钩端螺旋体病是由致病性钩端螺旋体引起的一种新兴传染病。人类和一些哺乳动物可以发展出严重形式的钩端螺旋体病,并伴有失调的炎症反应。这往往会导致死亡。肠道微生物群越来越被认为是全身健康的重要因素。然而,肠道菌群在严重钩端螺旋体病中的确切作用尚不清楚.这里,我们旨在探讨严重钩端螺旋体病仓鼠模型中肠道菌群的功能和潜在机制。我们的研究表明钩端螺旋体能够在肠道中繁殖,导致病理损伤,并诱导肠道和全身炎症反应。16SrRNA基因测序分析显示,钩端螺旋体感染改变了仓鼠肠道微生物群的组成,并增加了变形杆菌。此外,感染后肠道屏障通透性增加,表现为紧密连接的减少。在垂死的仓鼠的肠上皮中发现了易位的变形菌,通过荧光原位杂交确定,血清中脂多糖(LPS)水平升高。此外,肠道微生物群的消耗减少了存活时间,增加了钩端螺旋负荷,并促进钩端螺旋体感染后促炎细胞因子的表达。有趣的是,粪便过滤和垂死仓鼠的血清都增加了TNF-α的转录,IL-1β,与未感染仓鼠相比,巨噬细胞中的IL-10和TLR4。这些刺激活性被LPS中和使用多粘菌素B抑制。我们确定了一种LPS中和疗法,当与抗生素疗法或多克隆抗体疗法联合使用时,可显著提高严重钩端螺旋体病的存活率.总之,我们的研究不仅揭示了肠道菌群在严重钩端螺旋体病中的作用,而且为严重钩端螺旋体病提供了治疗策略.
Leptospirosis is an emerging infectious disease caused by pathogenic Leptospira spp. Humans and some mammals can develop severe forms of leptospirosis accompanied by a dysregulated inflammatory response, which often results in death. The gut microbiota has been increasingly recognized as a vital element in systemic health. However, the precise role of the gut microbiota in severe leptospirosis is still unknown. Here, we aimed to explore the function and potential mechanisms of the gut microbiota in a
hamster model of severe leptospirosis. Our study showed that leptospires were able to multiply in the intestine, cause pathological injury, and induce intestinal and systemic inflammatory responses. 16S rRNA gene sequencing analysis revealed that Leptospira infection changed the composition of the gut microbiota of hamsters with an expansion of Proteobacteria. In addition, gut barrier permeability was increased after infection, as reflected by a decrease in the expression of tight junctions. Translocated Proteobacteria were found in the intestinal epithelium of moribund hamsters, as determined by fluorescence in situ hybridization, with elevated lipopolysaccharide (LPS) levels in the serum. Moreover, gut microbiota depletion reduced the survival time, increased the leptospiral load, and promoted the expression of proinflammatory cytokines after Leptospira infection. Intriguingly, fecal filtration and serum from moribund hamsters both increased the transcription of TNF-α, IL-1β, IL-10, and TLR4 in macrophages compared with those from uninfected hamsters. These stimulating activities were inhibited by LPS neutralization using polymyxin B. Based on our findings, we identified an LPS neutralization therapy that significantly improved the survival rates in severe leptospirosis when used in combination with antibiotic therapy or polyclonal antibody therapy. In conclusion, our study not only uncovers the role of the gut microbiota in severe leptospirosis but also provides a therapeutic strategy for severe leptospirosis.