Impact of microbiome manipulation on age-related inflammation and immune system dysfunction

Abstract

The aging process can be described as a disease characterized by increasing inflammation and declining immune function. Gut microbiota may impact this process, as it is altered with both disease and advanced age. We examined if gut microbiota from young animals could reduce inflammation, cellular senescence, and immune system dysfunction in older animals. To do so, we performed fecal microbiota transplants (FMT) from young (14 weeks) to groups of young, middle-aged (50 weeks), and old (100 weeks) Balb/c mice. Groups (n=5) were pre-treated with ampicillin for 3 weeks followed by oral gavage with freshly homogenized fecal material (FMT groups) or PBS and euthanized 3 weeks later. Fecal samples were collected over time for microbial analyses. Small intestines, cecum, and colons were collected for gross and microscopic analyses. To examine changes to systemic immunity, splenic and whole blood B- and T-cells were stained for surface and intracellular marker expression (i.e. activation levels, senescence) by flow cytometry.

Overall, PBS control groups showed classic age-related effects. This included signs of molecular dysfunction in oldest mice with altered levels of the NfkB inhibitor IkBz and increased senescence subsets (P16INK4a+, β-gal+). A single FMT treatment had the most dramatic effects vs. PBS controls in older mice compared to other age groups. While treatment significantly reduced IkBz and microbial-sensing TLR2 expression, FMT did not have visible impact on cellular senescence. These results reinforce a critical role for the microbiome in age-related immune decline and suggest a regimen of FMT from healthy young subjects may be a potential strategy to lower chronic inflammation and improve immune function in the elderly.