The Young gut microbiota transplantation improves physical and psychological health of the old recipients through metabolic modulation

The gut microbiota evolves over lifetime and has significant impact on aging process. Targeting the gut microbiota represents a novel avenue to delay aging and aging-related physical and mental decline. However, underlying mechanism that the microbiota modulates aging process, particularly age-related physical and behavioral changes are not completely understood. We conducted fecal microbiome transplantation (FMT) from young or old male donor mice (3 months old) to the old male recipients (20 months old). Old recipients with young microbiota had a higher alpha diversity than the old recipients with old microbiota. When compared to FMT with old microbiota, FMT with young microbiota reduced body weight and prevented fat accumulation in the old recipients. FMT with young microbiota also lowered frailty, increased grip strength and alleviated depression and anxiety-like behavior in the old recipients. In consistent with observed physical changes, untargeted metabolomic analysis of blood and cecal contents revealed that FMT with young microbiota lowered age-related lipid metabolite levels and increased amino acid levels in the old recipients. Bulk RNAseq analysis of amygdala of the brain identified that FMT with young microbiota downregulated inflammatory pathways and upregulated oxidative phosphorylation in the old recipients. Our results demonstrate that the FMT with young microbiota has substantial positive influences on age-related body composition, frailty, and psychological behaviors. These effects are associated with regulations of host lipid and amino acids metabolism in periphery and transcriptional regulation of neuroinflammation and energy utilization in the brain.