• 随年龄增长,小鼠肝脏中的慢性炎症水平升高,与肠道菌群变化有关;
  • 口服抗生素、敲除感知菌群的MyD88和无菌小鼠分析表明,中年小鼠的菌群可促进促炎细胞因子表达、削弱DNA损伤修复(DDR);
  • 年轻小鼠进食高脂饮食,可使肠道菌群增多、炎症水平升高、DDR降低,用抗生素处理可逆转;
  • 使肝脏巨噬细胞回到未活化状态,可逆转年龄相关的促炎细胞因子升高和DDR降低;
  • 促炎细胞因子TNFα和IL-1β,可干扰巨噬细胞产生的HB-EGF的促DDR作用。
Gut [IF:19.819]

Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair



2019-10-05, Article

Abstract & Authors:展开

Objective : Failing to properly repair damaged DNA drives the ageing process. Furthermore, age-related inflammation contributes to the manifestation of ageing. Recently, we demonstrated that the efficiency of repair of diethylnitrosamine (DEN)-induced double-strand breaks (DSBs) rapidly declines with age. We therefore hypothesised that with age, the decline in DNA damage repair stems from age-related inflammation.
Design : We used DEN-induced DNA damage in mouse livers and compared the efficiency of their resolution in different ages and following various permutations aimed at manipulating the liver age-related inflammation.
Results : We found that age-related deregulation of innate immunity was linked to altered gut microbiota. Consequently, antibiotic treatment, MyD88 ablation or germ-free mice had reduced cytokine expression and improved DSBs rejoining in 6-month-old mice. In contrast, feeding young mice with a high-fat diet enhanced inflammation and facilitated the decline in DSBs repair. This latter effect was reversed by antibiotic treatment. Kupffer cell replenishment or their inactivation with gadolinium chloride reduced proinflammatory cytokine expression and reversed the decline in DSBs repair. The addition of proinflammatory cytokines ablated DSBs rejoining mediated by macrophage-derived heparin-binding epidermal growth factor-like growth factor.
Conclusions : Taken together, our results reveal a previously unrecognised link between commensal bacteria-induced inflammation that results in age-dependent decline in DNA damage repair. Importantly, the present study support the notion of a cell non-autonomous mechanism for age-related decline in DNA damage repair that is based on the presence of ‘inflamm-ageing’ cytokines in the tissue microenvironment, rather than an intrinsic cellular deficiency in the DNA repair machinery.

First Authors:
Avital Guedj

Correspondence Authors:
Jacob Rachmilewitz

All Authors:
Avital Guedj,Yael Volman,Anat Geiger-Maor,Julia Bolik,Neele Schumacher,Sven Künzel,John F Baines,Yuval Nevo,Sharona Elgavish,Eithan Galun,Hagai Amsalem,Dirk Schmidt-Arras,Jacob Rachmilewitz