Modulating the human gut microbiome-host system: a new drug discovery paradigm

Abstract

The human gut microbiome-host system represents a recently unleashed chemo-biological realm of crucial importance in human biology and health. So much so that new therapeutic approaches targeting it are emerging to prevent and treat a broad range of conditions, including inflammatory, metabolic, and cardiovascular diseases, infectious disorders, cancer, and neurodegeneration. From a drug discovery standpoint, this paradigm offers several distinctive advantages: it introduces novel therapeutic modalities (such as fecal microbiota transplantation, probiotics, prebiotics, and postbiotics), expands the biological search space to include the gut metagenome, unlocks new chemical space through microbial metabolites, and enables gut-localized pharmacokinetics with the potential to reduce systemic exposure and off-target effects. However, realizing this therapeutic potential critically depends on establishing causal links between specific microbiome features, microbial metabolites, and disease phenotypes. Achieving such causality requires the integration of diverse experimental and computational approaches across multiple scales, including epidemiological and clinical studies, metagenomics and longitudinal multi-omic profiling, gnotobiotic animal models, strain isolation and cultivation, biochemical and molecular analyses, and synthetic biology—supported by Artificial Intelligence, Bioinformatics, and Cheminformatics. In this Perspective, we provide a concise overview of this rapidly evolving field. We review the gut microbiome–host system and the principal tools used to interrogate it, with an emphasis on approaches that enable causality inference. We further evaluate current strategies for therapeutic intervention and conclude with an assessment of key achievements to date, as well as the major challenges and opportunities that will shape the future of microbiome-based drug discovery.