<p>The human holobiont, a host and its symbiotic microbiota, constitutes a multispecies entity where microbial interactions critically govern host physiology, immunity, and metabolism. Integrating holobiont theory with biosemiotics, this paper reframes host-microbe dynamics as co-evolved semiotic networks. Molecular signaling between gut microbiota and host cells adheres to Peircean triadic semiosis: microbial metabolites (representamen) encode environmental states (objects), eliciting physiological interpretants. Hoffmeyer’s semiotic scaffolding helps to explain stabilized interactions, exemplified by quorum sensing-regulated butyrate synthesis and secretory IgA-mediated symbiosis. Uexküll’s Umwelt theory resolves interspecies perceptual divides, positioning shared signs as multidirectional mediators. Within this biosemiotic paradigm, health emerges as semiotic coherence, a state of synchronized, context-appropriate signaling across holobiont agents. Dysbiosis manifests as a semiotic disorder, characterized by dysregulation of interspecies semiotic processes which propagates systemic pathophysiology. Therapeutic strategies, including probiotic supplementation and microbiota transplantation, function by reestablishing semiotic fidelity within these networks. By framing holobiont dynamics as semiotic phenomena, this work challenges reductionist models of host-microbe interactions and advances an interdisciplinary paradigm for understanding health and disease. Coherent cross‑species semiosis is necessary for health, which arises as an emergent property reflecting numerous negotiated meaning‑making processes between the host and its symbionts. Pathology results when these processes collapse. This synthesis advances interdisciplinary models for translational medicine and ecological theory, where health thrives not in isolation, but in the fluency of a co-authored language of life.</p>