Murine Gut Microbiome Meta-analysis Reveals Alterations in Carbohydrate Metabolism in Response to Aging

Abstract

Compositional and functional alterations to the gut microbiota during aging are hypothesized to potentially impact our health. Thus, determining aging-specific gut microbiome alterations is critical for developing microbiome-based strategies to improve health and promote longevity in the elderly. In this study, we performed a meta-analysis of publicly available 16S rRNA gene sequencing data from studies investigating the effect of aging on the gut microbiome in mice. Aging reproducibly increased gut microbial alpha diversity and shifted the microbial community structure in mice. We applied the bioinformatic tool PICRUSt2 to predict microbial metagenome function and established a random forest classifier to differentiate between microbial communities from young and old hosts and to identify aging-specific metabolic features. In independent validation data sets, this classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.75 to 0.97 in differentiating microbiomes from young and old hosts. We found that 50% of the most important predicted aging-specific metabolic features were involved in carbohydrate metabolism. Furthermore, fecal short-chain fatty acid (SCFA) concentrations were significantly decreased in old mice, and the expression of the SCFA receptor Gpr41 in the colon was significantly correlated with the relative abundances of gut microbes and microbial carbohydrate metabolic pathways. In conclusion, this study identified aging-specific alterations in the composition and function of the gut microbiome and revealed a potential relationship between aging, microbial carbohydrate metabolism, fecal SCFA, and colonic Gpr41 expression. IMPORTANCE: Aging-associated microbial alteration is hypothesized to play an important role in host health and longevity. However, investigations regarding specific gut microbes or microbial functional alterations associated with aging have had inconsistent results. We performed a meta-analysis across 5 independent studies to investigate the effect of aging on the gut microbiome in mice. Our analysis revealed that aging increased gut microbial alpha diversity and shifted the microbial community structure. To determine if we could reliably differentiate the gut microbiomes from young and old hosts, we established a random forest classifier based on predicted metagenome function and validated its performance against independent data sets. Alterations in microbial carbohydrate metabolism and decreased fecal short-chain fatty acid (SCFA) concentrations were key features of aging and correlated with host colonic expression of the SCFA receptor Gpr41. This study advances our understanding of the impact of aging on the gut microbiome and proposes a hypothesis that alterations in gut microbiota-derived SCFA-host GPR41 signaling are a feature of aging.