Intestinal bacteria and epithelial barrier disruption after alcohol and burn injury

酒精和烧伤后肠道细菌和上皮屏障破坏

• 批准号: 10180982
• 负责人: Mashkoor A Choudhry
• 金额: $ 40.96万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180982
• 关键词: Accident and Emergency department; Adverse effects; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcohols; American; Animals; Bacteria; Bacterial Translocation; Biogenesis; Blood Circulation; Burn injury; Caring; Cause of Death; Colitis; Complication; Critical Illness; Disease; Dose; Economic Burden; Enterobacteriaceae; Epithelial; Epithelial Cells; Ethanol; Exhibits; Family; Functional disorder; Gastrointestinal tract structure; Goals; Gram-Negative Bacteria; Homeostasis; Hour; Human; Hypoxia; Hypoxia Inducible Factor; Immune; Impaired wound healing; Impairment; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intestines; Intoxication; Leaky Gut; Length of Stay; Link; Lipopolysaccharides; Maintenance; MicroRNAs; Morbidity - disease rate; Mucous Membrane; Mus; Obesity; Organ; Pathogenesis; Patients; Pattern recognition receptor; Play; Predisposition; Probiotics; Reporting; Role; Sepsis; Small Intestines; Societies; Testing; Therapeutic; Time; Tissues; Trauma patient; Traumatic injury; United States; Ursidae Family; Wild Type Mouse; alcohol exposure; clinically relevant; design; effective therapy; gastrointestinal epithelium; gut bacteria; gut dysbiosis; gut microbiota; health economics; improved; inflammatory disease of the intestine; injured; insight; intestinal barrier; intestinal epithelium; microbiota; mortality; mouse model; negative affect; novel; novel therapeutic intervention; patient population; prevent; restoration; severe burns; severe injury; systemic inflammatory response

Alcohol-related traumatic and burn injuries remain a considerable health and economic burden to the American society. Studies have shown that patients who are intoxicated at the time of injury are more susceptible to infection and exhibit significantly higher morbidity and mortality compared to burn patients who are not intoxicated at the time of injury. Yet, the mechanism by which alcohol (ethanol) enhances post burn pathogenesis remains largely unclear. Gut barrier dysfunction is frequently associated with ethanol exposure and major injury. We have shown that the ethanol intoxication combined with moderate burn injury causes intestinal tissue damage, leakiness, and a significant increase in bacterial translocation within 24 hours after injury. We further observed a decrease in the expression of microRNA (miR-7a and miR-150) and microRNA biogenesis components Drosha and Argonaute-2 in intestinal epithelial cells (IEC) one day following alcohol and burn injury. Moreover, ethanol combined with burn injury increases bacterial load (Enterobacteriaceae) in the small intestine. Such an increase in Enterobacteriaceae may disrupt the bacteria/host interactions and potentiate the inflammatory response by activating pattern recognition receptors (PRR) expressed on IECs leading to intestine tissue damage and leakiness following ethanol and burn injury. Our hypothesis is that accumulation of Gram-negative bacteria (i.e. Enterobacteriaceae) in intestine following ethanol and burn injury perturbs gut microbiota-epithelial interactions, which become exacerbated by altered microRNA homeostasis, thus, culminating in gut inflammation and barrier disruption. The hypothesis will be tested in 3 Aims in a well-established mouse model of ethanol intoxication and burn injury. Studies in Aim 1 are designed to delineate the mechanism by which ethanol and burn induced changes in intestinal bacteria influence intestine barrier integrity following injury. Aim 2 will determine whether changes in gut bacteria alone or in combination with an increase in HIF-1α influence the expression of miR-150 and miR-7a and whether restoration of miR-150 and/or miR-7a in intestinal epithelial cells following alcohol and burn injury reduces gut inflammation and improves barrier integrity. Furthermore studies in Aim 3 will determine whether treatment of animals with probiotics reestablishes gut microbiota and intestine barrier integrity following alcohol and burn injury. The findings from these studies will reveal a novel role for gut microbiota in gut leakiness following ethanol intoxication and burn injury and in turn may help in developing new therapeutic strategies for patients suffering from a combined insult of ethanol and burn injury.

与酒精相关的创伤和烧伤损伤仍然是美国的大量健康和经济烧伤 社会。研究表明，受伤时陶醉的患者更容易受到 与不烧伤的患者相比，感染和表现出明显更高的发病率和死亡率 受伤时陶醉。然而，酒精（乙醇）增强燃烧后的机制 发病机理在很大程度上不清楚。肠道屏障功能障碍经常与乙醇暴露有关 和重大伤害。我们已经表明，乙醇肠毒性与现代烧伤原因相结合 肠组织损伤，泄漏性和细菌在24小时内显着增加 受伤。我们进一步观察到microRNA（miR-7a和miR-150）和microRNA的表达降低 饮酒后一天，生物发生成分Drosha和Argonaute-2在肠上皮细胞（IEC）中 和烧伤。此外，乙醇与烧伤的结合增加了细菌负荷（肠杆菌科） 小肠。肠杆菌科的这种增加可能会破坏细菌/宿主的相互作用和 通过激活IEC表达的模式识别受体（PRR），潜在的炎症反应 导致乙醇和烧伤损伤后导致肠道组织损伤和泄漏。我们的假设是 乙醇和烧伤损伤后的肠内革兰氏阴性细菌（即肠杆菌科）的积累 Perturbs肠道菌群上皮相互作用，这会因改变的microRNA稳态而加剧 因此，最终导致肠道注射和屏障破坏。该假设将以3个目标进行检验 乙醇肠毒性和烧伤损伤的小鼠模型。 AIM 1的研究旨在描述 乙醇和燃烧诱导肠道细菌变化的机制影响肠屏障 受伤后的完整性。 AIM 2将确定肠道细菌的变化是单独的还是与 HIF-1α的增加会影响miR-150和miR-7a的表达，以及miR-150和/或的恢复是否恢复 酒精和烧伤损伤后肠上皮细胞中的miR-7a减少了肠道注射并改善 障碍完整性。此外，AIM 3中的研究将确定益生菌的动物的治疗是否会重建 酒精和烧伤后的肠道菌群和肠屏障完整性。来自 这些研究将揭示肠道菌群在乙醇触觉和燃烧后的肠道泄漏中的新作用 受伤和又可能有助于制定新的治疗策略 侮辱乙醇和烧伤。

项目成果

Gut Microbial Changes and their Contribution to Post-Burn Pathology.

• DOI: 10.1097/shk.0000000000001736
• 发表时间: 2021-09-01
• 期刊: Shock (Augusta, Ga.)
• 作者: Luck ME;Herrnreiter CJ;Choudhry MA
• 通讯作者: Choudhry MA

Maintenance of gut barrier integrity after injury: Trust your gut microRNAs.

• DOI: 10.1002/jlb.3ru0120-090rr
• 发表时间: 2021-11
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Morris NL;Choudhry MA
• 通讯作者: Choudhry MA

Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury.

• DOI: 10.1002/jlb.3a0820-323rr
• 发表时间: 2021-06
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Morris NL;Cannon AR;Li X;Choudhry MA
• 通讯作者: Choudhry MA

IL-27 Promotes Intestinal Barrier Integrity following Ethanol Intoxication and Burn Injury.

IL-27 可促进乙醇中毒和烧伤后肠屏障的完整性。

• DOI: 10.4049/immunohorizons.2200032
• 发表时间: 2022
• 期刊: ImmunoHorizons
• 作者: Luck,MarisaE;Li,Xiaoling;Herrnreiter,CarolineJ;Cannon,AbigailR;Choudhry,MashkoorA
• 通讯作者: Choudhry,MashkoorA

Integrated analysis of dysregulated microRNA and mRNA expression in intestinal epithelial cells following ethanol intoxication and burn injury.

• DOI: 10.1038/s41598-021-99281-1
• 发表时间: 2021-10-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Herrnreiter CJ;Li X;Luck ME;Zilliox MJ;Choudhry MA
• 通讯作者: Choudhry MA