Elaine Holmes

The human gut microbiome is increasingly viewed as an active regulator of host physiology, extending beyond earlier taxonomy‐centered descriptions of a complex microbial community. Accumulating evidence supports an organ‐like conceptual framework in which the gut microbiome exhibits spatially structured organization, extensive metabolic capacity, and continuous bidirectional communication with host systems. Through the production of bioactive metabolites with endocrine‐like, immunomodulatory, and neuromodulatory properties, the microbiome contributes to metabolic, immune, and neuroendocrine regulation, thereby influencing systemic homeostasis and disease susceptibility. Recent advances in multi‐omics, spatial biology, and computational modeling are moving the field from taxonomic association toward functional interpretation, mechanistic insight, and causal inference. These approaches are beginning to reveal microbiome‐derived functional modules and host–microbe signaling networks that are shaped by host genetics, diet, medications, feeding patterns, circadian rhythms, and environmental exposures. In this review, we synthesize current mechanistic and translational evidence to conceptualize the gut microbiome as an organ‐like functional system, delineate its structural and functional organization, and propose a framework for mapping, modeling, and therapeutically targeting microbiome‐derived circuits to support precision medicine in metabolic, inflammatory, and selected gut–brain axis‐related disorders. The gut microbiome can be conceptualized as a distributed organ‐like functional system with spatially structured organization, broad biochemical capacity, and continuous bidirectional communication with the host. By transforming dietary, host‐derived, and environmental substrates into bioactive metabolites with endocrine‐like, immunomodulatory, and neuromodulatory activities, the microbiome contributes to metabolic, immune, and neuroendocrine pathways that shape systemic homeostasis and disease susceptibility. Emerging spatial, multi‐omics, and computational approaches are enabling systems‐level mapping of microbiome architecture, functional modules, and host–microbe signaling networks, moving the field beyond descriptive taxonomy toward mechanistic insight and causal inference. This organ‐level framework provides a conceptual and translational basis for developing precision microbiome medicine through the identification of targetable pathways, functional circuits, and personalized therapeutic strategies.