Is Colonic Crohn's Disease More Closely Related to Ulcerative Colitis or Crohn's Disease by Nature?

To the Editor: I read with great interest the article by Naftali et al recently published in this journal regarding the profile of microbiota in patients with different phenotypes of Crohn’s disease (CD). It revealed distinct microbiotas between ileum-restricted CD (iCD) and colonic CD (cCD), and the article suggests taking cCD as a distinct subtype of CD, whereas I wonder whether this is adequate and doubt the necessity of having cCD itself as a discrete subtype. Although cCD and iCD, 2 types of CD as currently classified, showed a distinct feature in microbiota in this study, cCD shared multiple similar features with ulcerative colitis (UC), such as poor response to anti–TNF-alpha treatment, poor association with NOD2, but close relationship with HLA-DRB*0103. Evidence I collected during last decade made me to believe that UC and CD are just 2 manifestations of the same morbidity, rather than 2 different diseases, as discussed in detail in the article I wrote several years ago with a unified hypothesis on the etiology of inflammatory bowel disease (IBD), including the cause and mechanism of IBD as well as the relationship between UC and CD. This hypothesis proposed that both UC and CD shared a similar primary cause, i.e., damage of the gut by the poorly inactivated digestive proteases because of reduction of gut bacteria in modern society along with the improved hygiene condition and inhibition by some dietary chemicals, such as saccharin and sucralose. They are both caused by the damage of gut barrier and infiltration of harmful agents from gut lumen, but differ in that the ubiquitous existence of bacteria in the colon result in infiltration of bacteria, recruitment of neutrophils, and formation of crypt abscess as the main characteristics in UC, whereas the characteristic granulomas in CD are mainly the result of increased infiltration of particles and antigens from gut lumen and the resultant recruitment and reaction of macrophages. As NOD2 and tumor necrosis factor-alpha are mainly expressed in macrophages but not neutrophils, it provided a simple explanation as why CD is more closely associated with NOD2 and responds better to anti–TNF-alpha treatment than UC. The relative sterile of the small intestine would make the formation of granulomas as the main pathological manifestations in the typical iCD. However, particles and antigens may also penetrate and be retained in the mucosa in the colon, resulting in the formation of granulomas as well. Thus, the current diagnosis of CD with finding out a granuloma as the gold standard would be quite problematic, as the chance of positive findings in the colon would greatly depend on how many samples are taken and factors such as how much indigestible particles (e.g., TiO2 in the processed food, etc.) in the diet. Even if a granuloma was found in the colon and diagnosed as CD according to current diagnostic criteria, damage of colon would still mainly lead to infiltration of gut bacteria, recruitment of neutrophils, and formation of crypt abscess as seen in UC. Thus, it would be no wonder that cCD shares many features with UC rather than typical iCD. In this regard, cCD would be more closely related to UC rather than CD in nature. Therefore, cCD would be likely better to be merged with UC rather than exists as a discrete subtype of CD.