Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI, USA.
Comparative Medicine and Integrative Biology, Michigan State University, East Lansing, MI, USA.
Microbiome. 2017 Aug 8;5(1):92. doi: 10.1186/s40168-017-0284-4.
Campylobacter jejuni is the leading antecedent infection to the autoimmune neuropathy Guillain-Barré syndrome (GBS), which is accompanied by an autoimmune anti-ganglioside antibody attack on peripheral nerves. Previously, we showed that contrasting immune responses mediate C. jejuni induced colitis and autoimmunity in interleukin-10 (IL-10)-deficient mice, dependent upon the infecting strain. Strains from colitis patients elicited T helper 1 (T1)-dependent inflammatory responses while strains from GBS patients elicited T2-dependent autoantibody production. Both syndromes were exacerbated by antibiotic depletion of the microbiota, but other factors controlling susceptibility to GBS are unknown.
Using 16S rRNA gene high-throughput sequencing, we examined whether structure of the gut microbial community alters host (1) gastrointestinal inflammation or (2) anti-ganglioside antibody responses after infection with C. jejuni strains from colitis or GBS patients. We compared these responses in C57BL/6 mice with either (1) stable human gut microbiota (microbiota) transplants or (2) conventional mouse microbiota (microbiota).
Inoculating germ-free C57BL/6 wild-type (WT) mice with a mixed human fecal slurry provided a murine model that stably passed its microbiota over >20 generations. Mice were housed in specific pathogen-free (SPF) facilities, while extra precautions of having caretakers wear sterile garb along with limited access ensured that no mouse pathogens were acquired. microbiota conferred many changes upon the WT model in contrast to previous results, which showed only colonization with no disease after C. jejuni challenge. When compared to microbiota mice for susceptibility to C. jejuni enteric or GBS patient strains, infected microbiota mice had (1) 10-100 fold increases in C. jejuni colonization of both strains, (2) pathologic change in draining lymph nodes but only mild changes in colon or cecal lamina propria, (3) significantly lower Th1/Th17-dependent anti-C. jejuni responses, (4) significantly higher IL-4 responses at 5 but not 7 weeks post infection (PI), (5) significantly higher Th2-dependent anti-C. jejuni responses, and (6) significantly elevated anti-ganglioside autoantibodies after C. jejuni infection. These responses in microbiota mice were correlated with a dominant Bacteroidetes and Firmicutes microbiota.
These data demonstrate that microbiota altered host-pathogen interactions in infected mice, increasing colonization and Th-2 and autoimmune responses in a C. jejuni strain-dependent manner. Thus, microbiota composition is another factor controlling susceptibility to GBS.
空肠弯曲菌是引起自身免疫性神经病吉兰-巴雷综合征（GBS）的主要前驱感染，其伴随外周神经的自身免疫性神经节苷脂抗体攻击。此前，我们表明，白细胞介素 10（IL-10）缺陷型小鼠中，由不同的感染菌株引起的对比免疫反应介导空肠弯曲菌诱导的结肠炎和自身免疫，这取决于感染的菌株。来自结肠炎患者的菌株引发 T 辅助 1（T1）依赖性炎症反应，而来自 GBS 患者的菌株引发 T2 依赖性自身抗体产生。两种综合征均因抗生素耗尽微生物群而加重，但控制 GBS 易感性的其他因素尚不清楚。
我们使用 16S rRNA 基因高通量测序，研究了空肠弯曲菌菌株来自结肠炎或 GBS 患者后，肠道微生物群落的结构是否改变宿主（1）胃肠道炎症或（2）抗神经节苷脂抗体反应。我们在具有（1）稳定的人肠道微生物群（微生物群）移植或（2）常规小鼠微生物群（微生物群）的 C57BL/6 小鼠中比较了这些反应。
将混合人粪便浆接种于无菌 C57BL/6 野生型（WT）小鼠中，提供了一种能够超过 20 代稳定传递其微生物群的小鼠模型。小鼠被安置在特定病原体-免费（SPF）设施中，而照顾者穿着无菌服装和限制进入的额外预防措施确保了没有获得任何小鼠病原体。微生物群赋予了 WT 模型许多变化，与之前的结果形成对比，之前的结果显示仅在空肠弯曲菌挑战后进行定植而无疾病。与微生物群小鼠相比，感染微生物群的小鼠对空肠弯曲菌肠道或 GBS 患者菌株的易感性（1）两种菌株的空肠弯曲菌定植增加了 10-100 倍，（2）引流淋巴结的病理变化，但结肠或盲肠固有层仅有轻度变化，（3）Th1/Th17 依赖性抗空肠弯曲菌反应显著降低，（4）感染后 5 周而非 7 周时 IL-4 反应显著升高，（5）Th2 依赖性抗空肠弯曲菌反应显著升高，以及（6）空肠弯曲菌感染后神经节苷脂自身抗体显著升高。微生物群小鼠中的这些反应与优势的拟杆菌门和厚壁菌门微生物群相关。
这些数据表明，微生物群改变了感染小鼠中的宿主-病原体相互作用，以依赖于空肠弯曲菌菌株的方式增加定植和 Th-2 和自身免疫反应。因此，微生物群组成是控制 GBS 易感性的另一个因素。
