Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China.
Front Cell Infect Microbiol. 2022 Oct 10;12:1015386. doi: 10.3389/fcimb.2022.1015386. eCollection 2022.
Sepsis is associated with a high risk of death, and the crosstalk between gut microbiota and sepsis is gradually revealed. Indole 3-propionic acid (IPA) is a gut microbiota-derived metabolite that exerts immune regulation and organ protective effects. However, the role of IPA in sepsis is not clear. In this study, the role of IPA in sepsis-related survival, clinical scores, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Aryl hydrocarbon receptor (AhR) highly specific inhibitor (CH223191) was used to observe the role of AhR in the protection of IPA against sepsis. The effects of IPA on bacterial phagocytosis by macrophages were investigated and vitro. The levels of IPA in feces were measured and analyzed in human sepsis patients and patient controls. First, we found that gut microbiota-derived IPA was associated with the survival of septic mice. Then, in animal model, IPA administration protected against sepsis-related mortality and alleviated sepsis-induced bacterial burden and organ injury, which was blunted by AhR inhibitor. Next, and vitro, IPA enhanced the macrophage phagocytosis through AhR. Depletion of macrophages reversed the protective effects of IPA on sepsis. Finally, on the day of ICU admission (day 0), septic patients had significantly lower IPA level in feces than patient controls. Also, septic patients with bacteremia had significantly lower IPA levels in feces compared with those with non-bacteremia. Furthermore, in septic patients, reduced IPA was associated with worse clinical outcomes, and IPA in feces had similar prediction ability of 28-day mortality with SOFA score, and increased the predictive ability of SOFA score. These findings indicate that gut microbiota-derived IPA can protect against sepsis through host control of infection by promoting macrophages phagocytosis and suggest that IPA may be a new strategy for sepsis treatment.
脓毒症与高死亡率相关，肠道微生物群与脓毒症的相互作用逐渐被揭示。吲哚 3-丙酸（IPA）是一种肠道微生物群衍生的代谢物，具有免疫调节和器官保护作用。然而，IPA 在脓毒症中的作用尚不清楚。在这项研究中，我们在盲肠结扎和穿刺诱导的多微生物脓毒症小鼠模型中评估了 IPA 在与脓毒症相关的生存、临床评分、细菌负荷和器官损伤中的作用。使用芳基烃受体（AhR）高度特异性抑制剂（CH223191）观察 AhR 在 IPA 对脓毒症保护中的作用。研究了 IPA 对巨噬细胞吞噬细菌的体外作用。测量并分析了人类脓毒症患者和患者对照粪便中的 IPA 水平。首先，我们发现肠道微生物群衍生的 IPA 与脓毒症小鼠的生存有关。然后，在动物模型中，IPA 给药可预防脓毒症相关的死亡率，并减轻脓毒症引起的细菌负荷和器官损伤，而 AhR 抑制剂则减弱了这种作用。接下来，在体外，IPA 通过 AhR 增强了巨噬细胞的吞噬作用。耗尽巨噬细胞会逆转 IPA 对脓毒症的保护作用。最后，在 ICU 入院当天（第 0 天），脓毒症患者粪便中的 IPA 水平明显低于患者对照。此外，患有菌血症的脓毒症患者粪便中的 IPA 水平明显低于非菌血症患者。此外，在脓毒症患者中，减少的 IPA 与更差的临床结局相关，粪便中的 IPA 与 SOFA 评分对 28 天死亡率的预测能力相似，并增加了 SOFA 评分的预测能力。这些发现表明，肠道微生物群衍生的 IPA 可以通过促进巨噬细胞吞噬作用来控制宿主感染，从而预防脓毒症，提示 IPA 可能是脓毒症治疗的新策略。
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