Crohn’s disease (CD), a subtype of inflammatory bowel disease (IBD), is caused by abnormal interactions between host cells and gut microbes. Some cases of CD are restricted to either the colon or ileum in the gut, but the influence of region on the molecular profile of CD remains unclear. To learn more, researchers recently investigated the molecular and microbial signatures of colonic and ileal CD using human stool samples. Neither bulk DNA sequencing nor host genetic analysis alone could distinguish between colonic and ileal CD. However, integrated “multi-omics” analyses of DNA, RNA, metabolites, and proteins easily differentiated colonic CD from ileal CD. Compared with ileal CD, colonic CD was associated with greater activation of immune cells called neutrophils, and colonic CD severity was correlated with the abundance of the bacterium Bacteroides vulgatus. In contrast, ileal CD was associated with higher primary and secondary bile acid levels, and, correspondingly, with decreased abundance of bile acid–sensitive bacteria and increased abundance of bile acid–resistant bacteria. Separate biomarkers related to colonic CD or ileal CD severity were also identified. Although more research is needed, the findings reveal clear differences between CD location subtypes and provide insights to improve CD assessment.