experimental murine model of NEC and in surgically resected human small intestine NEC tissue. Further, the effects of a dietary AhR ligand on the pro-inflammatory response and epithelial barrier dysfunction during NEC will be investigated using our experimental murine NEC in wild-type mice, mice with AhR cell-specific knockouts, and human preterm enteroids. This research has significant translational relevance and addresses a critical knowledge gap in the understanding of the immune-related mechanisms in NEC pathogenesis. The outcomes of this work will define how a dietary ligand supplement to infants with immature immunity and immure gut barrier function may serve as a novel immunotherapeutic and nutritional strategy to protect the intestine against this deadly disease.

项目总结/文摘

项目成果

A protocol for the induction of experimental necrotizing enterocolitis in neonatal mice.

• DOI: 10.1016/j.xpro.2021.100951
• 发表时间: 2021-12-17
• 期刊: STAR protocols
• 作者: Nolan LS;Gong Q;Hofmeister HN;Good M
• 通讯作者: Good M

Untargeted Metabolomic Analysis of Human Milk from Mothers of Preterm Infants.

• DOI: 10.3390/nu13103604
• 发表时间: 2021-10-14
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Nolan LS;Lewis AN;Gong Q;Sollome JJ;DeWitt ON;Williams RD;Good M
• 通讯作者: Good M

Selective hypermethylation is evident in small intestine samples from infants with necrotizing enterocolitis.

• DOI: 10.1186/s13148-022-01266-y
• 发表时间: 2022-04-11
• 期刊: Clinical epigenetics
• 影响因子: 5.7
• 作者: Good M;Chu T;Shaw P;Nolan LS;Wrobleski J;Castro C;Gong Q;DeWitt O;Finegold DN;Peters D
• 通讯作者: Peters D

Vaginal seeding after cesarean birth: Can we build a better infant microbiome?

剖腹产后阴道播种：我们能否建立更好的婴儿微生物组？

• DOI: 10.1016/j.medj.2021.07.003
• 发表时间: 2021
• 期刊: Med (New York, N.Y.)
• 作者: Kelly,JeannieC;Nolan,LilaS;Good,Misty
• 通讯作者: Good,Misty