Novel mechanism links genetic defect in IBD patients to gut leakiness
Study in mice and human tissue is the first to show how a disease
mutation weakens barrier properties of epithelial cells lining the gut

Date:
September 2, 2021
Source:
University of California - Riverside
Summary:
A team of researchers has identified a novel mechanism by which
loss-of- function mutations in the gene PTPN2, found in many
patients with inflammatory bowel disease, or IBD, affect how
intestinal epithelial cells maintain a barrier.



FULL STORY ==========================================================================
A team of researchers led by a biomedical scientist at the University
of California, Riverside, has identified a novel mechanism by which
loss-of- function mutations in the gene PTPN2, found in many patients
with inflammatory bowel disease, or IBD, affect how intestinal epithelial
cells maintain a barrier.


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The intestinal epithelium, a single layer of cells, plays a critical role
in human health by providing a barrier while also allowing nutrient and
water absorption. Intestinal epithelial cells are needed for regulating
immune function, communicating with the intestinal microbiota, and
protecting the gut from pathogen infection -- all of which critically
depend on an intact epithelial barrier.

Affecting roughly 3 million Americans, IBD is a set of chronic
intestinal diseases in which the lining of the gut becomes inflamed and
leaky. Increased gut leakiness has recently been confirmed to increase
the risk of developing IBD.

"This new publication is a culmination of a body of work from my
lab identifying how loss-of-function mutations in PTPN2 can increase
gut permeability or leakiness," said Declan F. McCole, a professor
of biomedical sciences in the UCR School of Medicine, who led the
study published in the Journal of Clinical Investigation. The journal
has selected the research paper as an "Editor's highlight." In the
study, which was conducted in mice, human cells, and tissue from
IBD patients, McCole and his colleagues showed that in IBD patients
carrying a loss-of-function PTPN2 mutation, the expression of claudin-2,
a protein that causes loss of water and sodium into the gut and promotes diarrhea, is increased. Using mouse models, the McCole lab identified
a dual mechanism that explains how claudin-2 expression increases and contributes to fluid loss.

PTPN2 typically acts as a brake on the expression of claudin-2, McCole explained. The loss-of-function mutation in PTPN2 that occurs in IBD
removes this brake and allows increased fluid loss.



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"In addition, PTPN2 also promotes an endogenous factor, called matriptase,
that removes claudin-2 from the area of the cell membrane where it
mediates its effects in allowing fluid loss to occur," McCole said.

The cumulative effect of reduced PTPN2 activity on both mechanisms was
elevated fluid loss. The researchers proved this defect could be reversed
by treating cells lacking PTPN2 with recombinant -- or synthetic --
matriptase.

"Our work improves understanding of how the genetics of IBD can contribute
to the altered physiology in patients that drives their symptoms,"
McCole said.

"It also supports our related work identifying how the class of drugs,
called JAK inhibitors, may be used to rescue 'leaky gut,' particularly
in patients with loss-of-function mutations in the PTPN2 gene.

The study also showed that a recently identified and rare novel mutation
in PTPN2, which causes gut epithelial damage in children, also increases
gut epithelial leakiness -- but without causing epithelial cell death.

"This suggests that patients who develop this condition may exhibit
'leaky gut' before full-blown disease occurs," McCole said.

McCole was supported in the study by co-first authors Moorthy Krishnan
and Marianne R. Spalinger of UCR, and Ronald Marchelletta of UC San
Diego. Other co-authors are Anica Sayoc-Becerra, Vinicius Canale, Rocio Alvarez, and Ali Shawki of UCR; as well as colleagues at UC San Diego, Cedars-Sinai Medical Center Los Angeles, the University of Chicago, the National Institutes of Health, University Hospital Zurich in Switzerland,
and McGill University in Montreal.

The study was supported by the National Institutes of Health, the
Crohn's and Colitis Foundation, the Swiss National Science Foundation,
and Pfizer Inc.

========================================================================== Story Source: Materials provided by
University_of_California_-_Riverside. Original written by Iqbal
Pittalwala. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ronald R. Marchelletta, Moorthy Krishnan, Marianne R. Spalinger,
Taylaur
W. Placone, Rocio Alvarez, Anica Sayoc-Becerra, Vinicius Canale, Ali
Shawki, Young Su Park, Lucas H.P. Bernts, Stephen Myers, Michel L.

Tremblay, Kim E. Barrett, Evan Krystofiak, Bechara Kachar,
Dermot P.B.

McGovern, Christopher R. Weber, Elaine M. Hanson, Lars Eckmann,
Declan F.

McCole. T cell protein tyrosine phosphatase protects intestinal
barrier function by restricting epithelial tight junction
remodeling. Journal of Clinical Investigation, Sept. 1, 2021;
DOI: 10.1172/JCI138230 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210902174812.htm

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