November 7, 2022

Gene mutations impair gut barrier

Mutations in a cell membrane transporter protein impair the integrity of the gut lining, contributing to chronic gastrointestinal distress for people with the mutations, Vanderbilt researchers report.

All of us suffer from gastrointestinal (GI) distress from time to time, but people with mutations in the SLC12A2 gene suffer from chronic GI infections, intestinal obstruction, constipation, nutrient malabsorption and blood in the intestine. 

To understand why this mutation causes such intense GI distress, Eric Delpire, PhD, and team used human epithelial colon cells to investigate the protein encoded by SLC12A2, NKCC1. 

The researchers found thatdeletion of NKCC1 in the cells impaired the integrity of the epithelial barrier, which is vital for maintaining gut homeostasis and preventing diseases. 

Function of the epithelial barrier is maintained by tight junctions that act as contact points between adjacent cells. Here, the researchers found that loss of NKCC1 increases levels of a tight junction protein called claudin-2, which drives the dysfunction of the epithelial barrier. 

The study, published in the American Journal of Physiology-Cell Physiology, suggests that upregulation of claudin-2 may contribute to the chronic intestinal inflammation that is observed in patients with mutations in NKCC1.

Co-authors include Rainelli Koumangoye, PhD, and Parker Penny.

This work was supported by National Institutes of Health grants DK093503 and TR002243, and by the Leducq Foundation.