Microbiome Signatures Definition: A Conceptual Advancement for Translational Microbiome Science

The term microbiome signatures has become increasingly prominent in microbiome research, yet its definition remains inconsistently applied and often oversimplified. However, a precise microbiome signatures definition is critical for advancing both basic science and translational applications. Most commonly, microbiome signatures are equated to lists of differentially abundant taxa associated with disease states. Our position is that this approach fails to capture the complexity and dynamics of microbial ecosystems. A more robust, complete, and actionable microbiome signatures definition must account not only for the presence or absence of taxa but also for their traits, interactions, and functional roles within specific environmental or host contexts.

Proposed Microbiome Signatures Definition

A microbiome signature is a reproducible ecological or functional pattern—reflected through taxa, their features, or their interactions—that emerges in association with a specific host state, environmental condition, or intervention. These signatures may not rely on identical taxa across all contexts, but instead on conserved microbial traits, directional shifts, or networked relationships that reflect underlying dysbiosis or homeostasis.

Rationale and Conceptual Framework

Existing definitions of microbiome signatures often emphasize taxonomic reproducibility and statistical significance in differential abundance. While these are incredibly valuable, a reductionist framing can obscure the importance of ecological and functional consistency that persists across studies, populations, and analytical methods. Our definition of microbiome signatures expands the scope to include not only microbial identities but also their traits, interactions, and emergent ecological relationships, thus capturing the true complexity of host-microbiome systems.

This definition rests on the following conceptual pillars:

• Functional Redundancy and Trait Conservation: Taxa may vary, but conserved microbial functions (e.g., bile acid deconjugation, urease activity, MMP induction, heavy metal tolerance, or efflux pump expression) persist across environments and cohorts, underscoring functional stability despite taxonomic variability.

• Ecological Plasticity and Environmental Filtering: Microbial community structures reflect selective pressures (e.g., diet, metals, host inflammation), which drive predictable patterns of trait enrichment.

• Networked and Directional Relationships: Signatures often include directional shifts in taxa ratios (e.g., Firmicutes: Bacteroidetes), co-occurrence patterns, or keystone dynamics.

Comparison to Prevailing Microbiome Signature Definitions

Most existing frameworks rely on statistical overrepresentation of taxa across case-control comparisons. However, such approaches are limited by cohort variability, methodological heterogeneity, and geographic or dietary differences. The proposed definition incorporates these realities, allowing for interpretation of conserved functional trajectories even in the absence of fixed taxonomic recurrence. Thus, our microbiome signatures definition transcends static taxonomic lists and acknowledges the emergent, context-dependent relationships between microbes, their environment, and the host.

Advantages for Translational Microbiome Research

This enriched conceptualization of microbiome signatures enhances their relevance in clinical and translational applications by supporting the development of microbiome-targeted interventions (MBTIs) based on microbial function, environmental pressures, and inter-species relationships, not merely taxonomic identity. It also facilitates the formulation of STOP advisories by linking host pathophysiology to trait-enriched dysbiosis, providing a mechanistic rationale for discontinuing practices that exacerbate microbial imbalance. Additionally, it strengthens the Microbial Signature Confidence Score (MSCS) framework by incorporating ecological and functional coherence, thereby improving the reliability of signature-based diagnostics. Finally, this definition enables cross-condition mapping of conserved dysbiotic features, such as MMP-expressing pathobionts shared between endometriosis and cancer, broadening the utility of microbiome signatures in comparative disease analysis.

Conclusion

This definition represents a conceptual advancement in the understanding of microbiome signatures. It aligns with ecological theory, systems biology, and translational medicine, providing a foundation for actionable and mechanistically grounded microbiome science. By recognizing the emergent, adaptive, and context-dependent nature of microbial patterns, this new microbiome signatures definition and framework enables improved mechanistic insight, and a new generation of signature-based diagnostics, therapeutics, and interventions.