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The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice.

ABSTRACT: Mutations in the CFTR chloride channel result in intestinal obstructive episodes in cystic fibrosis (CF) patients and in CF animal models. In this study, we explored the possibility of reducing the frequency of obstructive episodes in cftr^-/- mice through the oral application of a gut-selective NHE3 inhibitor tenapanor and searched for the underlying mechanisms involved. Sex- and age-matched cftr^+/+ and cftr^-/- mice were orally gavaged twice daily with 30 mg kg^-1 tenapanor or vehicle for a period of 21 days. Body weight and stool water content was assessed daily and gastrointestinal transit time (GTT) once weekly. The mice were sacrificed when an intestinal obstruction was suspected or after 21 days, and stool and tissues were collected for further analysis. Twenty-one day tenapanor application resulted in a significant increase in stool water content and stool alkalinity and a significant decrease in GTT in cftr^+/+ and cftr^-/- mice. Tenapanor significantly reduced obstructive episodes to 8% compared to 46% in vehicle-treated cftr^-/- mice and prevented mucosal inflammation. A decrease in cryptal hyperproliferation, mucus accumulation, and mucosal mast cell number was also observed in tenapanor- compared to vehicle-treated, unobstructed cftr^-/- mice. Overall, oral tenapanor application prevented obstructive episodes in CFTR-deficient mice and was safe in cftr^+/+ and cftr^-/- mice. These results suggest that tenapanor may be a safe and affordable adjunctive therapy in cystic fibrosis patients to alleviate constipation and prevent recurrent DIOS.

SUBMITTER: Tan X

PROVIDER: S-EPMC9456459 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice.

Tan Xinjie X Kini Archana A Römermann Dorothee D Seidler Ursula U

International journal of molecular sciences 20220901 17

Mutations in the CFTR chloride channel result in intestinal obstructive episodes in cystic fibrosis (CF) patients and in CF animal models. In this study, we explored the possibility of reducing the frequency of obstructive episodes in cftr-/- mice through the oral application of a gut-selective NHE3 inhibitor tenapanor and searched for the underlying mechanisms involved. Sex- and age-matched cftr+/+ and cftr-/- mice were orally gavaged twice ...[more]

PMID: 36077390

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Project description:AIMS/HYPOTHESIS:Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to increase the half-life of incretins. Although they are administered orally, little is known about their effects on the gut microbiota and functions, despite the fact that some bacteria present in the gut microbiota exhibit DPP-4-like activity. Our objective was to study the impact of the DPP-4 inhibitor vildagliptin on gut functions and the intestinal ecosystem in a murine model of obesity induced by a Western diet (WD). METHODS:Twenty seven male C57BL/6J mice were randomised to receive a control diet, a WD (45% kJ from fat and 17% kJ from sucrose) or a WD + vildagliptin (0.6 mg/ml in drinking water) for 8 weeks. RESULTS:Vildagliptin significantly reduced DPP-4 activity in the caecal content and faeces. Vildagliptin impacted on the composition of the gut microbiota and its metabolic activity. It mainly decreased Oscillibacter spp. (a direct effect independent of DPP-4 activity was shown on cultured O. valericigenes), increased Lactobacillus spp. and propionate, and reduced the ligands of Toll-like receptors 2 and 4. Vildagliptin protected against the reductions in crypt depth and ileal expression of antimicrobial peptides induced by the WD. In the liver, the expression of immune cell populations (Cd3g and Cd11c [also known as Itgax]) and cytokines was decreased in the WD + vildagliptin-fed mice compared with the WD-fed group. Ex vivo exposure of precision-cut liver slices to vildagliptin showed that this response was not related to a direct effect of the drug on the liver tissue. CONCLUSIONS/INTERPRETATION:Our study is the first to consider the DPP-4-like activity of the gut microbiota as a target of DPP-4 inhibition. We propose that vildagliptin exerts beneficial effects at the intestinal level in association with modulation of gut microbiota, with consequences for hepatic immunity. If relevant in humans, this could open new therapeutic uses of DPP-4 inhibition to tackle gut dysfunctions in different pathophysiological contexts. DATA AVAILABILITY:The sequences used for analysis can be found in the MG-RAST database under the project name MYNEWGUT3.

Dataset Information

The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice.

Publications

The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice.

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