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

Abstract

ObjectiveFailing 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.DesignWe 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.ResultsWe 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.ConclusionsTaken 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.

The two facets of gp130 signalling in liver tumorigenesis

“…Furthermore, hepatocyte carcinogenesis was shown to be accelerated via enhanced genomic instability [92,93]. While impaired DNA damage response during chronic inflammation is mainly mediated by TNF α [70,94], survival and proliferation of genomic unstable hepatocytes are driven by gp130 trans-signalling by preventing p53-induced hepatocyte apoptosis (Fig. 2b) [45,93,95].…”

“…Obesity is linked to an increased risk of tumour development and was shown to promote HCC formation via enhanced TNF α and IL-6 secretion [69]. Alterations in the intestinal microbiota composition called "dysbiosis" are common to obesity, age-dependent inflammation [70], and chronic liver disease [71]. Venous blood that drains from the intestine first passes the liver and KCs serve as gatekeepers that protect against intestinal-derived pathogens.…”

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“…Aktywacja szlaku DDR w wątrobie ulegała osłabieniu już u 6-cio miesięcznych zwierząt [62]. Ponadto, sugeruje się, że związane z wiekiem zmiany w powstawaniu stanu zapalnego o niskim stopniu nasilenia oraz osłabiona odpowiedź DDR w wątrobie myszy wynikają ze zmian w mikrobiocie jelitowej tych zwierząt [63].…”

ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation

“…EGFR signalling has a dual role in the liver. EGFR signalling on hepatocytes was demonstrated to enhance intrinsic DNA damage repair and chronic inflammatory signalling in obese mice via IL-1β and TNFα abrogates this tumour suppressing effect of EGFR ( Figure 2 d) [ 111 ]. In contrast, similar to its role in intestinal tumour formation, autocrine activation of EGFR on Kupffer cells was demonstrated to promote IL-6 secretion ( Figure 2 d) [ 112 ].…”