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To highlight the evidence supporting the role of altered commensal gut flora in human disease. While the contribution of the indigenous gut microbial community is widely recognized, only recently has there been evidence pointing to indigenous flora in disease.This review discusses recent evidence pointing to the role of altered commensal gut flora in such common conditions as irritable bowel syndrome and inflammatory bowel disease. Recent studies document the intricate relationship between the vast population of microbes that live in our gut and the human host. Since increased intestinal permeability and immune activation are consequences of an altered host–gut microbial relationship, what are the clinical effects of this shift in relationship?We focus on the example of an abnormal expansion of gut microbial flora into the small bowel or small intestinal bacterial overgrowth and discuss the effects of bacterial overgrowth on the human host in acute pancreatitis, bacterial gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, hepatic encephalopathy, and fibromyalgia and burn injury. The identification of the underlying role of altered commensal gut microbiota in these and other human diseases could lead to novel diagnostic and therapeutic strategies that would improve clinical outcome.