Blood transcriptome bridges orthogonal immunotypes and gut microbiome enterotypes in humans Fabio Affaticati et al. Cell Reports Unveiling the systemic effects of disease and health requires a holistic approach that has mainly revolved around well-established, determinable molecular relationships such as the protein synthesis cascade and epigenetic mechanisms. In this study, we integrate multi-modal data from a cohort of 394 individuals to identify direct linkage of branches spanning human biological functions often not studied in conjunction, using clinical data, gut microbial abundances, blood immune cell compositions, blood transcriptomic ^p T cell receptor data. Contrary to current paradigms, we demonstrate that immunotypes and enterotypes are orthogonal, likely fulfilling distinct roles in maintaining homeostasis, bridged via the blood transcriptome. We identify two distinct inflammatory profiles: the first driven by interferon signaling and the other characterized by non-viral, NF-kB and IL-6 markers. Lastly, we present compelling data showing strong associations of Ruminococcaceae and Christensenellaceae bacteria with healthy immunotype and transcriptomic patterns, highlighting their potential role in immune health.