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.

与酒精有关的创伤和烧伤仍然是美国人相当大的健康和经济负担 社会研究表明，受伤时处于醉酒状态的患者更容易受到 感染，并显示出显着更高的发病率和死亡率相比，烧伤病人谁不 在受伤的时候喝醉了。然而，酒精（乙醇）增强烧伤后 发病机制仍不清楚。肠道屏障功能障碍通常与乙醇暴露有关 严重受伤。我们已经证明，酒精中毒合并中度烧伤会导致 肠组织损伤，渗漏，以及24小时内细菌移位的显著增加， 损伤我们进一步观察到microRNA（miR-7a和miR-150）和microRNA（miR-150）的表达减少。 酒精后一天肠上皮细胞（IEC）中的生物合成组分Drosha和Argonaute-2 和烧伤。此外，乙醇与烧伤结合会增加细菌负荷（肠杆菌科）， 小肠。肠杆菌科的这种增加可能破坏细菌/宿主相互作用， 通过激活IEC上表达的模式识别受体（PRR）增强炎症反应 导致乙醇和烧伤后肠组织损伤和渗漏。我们的假设是 乙醇和烧伤后肠道中革兰氏阴性菌（即肠杆菌科）的积累 扰乱肠道微生物-上皮相互作用，其因改变的microRNA稳态而加剧， 从而最终导致肠道炎症和屏障破坏。该假设将在3个目标中进行检验， 酒精中毒和烧伤小鼠模型。目标1中的研究旨在描述 乙醇和烧伤引起的肠道菌群变化影响肠屏障的机制 受伤后的完整性。目标2将确定肠道细菌的变化是否单独或与 HIF-1α的增加影响miR-150和miR-7a的表达，以及miR-150和/或 酒精和烧伤损伤后肠上皮细胞中的miR-7a减少肠道炎症并改善 屏障完整性此外，目标3中的研究将确定用益生菌治疗动物是否能重建 酒精和烧伤后的肠道微生物群和肠屏障完整性。的结果 这些研究将揭示肠道微生物群在乙醇中毒和烧伤后肠道渗漏中的新作用 损伤，反过来可能有助于开发新的治疗策略，为患者患有联合 乙醇损伤和烧伤。

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

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

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