ACE2 shedding exacerbates sepsis induced gut leak via loss of microbial metabolite 5-MTP

Sepsis, a critical organ dysfunction resulting from an aberrant host response to infection, remains a leading cause of mortality in ICU patients. Recent evidence suggests that angiotensin converting enzyme 2 (ACE2) contributes to intestinal barrier function, the mechanism of which is yet to be explored. The findings of this study indicate that ACE2 shedding significantly weakens the integrity of the intestinal barrier in septic conditions. Mice lacking ACE2 exhibited increased intestinal permeability and higher mortality rates post-sepsis compared to their wild-type counterparts. Notably, ACE2 deficiency was associated with distinct alterations in gut microbiota composition and reductions in protective metabolites, such as 5-methoxytryptophan (5-MTP). 5-MTP was barely detected in ABX mice, while its level was reversed by FMT of WT mice. Supplementing septic mice with 5-MTP ameliorated gut leak through enhanced epithelial cell proliferation and repairment. The relationship between intestinal barrier integrity and the expression of ACE2 in septic mice was explored in both ACE2 knockout and overexpressing mice. Intestinal barrier function was assessed through measurements of intestinal tight junction proteins and permeability tests. The resulting bacteria translocation and multi-organ dysfunction were also evaluated. To investigate the mechanism by which 5-MTP counteract the sepsis induced barrier damage, RNA-seq was performed on WT CLP mice treated with either 5-MTP or PBS.

脓毒症（Sepsis）是指宿主对感染产生异常应答后引发的急性器官功能障碍，仍是重症监护病房（ICU）患者死亡的主要诱因之一。近期研究表明，血管紧张素转换酶2（ACE2）对肠屏障功能具有调控作用，但其具体分子机制尚未阐明。本研究结果显示，在脓毒症状态下，血管紧张素转换酶2的脱落会显著削弱肠屏障完整性。与野生型小鼠相比，血管紧张素转换酶2敲除小鼠在脓毒症造模后肠通透性更高、死亡率也更高。值得注意的是，血管紧张素转换酶2缺乏会导致肠道菌群组成发生显著改变，并使5-甲氧基色氨酸（5-MTP）等保护性代谢物水平降低。ABX小鼠体内几乎无法检测到5-MTP，而通过野生型小鼠粪便菌群移植（FMT）可逆转其5-MTP水平。给脓毒症小鼠补充5-MTP可通过增强上皮细胞增殖与修复能力改善肠漏症状。本研究通过构建血管紧张素转换酶2敲除与过表达小鼠模型，探究了脓毒症小鼠肠屏障完整性与血管紧张素转换酶2表达水平之间的关联。研究通过检测肠道紧密连接蛋白表达及开展肠通透性实验评估肠屏障功能，同时对细菌移位及多器官功能障碍情况进行了评价。为阐明5-MTP对抗脓毒症诱导的肠屏障损伤的具体机制，本研究对经5-MTP或磷酸盐缓冲液（PBS）处理的野生型盲肠结扎穿刺（CLP）小鼠进行了RNA测序（RNA-seq）。