Effects of the Gut Microbiome on Aged‐Related Cognitive Decline and Inflammation

Abstract

IntroductionAging is associated with low level inflammation and cognitive decline. We tested the hypothesis that the gut microbiome has a major role in these age‐related changes and that this age‐related decline is transferrable through the gut microbiome in mice.MethodsFor this study we gavaged a suspension of fresh fecal contents from aged (~20 months) or young (~3 months) BL/6 mice into germ‐free BL/6 mice (N=10 per group). The absence of gut bacteria in germ‐free mice reduced competition and enhanced the colonization of the aged or young microbiomes. Gavages began in the germ‐free mice at 12 weeks of age and were repeated monthly for 3 months. Behavioral testing and collection of fecal samples occurred over the study period. After 3 months, mice were euthanized, and the brain and colon were harvested for assessing the inflammatory state using flow cytometry. Bacterial community structures and relative abundances were measured in fecal samples by sequencing the bacterial 16S rRNA gene. Short‐chain fatty acids (SCFA) were measured in feces using LC‐MS.ResultsMice with an aged microbiome demonstrated depressive‐like behavior, impaired short‐term memory, and impaired spatial memory for at least 3 months after the initial gavage using the tail‐suspension (P=0.008), the Novel Object Recognition (P<0.001), and the Barnes Maze (P=0.019) tests respectively. The aged microbiome increased inflammation as revealed by flow cytometry studies. In brain γΔ T cells were increased (P=0.017) with an aged microbiome. In the gut, leukocytes were increased (P<0.001) and Tregs were decreased (P=0.029) with an aged microbiome. Mice with aged and young microbiomes showed clear differences in bacterial α diversity (Simpsons and Fisher, P<0.001 for both) and β diversity (weighted and unweighted PCoA, P=0.001 for both). At 3 months after the initial gavage, the bacteria families, Defluviitaleaceae and Lactobacillaceae, were significantly decreased in mice with aged microbiomes (P<0.001 and P=0.01 respectively). Fecal SCFAs, including acetate, propionate, and butyrate (P<0.01 for each), were decreased in mice with an aged microbiome. These 3 SCFAs are gut protective and anti‐inflammatory. Of note, Lactobacillus, a SCFA‐producing genus, was decreased 3‐fold in mice with an aged microbiome (P=0.009).ConclusionWe conclude that the gut microbiome has a major role in aged‐related cognitive impairment and inflammation. Furthermore, cognitive decline and an enhanced inflammatory state associated with aging can be transferred via the gut microbiome. Thus, manipulating the gut microbiome can protect from the detrimental effects associated with aging.Support or Funding InformationRO1 AG058463 (RMB and LDM)RO1 NS103592 (LDM and RMB)