• Bicarbonate secretion
• Collecting duct
• DIOS
• Intestine
• Kidney
• Metabolic alkalosis
• Mucoviscidosis
• NHE3
• Pancreas
• Pancreatitis
• Tenapanor

• Humans
• Cystic Fibrosis/genetics
• Cystic Fibrosis/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Intestines
• Kidney
• Pancreas

• Bladder dysfunction
• Detrusor muscle atrophy
• Electrolyte imbalance
• SLC9A3

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.

• Animals
• Cystic Fibrosis/complications
• Cystic Fibrosis/drug therapy
• Cystic Fibrosis/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Intestinal Obstruction
• Isoquinolines
• Mice
• Mice, Inbred CFTR
• Sodium-Hydrogen Exchanger 3
• Sulfonamides
• Water

• CSD
• NHE3
• SLC9A3
• compound heterozygous
• parenteral nutrition
• urinary sodium

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. They are involved in pH_i regulation of intestinal epithelial cells. Combined use of a knockout mouse model, intestinal organoid technology, and specific inhibitors revealed previously unrecognized actions of NHE2 and NHE8 in enterocyte proliferation and differentiation. NHE3 (Slc9a3), expressed in the apical membrane of differentiated intestinal epithelial cells, functions as the predominant nutrient-independent Na⁺ absorptive mechanism in the gut. The new selective NHE3 inhibitor (Tenapanor) allowed discovery of novel pathophysiological and drug-targetable NHE3 functions in cystic-fibrosis associated intestinal obstructions. NHE4, expressed in the basolateral membrane of parietal cells, is essential for parietal cell integrity and acid secretory function, through its role in cell volume regulation. This review focuses on the expression, regulation and activity of the five plasma membrane Na⁺/H⁺ exchangers in the gastrointestinal tract, emphasizing their role in maintaining intestinal homeostasis, or their impact on disease pathogenesis. We point to major open questions in identifying NHE interacting partners in central cellular pathways and processes and the necessity of determining their physiological role in a system where their endogenous expression/activity is maintained, such as organoids derived from different parts of the gastrointestinal tract.

• Na+/H+ exchanger 3
• angiotensin II
• hypertension
• kidney
• proximal tubule

Plasma membrane sodium–hydrogen exchangers (NHE) transport Na⁺ into cells in exchange for H⁺. While there are nine isoforms of NHE in humans, this review focuses on the NHE3 isoform, which is abundantly expressed in the gastrointestinal tract, where it plays a key role in acid–base balance and water homeostasis. NHE3 inhibition in the small intestine results in luminal sodium and water retention, leading to a general decrease in paracellular water flux and diffusional driving force, reduced intestinal sodium absorption, and increased stool sodium excretion. The resulting softer and more frequent stools are the rationale for the development of tenapanor as a novel, first-in-class NHE3 inhibitor to treat irritable bowel syndrome with constipation. NHE3 also has additional therapeutic implications in nephrology. Inhibition of intestinal NHE3 also lowers blood pressure by reducing intestinal sodium absorption. Perhaps, the most novel effect is its ability to decrease intestinal phosphate absorption by inhibiting the paracellular phosphate absorption pathway. Therefore, selective pharmacological inhibition of NHE3 could be a potential therapeutic strategy to treat not only heart failure and hypertension but also hyperphosphatemia. This review presents an overview of the molecular and physiological functions of NHE3 and discusses how these functions translate to potential clinical applications in nephrology.

• chronic kidney disease
• heart failure
• hyperphosphatemia
• paracellular phosphate absorption pathway
• sodium–hydrogen exchanger 3
• sodium–hydrogen exchanger 3 inhibitors

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.

• cystic fibrosis
• lung
• modifier genes

• Cystic Fibrosis/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Genes, Modifier
• Genome-Wide Association Study
• Humans
• Mutation

• DIOS
• anion secretion
• fluid secretion
• intestinal fluid absorption
• mucoviscidosis
• sodium hydrogen exchange

The sodium–hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na⁺ and fluid absorption as well as acid–base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3^IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3^IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3^IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3^IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3^IEC-KO mice show a ~25% mortality rate. The contribution of intestinal NHE3 to acid–base and Na⁺ homeostasis under normal conditions becomes evident in NHE3^IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid–base, Na⁺ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.

• congenital sodium diarrhea
• gastrointestinal physiology
• homeostasis
• renal physiology
• sodium hydrogen exchange

• Atrial fibrillation
• Intestinal sodium absorption
• Salt
• Sodium-proton-exchanger Subtype 3 (NHE 3)

• fecal metabolic profiles
• fecal microbiota profiles
• high-salt diet
• lactulose
• salt-sensitive hypertension

• Animals
• Blood Pressure/drug effects
• Gastrointestinal Microbiome/drug effects
• Hypertension/prevention & control
• Interleukin-17/genetics
• Interleukins/genetics
• Intestines/drug effects
• Intestines/microbiology
• Lactulose/pharmacology
• Male
• Mice
• Mice, Inbred C57BL
• Sodium Chloride, Dietary/administration & dosage
• Tryptophan/metabolism
• Interleukin-22

• Congenital bilateral absence of vas deferens
• Cystic fibrosis transmembrane conductance regulator
• Solute carrier family 9 isoform 3

• AQP2
• NHE-3
• collecting duct
• urea
• water deprivation

• Animals
• Aquaporin 2/metabolism
• Arginine Vasopressin/metabolism
• Calcium Signaling
• Diuresis
• Gene Deletion
• Guanine Nucleotide Exchange Factors/genetics
• Kidney/metabolism
• Kidney/physiology
• Kidney Concentrating Ability/genetics
• Mice
• Mice, Knockout
• Osmosis
• Polyuria/genetics
• Sodium-Hydrogen Exchanger 3/metabolism

• R01 DK095029 NIDDK NIH HHS
• R35 GM122536 NIGMS NIH HHS
• R01 GM066170 NIGMS NIH HHS
• R01 DK107263 NIDDK NIH HHS
• R01 DK119170 NIDDK NIH HHS

• cystic fibrosis
• intestine
• linaclotide

• Aminophenols/therapeutic use
• Cystic Fibrosis/genetics
• Cystic Fibrosis/therapy
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/physiology
• Genetic Therapy/methods
• Genotype
• Humans
• Mutation
• Phenotype
• Quinolones/therapeutic use

• R01 HD068901 NICHD NIH HHS
• R01 HL094585 NHLBI NIH HHS
• R01 HL117843 NHLBI NIH HHS

The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect, characteristic of these mice. In vitro studies of mouse intestinal organoids revealed that exacerbation of the primary defect was associated with reduced arginine uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP-mediated regulation of the major CF-causing mutant protein. Together, these studies highlight the role of this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF mutant and potentially, its promise as a therapeutic target.

• F508del-CFTR
• amino acid transporter
• colonic cell line
• human biology
• medicine
• mouse
• nitric oxide signaling
• organoids

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF) and are associated with congenital bilateral absence of the vas deferens (CBAVD), which is the major cause of infertility in male patients with CF. However, most Taiwanese patients with CBAVD do not carry major CFTR mutations. Some patients have a single copy deletion of the solute carrier family 9 isoform 3 (SLC9A3) gene. SLC9A3 is a Na⁺/H⁺ exchanger, and depleted Slc9a3 in male mice causes infertility due to the abnormal dilated lumen of the rete testis and efferent ductules. Furthermore, SLC9A3 interacts with CFTR in the pancreatic duct and functions as a genetic modifier of CF. However, SLC9A3 function and its relation to CFTR expression in the male reproductive tract in vivo remain elusive. In the present study, we found that CFTR expression was dramatically decreased in the epididymis and vas deferens of Slc9a3 knockout mice. Adult Slc9a3^-/- mice showed not only significantly decreased epididymis and vas deferens weight but also increased testis weight. Furthermore, Slc9a3^-/- mice developed obstructive azoospermia because of abnormal abundant secretions and calcification in the lumen of the reproductive tract. Ultrastructural analysis of the epithelium in Slc9a3^–/–epididymis and vas deferens displayed disorganized and reduced number of stereocilia and numerous secretory apparatuses. Our data revealed that interdependence between SLC9A3 and CFTR is critical for maintaining a precise microenvironment in the epithelial cytoarchitecture of the male reproductive tract. The Slc9a3-deficient mice with impaired male excurrent ducts in this study provide proof for our clinical findings that some Taiwanese of CBAVD carry SLC9A3 deletion but without major CFTR mutations.

Cystic fibrosis (CF) is the most common inherited life-threatening disease in Caucasians. The most well-known cause of CF is a genetic defect in CFTR, an apical membrane chloride and bicarbonate channel. The symptoms of CF include defects in the respiratory, digestive, and male reproductive systems. Most male patients with CF are infertile due to congenital bilateral absence of the vas deferens (CBAVD), which leads to obstructive azoospermia. Nevertheless, Taiwanese patients with CBAVD do not carry the common mutations of CFTR found in Caucasians. We have identified a potential candidate, SLC9A3, of which a single copy is lost in Taiwanese patients with CBAVD. In addition to the previously reported role of SLC9A3 in the digestive system and efferent ductules, we now report that the SLC9A3 deficiency causes obstructive azoospermia and impairs the epithelial structure of the reproductive tract. Loss of SLC9A3 also leads to dramatic reduced expression of CFTR in the reproductive tract. We suggest that the interplay between SLC9A3 and CFTR is responsible for CF-related infertility. Thus, we have characterized a potential critical player in the pathogenesis of CBAVD and provide a new diagnostic candidate for Asian patients with CBAVD.

• Animals
• Cystic Fibrosis Transmembrane Conductance Regulator/biosynthesis
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Gene Expression Regulation, Developmental
• Humans
• Infertility, Male/genetics
• Infertility, Male/pathology
• Male
• Mice
• Mice, Knockout
• Mutation
• Oligospermia/genetics
• Oligospermia/pathology
• Pancreatic Ducts/metabolism
• Pancreatic Ducts/pathology
• Respiratory Tract Infections/genetics
• Respiratory Tract Infections/pathology
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers/genetics

• aldosterone
• distal tubule
• hypernatremia
• hyponatremia
• proximal tubule

• SLC11A2
• SLC9A2
• SLC9A3
• acidic microclimate
• hereditary hemochromatosis
• iron absorption
• iron overload

• Animals
• Biological Transport
• Gene Expression Regulation/physiology
• Humans
• Intestinal Mucosa/metabolism
• Iron/metabolism
• Mice
• Mice, Knockout
• Microvilli/physiology
• Oocytes
• Sodium/metabolism
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers/genetics
• Sodium-Hydrogen Exchangers/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Water-Electrolyte Imbalance
• Xenopus

• R01 DK050594 NIDDK NIH HHS
• R01 DK079979 NIDDK NIH HHS
• R01 DK080047 NIDDK NIH HHS
• P30 DK078392 NIDDK NIH HHS
• T35 DK060444 NIDDK NIH HHS

• CFTR
• V-ATPase
• cAMP-regulated traffic
• intestine

As is the case in all areas of gastroenterology and hepatology, in 2009 and 2010 there were many advances in our knowledge and understanding of small intestinal diseases. Over 1000 publications were reviewed, and the important advances in basic science as well as clinical applications were considered. In Part II we review six topics: absorption, short bowel syndrome, smooth muscle function and intestinal motility, tumors, diagnostic imaging, and cystic fibrosis.

• Absorption
• Cystic fibrosis
• Diagnostic imaging
• Intestinal motility
• Short bowel syndrome
• Smooth muscle function
• Tumors

• Amino Acid Transport Systems
• Amino Acid Transport Systems, Neutral/genetics
• Antiporters/genetics
• Cell Membrane/metabolism
• Cystic Fibrosis/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Humans
• Ileus/genetics
• Intestinal Obstruction/etiology
• Meconium
• Polymorphism, Single Nucleotide/genetics
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers/genetics
• Sulfate Transporters

• R03 HG004314-02 NHGRI NIH HHS
• R03 HG004314 NHGRI NIH HHS
• R01 HL095396-04 NHLBI NIH HHS
• K23 DK083551 NIDDK NIH HHS
• R01 DK066368 NIDDK NIH HHS
• K23 DK083551-04 NIDDK NIH HHS
• R01 HL068927 NHLBI NIH HHS
• MOP 84287 CIHR
• R01 HL068927-10 NHLBI NIH HHS
• HG-0004314 NHGRI NIH HHS
• R01 HL068890 NHLBI NIH HHS
• P30 DK027651-26S1 NIDDK NIH HHS
• R01 HL68927 NHLBI NIH HHS
• P30 DK027651 NIDDK NIH HHS
• R01 HL068890-10 NHLBI NIH HHS
• MOP 258916 CIHR
• R01 HL095396 NHLBI NIH HHS
• R01 DK066368-05 NIDDK NIH HHS

• Animals
• Cystic Fibrosis/complications
• Cystic Fibrosis/genetics
• Cystic Fibrosis/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Genetic Association Studies
• Goblet Cells/pathology
• Haplotypes
• Humans
• Intestinal Obstruction/complications
• Intestinal Obstruction/genetics
• Intestinal Obstruction/metabolism
• Methionine Sulfoxide Reductases/genetics
• Methionine Sulfoxide Reductases/metabolism
• Mice
• Mice, Inbred CFTR
• Polymorphism, Single Nucleotide

• P30 DK027651 NIDDK NIH HHS
• K23 DK083551 NIDDK NIH HHS
• AG027363 NIA NIH HHS
• DK083551 NIDDK NIH HHS
• HL068890 NHLBI NIH HHS
• R37 DK044003 NIDDK NIH HHS
• R01 DK044003 NIDDK NIH HHS
• GM088823 NIGMS NIH HHS
• R24 OD011087 NIH HHS
• HL068927 NHLBI NIH HHS
• R01 GM088823 NIGMS NIH HHS
• R03 AG027363 NIA NIH HHS
• R01 HL068927 NHLBI NIH HHS
• R01 HL068890 NHLBI NIH HHS
• DK027651 NIDDK NIH HHS

• Animals
• Cluster Analysis
• Cystic Fibrosis/complications
• Cystic Fibrosis/genetics
• Cystic Fibrosis/metabolism
• Cystic Fibrosis/pathology
• Disease Models, Animal
• Female
• Gene Expression Profiling
• Gene Expression Regulation/genetics
• Ileum/metabolism
• Intestinal Diseases/etiology
• Intestinal Diseases/metabolism
• Intestinal Diseases/pathology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Phenotype
• Polymerase Chain Reaction

• anion exchanger
• bicarbonate
• ion transport