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The gut microbiota plays a crucial role in human health and the progression of diseases. As key mediators of the interactions between gut microbiota and host diseases, metabolite changes have a significant influence on disease development and progression. However, without experimental validation by metabolomics, identifying the level of metabolite changes in specific diseases remains challenging. For this reason, we devised a scoring function to quantitatively estimate metabolite changes across disease phenotypes by integrating changes in the relative abundance of gut microbes owning these metabolites, and hereby developed the online repository to reserve these associations of metabolites and diseases. The consequent GMMAD with v2.0 currently contains 83 diseases and 6966 metabolites. Among them, 85,136 associations are of statistical significance (paired-sample t-test, p-value < 0.05 and FDR < 0.1). Notably, the scoring function showed 84.06% consistency with experimentally validated disease-metabolite associations, outperforming the prior semi-qualitative method (72.5%). Aided by this resource, we identified 130 beneficial metabolites across 27 diseases. Among them, literature supports that 48 could ameliorate the disease status in animals or clinical trials. We listed these 48 promising drug molecules on the website. Furthermore, we constructed a metabolite-gene association network and provided information on the origins of metabolites. All the metabolite-associated information would help researchers reveal the mechanisms of how gut microbes regulate disease progression and guide drug development. The GMMAD v2.0 is freely accessible at http://gepa.org.cn/GMMAD2/.

BACKGROUND: The natural products, metabolites, of gut microbes are crucial effect factors on diseases. Comprehensive identification and annotation of relationships among disease, metabolites, and microbes can provide efficient and targeted solutions towards understanding the mechanism of complex disease and development of new markers and drugs.
RESULTS: We developed Gut Microbial Metabolite Association with Disease (GMMAD), a manually curated database of associations among human diseases, gut microbes, and metabolites of gut microbes. Here, this initial release (i) contains 3,836 disease-microbe associations and 879,263 microbe-metabolite associations, which were extracted from literatures and available resources and then experienced our manual curation; (ii) defines an association strength score and a confidence score. With these two scores, GMMAD predicted 220,690 disease-metabolite associations, where the metabolites all belong to the gut microbes. We think that the positive effective (with both scores higher than suggested thresholds) associations will help identify disease marker and understand the pathogenic mechanism from the sense of gut microbes. The negative effective associations would be taken as biomarkers and have the potential as drug candidates. Literature proofs supported our proposal with experimental consistence; (iii) provides a user-friendly web interface that allows users to browse, search, and download information on associations among diseases, metabolites, and microbes. The resource is freely available at http://guolab.whu.edu.cn/GMMAD .
CONCLUSIONS: As the online-available unique resource for gut microbial metabolite-disease associations, GMMAD is helpful for researchers to explore mechanisms of disease- metabolite-microbe and screen the drug and marker candidates for different diseases.