The gut microbiota produces a vast and structurally diverse array of small molecules. Remarkably, bacterial processing of ingested food and drug compounds alone accounts for the production of thousands of metabolites, many of which are not well studied despite possessing disease connections. Among these, microbiota-dependent metabolites (MDMs) are significant predictors of kidney disease progression, yet their mechanistic roles in kidney signaling and disease remain largely unexplored. Our research investigates how these microbial metabolites mediate inter-nephron and inter-organ signaling that governs fibrosis and repair in the kidney. We develop and use microbiome-focused metabolomics platforms to identify and quantify diverse MDMs. We employ a kidney organoid model system to study the impact of these molecules on inter-nephron signaling and fibrosis. We also employ cheminformatics and network topology methods to decode microbial production dynamics. By understanding these microbial chemical interactions, we aim to design targeted microbiome interventions to protect and restore kidney health.