Holobiontic Intercellular Relationships Between the Oral Cavity and the Rest of the Human Organism: A Narrative Review.

The holobiont represents a fundamental concept in modern biology, defining the organism as a complex unit composed of the host and its symbionts (microbes, viruses) that live together, forming an integrated biological system in which the host and microbes collaborate and influence each other (genetically and metabolically) and evolve as a single entity, rather than the host evolving in isolation. It is recognized that the health and functioning of the host fundamentally depend on its microbiome, consolidating the entire assembly as a unit of evolutionary selection with a shared genome called the hologenome. The oral microbiota plays an essential role in maintaining homeostasis and in modulating epigenetic processes, having unique characteristics due to the oral environment and microbial diversity. The aim of this narrative review is to explore how the oral microbiota interacts with host cells through microbial metabolites, including short-chain fatty acids (SCFAs), microRNAs (miRNAs), extracellular vesicles, and cellular signaling pathways, influencing prenatal and perinatal development as well as overall health. By critically integrating current evidence, this narrative review provides an updated conceptual framework linking the oral microbiota, the holobiont concept, epigenetic regulation, and prenatal and postnatal life. It advances the interpretation of the current literature by bringing together molecular, immunological, and developmental mechanisms that are commonly discussed separately, highlighting the oral microbiota as an active epigenetic regulator within the human holobiont. The effects of oral dysbiosis on both local and systemic health are analyzed, including inflammatory responses, periodontal health, and the risk of chronic diseases or cancer. In addition, the importance of maintaining microbiome homeostasis starting from the gestational period is discussed, in order to prevent epigenetic disturbances that may affect fetal development and postnatal oral health. Collectively, the available evidence supports the biological relevance of the oral holobiont in health and disease while highlighting its potential clinical implications. However, further mechanistic and longitudinal studies are needed to validate these associations and to clarify the causal pathway underlying host-microbiota interactions.