# DRA involvement in linaclotide-stimulated bicarbonate secretion during loss of CFTR function

## TL;DR

Linaclotide may help treat cystic fibrosis by boosting bicarbonate secretion in the duodenum when the CFTR protein is not functioning.

## Contribution

The study reveals that linaclotide stimulates bicarbonate secretion via DRA when CFTR is dysfunctional, suggesting a new therapeutic approach for cystic fibrosis.

## Key findings

- Linaclotide increases bicarbonate secretion in mouse and human duodenum when CFTR is absent or inhibited.
- DRA inhibition eliminates linaclotide-stimulated bicarbonate secretion during loss of CFTR activity.
- Loss of CFTR activity and linaclotide treatment increase apical brush border expression of DRA in enteroids.

## Abstract

Duodenal bicarbonate secretion is critical to epithelial protection, as well as nutrient digestion and absorption, and is impaired in cystic fibrosis (CF). We examined if linaclotide, typically used to treat constipation, may also stimulate duodenal bicarbonate secretion. Bicarbonate secretion was measured in vivo and in vitro using mouse and human duodenum (biopsies and enteroids). Ion transporter localization was identified with confocal microscopy, and de novo analysis of human duodenal single-cell RNA sequencing (scRNA-Seq) data sets was performed. Linaclotide increased bicarbonate secretion in mouse and human duodenum in the absence of cystic fibrosis transmembrane conductance regulator (CFTR) expression (Cftr-knockout mice) or function (CFTRinh-172). Na+/H+ exchanger 3 inhibition contributed to a portion of this response. Linaclotide-stimulated bicarbonate secretion was eliminated by down-regulated in adenoma (DRA, SLC26A3) inhibition during loss of CFTR activity. ScRNA-Seq identified that 70% of villus cells expressed SLC26A3, but not CFTR, mRNA. Loss of CFTR activity and linaclotide increased apical brush border expression of DRA in non-CF and CF differentiated enteroids. These data provide further insights into the action of linaclotide and how DRA may compensate for loss of CFTR in regulating luminal pH. Linaclotide may be a useful therapy for CF individuals with impaired bicarbonate secretion.

Linaclotide stimulates duodenal bicarbonate secretion upon loss of CFTR function by increasing membrane trafficking and activity of DRA, indicating potential therapeutic value in cystic fibrosis.