Microbiome evolution during host aging

Host-microbiota interactionsCommensal microbes and their multicellular eukaryotic hosts constitute a highly integrated system-termed the holobiont [1]-which undergoes dynamic changes through time as it integrates and responds to signals from the environment.Dwelling at the interface between host epithelia and the external environment, commensal microbes actively modulate development, nutrient absorption, and disease onset in the host.Host metabolism is significantly modulated by commensal microbes, and the gut microbial composition significantly affects blood metabolite composition [2].Microbial communities differ among epithelia, reaching the highest complexity and taxonomic diversity in the oral cavity and in the gastrointestinal tract [3,4].Environmental factors, such as diet, drug use, and social environment, shape the composition of epithelia-associated microbiota [5][6][7], and environmental heterogeneity-rather than host genetics-can explain much of the interindividual differences in microbiota composition in humans [8].The assembly of specific host-associated communities, however, is also dictated by the host cell composition and activity, by the molecular components of the mucus layer, by the gut peristaltic contractility [9], and by epithelial integrity [10].In primates, recent evidence supports that host phylogenetic relatedness and gut physiology are overall better predictors of microbiota composition than diet [11].Together, the microbiota is a dynamic community, subject to changes in conjunction with host evolution and through the lifetime of individual hosts. Microbiota changes through timeJust as the composition of the microbiota varies within and between tissues [12], microbial consortia do also vary through time within individual tissues.Microbial composition in the gut of newborns is dramatically shaped by diet and varies depending on whether the infant is fed with maternal milk [13] or formula [14].Drug administration and antibiotic use importantly shape the host gut microbiota, leading to significant community shifts and increased abundance of otherwise rare microbial taxa [15].Although individual gut microbiota are largely unstable in the first years of life, they become more stable during adulthood [13, 16] and undergo dramatic changes in richness and composition upon onset of disease and frailty [17,18].The onset of specific diseases, such as cancer, obesity, diabetes, or inflammatory bowel disease (IBD), is associated with specific microbial signatures [19,20].Studies in humans and laboratory model organisms, such as flies, fish, and mice, have additionally shown that the composition of the gut microbiota dramatically changes during aging and is associated with host health and life span [17,[21][22][23][24].In mice, e.g., lipopolysaccharide (LPS) from gut microbiota can accelerate agedependent inflammation ("inflammaging(definition)") [25], and mice lacking Toll-Like receptor 4 (TLR4), which is the LPS receptor, are protected from age-dependent inflammation [26], showing that a microbial-specific substrate induces aging-specific phenotypes.Inflammaging can be further