Multikingdom Gut Microbiome and Immune Aging: A Host-Microbial Signaling Perspective.

Abstract

Immune aging comprises heterogeneous changes in hematopoietic output, immune-cell function, inflammatory regulation, and tissue-specific immune states. In parallel, the gut microbiome undergoes ecological and functional remodeling across the bacteriome, mycobiome, virome, and archaeome, but these changes do not define a single "aged microbiome" and vary with host health, frailty, diet, medication exposure, and environmental context. Here, we examine how multikingdom gut microbiome remodeling intersects with distinct trajectories of immune aging. Rather than treating dysbiosis as a uniform upstream cause of immunosenescence, we organize the evidence around four interconnected processes: microbial signal generation, tissue access and compartmentalization, host sensing, and cell-specific interpretation. Age-associated changes in microbial metabolites and immunostimulatory products can influence epithelial barrier function, inflammatory signaling, immunometabolism, hematopoiesis, and lymphoid and myeloid cell states, but evidence strength varies substantially across pathways and microbial kingdoms. Causal support is most developed for selected bacteriome-associated mechanisms in experimental models, whereas aging-specific mechanistic evidence for the mycobiome, virome, and archaeome remains comparatively limited. Importantly, this relationship is reciprocal, because intrinsic immune and tissue aging can also reshape microbial ecology and functional capacity. We therefore view the gut microbiome as a dynamic and potentially modifiable component of immune aging rather than an autonomous driver of immunosenescence. This perspective shifts the translational focus from restoring a youthful microbiome toward targeting microbiome-associated functions and host-response pathways linked to specific immune-aging phenotypes.