Healthy microbiome-moving towards functional interpretation.

Background: Microbiome-based disease prediction has significant potential as an early, noninvasive marker of multiple health conditions linked to dysbiosis of the human gut microbiota, thanks in part to decreasing sequencing and analysis costs. Microbiome health indices and other computational tools currently proposed in the field often are based on a microbiome's species richness and are completely reliant on taxonomic classification. A resurgent interest in a metabolism-centric, ecological approach has led to an increased understanding of microbiome metabolic and phenotypic complexity, revealing substantial restrictions of taxonomy-reliant approaches.

Findings: In this study, we introduce a new metagenomic health index developed as an answer to recent developments in microbiome definitions, in an effort to distinguish between healthy and unhealthy microbiomes, here in focus, inflammatory bowel disease (IBD). The novelty of our approach is a shift from a traditional Linnean phylogenetic classification toward a more holistic consideration of the metabolic functional potential underlining ecological interactions between species. Based on well-explored data cohorts, we compare our method and its performance with the most comprehensive indices to date, the taxonomy-based Gut Microbiome Health Index (GMHI), and the high-dimensional principal component analysis (hiPCA) methods, as well as to the standard taxon- and function-based Shannon entropy scoring. After demonstrating better performance on the initially targeted IBD cohorts, in comparison with other methods, we retrain our index on an additional 27 datasets obtained from different clinical conditions and validate our index's ability to distinguish between healthy and disease states using a variety of complementary benchmarking approaches. Finally, we demonstrate its superiority over the GMHI and the hiPCA on a longitudinal COVID-19 cohort and highlight the distinct robustness of our method to sequencing depth.

Conclusions: Overall, we emphasize the potential of this metagenomic approach and advocate a shift toward functional approaches to better understand and assess microbiome health as well as provide directions for future index enhancements. Our method, q2-predict-dysbiosis (Q2PD), is freely available (https://github.com/Kizielins/q2-predict-dysbiosis).