Irritable bowel syndrome (IBS) is a prevalent disorder of gut-brain interaction without a reliable cure. Evidence suggests that an alteration of the gut microbiome may contribute to IBS pathogenesis, motivating the development of microbiome-targeted therapies to alleviate IBS symptoms. However, IBS-specific microbiome signatures are variable across cohorts. A total of 9204 datasets were meta-analyzed, derived from fourteen IBS microbiome discovery cohorts, three validation cohorts for diet-microbiome interactions, and five rifaximin therapy cohorts. The consistent bacterial species and functional signatures associated with IBS were identified. Network analysis revealed two distinct IBS-enriched microbiota clusters; obligate anaerobes that are found commonly in the gut, and facultative anaerobes typically present in the mouth, implying a possible association between oral bacterial translocation to gut and IBS pathogenesis. By analyzing diet-microbiome interactions, microbiota-targeted diets that can potentially modulate the altered gut microbiota of IBS subjects toward a healthy status were identified. Furthermore, rifaximin treatment of IBS subjects was linked with a reduction in the abundance of facultatively anaerobic pathobionts. Gut microbiome signatures were identified across IBS cohorts that may inform the development of therapies for microbiome modulation in IBS. The microbiota-targeted diet patterns described may enable nutritional intervention trials in IBS and for assisting dietary management.