Pawel Kiela (Arizona), Connection between epithelial Na+/H+ exchange, gut microbiome, inflammation, colon cancer

Abstract:

Pathogenic microorganisms as well as inflammatory mediators associated with acute infections or with chronic inflammatory bowel diseases (IBD) lead to inhibition of epithelial Na+/H+ exchange, a phenomenon commonly interpreted as leading to infection/inflammation- associated diarrhea. Moreover, chronic NHE3 deficiency exacerbates inflammation in part by promoting microbial dysbiosis. Our recent work indicates, however, that the effects of NHE3 inhibition are much more complex and may not be unidirectional in promoting pathology. Biology offers a plethora of examples of “double-edged swords”, whereby the same process, molecule or its regulation, plays protective or detrimental roles depending on the context, source, or the extent/duration of response. Short term inhibition of NHE3 may represent an evolutionarily permissible process in certain cases (infection or epithelial restitution), while in more chronic diseases like IBD or colorectal cancer, decreased or eliminated NHE3 activity leads to changes in gut microbiota and epithelial cell metabolism that furthers the disease process. These studies change the way we view Na+/H+ exchange in the context of infection/inflammation and colorectal cancer progression and shed new light into the novel roles of NHE3 in mucosal homeostasis and disease progression.