Claudin expression regulates mucus function

PAR-21-155 Capaldo
Project Summary:
Inflammatory Bowel Diseases (IBDs), encompassing both Crohn’s Disease (CD) and
Ulcerative Colitis (UC), involve recurring immune activation and progressive degradation
of the intestinal lining. IBDs are idiopathic diseases and current therapies frequently fail to
ameliorate inflammatory symptoms, contributing to disease progression. Poor outcomes
may be due to the complexities of IBD pathogenesis, which involve both genetic and
environmental factors such as a high fat, low fiber western diet. Therefore, it is vital that
new therapeutic strategies demonstrate efficacy in the context of genetic predisposition to
IBD. This proposal aims to explore both a novel hypothesis for gene-related IBD
pathogenesis, and evaluate the efficacy of a potential dietary therapy in a knockout
mouse model of IBD. Importantly, loss of the cellular and/or mucus barriers of the gut is
a common etiological feature of all human IBDs; including changes in mucus consistency
and claudin protein expression. Our preliminary data suggest a novel functional
relationship between the claudin-based barrier and the mucus barrier. Therefore, this
proposal will address the following hypothesis: Inflammatory cytokines disrupt ion/fluid
homeostasis in the colon through aberrant claudin expression, resulting in a
weakened mucus barrier and increased susceptibility to disease. Aim 1 will directly
test the hypothesis that, during inflammation, claudin proteins function to reduce mucus
density and the ability of mucus to form an effective barrier. While our preliminary data
strongly support this hypothesis, it is unclear if therapies can be directed at altering claudin
expression. Indeed, claudin function and regulation is very poorly understood. However,
high fiber/fermentable fiber diets have been demonstrated in mice to support mucophilic
bacteria in the colon, thereby increasing mucus density and protective function. Will diets
that support the mucus barrier prove effective in patients bearing genetic deficiencies that
weaken the cellular barrier? In Aim 2 we will determine if an increase in mucus density
has therapeutic benefit in a mouse model of IBD, Hepatocyte Nuclear Factor alpha
(HNF4) knockout mice. HNF4 mutations are found in UC and CD, have been shown to
cause changes in claudin gene expression, and removal of Hnf4a in the intestine is
sufficient to cause colitis in mice. We will assess mucus function in these mice in vivo, and
determine if dietary fiber will alleviate or exacerbate colitis symptoms in mice that are
genetically predisposed to chronic colitis development.

Grant Number: 1R15DK127369-01A1
NIH Institute/Center: NIH
Principal Investigator: Christopher Capaldo