Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency

Abstract

Background In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation. Aims The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome. Methods Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice. Results Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium-glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport. Conclusions In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption. Keywords Short bowel syndrome • Mouse model • Ussing chamber • Teduglutide • Barrier function • Nucleotide oligomerization domain 2 Abbreviations GLP-2 Glucagon-like peptide 2 Nod2 Nucleotide oligomerization domain 2 RAAS Renin-angiotensin-aldosterone system PS Parenteral support

Dapiglutide, a novel dual GLP‐1 and GLP‐2 receptor agonist, attenuates intestinal insufficiency in a murine model of short bowel

“…Mice develop severe diarrhea and thus high content of stool water after ICR 22 . Previous studies have shown that treatment with the GLP‐2R agonist teduglutide reduced stool water content in the early phase (eg, at day 7) but not in the late phase (eg, at day 14) 24 . To test whether dapiglutide promotes similar effects, stool water content was measured.…”

“…The humane end point included a wellness score below 4 points and weight loss >20%. Stool was collected on postoperative days 2, 7, 10, and 14 and analyzed as described previously 24 . In brief, mice were singly placed into an empty cage covered with tissue paper and observed.…”

“…Villus length in a given segment is homogeneous. In a blinded manner, the mucosal height was determined as described previously, 24 by measuring it per sample at five well‐oriented, full‐length crypt‐villus units from the crypt base to the villus tip using an Axio Observer inverted microscope (Zeiss) and ZEN 2.3 software. Luminal diameter was measured from the same samples from serosa to serosa in two dimensions.…”

Preclinical insights into the gut‐skeletal muscle axis in chronic gastrointestinal diseases

“…GLP‐1 agonists, which are widely used for the treatment of diabetes mellitus, have recently been proposed to ameliorate muscle wasting by suppressing myostatin and muscle atrophic factors (such as atrogin‐1 and muscle RING‐finger protein‐1 ( MuRF‐1 )), and enhancing myogenic factors including MyoG and MyoD 40 . Pharmacologic GLP‐2‐stimulation promotes gut‐specific growth, enhances intestinal epithelial function and alleviates malnutrition, likely secondary contributes to the gut‐specific pro‐absorptive effects 41 . Similarly, ghrelin has been suggested to exert protective effects on fasting‐induced muscle atrophy in ageing mice through an enhanced expression of myogenic genes and decreased expression of degradation genes 42 .…”

“…40 Pharmacologic GLP-2-stimulation promotes gut-specific growth, enhances intestinal epithelial function and alleviates malnutrition, likely secondary contributes to the gut-specific pro-absorptive effects. 41 Similarly, ghrelin has been suggested to exert protective effects on fasting-induced muscle atrophy in ageing mice through an enhanced expression of myogenic genes and decreased expression of degradation genes. 42 The effects of these hormones on muscle wasting associated with chronic gastrointestinal diseases have not been studied yet.…”