Mucosal Immunology (2017) 10, 307–317; doi:10.1038/mi.2016.128; published online 25 January 2017

Gut permeability and mucosal inflammation: bad, good or context dependent

R Ahmad1, M F Sorrell2, S K Batra1,3,4, P Dhawan1,4,5 and A B Singh1,4,5

  1. 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, Nebraska, USA
  2. 2Department of Internal Medicine, Omaha, Nebraska, USA
  3. 3Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA
  4. 4Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska USA
  5. 5VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska USA

Correspondence: AB Singh, (

Received 21 July 2016; Accepted 29 November 2016
Advance online publication 25 January 2017



Inflammatory bowel disease (IBD) is a multifactorial disease. A breach in the mucosal barrier, otherwise known as “leaky gut,” is alleged to promote mucosal inflammation by intensifying immune activation. However, interaction between the luminal antigen and mucosal immune system is necessary to maintain mucosal homeostasis. Furthermore, manipulations leading to deregulated gut permeability have resulted in susceptibility in mice to colitis as well as to creating adaptive immunity. These findings implicate a complex but dynamic association between mucosal permeability and immune homeostasis; however, they also emphasize that compromised gut permeability alone may not be sufficient to induce colitis. Emerging evidence further supports the role(s) of proteins associated with the mucosal barrier in epithelial injury and repair: manipulations of associated proteins also modified epithelial differentiation, proliferation, and apoptosis. Taken together, the role of gut permeability and proteins associated in regulating mucosal inflammatory diseases appears to be more complex than previously thought. Herein, we review outcomes from recent mouse models where gut permeability was altered by direct and indirect effects of manipulating mucosal barrier-associated proteins, to highlight the significance of mucosal permeability and the non-barrier-related roles of these proteins in regulating chronic mucosal inflammatory conditions.