Department of General Surgery, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
Medical School of Chinese PLA, Beijing, 100853, China.
Mil Med Res. 2022 Jul 6;9(1):37. doi: 10.1186/s40779-022-00397-w.
Traumatic colon injury (TCI) is a common disease during wartime. Prolongation of posttraumatic survival time is an effective approach to patient outcome improvement. However, there is a lack of basic research in this field. This study aimed to elucidate the mechanisms underlying TCI progression and to develop novel regimens to buy time for TCI patients on the battlefield.
A total of 669 Sprague-Dawley rats were used in this study. Surgical colon incision was performed to generate the TCI rat model. The landscape of colon microbiota compositions was depicted using 16S rRNA sequencing and metabolites in the intestinal contents were detected by metabolomics profiling. The signaling transduction in the intestinal epithelium was investigated using antibody microarrays and Western blotting. The enzyme-linked immunosorbent assay was conducted to measure the levels of interleukin-6 and tumor necrosis factor-α in intestines and plasma for the detection of inflammatory responses. Diamine oxidase, D-lactate and endotoxin in plasma and protein expression of zonula occludens 1 and occludin were selected as the indicators of intestinal barrier permeability. To investigate alterations of microbiota symbiosis, the relative abundances of specific bacterial genera were detected using quantitative real-time PCR.
As a type of lethal injury, TCI induced acute disruption of intestinal homeostasis, characterized by inflammatory responses, intestinal barrier hyperpermeability and microbiota dysbiosis (P < 0.05). Significant alterations in bacterial metabolic patterns were detected with decreases in many metabolites. After a series of screenings, we found that oral administration of asparagine (Asn) and 3-indolepropionic acid (IPA) effectively prolonged posttraumatic survival time [Asn plus IPA vs. Vehicle: hazard ratio (HR) = 0.105, 95% CI 0.031-0.356, P = 0.0003] and restored intestinal homeostasis in TCI rats (P < 0.05). Mechanistically, this combinational strategy protected the rats against TCI through synergistic activation of Akt signaling in the intestinal epithelium (P < 0.05).
Abrupt dysregulation of intestinal homeostasis plays a critical role in the progression toward TCI-induced death. Oral administration of Asn plus IPA may serve as an effective regimen to restore intestinal functions and prolong the posttraumatic survival time.
创伤性结肠损伤（TCI）是战时的一种常见疾病。延长创伤后生存时间是改善患者预后的有效方法。然而，该领域缺乏基础研究。本研究旨在阐明 TCI 进展的机制，并开发新方案为战场上的 TCI 患者争取时间。
本研究共使用了 669 只 Sprague-Dawley 大鼠。通过手术结肠切开术建立 TCI 大鼠模型。通过 16S rRNA 测序描绘结肠微生物群落组成图谱，并通过代谢组学分析检测肠道内容物中的代谢物。使用抗体微阵列和 Western blot 研究肠上皮中的信号转导。通过酶联免疫吸附试验检测肠道和血浆中白细胞介素-6 和肿瘤坏死因子-α的水平，以检测炎症反应。选择血浆中二胺氧化酶、D-乳酸和内毒素以及紧密连接蛋白 1 和闭合蛋白的蛋白表达作为肠道屏障通透性的指标。为了研究微生物共生的变化，使用定量实时 PCR 检测特定细菌属的相对丰度。
作为一种致命性损伤，TCI 导致肠道内稳态的急性破坏，其特征为炎症反应、肠道屏障通透性增加和微生物群落失调（P<0.05）。检测到许多代谢物减少，细菌代谢模式发生显著变化。经过一系列筛选，我们发现口服天冬酰胺（Asn）和 3-吲哚丙酸（IPA）可有效延长创伤后生存时间[Asn 加 IPA 与载体相比：风险比（HR）=0.105，95%置信区间 0.031-0.356，P=0.0003]并恢复 TCI 大鼠的肠道内稳态（P<0.05）。在机制上，这种联合策略通过协同激活肠上皮中的 Akt 信号通路保护大鼠免受 TCI 的侵害（P<0.05）。
肠道内稳态的突然失调在 TCI 导致死亡的进展中起着关键作用。口服 Asn 加 IPA 可能是恢复肠道功能和延长创伤后生存时间的有效方案。
