O'Mahony Caitlin, Scully Paul, O'Mahony David, Murphy Sharon, O'Brien Frances, Lyons Anne, Sherlock Graham, MacSharry John, Kiely Barry, Shanahan Fergus, O'Mahony Liam
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
PLoS Pathog. 2008 Aug 1;4(8):e1000112. doi: 10.1371/journal.ppat.1000112.
Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-kappaB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-kappaB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to naïve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-kappaB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis-fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-kappaB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-kappaB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.
宿主抵御感染需要一系列先天性和适应性免疫反应，而这些反应可能导致组织损伤。这种免疫介导的病理状况可以通过适当的调节性T细胞（Treg）活性来控制。本研究的目的是确定肠道微生物群组成对与感染相关的Treg细胞活性和核因子κB（NF-κB）激活的影响。小鼠食用共生微生物婴儿双歧杆菌35624，随后感染鼠伤寒沙门氏菌或注射脂多糖（LPS）。使用生物光子成像对体内NF-κB激活进行定量。使用流式细胞术评估CD4+CD25+Foxp3+T细胞表型和细胞因子水平，同时使用磁珠分离CD4+T细胞以过继转移至未接触过抗原的动物。体内成像显示，在食用婴儿双歧杆菌的小鼠中，感染和LPS诱导的NF-κB活性受到显著抑制，这先于鼠伤寒沙门氏菌数量的减少和小鼠疾病行为评分的降低。此外，促炎细胞因子分泌、T细胞增殖和树突状细胞共刺激分子表达均显著降低。相比之下，在食用婴儿双歧杆菌的小鼠的黏膜和脾脏中，CD4+CD25+Foxp3+T细胞数量显著增加。CD4+CD25+T细胞的过继转移传递了NF-κB抑制活性。食用单一共生微生物可驱动Treg细胞的生成和功能，这些Treg细胞可在体内控制过度的NF-κB激活。这些细胞间相互作用为更全面理解共生体-宿主-病原体三者关系提供了基础，这三者关系有助于维持宿主稳态机制，以保护机体免受因易位病原体或全身性LPS导致的先天性免疫系统异常激活。
