The aging process has been previously related to increased levels of inflammatory mediators such as cytokines and acute phase proteins in the bloodstream and tissues and to a perturbed gut microbiota. However, the underlying causes of age-associated inflammation remain unclear and it is not known whether this association is correlative or whether the gut microbiota is a cause of age-associated inflammation.
The researchers raised mice in germ-free (GF) conditions (GF old and young mice) and compared them to their conventionally raised counterparts (conventional old and young mice). Conventionally raised old mice showed an increase in intestinal permeability -mainly, altered paracellular permeability in the ileum and colon- and an increase in both levels of the bacterial cell wall component muramyl dipeptide (MDP) and pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin-6 (IL-6) in circulation compared to conventionally raised young mice. However, GF mice did not display an age-related increase in intestinal permeability, nor an increase in circulating pro-inflammatory cytokine levels. Besides this, a higher proportion of GF mice lived to 600 days than their conventional counterparts, and macrophages derived from aged GF mice maintained anti-microbial activity.
To study whether age-associated dysbiosis could increase age-associated inflammation, the researchers colonized, via co-housing, young and old GF mice with the fecal microbiota of old and young conventionally raised mice. Co-housing GF mice with old, but not young, conventionally raised mice increased paracellular permeability and pro-inflammatory cytokines circulating in the blood. These results demonstrate that age-associated intestinal barrier dysfunction and inflammation is dependent on the presence of the intestinal microbial community.
Then the researchers explored the relationship between TNF, age-associated inflammation, and gut dysbiosis based on previous findings that TNF has been shown to increase intestinal permeability in vitro and anti-TNF treatment can alter intestinal permeability in vivo. Old TNF-deficient mice with a microbiota, which do not have increased levels of circulating bacterial products and are protected from age-associated inflammation, were protected from age-associated inflammation (similar to old GF mice) and the researchers hypothesized that “unlike the GF mice, which are protected by virtue of not being exposed to bacteria, the TNF mice may be protected because they do not undergo microbial dysbiosis with age, which we demonstrate confers intestinal permeability and systemic inflammation in the context of the aged host”. Furthermore, treatment with an anti-TNF drug approved for human use (adalimumab) reversed age-related changes in the gut microbiome, which suggests that the age-related dysbiosis can be reversed by reducing TNF levels.
In conclusion, age-associated intestinal barrier dysfunction and inflammation is dependent on the presence of a gut microbiota in mice. While the application to humans is not yet known, reversing age-related gut microbiota changes may be a promising strategy for reducing age-associated inflammation and the accompanying morbidity.
Thevaranjan N, Puchta A, Schulz C, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017; 21(4):455-66. doi: 10.1016/j.chom.2017.03.002.