Mapping the multigenomic human system: structural asymmetry and interface gaps in host-exogenous biological...

Host-microbiome research has expanded rapidly over the past two decades, generating extensive evidence linking microbial communities to immune regulation, metabolism, epithelial barrier integrity, and neuroendocrine signaling. Despite this progress, the organizational architecture through which exogenous biological signals become integrated into human physiological regulation remains comparatively under-synthesized. In particular, the regulatory interfaces connecting ecological microbial interaction with cellular and systemic physiological responses remain insufficiently integrated within the current literature.

This study aimed to perform a structured synthesis of host-exogenous biological interaction in order to examine how evidence is distributed across distinct levels of biological integration and to evaluate whether the literature supports a coherent multigenomic interpretative framework for human physiological organization.

A prospectively registered systematic synthesis was conducted using a Work Breakdown Structure (WBS)-based analytical architecture. Literature searches were organized into three predefined integration layers: functional physiological coupling, regulatory-interface mediation, and explicit genetic-level interaction. Following structured screening and architectural refinement, 168 studies were retained for cross-domain synthesis. Evidence was analyzed through sequential stages of structural mapping, cross-domain convergence analysis, and structural plausibility assessment.

The synthesis revealed a pronounced asymmetry within the evidentiary landscape. Functional host-microbe coupling is extensively consolidated across immune, metabolic, barrier, and neuroendocrine domains. In contrast, regulatory interfaces-particularly membrane-associated signaling environments and microenvironment-dependent regulatory dynamics-remain comparatively under-integrated. Cross-domain analysis identified recurrent stabilization-related processes involving barrier remodeling, immune recalibration, metabolic reprogramming, neuroendocrine coupling, and ecological signal amplification. These mechanisms frequently converged at membrane-associated signaling platforms operating within physicochemical microenvironments capable of shaping cellular decision processes.

These findings support a systems-level interpretation in which the human organism may be understood as a symbiotic multigenomic system characterized by continuous signal integration across interacting genomic sources. Membrane-associated signaling interfaces appear to function as important regulatory nodes where ecological signals, host physiological state, and microenvironmental constraints interact to shape long-term physiological organization. Reframing host-exogenous biological interaction within this multigenomic systems perspective may therefore provide a conceptual foundation for future research investigating how stabilized regulatory configurations emerge and persist across human physiological systems.