Improved Metabolite Prediction Using Microbiome Data-Based Elastic Net Models

Microbiome data are becoming increasingly available in large health cohorts, yet metabolomics data are still scant. While many studies generate microbiome data, they lack matched metabolomics data or have considerable missing proportions of metabolites. Since metabolomics is key to understanding microbial and general biological activities, the possibility of imputing individual metabolites or inferring metabolomics pathways from microbial taxonomy or metagenomics is intriguing. Importantly, current metabolomics profiling methods such as the HMP Unified Metabolic Analysis Network (HUMAnN) have unknown accuracy and are limited in their ability to predict individual metabolites. To address this gap, we developed a novel metabolite prediction method, and we present its application and evaluation in an oral microbiome study. The new method for predicting metabolites using microbiome data (ENVIM) is based on the elastic net model (ENM). ENVIM introduces an extra step to ENM to consider variable importance (VI) scores, and thus, achieves better prediction power. We investigate the metabolite prediction performance of ENVIM using metagenomic and metatranscriptomic data in a supragingival biofilm multi-omics dataset of 289 children ages 3–5 who were participants of a community-based study of early childhood oral health (ZOE 2.0) in North Carolina, United States. We further validate ENVIM in two additional publicly available multi-omics datasets generated from studies of gut health. We select gene family sets based on variable importance scores and modify the existing ENM strategy used in the MelonnPan prediction software to accommodate the unique features of microbiome and metabolome data. We evaluate metagenomic and metatranscriptomic predictors and compare the prediction performance of ENVIM to the standard ENM employed in MelonnPan. The newly developed ENVIM method showed superior metabolite predictive accuracy than MelonnPan when trained with metatranscriptomics data only, metagenomics data only, or both. Better metabolite prediction is achieved in the gut microbiome compared with the oral microbiome setting. We report the best-predictable compounds in all these three datasets from two different body sites. For example, the metabolites trehalose, maltose, stachyose, and ribose are all well predicted by the supragingival microbiome.