BACKGROUND: Microbiome biomarker discovery for patient diagnosis, prognosis, and risk evaluation is attracting broad interest. Selected groups of microbial features provide signatures that characterize host disease states such as cancer or cardio-metabolic diseases. Yet, the current predictive models stemming from machine learning still behave as black boxes and seldom generalize well. Their interpretation is challenging for physicians and biologists, which makes them difficult to trust and use routinely in the physician-patient decision-making process. Novel methods that provide interpretability and biological insight are needed. Here, we introduce "predomics", an original machine learning approach inspired by microbial ecosystem interactions that is tailored for metagenomics data. It discovers accurate predictive signatures and provides unprecedented interpretability. The decision provided by the predictive model is based on a simple, yet powerful score computed by adding, subtracting, or dividing cumulative abundance of microbiome measurements. RESULTS: Tested on >100 datasets, we demonstrate that predomics models are simple and highly interpretable. Even with such simplicity, they are at least as accurate as state-of-the-art methods. The family of best models, discovered during the learning process, offers the ability to distil biological information and to decipher the predictability signatures of the studied condition. In a proof-of-concept experiment, we successfully predicted body corpulence and metabolic improvement after bariatric surgery using pre-surgery microbiome data. CONCLUSIONS: Predomics is a new algorithm that helps in providing reliable and trustworthy diagnostic decisions in the microbiome field. Predomics is in accord with societal and legal requirements that plead for an explainable artificial intelligence approach in the medical field.