Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI), Jena, Germany.
Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University, Jena, Germany.
Crit Care. 2023 Sep 27;27(1):372. doi: 10.1186/s13054-023-04620-5.
Sepsis-induced immunosuppression is a frequent cause of opportunistic infections and death in critically ill patients. A better understanding of the underlying mechanisms is needed to develop targeted therapies. Circulating bile acids with immunosuppressive effects were recently identified in critically ill patients. These bile acids activate the monocyte G-protein coupled receptor TGR5, thereby inducing profound innate immune dysfunction. Whether these mechanisms contribute to immunosuppression and disease severity in sepsis is unknown. The aim of this study was to determine if immunosuppressive bile acids are present in endotoxemia and septic shock and, if so, which patients are particularly at risk.
To induce experimental endotoxemia in humans, ten healthy volunteers received 2 ng/kg E. coli lipopolysaccharide (LPS). Circulating bile acids were profiled before and after LPS administration. Furthermore, 48 patients with early (shock onset within < 24 h) and severe septic shock (norepinephrine dose > 0.4 μg/kg/min) and 48 healthy age- and sex-matched controls were analyzed for circulating bile acids. To screen for immunosuppressive effects of circulating bile acids, the capability to induce TGR5 activation was computed for each individual bile acid profile by a recently published formula.
Although experimental endotoxemia as well as septic shock led to significant increases in total bile acids compared to controls, this increase was mild in most cases. By contrast, there was a marked and significant increase in circulating bile acids in septic shock patients with severe liver failure compared to healthy controls (61.8 µmol/L vs. 2.8 µmol/L, p = 0.0016). Circulating bile acids in these patients were capable to induce immunosuppression, as indicated by a significant increase in TGR5 activation by circulating bile acids (20.4% in severe liver failure vs. 2.8% in healthy controls, p = 0.0139).
Circulating bile acids capable of inducing immunosuppression are present in septic shock patients with severe liver failure. Future studies should examine whether modulation of bile acid metabolism can improve the clinical course and outcome of sepsis in these patients.
脓毒症引起的免疫抑制是危重病患者发生机会性感染和死亡的常见原因。为了开发靶向治疗方法，我们需要更好地了解潜在的机制。最近在危重病患者中发现了具有免疫抑制作用的循环胆汁酸。这些胆汁酸激活单核细胞 G 蛋白偶联受体 TGR5，从而导致先天免疫功能严重障碍。这些机制是否导致脓毒症中的免疫抑制和疾病严重程度尚不清楚。本研究旨在确定内毒素血症和感染性休克中是否存在免疫抑制性胆汁酸，如果存在，哪些患者风险特别高。
为了在人体中诱导实验性内毒素血症，10 名健康志愿者接受 2ng/kg 的大肠杆菌脂多糖（LPS）。在 LPS 给药前后对循环胆汁酸进行了分析。此外，分析了 48 例早期（休克发作<24 小时内）和严重感染性休克（去甲肾上腺素剂量>0.4μg/kg/min）以及 48 名年龄和性别匹配的健康对照者的循环胆汁酸。为了筛选循环胆汁酸的免疫抑制作用，使用最近发表的公式计算每个个体胆汁酸谱诱导 TGR5 激活的能力。
尽管实验性内毒素血症和感染性休克与对照组相比导致总胆汁酸显著增加，但在大多数情况下这种增加是轻微的。相比之下，与健康对照组相比，严重肝功能衰竭的感染性休克患者的循环胆汁酸明显且显著增加（61.8μmol/L 比 2.8μmol/L，p=0.0016）。这些患者的循环胆汁酸能够诱导免疫抑制，因为循环胆汁酸诱导 TGR5 激活显著增加（严重肝功能衰竭组为 20.4%，健康对照组为 2.8%，p=0.0139）。
在严重肝功能衰竭的感染性休克患者中存在能够诱导免疫抑制的循环胆汁酸。未来的研究应探讨调节胆汁酸代谢是否可以改善这些患者脓毒症的临床过程和结局。
