Background: Previous population studies have indicated age-associated changes in the gut microbiota. However, the actual age effects on microbiota are inevitably confounded by varying environmental factors such as diets and antibiotic use in the populations. Captive crab-eating macaques reared in a well-controlled environment can provide a useful model to recapitulate dynamic age-associated changes in the healthy primate gut microbiota.Results: We show evidence supporting lifelong age-associated changes in the healthy gut microbiota of captive macaques. The Firmicutes to Bacteroidetes ratio and beta diversity but not alpha diversity changed significantly with age. The most significantly age-associated genera were mainly composed of commensals, such as Faecalibacterium . Unexpectedly, a subset of the age-associated microbes were suspicious pathogens such as Helicobacter and Campylobacter , which were enriched in infant macaques, and possibly associated with gut mucosa development. These age-associated microbes were main contributors to the gut microbiota networks. Importantly, topology analysis showed that connectivity of these networks changed with age, and its rapid decrease in elderly macaques might indicate altered microbial interactions associated with host aging. Prevotella 9 , one of the most abundant age-associated genera, was the driver responsible for the gut microbiota maturation from infants to young adults. In adults, Rikenellaceae RC9 gut group and Megasphaera were two key drivers that continuously played an active role in driving microbial community changes of across different stages of adulthood. We also showed evidence of age-associated changes in gut microbial phenotypes and functions, in particular pathways of immunomodulatory metabolite synthesis, and metabolism of lipids and carbohydrates. The driver microbes were key players involved in these functions.Conclusions: Our current study in captive macaques demonstrate evident age-associated changes during the lifelong process of healthy gut microbiota development. The enrichment of suspicious pathogens in healthy infant macaques might indicate the importance of appropriate exposure to these microbes for the developing immune system. The current study provides new insights into the pivotal role of driver microbes and microbial interactions in gut microbiota, and further underlines the importance of network analysis in microbiome studies. Our findings also provide a baseline for better understanding of disease-related changes in the primate gut microbiota.
