Stabilized adaptive states in microbiome–human integrated physiology: reframing health and chronic disease as symbiotic biological states

Background: Modern medicine has achieved remarkable precision in identifying molecular mechanisms and developing targeted interventions. However, a persistent clinical paradox remains: many chronic conditions-including metabolic, autoimmune, neuropsychiatric, and oncological disorders-exhibit long-term stability, resistance to guideline-concordant treatment, and recurrent trajectories. Despite extensive mechanistic characterization, the organizational basis of this stability remains insufficiently explained. Conceptual gap: In acute contexts such as infection and environmental intoxication, organisms can remain internally coherent while temporarily prioritizing non-host biological demands. This state-based perspective, however, has rarely been extended to chronic disease. At the same time, microbiome research has demonstrated that human physiology operates within a multigenomic system, in which exogenous gene repertoires contribute substantial metabolic and signaling capacity. Epigenetic research further indicates that repeated ecological exposures can progressively stabilize adaptive biological states over time. Proposed framework: We propose a conceptual framework in which health and disease are interpreted as stabilized adaptive states emerging from hierarchical signal integration within a multigenomic human system. In this model, chronic pathology reflects coherent but constrained regulatory configurations, rather than simple dysregulation or isolated system failure. Central to this interpretation is membrane-level decisional architecture, which governs signal routing, threshold modulation, and downstream transcriptional responses across tissues. Implications: This framework reorganizes existing evidence into a systems-level interpretation of chronic disease stability, providing a basis for generating testable hypotheses regarding state transitions, responsiveness to perturbation, and restoration of physiological flexibility. Rather than introducing new therapeutic doctrines, the model aims to clarify how biological systems stabilize over time and how such stabilization may be investigated within existing experimental paradigms. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261295889, CRD420261295889; https://www.crd.york.ac.uk/PROSPERO/view/CRD420261295945, CRD420261295945.