Immune Responses to Broad-Spectrum Antibiotic Treatment and Fecal Microbiota Transplantation in Mice.
Immune Responses to Broad-Spectrum Antibiotic Treatment and Fecal Microbiota Transplantation in Mice.
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DOI：
10.3389/fimmu.2017.00397
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发表时间：
2017
影响因子：
7.3
通讯作者：
Heimesaat MM
中科院分区：
文献类型：
--
作者：
Ekmekciu I;von Klitzing E;Fiebiger U;Escher U;Neumann C;Bacher P;Scheffold A;Kühl AA;Bereswill S;Heimesaat MM
令人信服的证据表明，共生肠道微生物区系在宿主生理中的关键作用以及抗生素治疗后其扰动的有害影响。本研究的目的是研究抗生素引起的肠道微生物区系耗竭和随后恢复对小鼠粘膜和系统免疫的影响。为了解决这个问题，传统的C57BL/6J小鼠接受了8 周的广谱抗生素治疗。通过口服粪便微生物区系移植恢复肠道微生物区系，最早在口服粪便微生物区系移植后7 天，小肠中的CD_4~+、CD_8~+和B220~+细胞以及结肠中的CD_4~+细胞数量得以重建。然而，在FMT后的28天，结肠的CD4+和B220+细胞数量与继发性非生物(ABX)小鼠的数量相当。值得注意的是，在抗生素治疗后，结肠中的CD8+细胞数量减少，而FMT不足以恢复这个免疫细胞亚群。此外，缺乏肠道微生物刺激会导致小肠、结肠、肠系膜淋巴结(MLN)和脾中记忆/效应器T细胞、调节性T细胞和激活的树突状细胞的百分比下降。同时给予抗生素治疗会导致各隔室中γ+细胞产生的细胞因子(干扰素-干扰素、白介素17、白介素22和白介素10)减少。然而，这些影响在FMT时完全恢复。综上所述，广谱抗生素治疗导致免疫细胞谱发生深刻的局部(即小肠和大肠)、外周(即MLN)和全身性(即脾)变化，这些变化至少部分可以在FMT后恢复。进一步的研究需要揭开微生物群驱动的免疫稳态变化背后的不同的分子机制，从而为人类免疫病理学提供新的治疗甚至预防方法。
Compelling evidence demonstrates the pivotal role of the commensal intestinal microbiota in host physiology and the detrimental effects of its perturbations following antibiotic treatment. Aim of this study was to investigate the impact of antibiotics induced depletion and subsequent restoration of the intestinal microbiota composition on the murine mucosal and systemic immunity. To address this, conventional C57BL/6j mice were subjected to broad-spectrum antibiotic treatment for 8 weeks. Restoration of the intestinal microbiota by peroral fecal microbiota transplantation (FMT) led to reestablishment of small intestinal CD4+, CD8+, and B220+ as well as of colonic CD4+ cell numbers as early as 7 days post-FMT. However, at d28 following FMT, colonic CD4+ and B220+ cell numbers were comparable to those in secondary abiotic (ABx) mice. Remarkably, CD8+ cell numbers were reduced in the colon upon antibiotic treatment, and FMT was not sufficient to restore this immune cell subset. Furthermore, absence of gut microbial stimuli resulted in decreased percentages of memory/effector T cells, regulatory T cells, and activated dendritic cells in the small intestine, colon, mesenteric lymph nodes (MLN), and spleen. Concurrent antibiotic treatment caused decreased cytokine production (IFN-γ, IL-17, IL-22, and IL-10) of CD4+ cells in respective compartments. These effects were, however, completely restored upon FMT. In summary, broad-spectrum antibiotic treatment resulted in profound local (i.e., small and large intestinal), peripheral (i.e., MLN), and systemic (i.e., splenic) changes in the immune cell repertoire that could, at least in part, be restored upon FMT. Further studies need to unravel the distinct molecular mechanisms underlying microbiota-driven changes in immune homeostasis subsequently providing novel therapeutic or even preventive approaches in human immunopathologies.