Background <p>Functional gastrointestinal disorders present diagnostic and therapeutic challenges, and there is a strong need for molecular markers that enable early health insights and intervention. Herein, we present an approach to assess the gut microbiome with stool-based gut metatranscriptome data from a large adult human population (<i>n</i> = 80,570), using irritable bowel syndrome as an example that features both an abnormal gut microbiome and a spectrum of distinct conditions.</p> Methods <p>We develop a suite of eight gut microbial functional pathway scores, each of which represents the activity of a set of interacting microbial functional features (based on KEGG orthology) relevant to known gut biochemical activities. We use a normative approach within a subpopulation (<i>n</i> = 9,350) to define “Good” and ”Not Optimal” activities for these transcriptome-based gut pathway scores.</p> Results <p>We hypothesize that Not Optimal scores are associated with irritable bowel syndrome (IBS) and its subtypes (i.e., IBS-Constipation, IBS-Diarrhea, IBS-Mixed Type). We show that Not Optimal functional pathway scores are associated with higher odds of IBS or its subtypes within an independent cohort (<i>n</i> = 71,220) using both the Rome IV Diagnostic Questionnaire as well as self-reported phenotypes.</p> Conclusions <p>Rather than waiting to diagnose IBS after symptoms appear, these functional pathway scores can help to provide early health insights into molecular pathways that may contribute to IBS. These molecular endpoints could also assist with measuring the efficacy of practical interventions, developing related algorithms, providing personalized nutritional recommendations, diagnostic support, and treatments for gastrointestinal disorders like IBS.</p>