Inflammatory Bowel Disease: An Update on the Fundamental Biology and Clinical Management

      The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), affect approximately 1–2 of every 1000 people in developed countries. These chronic diseases result in significant morbidity and mortality. Quality of life and life expectancy are compromised. While there is no cure for these diseases, the last two decades have been a period of major advances in our understanding of the biology of intestinal inflammation and how it is related to IBD. This in turn has led to the development and refinement of several new treatment strategies. It has been 8 years since Gastroenterology last published a special supplemental issue related to IBD. In 2004, the special issue focused nearly exclusively on new treatment options that had been developed in the 1990s and the first few years of the new millennium. In this current special issue, we again provide updates on challenging treatment paradigms, but have elected to focus much of the issue on the numerous advances in our understanding of the biology of the disease, findings that are likely to lead to many new treatment modalities in the coming years. This issue, can be divided into 3 sections: genetic and environmental factors that influence the development of IBD (Articles 1–3), host immune dysregulation and the development of IBD (Articles 4–9), and state of the art clinical aspects of the diagnosis and therapy of IBD (Articles 10–15).
      The first article by Drs Judy Cho and Steven Brant (pages 1704–1712) addresses the recent advances in understanding the genetic basis of IBD. Following studies on the identification of a locus on chromosome 16 that was linked to CD, in 2001, with much fanfare, NOD2 was identified as the first IBD gene. Since that time, evolution in technology which allows for relatively inexpensive whole genome association studies has resulted in the identification of more than 70 genomic loci associated with Crohn's disease and only slightly fewer for UC. This article details the rapid progress made in the search for IBD genes, the implications of these findings on our current understanding of the pathogenesis of IBD, and how these findings could lead to new treatment pathways. Many of the genes that have been linked to IBD participate in the host immune and adaptive response to microbial organisms and the maintenance of homeostasis within the epithelium and its relationship to the microbiota and immune system. This has furthered the hypothesis that IBD represents an aberrant response to microbes that are normally present in the human intestines. Indeed, there is compelling evidence that gut bacteria, collectively known as the gut microbiota, is amongst the most important environmental factors in the pathogenesis of IBD. In the second article, Drs Maria Gloria Dominguez–Bello, Martin J. Blaser, Ruth E. Ley, and Rob Knight (pages 1713–1719) describe the development and function of the normal commensal microbiota. Similar to advances in genetics, the ability to rapidly sequence bacterial DNA has allowed for identification of the huge proportion of the human gut microbial community that is unable to be cultured. Dr Knight and colleagues explain how this technology has been utilized to understand how the human gut microbiome is established in infancy, how it evolves with aging, and the potential implications for health and disease. In the third article by Drs Benoit Chassaing and Arlette Darfeuille–Michaud (pages 1720–1728), these concepts are extended to IBD. The authors review the evidence that the gut microbiota play a role in the pathogenesis of IBD, including the notion that gut microbiota may either be dysbiotic as a community or as pathobiont individually (harmful to the host) or that specific pathogens may play a role. Taken together, these three articles provide a detailed current description of the interplay between host genetics, enteric microbiology, and IBD pathogenesis.
      Currently, it is believed that genetic alterations, along with environmental influences, result in a dysregulated mucosal immune response to constituents of the intestinal environment, notably the gut microbiota. In the fourth article, Drs Clara Abraham and Ruslan Medzhitov (pages 1729–1737) focus on innate immune mechanisms by which the host interacts with the gut microbiota in the normal state and how perturbation of this finely tuned system, in part due to the genetic alterations discussed in the first article, may play a role in the pathogenesis of IBD. The intestinal epithelium is a critical component of the mucosal immune system as the interface between the external luminal environment of the gut and the host. In the fifth article, Drs Arthur Kaser and Richard Blumberg (pages 1738–1747) review how dysregulation of critical cellular functions, which are involved in maintaining epithelial homeostasis in the context of the commensal microbiota such as autophagy and the unfolded protein response as a consequence of ER stress as well as the NOD2 signaling pathway in the intestinal epithelium, play roles in the development of IBD. The integrity of the intestinal epithelium is also important for the maintenance of barrier function. In the sixth article, Drs Louise E. Glover and Sean P. Colgan (pages 1748–1755) review the roles that hypoxia-inducible factor (HIF) and angiogenesis play in protecting the epithelial barrier in the setting of intestinal inflammation.
      The intestinal epithelial barrier separates the external environment from the internal environment of the host, including the mucosal immune system, the importance of which is apparent in the observation that 80% of lymphocytes in the body can be found in the intestinal tract. The next 3 articles review the complex interplay between various lymphocyte subsets and their role in the regulation of the intestinal inflammatory response relevant to IBD. In the seventh article, Drs Warren Strober and Ivan J. Fuss (pages 1756–1767) review the landscape of cytokines produced by and define the function of Th1, Th2, and Th17 lymphocyte populations in both animal models of intestinal inflammation and in human IBD. The intestinal mucosal immune system maintains immune surveillance to promote a dialogue between the host and the antigen and microbial rich external environment of the intestinal lumen. Drs Thomas MacDonald, Ivan Monteleone, Massimo Claudio Fantini, and Giovanni Monteleone, (pages 1768–1775) in the eighth article, review the dynamic interaction between multiple leukocyte subsets responsible for protective immunity while maintaining mucosal homeostasis to prevent unrestrained inflammation, the hallmark of IBD. Finally, in the ninth article, Drs Eduardo J. Villablanca, Barbara Cassani, Ulrich H. von Andrian, and J. Rodrigo Mora (pages 1776–1784) describe the current knowledge of the mechanisms by which lymphocytes are recruited to intestinal mucosal sites, through a process known as “homing”, to establish both protective and pathologic immune responses. Implications for how these pathways can be targeted for the development of pharmacologic agents useful in IBD therapeutics is also discussed.
      While the initial 9 articles describe recent advances in the understanding of pathophysiologic mechanisms of IBD, the remaining 6 articles define implications for clinical aspects of IBD patient care. In the tenth article, Drs Jacque Cosnes, Corinne Gower–Rousseau, Philippe Seksik, and Antoine Cortot (pages 1785–1794) describe the epidemiology and natural history of IBD. Among the several topics covered is a detailed description of the incidence and prevalence of IBD throughout the world, how this has changed over time, and how this relates to potential hypotheses regarding environmental factors that may contribute to the etiology of IBD. In the eleventh article, Drs Joel G. Fletcher, Jeff L. Fidler, David H. Bruining, and James E. Huprich (pages 1795–1806) detail advances in intestinal imaging in IBD that have occurred in the last decade. This encyclopedic discussion of the field compares and contrasts CT enterography, MR enterography, capsule endoscopy, chromoendoscopy, ultrasound, PET/CT, fluoroscopy, endoscopic ultrasound and pelvic MRI. Importantly, the authors discuss several new strategies to increase the acceptability of these technologies, such as methods to reduce levels of radiation exposure. Diseases with chronic inflammation are often associated with an increase in the development of neoplasia and IBD is no exception. In the 12th article, Drs Tom A. Ullman and Steve H. Itzkowitz (pages 1807–1816) review the clinicopathological features of colitis-associated cancer and the molecular basis for its development, including the role of the gut microbiota and immune system. There has been increasing interest in developing biomarkers to facilitate care of patients with IBD. Dr James Lewis (pages 1817–1826) discusses the utility of currently available biomarkers in the diagnosis and treatment of IBD in the 13th article. The discussion includes the role of biomarkers during all stages of the management of IBD, from deciding which patients, in whom the diagnosis is considered, should undergo more invasive testing, to predicting the natural history of the disease, and finally to making therapeutic adjustments based on the results of biomarker testing.
      In the final 2 articles, Drs Daniel Burger and Simon Travis (pages 1827–1837) provide a thought provoking discussion of our current treatment strategies and Drs Scott Plevy and Stephan Targan (pages 1838–1846) review opportunities for novel therapeutic approaches. Both articles specifically address areas of controversy in a manner that should foster further discussion within the field. Drs Burger and Travis' review challenges some of the current paradigms currently used for the treatment of UC and CD, while Drs Plevy and Targan interpret the current state of knowledge regarding the basic biology of the mucosal inflammatory response, and from this hypothesize where future innovative therapeutic opportunities may exist. Although our understanding of the etiology of IBD has made great advances, therapeutic applications have lagged behind, but are poised for additional major breakthroughs. These will include novel agents and refined strategies to best implement our currently available therapeutics. These final 2 articles offer insights as to what the future may hold for the field.
      In putting together this special issue of Gastroenterology, we sought to cover the major breakthroughs in the field. Due to page limitations, not every topic could be covered. Even among the topics that were included, the authors were forced to be selective in their discussion. Nonetheless, we feel that this collection of articles will serve as a highly valuable update for those who are immersed in the field, a user friendly entre into the field for those who follow the IBD literature more casually, and a trigger to prompt discussion about the pathology and therapy of IBD for everyone who reads Gastroenterology.