Escherichia coli Nissle Improves Short-Chain Fatty Acid Absorption and Barrier Function in a Mouse Model for Chronic Inflammatory Diarrhea.

Background: Defects in SLC26A3, the major colonic Cl-/HCO3- exchanger, result in chloride-rich diarrhea, a reduction in short-chain fatty acid (SCFA)-producing bacteria, and a high incidence of inflammatory bowel disease in humans and in mice. Slc26a3-/- mice are, therefore, an interesting animal model for spontaneous but mild colonic inflammation and for testing strategies to reverse or prevent the inflammation. This study investigates the effect of Escherichia coli Nissle (EcN) application on the microbiome, SCFA production, barrier integrity, and mucosal inflammation in slc26a3-/- mice.

LRBA, a BEACH protein mutated in human immune deficiency, is widely expressed in epithelia, exocrine and endocrine glands, and neurons.

Mutations in LRBA, a BEACH domain protein, cause severe immune deficiency in humans. LRBA is expressed in many tissues and organs according to biochemical analysis, but little is known about its cellular and subcellular localization, and its deficiency phenotype outside the immune system. By LacZ histochemistry of Lrba gene-trap mice, we performed a comprehensive survey of LRBA expression in numerous tissues, detecting it in many if not all epithelia, in exocrine and endocrine cells, and in subpopulations of neurons.

The electroneutral Na-HCO cotransporter NBCn1 (SLC4A7) modulates colonic enterocyte pH, proliferation, and migration.

NBCn1 (SLC4A7) is one of the two major Na-HCO cotransporters in the human colonic epithelium, expressed predominantly in the highly proliferating colonocytes at the cryptal base. Increased NBCn1 expression levels are reported in tumors, including colorectal cancer. The study explores its importance for maintenance of the intracellular pH (pH), as well as the proliferative, adhesive, and migratory behavior of the self-differentiating Caco2BBe colonic tumor cell line.

cGMP-dependent kinase 2, Na/H exchanger NHE3, and PDZ-adaptor NHERF2 co-assemble in apical membrane microdomains.

Aim: Trafficking, membrane retention, and signal-specific regulation of the Na/H exchanger 3 (NHE3) are modulated by the Na/H Exchanger Regulatory Factor (NHERF) family of PDZ-adapter proteins. This study explored the assembly of NHE3 and NHERF2 with the cGMP-dependent kinase II (cGKII) within detergent-resistant membrane microdomains (DRMs, "lipid rafts") during in vivo guanylate cycle C receptor (Gucy2c) activation in murine small intestine.

Methods: Small intestinal brush border membranes (siBBMs) were isolated from wild type, NHE3-deficient, cGMP-kinase II-deficient, and NHERF2-deficient mice, after oral application of the heat-stable Escherichia coli toxin (STa) analog linaclotide.

Bicarbonate secretion and acid/base sensing by the intestine.

The transport of bicarbonate across the enterocyte cell membrane regulates the intracellular as well as the luminal pH and is an essential part of directional fluid movement in the gut. Since the first description of "active" transport of HCO ions against a concentration gradient in the 1970s, the fundamental role of HCO transport for multiple intestinal functions has been recognized. The ion transport proteins have been identified and molecularly characterized, and knockout mouse models have given insight into their individual role in a variety of functions.

Inhibition of mucus secretion by niclosamide and benzbromarone in airways and intestine.

The Ca activated Cl channel TMEM16A (anoctamin 1; ANO1) is expressed in secretory epithelial cells of airways and intestine. Previous studies provided evidence for a role of ANO1 in mucus secretion. In the present study we investigated the effects of the two ANO1-inhibitors niclosamide (Niclo) and benzbromarone (Benz) in vitro and in vivo in mouse models for cystic fibrosis (CF) and asthma.

Reduced surface pH and upregulated AE2 anion exchange in SLC26A3-deleted polarized intestinal epithelial cells.

Loss of function mutations in the gene cause chloride-losing diarrhea in mice and humans. Although systemic adaptive changes have been documented in these patients and in the corresponding knockout mice, how colonic enterocytes adapt to loss of this highly expressed and highly regulated luminal membrane anion exchanger remains unclear. To address this question, was deleted in the self-differentiating Caco2BBe colonic cell line by the CRISPR/Cas9 technique.

Acceptability Criteria of Precision Medicine: Lessons From Patients' Experiences With the GUIDE-IBD Trial Regarding the Use of Mobile Health Technology.

Background: Research about mobile health technologies for inflammatory bowel diseases reveals that these devices are mainly used to predict or self-report disease activity. However, in the near future these tools can be used to integrate large data sets into machine learning for the development of personalized treatment algorithms. The impact of these technologies on patients' well-being and daily lives has not yet been investigated.

The Anion Channel TMEM16a/Ano1 Modulates CFTR Activity, but Does Not Function as an Apical Anion Channel in Colonic Epithelium from Cystic Fibrosis Patients and Healthy Individuals.

Studies in human colonic cell lines and murine intestine suggest the presence of a Ca-activated anion channel, presumably TMEM16a. Is there a potential for fluid secretion in patients with severe cystic fibrosis transmembrane conductance regulator () mutations by activating this alternative pathway? Two-dimensional nondifferentiated colonoid-myofibroblast cocultures resembling transit amplifying/progenitor (TA/PE) cells, as well as differentiated monolayer (DM) cultures resembling near-surface cells, were established from both healthy controls (HLs) and patients with severe functional defects in the gene (PwCF). F508del mutant and CFTR knockout (null) mice ileal and colonic mucosa was also studied.

Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases: results from the phase 2, randomised, double-blind, placebo-controlled MANTA and MANTA-RAy studies.

Objectives: The phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases.

Methods: MANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition.

Human Colonoid-Myofibroblast Coculture for Study of Apical Na/H Exchangers of the Lower Cryptal Neck Region.

Cation and anion transport in the colonocyte apical membrane is highly spatially organized along the cryptal axis. Because of lack of experimental accessibility, information about the functionality of ion transporters in the colonocyte apical membrane in the lower part of the crypt is scarce. The aim of this study was to establish an in vitro model of the colonic lower crypt compartment, which expresses the transit amplifying/progenitor (TA/PE) cells, with accessibility of the apical membrane for functional study of lower crypt-expressed Na/H exchangers (NHEs).

SLC26A9 in airways and intestine: secretion or absorption?

SLC26A9 is one out of 11 proteins that belong to the SLC26A family of anion transporters. Apart from expression in the gastrointestinal tract, SLC26A9 is also found in the respiratory system, in male tissues and in the skin. SLC26A9 has gained attention because of its modifier role in the gastrointestinal manifestation of cystic fibrosis (CF).

CFTR-beyond the airways: Recent findings on the role of the CFTR channel in the pancreas, the intestine and the kidneys.

With increased longevity of patients suffering from cystic fibrosis, and widespread lung transplantation facilities, the sequelae of defective CFTR in other organs than the airways come to the fore. This minireview highlights recent scientific progress in the understanding of CFTR function in the pancreas, the intestine and the kidney, and explores potential therapeutic strategies to combat defective CFTR function in these organs.

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

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 mice through the oral application of a gut-selective NHE3 inhibitor tenapanor and searched for the underlying mechanisms involved. Sex- and age-matched and mice were orally gavaged twice daily with 30 mg kg tenapanor or vehicle for a period of 21 days.

Safety and tolerability of spesolimab in patients with ulcerative colitis.

Background: Interleukin (IL)-36 signaling has been shown to be increased in ulcerative colitis (UC). Spesolimab, a novel humanized monoclonal antibody, targets the IL-36 pathway.

Research Design And Methods: We report safety, immunogenicity, and efficacy data of intravenous (IV) spesolimab in UC.

The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity.

The five plasma membrane Na/H exchanger (NHE) isoforms in the gastrointestinal tract are characterized by distinct cellular localization, tissue distribution, inhibitor sensitivities, and physiological regulation. NHE1 (Slc9a1) is ubiquitously expressed along the gastrointestinal tract in the basolateral membrane of enterocytes, but so far, an exclusive role for NHE1 in enterocyte physiology has remained elusive. NHE2 (Slc9a2) and NHE8 (Slc9a8) are apically expressed isoforms with ubiquitous distribution along the colonic crypt axis.

Development of a Convolutional Neural Network-Based Colonoscopy Image Assessment Model for Differentiating Crohn's Disease and Ulcerative Colitis.

Objective: Evaluation of the endoscopic features of Crohn's disease (CD) and ulcerative colitis (UC) is the key diagnostic approach in distinguishing these two diseases. However, making diagnostic differentiation of endoscopic images requires precise interpretation by experienced clinicians, which remains a challenge to date. Therefore, this study aimed to establish a convolutional neural network (CNN)-based model to facilitate the diagnostic classification among CD, UC, and healthy controls based on colonoscopy images.

Alterations of mucosa-attached microbiome and epithelial cell numbers in the cystic fibrosis small intestine with implications for intestinal disease.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Defective CFTR leads to accumulation of dehydrated viscous mucus within the small intestine, luminal acidification and altered intestinal motility, resulting in blockage. These changes promote gut microbial dysbiosis, adversely influencing the normal proliferation and differentiation of intestinal epithelial cells.

SLC26A9 deficiency causes gastric intraepithelial neoplasia in mice and aggressive gastric cancer in humans.

Background: Solute carrier family 26 member (SLC26A9) is a Cl uniporter with very high expression levels in the gastric mucosa. Here, we describe morphological and molecular alterations in gastric mucosa of slc26a9 mice and in selective parietal cell-deleted slc26a9/Atp4b-Cre mice and correlate SLC26A9 expression levels with morphological and clinical parameters in a cohort of gastric cancer (GC) patients.

Methods: The expression patterns of genes related to transport and enzymatic function, proliferation, apoptosis, inflammation, barrier integrity, metaplasia and neoplasia development were studied by immunohistochemistry (IHC), quantitative RT-PCR, in situ hybridization and RNA microarray analysis.

Upregulation of antimicrobial peptide expression in slc26a3-/- mice with colonic dysbiosis and barrier defect.

Genetic defects in SLC26A3 (DRA), an intestinal Cl/HCO exchanger, result in congenital chloride diarrhea (CLD), marked by lifelong acidic diarrhea and a high risk of inflammatory bowel disease. mice serve as a model to understand the pathophysiology of CLD and search for treatment options. This study investigates the microbiota changes in colon, the genotype-related causes for the observed microbiota alterations, its inflammatory potential, as well as the corresponding host responses.

Loss of luminal carbonic anhydrase XIV results in decreased biliary bicarbonate output, liver fibrosis, and cholangiocyte proliferation in mice.

Carbonic anhydrase XIV (Car14) is highly expressed in the hepatocyte, with predominance in the canalicular membrane and its active site in the extracellular milieu. The aim of this study is to determine the physiological relevance of Car14 for biliary fluid and acid/base output, as well as its role in the maintenance of hepatocellular and cholangiocyte integrity. The common bile duct of anesthetized car14 and car14 mice was cannulated and hepatic HCO output was measured by microtitration and bile flow gravimetrically before and during stimulation with intravenously applied tauroursodeoxycholic acid (TUDCA).

Sodium/hydrogen-exchanger-2 modulates colonocyte lineage differentiation.

Aim: The sodium/hydrogen exchanger 2 (NHE2) is an intestinal acid extruder with crypt-predominant localization and unresolved physiological significance. Our aim was to decipher its role in colonic epithelial cell proliferation, differentiation and electrolyte transport.

Methods: Alterations induced by NHE2-deficiency were addressed in murine nhe2 and nhe2 colonic crypts and colonoids, and NHE2-knockdown and control Caco2Bbe cells using pH-fluorometry, gene expression analysis and immunofluorescence.

Functional characterization of the sodium/hydrogen exchanger 8 and its role in proliferation of colonic epithelial cells.

Intestinal NaCl, HCO, and fluid absorption are strongly dependent on apical Na/H exchange. The intestine expresses three presumably apical sodium-hydrogen exchanger (NHE) isoforms: NHE2, NHE3, and NHE8. We addressed the role of NHE8 [solute carrier 9A8 (SLC9A8)] and its interplay with NHE2 (SLC9A2) in luminal proton extrusion during acute and chronic enterocyte acidosis and studied the differential effects of NHE8 and NHE2 on enterocyte proliferation.

Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.

Background: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.

Methods: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries.