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Anammox granulation is an efficient solution proffered to enrich slow-growing anammox bacteria (AnAOB), but the lack of effective granulation strategies for low-strength domestic wastewater impedes its application. In this study, a novel granulation model regulated by Epistylis spp. for highly enriched AnAOB was revealed for the first time. Notably, anammox granulation was achieved within 65 d of domestic wastewater treatment. The stalks of Epistylis spp. were found to act as the skeleton of granules and provide attachment points for bacterial colonization, and the expanded biomass layer in turn provided more area for the unstalked free-swimming zooids. Additionally, Epistylis spp. exerted much less predation stress on AnAOB than on nitrifying bacteria, and AnAOB tended to grow in aggregates in the interior of granules, thus favoring the growth and retention of AnAOB. Ultimately, the relative abundance of AnAOB reached up to a maximum of 8.2% in granules (doubling time of 9.9 d) compared to 1.1% in flocs (doubling time of 23.1 d), representing the most substantial disparity between granules and flocs. Overall, our findings advance the current understanding of interactions involved in granulation between protozoa and microbial communities and offer new insight into the specific enrichment of AnAOB under the novel granulation model.