<i>Lactobacillus rhamnosus GG</i> Colonization in Early Life Ameliorates Inflammaging of Offspring by Activating SIRT1/AMPK/PGC‐1<i>α</i> Pathway

Abstract

Inflammaging refers to chronic, low-grade inflammation during aging, which contributes to the pathogenesis of age-related diseases. Studies have shown that probiotic intervention in the aging stage could delay aging-related disorders. However, whether the application of probiotics in early life could have antiaging effects on offspring was unknown. Here, we investigated the effects of <i>Lactobacillus rhamnosus GG</i> (<i>LGG</i>) colonization in early life on inflammaging of offspring. Pregnant mice with the same conception time were given <i>LGG</i> live bacteria (LC group) or <i>LGG</i> fixed bacteria (NC group) from the 18th day after pregnancy until natural birth. The progeny mice were treated with 10⁷ cfu of live or fixed LGG for 0-5 days after birth, respectively. <i>LGG</i> colonization could be detected in the feces of 3-week offspring. The 16S rRNA sequencing analysis of 3-week-old offspring showed that colonization of <i>LGG</i> in early life could alter the composition and diversity of gut microbiota. Interestingly, the beneficial effects of <i>LGG</i> colonization in early life on the microbiota lasted to 8 months old. The abundance of longevity-related bacteria (<i>Lactobacillus</i>, <i>Bifidobacterium</i>, and <i>Akkermansia muciniphila</i>) increased significantly in the <i>LGG</i> colonization group. In addition, <i>LGG</i> colonization increased the abundance of short-chain fatty acid- (SCFA-) producing bacteria and the production of cecal SCFAs. <i>LGG</i> colonization in early life protected the intestinal barrier, enhanced antioxidant defense, attenuated epithelial cell DNA damage, and inhibited intestinal low-grade inflammation in 8-month-old progeny mice. Mechanically, <i>LGG</i> could upregulate Sirtuin1 (SIRT1)/Adenosine 5'-monophosphate-activated protein kinase (AMPK)/Peroxisome proliferator-activated receptor <i>γ</i> coactivator 1-<i>α</i> (PGC-1<i>α</i>) pathway and repress activation of nuclear factor-kappa B (NF-<i>κ</i>B), while the protective effect of <i>LGG</i> was blunted after SIRT1 gene silencing. Together, <i>LGG</i> colonization in early life could ameliorate inflammaging of offspring, which would provide a new strategy for the prevention of age-related diseases.