Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305.
Department of Comparative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3688-3694. doi: 10.1073/pnas.1814273116. Epub 2019 Feb 11.
Sepsis is a deleterious immune response to infection that leads to organ failure and is the 11th most common cause of death worldwide. Despite plaguing humanity for thousands of years, the host factors that regulate this immunological response and subsequent sepsis severity and outcome are not fully understood. Here we describe how the Western diet (WD), a diet high in fat and sucrose and low in fiber, found rampant in industrialized countries, leads to worse disease and poorer outcomes in an LPS-driven sepsis model in WD-fed mice compared with mice fed standard fiber-rich chow (SC). We find that WD-fed mice have higher baseline inflammation (metaflammation) and signs of sepsis-associated immunoparalysis compared with SC-fed mice. WD mice also have an increased frequency of neutrophils, some with an "aged" phenotype, in the blood during sepsis compared with SC mice. Importantly, we found that the WD-dependent increase in sepsis severity and higher mortality is independent of the microbiome, suggesting that the diet may be directly regulating the innate immune system through an unknown mechanism. Strikingly, we could predict LPS-driven sepsis outcome by tracking specific WD-dependent disease factors (e.g., hypothermia and frequency of neutrophils in the blood) during disease progression and recovery. We conclude that the WD is reprogramming the basal immune status and acute response to LPS-driven sepsis and that this correlates with alternative disease paths that lead to more severe disease and poorer outcomes.
脓毒症是一种有害的免疫反应，可导致器官衰竭，是全球第 11 大常见死亡原因。尽管脓毒症困扰了人类几千年，但调节这种免疫反应以及随后的脓毒症严重程度和结局的宿主因素仍未完全了解。在这里，我们描述了西方饮食（WD）——一种高脂肪、高蔗糖、低纤维的饮食——如何导致在 LPS 驱动的脓毒症模型中，与喂食标准富含纤维的饲料（SC）的小鼠相比，WD 喂养的小鼠出现更严重的疾病和更差的结局。我们发现，与 SC 喂养的小鼠相比，WD 喂养的小鼠具有更高的基线炎症（代谢性炎症）和脓毒症相关免疫麻痹的迹象。WD 小鼠在脓毒症期间血液中的中性粒细胞频率也更高，其中一些具有“衰老”表型。重要的是，我们发现，WD 依赖性脓毒症严重程度增加和死亡率增加与微生物组无关，这表明饮食可能通过未知机制直接调节先天免疫系统。引人注目的是，我们可以通过跟踪疾病进展和恢复过程中特定的 WD 依赖性疾病因素（例如，低温和血液中性粒细胞频率）来预测 LPS 驱动的脓毒症结局。我们得出结论，WD 正在重新编程基础免疫状态和对 LPS 驱动的脓毒症的急性反应，这与导致更严重疾病和更差结局的替代疾病途径相关。
