创作:mildbreeze 审核:mildbreeze 06月01日
  • C9orf72缺陷小鼠在不同动物房(H和B)饲养时,其生存率、炎症和自身免疫表型有明显区别,与肠道菌群的差异有关;
  • 与病情轻、生存久的B鼠相比,病情重、生存短的H鼠的菌群多样性较低,一些微生物的丰度也不同,H鼠粪便的免疫刺激性更强;
  • 长期使用抗生素能预防和抑制H鼠的炎症和自身免疫表型,粪菌移植试验也支持肠道菌群的调控作用;
  • 肠道菌群可调节外周免疫细胞对脊髓的浸润和小神经胶质活化,从而影响C9orf72缺陷小鼠的神经炎症。
Nature [IF:43.07]

C9orf72 suppresses systemic and neural inflammation induced by gut bacteria



05-13, Article

Abstract & Authors:展开

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3,4,5,6,7,8,9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6,7,8,9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics—as well as transplanting gut microflora from a protective environment—attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.

First Authors:
Aaron Burberry

Correspondence Authors:
Kevin Eggan

All Authors:
Aaron Burberry,Michael F Wells,Francesco Limone,Alexander Couto,Kevin S Smith,James Keaney,Gaëlle Gillet,Nick van Gastel,Jin-Yuan Wang,Olli Pietilainen,Menglu Qian,Pierce Eggan,Christopher Cantrell,Joanie Mok,Irena Kadiu,David T Scadden,Kevin Eggan