来自重庆医科大学附属第一医院检验科的研究团队通过构建肠道菌群缺失小鼠模型对微生物群与宿主抵抗侵袭性念珠菌病能力之间的作用关系进行了探讨。结果显示：肠道菌群主要通过调控Th17免疫反应在侵袭性念珠菌病中发挥保护作用，且宿主对侵袭性念珠菌感染抵抗能力下降与肠道菌群被破坏密切相关。该项研究于2020年5月在线发表于重症监护杂志《Critical Care》。
侵袭性念珠菌病是由多种念珠菌引起的一组感染综合征的统称，其会导致多种不良负担，如重症监护病房住院时间延长、医疗花费增高等。侵袭性念珠菌病会引起严重的临床症状，危及患者生命。然而，对于侵袭性念珠菌病，临床抗真菌治疗策略的选择存在争议，且抗真菌治疗对侵袭性念珠菌病患者的预后及结局的影响仍未明确。因此，侵袭性念珠菌病的积极有效治疗是目前医学面临的一大挑战，对临床意义重大。
肠道菌群目前被视为人体最大的虚拟免疫代谢器官。肠道微生物与宿主在长久的进化中相互影响，肠道菌群中微生物庞大的数量和丰富的种类及其大量的相关代谢产物对宿主产生广泛而复杂的作用。肠道菌群的组成的改变及其产生的代谢物质变化不仅关系到胃肠道疾病，也被证明与胃肠道以外的功能紊乱有关。
为探究肠道菌群在侵袭性念珠菌病中的作用，本研究采用肠道菌群清除小鼠模型（ABX小鼠），再通过白色念珠菌尾静脉注射小鼠，构建侵袭性念珠菌感染状态，监测菌群清除小鼠与正常小鼠在侵袭性念珠菌感染后的不同反应，结果显示缺失肠道菌群的小鼠在侵袭性念珠菌感染后，生存能力下降，组织真菌负荷增高且组织损伤严重，Th17与Th1型细胞反应显著降低；随后对菌群清除小鼠进行细胞因子蛋白治疗实验，其中IL-17A治疗后小鼠感染程度及生存能力均改善，表明肠道菌群主要通过Th17型细胞反应及IL-17A在侵袭性念珠菌病中发挥保护作用；随后，将粪菌移植应用于菌群清除小鼠，结果显示恢复其肠道菌群后小鼠感染程度及生存能力均改善，其血清中IL-17A及IFN-γ水平也显著增高；此外还对菌群清除前后小鼠的肠道菌群进行测序以表征其肠道菌群结构和组成。本研究表明肠道菌群可以提高宿主抵抗侵袭性念珠菌感染的能力，并通过调控宿主的免疫反应发挥抗真菌免疫作用，肠道菌群的微生物结构及组成变化与宿主抗真菌免疫机制有关，因此从肠道菌群角度发现侵袭性念珠菌病的治疗策略值得进一步探索。
Figure 1. Decreased survival ability of ABX mice in invasive candidiasis.A) Fecal bacteria quantification of non-infected ABX and CNV mice in aerobic and anaerobic environments (n=4). (B) Feces smear stained using Gram stain from non-infected ABX and CNV mice. (C) Representative examples of H&E-stained kidney from non-infected ABX and CNV mice. (D) The serum concentrations of ALT, AST, BUN and creatinine of non-infected ABX and CNV mice. (E) Weight curve of non-infected ABX and CNV mice. (F) Body weight loss of ABX and CNV mice were daily monitored after intravenous injection with fungal yeasts (2 × 105 CFUs， C.albicans strain SC5314) and depicted with plot (n=6). (G) Survival analysis of the ABX and CNV mice after injection (n=10). Data were expressed as mean ± SEM and P values were analyzed by Mann-Whitney U test (A, D), two-way ANOVA (C) and log-rank test (D). Two-tailed P values<0.05 were considered statistically significant. Results are representative of three independent experiments.
Figure 2. FMT (Fecal microbiota transplantation) alleviated morbid conditions of microbiota-deleted mice in invasive candidiasis. (A-B) Plot of weight loss (A) over time after infection in comparison to starting weight (n=5) and survival analysis (B) (n=8) for both FMT group and PBS group at day 3 after infection. (C-E) Fungal burden of the kidneys (C) (n=8), serum concentration of IFN-γ (D) (n=7) and IL-17A (E) (n=5) in mice from FMT group and PBS group at day 3 after infection. Data were expressed as mean ± SEM. P values were analyzed by two-way ANOVA (A), log-rank test (B) and Mann-Whitney U test (C-E). Two-tailed P values<0.05 were considered statistically significant. Results are representative of three independent experiments.
