Does the association with NOD2, autophagy and some pathogens really mean Crohn's disease is caused by uncontrolled infection?

Dear Sir,

As we know, inflammatory bowel disease (IBD) including both ulcerative colitis (UC) and Crohn's disease (CD) emerged and became epidemic since the last century,¹ suggesting that environmental factors would have played the predominant role. From the very beginning, many infectious agents encompassing bacteria, fungi, parasites, and viruses, had been suspected as the cause of IBD, but none of them can be firmly established due to the lack of consistent detection of the existence of the pathogen in the patients, the failure of the treatment specific for the organism, and the effective treatment of IBD by some immunosuppressive agents.¹ However, the notion that IBD like CD is caused by uncontrolled infection re-emerged along with recent findings by virtue of the development of new technology, such as: 1) the finding of the link between CD and NOD2, an intracellular receptor recognizing muramyl dipeptide (MDP) existing in certain kinds of bacteria; 2) the finding of the link between CD and autophagy-associated genes like ATG16L1 that may affect the destruction and clearance of some pathogens; 3) the finding of the striking overlap between susceptibility loci for IBD and mycobacterial infection; 4) the increased detection of adhesive and invasive Escherichia coli (AIDE), Mycobacterium avium paratuberculosis (MAP), etc., in the gut tissue of patients with CD.²,³ On the other hand, the evidence against the notion of uncontrolled infection is also mounting. The suppression of the immune system by TNF-alpha antibodies increases the risk of infection to bacteria, fungi, and viruses,⁴ but it has been one of the most effective treatments for CD. Recent study also found that the CD-associated mutation or deficiency of the ATG16L1 gene conferred protection from bacterial invasion and infection.⁵ In facing these contradictions, we may need more thorough and insightful thinking to get into the nature behind these phenomena. Here I would like to provide some tentative explanation. From the evidence I gathered, I suspected that weakening of the gut barrier due to the damage by the poorly inactivated digestive proteases as the result of the reduction of gut bacteria by some dietary chemicals like saccharin and sucralose might be the root mechanism for IBD.⁶ Study had found that the NOD2 mutation is associated with impaired intolerance for repeated exposure to bacterial products.⁷ Thus, in my opinion, the sustained inflammation in CD would be more likely caused by the escalated reaction to the increased filtration of gut bacteria and their debris rather than deficiency of the immune system and uncontrolled growth and infection of some pathogens. This notion would be in accordance with the fact that immune suppression resulted in the healing of the mucosa and the alleviation of clinical symptoms rather than the exacerbation of the disease.