Gut microbiota dysbiosis shapes brain T-cell immunity in accelerated aging.

The bidirectional communication between the gut microbiota, immune system, and central nervous system-the gut‒brain axis-plays a vital role in maintaining brain health. Its disruption can lead to neuroinflammation and cognitive decline. However, the relationship between the gut microbiota and age-related changes in brain immunity remains unclear. This study examined gut microbiota composition and T-cell profiles in senescence-accelerated SAMP8 mice and senescence-resistant SAMR1 controls at young adult and aged stages. The accelerated-aging phenotype of SAMP8 mice was confirmed by reduced behavioral performance and brain transcriptomic alterations. Fecal microbiota profiles were obtained using culture-dependent plating and 16S rRNA gene sequencing. T-cell phenotypes were determined by flow cytometry on brain and splenic leukocytes. Strain, age, and sex were drivers of microbiota composition variation. Microbial diversity differed between strains independently of age. Several bacterial genera had altered abundances in young SAMP8 mice, with only Intestinimonas remaining higher in aged SAMP8. T-cell profiling revealed strain- and age-specific immune signatures. In the brain, SAMP8 mice exhibited a higher CD4⁺/CD8⁺ ratio, and higher levels of pro-inflammatory cytokine-producing CD4⁺ T cells compared to SAMR1. In contrast, the spleens of SAMP8 mice had a lower CD4⁺/CD8⁺ ratio. Only the spleens of aged SAMP8 mice showed increased T-cell activation (effector/naïve ratios) and higher levels of pro-inflammatory cytokine-producing CD4⁺ and CD8⁺ T cells, suggesting age- and tissue-specific immune alterations. Nine bacterial genera correlated with immune cell frequencies and ratios. Notably, Intestinimonas showed a discordant association with the CD4⁺/CD8⁺ ratio in the brain (negative) and spleen (positive). Furthermore, CD8⁺ T cells correlated with microbiota composition variation more strongly than strain, age, and sex. Together, these findings link the gut microbiota to age-dependent immune remodeling in the brain and imply that altered microbial communities could influence pro-inflammatory T-cell responses, thereby contributing to accelerated brain aging.