Mayo Clinic, Rochester, Minnesota.
Arthritis Rheumatol. 2016 Dec;68(12):2878-2888. doi: 10.1002/art.39785.
The gut microbiome regulates host immune homeostasis. Rheumatoid arthritis (RA) is associated with intestinal dysbiosis. This study was undertaken to test the ability of a human gut-derived commensal to modulate immune response and treat arthritis in a humanized mouse model.
We isolated a commensal bacterium, Prevotella histicola, that is native to the human gut and has systemic immune effects when administered enterally. Arthritis-susceptible HLA-DQ8 mice were immunized with type II collagen and treated with P histicola. Disease incidence, onset, and severity were monitored. Changes in gut epithelial proteins and immune response as well as systemic cellular and humoral immune responses were studied in treated mice.
When treated with P histicola in prophylactic or therapeutic protocols, DQ8 mice exhibited significantly decreased incidence and severity of arthritis compared to controls. The microbial mucosal modulation of arthritis was dependent on regulation by CD103+ dendritic cells and myeloid suppressors (CD11b+Gr-1+ cells) and by generation of Treg cells (CD4+CD25+FoxP3+) in the gut, resulting in suppression of antigen-specific Th17 responses and increased transcription of interleukin-10. Treatment with P histicola led to reduced intestinal permeability by increasing expression of enzymes that produce antimicrobial peptides as well as tight junction proteins (zonula occludens 1 and occludin). However, the innate immune response via Toll-like receptor 4 (TLR-4) and TLR-9 was not affected in treated mice.
Our results demonstrate that enteral exposure to P histicola suppresses arthritis via mucosal regulation. P histicola is a unique commensal that can be explored as a novel therapy for RA and may have few or no side effects.
肠道微生物组调节宿主免疫稳态。类风湿关节炎（RA）与肠道菌群失调有关。本研究旨在测试一种源自人类肠道的共生菌调节免疫反应并在人源化小鼠模型中治疗关节炎的能力。
我们分离出一种共生菌Prevotella histicola，它是人类肠道中的固有细菌，当经肠内给予时具有全身免疫作用。用 II 型胶原免疫易患关节炎的 HLA-DQ8 小鼠，并给予 P histicola 治疗。监测疾病的发生率、发病和严重程度。研究治疗小鼠的肠道上皮蛋白和免疫反应以及全身细胞和体液免疫反应的变化。
用 P histicola 进行预防或治疗方案治疗时，与对照组相比，DQ8 小鼠的关节炎发生率和严重程度显著降低。微生物黏膜对关节炎的调节依赖于 CD103+树突状细胞和髓样抑制物（CD11b+Gr-1+细胞）的调节，以及在肠道中产生 Treg 细胞（CD4+CD25+FoxP3+），从而抑制抗原特异性 Th17 反应和增加白细胞介素-10 的转录。用 P histicola 治疗可通过增加产生抗菌肽的酶以及紧密连接蛋白（闭合蛋白 1 和闭合蛋白）的表达来降低肠道通透性。然而，治疗小鼠的 TLR-4 和 TLR-9 固有免疫反应不受影响。
我们的结果表明，经肠内暴露于 P histicola 可通过黏膜调节抑制关节炎。P histicola 是一种独特的共生菌，可以作为 RA 的一种新疗法进行探索，可能具有很少或没有副作用。
