The microbial basis of inflammatory bowel diseases

The inflammatory bowel diseases (IBD) are a group of chronic diseases that result from a confluence of genetic and environmental triggers. IBD have two main clinical phenotypes, ulcerative colitis (UC) and Crohn’s disease (CD). UC is characterized by mucosal inflammation that is limited to the colon, beginning in the rectum and extending proximally in a continuous and circumferential fashion. CD, in contrast, can occur at any location in the gastrointestinal tract, from mouth to anus, though each patient’s CD typically involves a specific region, such as the small bowel or colon. CD is characterized by focal lesions that progress to ulcerations that can extend through the bowel wall and result in the development of fistulas, abscesses, and strictures. A microbial basis for IBD has long been suspected, starting with the early descriptions of potential infectious agents associated with UC in the 19th century and CD in the early 20th century (1, 2). Despite these associations, no single agent has been proven to cause IBD. As a result, research and clinical management strategies shifted away from the notion that IBD are infectious diseases, and instead toward understanding and treating the underlying immune and inflammatory processes. However, the development of cultivation-independent approaches to characterize structural and functional profiles of complex microbial communities revealed many new insights into the relationships between host and microbes. At the same time, the pivotal role of indigenous gut microbes in causing IBD became apparent with the first descriptions of IBD susceptibility genes, as many were involved in mediating host responses to gut microbes. Most experts now recognize that intestinal dysbiosis, or the imbalance in the structural and/or functional properties of the gut microbiota that can disrupt host-microbe homeostasis, is integral to the pathogenesis of IBD (3–5). However, the field remains descriptive, and some of the most basic questions about the role of the gut microbiota in IBD remain unanswered. Is the intestinal dysbiosis a cause or consequence of IBD? Are these diseases caused by the emergence of pathobionts and/or disappearance of symbionts, or merely due to an aberrant host immune response to commensal microbiota? Are the host-microbe disturbances constant or changing throughout the natural history of these diseases? What role do environmental and dietary factors play in determining the risk and course of IBD? Can IBD be prevented or treated by correcting the intestinal dysbiosis? Answering these questions will significantly advance the field and improve the understanding and management of human IBD. The clinical ramifications of the gut dysbiosis in IBD can only be sorted out by relating these findings to the natural history and complexities of these diseases.