DNA sequencing has transformed our understanding of the microbiome in health and disease, yet microbiome-based interventions remain scarce in clinical practice. One challenge lies in reference-based computational pipelines, which report numerous false-positive species, compromising accuracy and reproducibility across cohorts (“garbage in, garbage out”). Fourier transform-based algorithms enhance species-level annotations and minimize contamination signals. Moreover, software that integrates longitudinal DNA, RNA, and metabolomics data enables monitoring early bacterial stress-sensing. Since stress responses are often stimulus-specific, transcriptional programs of bacteria point to the stressors itself and may inform targeted therapies; for example, supplementing commensal strains that consume gluconate decolonizes antibiotic-resistant Enterobacteriaceae through ecological competition.