CoMMiT: Co-informed inference of microbiome-metabolome interactions via transfer learning

Abstract: Recent multi-omic microbiome studies enable integrative analysis of microbes and metabolites, uncovering their associations with various host conditions. Such analyses require multivariate models capable of accounting for the complex correlation structures between microbes and metabolites. However, existing multivariate models often suffer from low statistical power for detecting microbiome-metabolome interactions due to small sample sizes and weak biological signals. To address these challenges, we introduce CoMMiT, Co-informed inference of Microbiome-Metabolome Interactions via novel Transfer learning models. Unlike conventional transfer-learning methods that borrow information from external datasets, CoMMiT leverages similarities across metabolites within a single cohort, reducing the risk of negative transfer often caused by differences in sequencing platforms and bioinformatic pipelines across studies. CoMMiT operates under the flexible assumption that auxiliary metabolites are collectively informative for the target metabolite, without requiring individual auxiliary metabolites to be informative. CoMMiT uses a novel data-driven approach to selecting the optimal set of auxiliary metabolites. Using this optimal set, CoMMiT employs a de-biasing framework to enable efficient calculation of p-values, facilitating the identification of statistically significant microbiome-metabolome interactions. Applying CoMMiT to a feeding study reveals biologically meaningful microbiome-metabolome interactions under a low glycemic load diet, demonstrating the diet-host link through gut metabolism.