A benign helminth alters the host immune system and the gut microbiota in a rat model system

Helminths and bacteria are major players in the mammalian gut ecosystem and each influences the host immune system and health. Declines in helminth prevalence and bacterial diversity appear to play a role in the dramatic rise of immune mediated inflammatory diseases (IMIDs) in western populations. Helminths are potent modulators of immune system and their reintroduction is a promising therapeutic avenue for IMIDs. However, the introduction of helminths represents a disturbance for the host and it is important to understand the impact of helminth reintroduction on the host, including the immune system and gut microbiome. We tested the impact of a benign tapeworm, Hymenolepis diminuta, in a rat model system. We find that H. diminuta infection results in increased interleukin 10 gene expression in the beginning of the prepatent period, consistent with induction of a type 2 immune response. We also find induction of humoral immunity during the patent period, shown here by increased IgA in feces. Further, we see an immuno-modulatory effect in the small intestine and spleen in patent period, as measured by reductions in tissue immune cells. We observed shifts in microbiota community composition during the patent period (beta-diversity) in response to H. diminuta infection. However, these compositional changes appear to be minor; they occur within families and genera common to both treatment groups. There was no change in alpha diversity. Hymenolepis diminuta is a promising model for helminth therapy because it establishes long-term, stable colonization in rats and modulates the immune system without causing bacterial dysbiosis. These results suggest that the goal of engineering a therapeutic helminth that can safely manipulate the mammalian immune system without disrupting the rest of the gut ecosystem is in reach.

蠕虫（Helminths）与细菌是哺乳动物肠道生态系统的关键组成类群，二者均可调控宿主免疫系统与健康状态。西方人群中免疫介导炎症性疾病（Immune Mediated Inflammatory Diseases, IMIDs）的发病率呈急剧上升趋势，现有研究表明该现象与蠕虫流行率下降、细菌多样性降低存在关联。蠕虫是免疫系统的强效调节剂，重新引入蠕虫被认为是治疗IMIDs的极具前景的治疗策略。然而，蠕虫定植会对宿主造成一定程度的扰动，因此明确蠕虫重新引入对宿主（包括免疫系统与肠道微生物组）的影响具有重要意义。
本研究以大鼠为模型，探究无害绦虫缩小膜壳绦虫（Hymenolepis diminuta）的宿主效应。实验结果显示，在感染潜伏期（prepatent period）初期，缩小膜壳绦虫感染可上调白细胞介素10的基因表达，这与2型免疫应答的诱导特征一致。在显症期（patent period），研究还观察到体液免疫被激活，具体表现为粪便中免疫球蛋白A（IgA）水平升高。此外，显症期小肠与脾脏组织中的免疫细胞数量显著降低，证实该绦虫可发挥免疫调节作用。
针对肠道微生物组，本研究发现缩小膜壳绦虫感染会在显症期引发微生物群落组成的改变（β多样性（beta-diversity）偏移），但此类组成变化程度较轻，仅发生于两个处理组共有的科与属水平类群中，且α多样性（alpha diversity）未出现显著变化。
缩小膜壳绦虫是蠕虫治疗的极具潜力的模型生物，因其可在大鼠体内实现长期稳定定植，且能在不引发菌群失调的前提下调控宿主免疫系统。本研究结果表明，开发一种可安全调控哺乳动物免疫系统、同时不破坏肠道生态系统稳态的治疗性蠕虫的目标已近在咫尺。