Aging of the adaptive immune system affects the gut microbiome and systemic levels of vitamin B6

Age-associated dysregulation of the gut microbiota is a hallmark of aging and has been linked to multiple age-related diseases, yet upstream host factors driving these changes remain incompletely defined. Extensive bidirectional crosstalk between gut microbiota and mucosal immunity has been described. Aging is accompanied by a progressive decline in immune function, collectively termed aging-associated immune remodeling (AAIR). AAIR encompasses widespread compositional and functional changes that impair an effective response to pathogens, vaccines, and tissue damage. We examined whether AAIR is an upstream host factor influencing the composition of the microbiome upon aging.

Hallmarks of AAIR were also present in the ileal lamina propria, including reduced naïve CD4⁺ and CD8⁺ T cell populations and expansion of memory and regulatory T cell subsets. To test whether mucosal AAIR reflects intrinsic aging of the hematopoietic system, we used an HSC transplantation model where young RAG1^-/- recipients develop an adaptive immune system derived exclusively from either young or aged donor HSC in an otherwise young host environment. Recipients of aged HSCs recapitulated key features of mucosal AAIR, particularly loss of naïve T cells, demonstrating that AAIR in the ileal LP is driven at least in part by aged HSCs. Shotgun metagenomic sequencing of fecal samples revealed that ileal AAIR is associated with alterations in gut microbiota. In detail, there was a reduced abundance of taxa associated with the vitamin B6 (VB6) biosynthesis and salvage pathways. Accordingly, VB6 levels in serum were reduced in mice with aged immune systems.

Our findings link AAIR to reduced microbial VB6 pathway abundance and lower systemic VB6 availability, suggesting that immune aging shapes the functional output of the microbiome in ways that diminish its VB6 biosynthetic capacity. This postulates an immune-microbiome-VB6 association that warrants further investigations for therapeutic strategies to increase VB6 levels upon aging. Video Abstract.