Clostridium difficile is the leading cause of nosocomial infections in the United States. Clinical disease outcomes after C. difficile infection (CDI) are dependent on intensity of host inflammatory responses. Specifically, peak peripheral white blood cell (WBC) count >20 × 10⁹ l^-1 is an indicator of adverse outcomes in CDI patients, and is associated with higher 30-day mortality. We show that homozygosity for a common single nucleotide polymorphism (Q to R mutation in leptin receptor that is present in up to 50% of people), significantly increases the risk of having peak peripheral WBC count >20 × 10⁹ l^-1 (odds ratio=5.41; P=0.0023) in CDI patients. In a murine model of CDI, we demonstrate that mice homozygous for the same single nucleotide polymorphism (RR mice) have more blood and tissue leukocytes (specifically neutrophils), exaggerated tissue inflammation, and higher mortality as compared with control mice, despite similar pathogen burden. Further, we show that neutrophilia in RR mice is mediated by gut microbiota-directed expression of CXC chemokine receptor 2 (CXCR2), which promotes the release of neutrophils from bone marrow reservoir. Overall these studies provide novel mechanistic insights into the role of human genetic polymorphisms and gut microbiota in regulating the fundamental biological process of CDI-induced neutrophilia.

中文翻译：

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瘦素受体 q223r 多态性影响艰难梭菌感染后的中性粒细胞动员。

艰难梭菌是美国医院感染的主要原因。艰难梭菌感染 (CDI) 后的临床疾病结果取决于宿主炎症反应的强度。具体而言，外周血白细胞 (WBC) 峰值计数 >20 × 10 ⁹  l ^-1是 CDI 患者不良结局的指标，并且与较高的 30 天死亡率相关。我们表明，常见单核苷酸多态性的纯合性（存在于多达 50% 的人中的瘦素受体 Q 到 R 突变）显着增加了外周血白细胞计数峰值 >20 × 10 ⁹  l ^-1的风险(比值比=5.41；P=0.0023)在CDI患者中。在 CDI 小鼠模型中，我们证明与对照小鼠相比，具有相同单核苷酸多态性的纯合小鼠（RR 小鼠）具有更多的血液和组织白细胞（特别是嗜中性粒细胞）、夸大的组织炎症和更高的死亡率，尽管病原体负担相似. 此外，我们表明 RR 小鼠的中性粒细胞增多是由肠道微生物群定向表达 CXC 趋化因子受体 2 (CXCR2) 介导的，它促进了骨髓库中中性粒细胞的释放。总的来说，这些研究为人类遗传多态性和肠道微生物群在调节 CDI 诱导的中性粒细胞增多的基本生物学过程中的作用提供了新的机制见解。