Evolutionary history and gut microbial genome size in health and disease

Host-microbe codiversification reflects a shared evolutionary history between hosts and their associated microbial lineages. These patterns indicate stable, multi-generational symbiotic relationships maintained by diverse mechanisms, including vertical and familial transmission. While host-microbe codiversification has been observed in mammals, including human populations, it remains unclear whether the loss of evolutionarily stable symbionts predicts host disease status. In this study, we conducted a meta-analysis of 41 published studies spanning five disease categories (autism, neurodegenerative diseases, diabetes, inflammatory bowel disease, and obesity) to examine how a range of host disease conditions is associated with codiversified gut microbes and their genomic characteristics. By cross-referencing these studies against a list of globally prevalent codiversifying taxa, we tested whether host-microbe evolutionary stability predicts health status. Across four of five diseases, microbes with stronger evidence of codiversification were consistently more abundant in healthy hosts and depleted in disease states, though none of the individual associations were significant after phylogenetic correction. Microbial genome size, which can reflect long-term host adaptation, was positively correlated with disease index scores in four of five diseases, with significant phylogenetically corrected associations observed for autism, neurodegenerative diseases, diabetes, and IBD. Predicted microbial traits further showed that these larger-genome, disease-associated microbes were enriched for specific metabolic traits in multiple disease categories, including mucate utilization, lysine decarboxylase activity, and trehalose breakdown. Together, these findings are consistent with the hypothesis that disease-associated gut environments favor metabolically flexible, larger-genome microbes while reducing the abundance of host-dependent, smaller-genome symbionts. Overall, our results highlight the link between host health status, the evolutionary history of gut microbes, and their genomic and functional variation, providing an evolutionary framework for understanding the decoupling of host-microbe associations observed in human disease.