The hallmarks of host-microbiome decoupling.

The human host and its resident microbiome maintain continuous interactions that influence immune regulation, metabolism, neuroendocrine signaling, epithelial barrier function, and circadian organization. Although multi-omics approaches have improved mechanistic understanding of host-microbiome interactions, dominant translational models remain largely based on compositional descriptions and often do not capture persistence, systemic propagation, or temporal instability in microbiome-associated disease. Host-microbiome decoupling is defined here as a progressive reduction in functional coordination between host regulatory systems and microbial ecological behavior. The concept refers to conditions in which microbial signals, activities, or rhythmic patterns no longer remain aligned with host physiological regulation. A hallmarks-based framework is proposed to examine biological domains in which coordination between host regulation and microbial ecology deteriorates. Core hallmarks include breakdown of signaling fidelity, microbiome-driven immune miscalibration, barrier compartment failure, endocrine-microbiome uncoupling, ecological destabilization, and temporal desynchronization between host circadian programs and microbial oscillations. Additional dimensions include pathological microbial metabolite dominance with epigenetic embedding, endocrine and neuro-microbiome regulatory uncoupling, ecological destabilization of microbiome functional capacity, and temporal desynchronization between host circadian programs and microbial oscillations. Across inflammatory, metabolic, neurodegenerative, and neoplastic conditions, microbial activity may operate outside normal ecological constraints, influencing immune regulation, metabolic signaling, neuroimmune communication, and tumor-associated processes. Within this framework, resilience, signaling proportionality, host responses appropriately scaled to microbial input, and temporal coordination represent central properties of host-microbiome compatibility.