The International Rome Committee defines Disorders of Gut-Brain Interactions (DGBI) based upon distinct combinations of chronic and/or recurrent unexplained gastrointestinal symptoms. Yet patients often experience overlapping DGBI. Patients with DGBI frequently also suffer from extraintestinal symptoms, including fatigue, sleep disturbances, anxiety, and depression. Patients with overlapping DGBI typically experience more severe GI symptoms and increased psychosocial burden. Concerning the pathophysiology, DGBI are associated with disruptions in gut motility, function of the brain and enteric neurons, immune function, and genetic markers, with recent findings revealing gut microbiome alterations linked to these mechanisms of DGBI. Emerging evidence summarized in this review suggests that the microbiome influences various established disease mechanisms of different DGBI groups. Overall, changes in the gastrointestinal microbiome do not seem to be linked to a specific DGBI subgroup but may play a key role in the manifestation of different DGBI and, subsequently, overlap of DGBI. Understanding these shared mechanisms and the role of the gastrointestinal microbiome, particularly for overlapping DGBI, might aid in developing more precise diagnostic criteria and treatment strategies while developing personalized interventions that target specific mechanisms to improve patient outcomes.