Inactivation of Digestive Proteases and Degradation of Mucus: The Possible Key Factors That Determined the Different Effects on the Gut by Antibiotics.

To the Editor: I read with great interest the article by Ward et al published recently in this journal regarding the effect of antibiotics on dextran sulfate sodium–induced colitis.1 It is found that treatment with broadspectrum antibiotics protected mice against colitis by changes in gut microbiota. However, as discussed in the article,1 this is in contrast to multiple studies demonstrating antibiotics increased the risk of inflammatory bowel disease in human and colitis in animals in a variety of models. The mechanism behind this remains elusive. At present, the mainstream of research including this article still mainly focused on immune response of the body or the production of some bioactive agents such as short chain fatty acids by gut bacteria. Here I suggest that inactivation of digestive proteases within gut lumen and degradation of the mucus at gut surface may be actually the primary determinant factors for the observed effects of antibiotics. The evidence that I collected during the last 15 years made me to believe that impaired inactivation of digestive proteases due to reduction in gut bacteria in modern society may have played a causative role in the pathogenesis of inflammatory bowel disease.2,3 Studies showed that under conventional conditions, pancreatic digestive proteases are hardly detectable in the lower gut, whereas a large amount of them appeared in the large intestine of animals raised under germ-free conditions, suggesting the critical role of gut bacteria in inactivation of these digestive proteases in the lower intestine. Different kinds and doses of antibiotics may have different effects on digestive proteases inactivation. Nevertheless, mucin, the structural molecule of the protective mucus layer, is composed of 15% of a central core peptide and 85% of side carbohydrate branches that can only be effectively degraded in the existence of both digestive proteases from the pancreas and glycosidases from gut bacteria.4 Thus, as discussed in my articles,3,4 certain extent of reduction of gut bacteria by antibiotics may exacerbate the injury of gut as the result of accelerated degradation of the protective mucus layer by the synergic action of poorly inactivated digestive proteases and glycosides in the remaining gut bacteria, while further extensive reduction in gut bacteria may become less detrimental or even protective because of the striking decrease in bacterial glycosides and retarded degradation of the mucus layer as well as decreased infiltration of bacterial toxicant due to the decrease in bacterial load in gut lumen. This may have contributed explain the less gut damage in both poor hygiene and germ-free conditions,4 as well as the different effects of antibiotics on the gut. Therefore, I recommend conducting more research in this regard.