Oral administration of <i>Lactobacillus kefiri</i> Fanghua reduces immune senescence and aging phenotypes

It has been suggested that immune senescence contributes to the aging of solid organs and that blocking immune senescence can alleviate the aging of organs. Aging is a systemic physiological change. It is currently difficult to achieve the goal of long-term delaying aging through drugs. Improving immunity and delaying aging through probiotics is a feasible research direction. Here, we first screened for a strain of <i>Lactobacillus kefiri</i> Fanghua (<i>L</i>. <i>kefiri</i>-FH) derived from Tibetan kefir and confirmed its function in restoring immunosuppression. Spleen weight, thymus weight, and whole blood cells were restored. The expression of programmed cell death-ligand 1 (<i>PD-1</i>), <i>P16^ink4a</i>, and senescence-associated secretory phenotype (SASP)-related genes in the spleen and thymus was decreased. Second, we further confirmed the phenotype of <i>L</i>. <i>kefiri</i>-FH in improving solid organ function in 16-month-old mice as well as prolonging the lifespan of <i>Caenorhabditis elegans</i>. Mechanistically, whole genome sequencing and metabolomic analysis indicated that <i>L</i>. <i>kefiri</i>-FH contained three genes related to bile acid metabolism and increased lithocholic acid (LCA) in the intestine. We also confirmed that LCA increased G-protein-coupled bile acid receptor (<i>Gpbar5</i> or <i>TGR5</i>) gene expression in dendritic cells (DCs) and inhibited the induction of T helper (Th) 1 and Th17 cells. Overall, our findings establish a causal relationship between the intestinal microenvironment, immune senescence, and solid organ aging, suggesting a way to regulate the intestinal microenvironment through diet, which thereby improves immune senescence and subsequently reduces solid organ aging.