I. PRELIMINARY CONSIDERATIONS There are many chronic diseases of unknown etiology that continue to resist all efforts to reveal their specific cause and unveil the mechanisms of tissue injury. Crohn 's disease is a prototype of such diseases. After being identified as a distinct clinical entity well over half a century ago, Crohn 's disease remains a true enigma despite having its clinical heterogeneity recognized and classified, increasing worldwide incidence documented, genetic and epidemiological aspects explored, plausible causes investigated, and every conceivable therapy tested The fact that so many attempts have been made to understand this illness and that relatively few answers have been obtained may be telling about the true nature of this disease. Perhaps the clinical manifestations are broad and unpredictable because Crohn 's disease represents many different illnesses. The fact that no clear and undisputed causative microorganism has been found may be because such an agent does not exist, or, on the contrary, a number of them cause Crohn's disease. Maybe its rapidly increasing incidence around the globe is due to various environmental factors that simply modulate a very common response of the bowel to nonspecific insults. Moreover, an almost endless armamentarium of drugs and diets have been experimented with, often giving less than desirable results, indicating that almost every approach is justified, because we are treating different patients with different illnesses having nothing in common except the name (Crohn's disease) used to diagnose and classify them. These somewhat extreme but not unrealistic perspectives can be translated into two polarized points of view: Crohn 's disease is a single and unique clinical entity whose complexity is beyond our present comprehension or Crohn 's disease does not exist as a distinct entity but represents a syndrome with multiple etiologies that are lumped under one heading for lack of sufficient knowledge (1). Whatever the case, investigators and clinicians are left with the unresolved challenge of finding the cause, understanding the mechanisms of relentless bowel inflammation, and improving the fonns of treatment. In this chapter, possible causes and potential mechanisms of Crohn 's disease are discussed. Information, studies and concepts whose value and reliability are uncertain are included; however, this is justifiable given the many unanswered questions surrounding the disease. Some import-
ant components of the pathogenesis of Crohn 's disease. such as epidemiology. immunogenetics. and smoking. are discussed in detail elsewhere in this book. Other forms of gut inflammation. such as ulcerative colitis. celiac disease, or infections. are discussed to point out differences between various forms of inflammatory bowel disease and to underline aspects unique to Crohn 's disease.