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对美国人来说仍然是一个相当大的健康和经济负担

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