Within the human gut reside diverse microbes coexisting with the host in a mutually advantageous relationship. Evidence has revealed the pivotal role of the gut microbiota in shaping the immune system. To date, only a few of these microbes have been shown to modulate specific immune parameters. Herein, we broadly identify the immunomodulatory effects of phylogenetically diverse human gut microbes. We monocolonized mice with each of 53 individual bacterial species and systematically analyzed host immunologic adaptation to colonization. Most microbes exerted several specialized, complementary, and redundant transcriptional and immunomodulatory effects. Surprisingly, these were independent of microbial phylogeny. Microbial diversity in the gut ensures robustness of the microbiota’s ability to generate a consistent immunomodulatory impact, serving as a highly important epigenetic system. This study provides a foundation for investigation of gut microbiota-host mutualism, highlighting key players that could identify important therapeutics. Display omitted •Human gut microbiota comprises a treasure trove of immunomodulatory bacteria•Diverse and redundant immune and transcriptional responses follow monocolonization•Immunologic and transcriptional changes are not related to microbial phylogeny•Following monocolonization, immune recalibration varies to strains within a species Each of 53 human-resident bacterial species studied in monoculture in mice modulates the host immune system, providing a baseline for investigating how consortia of gut microbes interact with their host.