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To understand the dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune, and clinical markers of microbiomes from four body sites in 86 participants over 6 years. We found that microbiome stability and individuality are body-site specific and heavily influenced by the host. The stool and oral microbiome are more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. We identify individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlate across body sites, suggesting systemic dynamics influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals show altered microbial stability and associations among microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease., Competing Interests: Declaration of interests M.P.S. is a co-founder and the scientific advisory board member of Personalis, Qbio, January, SensOmics, Filtricine, Akna, Protos, Mirvie, NiMo, Onza, Oralome, Marble Therapeutics, and Iollo. He is also on the scientific advisory board of Danaher, Genapsys, and Jupiter. A.H. is a founder and shareholder of Arxeon. Y.Z. and G.M.W. are co-founders of General Biomics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)