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World J Gastroenterol. Jul 14, 2012; 18(26): 3353-3374
Published online Jul 14, 2012. doi: 10.3748/wjg.v18.i26.3353
Recent advances in small bowel diseases: Part II
Alan BR Thomson, Angeli Chopra, Michael Tom Clandinin, Hugh Freeman
Alan BR Thomson, Department of Medicine, University of Western Ontario, London, ON N6A 5A5, Canada
Angeli Chopra, Division of General Internal Medicine, University of Alberta, Edmonton, AB T6G 2X8, Canada
Michael Tom Clandinin, Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R1, Canada
Hugh Freeman, Division of Gastroenterology, University of British Columbia, Vancouver, BC V6T 2B5, Canada
Author contributions: Thomson ABR conceived the need for an up-to-date review for gastroenterological scientists and clinicians, reviewed designated portions of the literature, prepared the first draft of this portion, as well as the final draft which was approved by co-authors; Chopra A, Clandinin MT and Freeman H contributed equally to reviewing designated portions of the literature and preparing the first draft of these portions.
Correspondence to: Alan BR Thomson, Adjunct Professor, Department of Medicine, University of Western Ontario, London, ON N6A 5A5, Canada.
Telephone: +1-519-6858300 Fax: +1-519-6633232
Received: January 6, 2011
Revised: April 5, 2012
Accepted: April 13, 2012
Published online: July 14, 2012


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.

Key Words: Absorption, Cystic fibrosis, Diagnostic imaging, Intestinal motility, Short bowel syndrome, Smooth muscle function, Tumors


For triglycerides (TG), it has been traditionally considered that lipid uptake is by way of passive permeation through the lipophilic portion of the intestinal brush border membrane (BBM). However, enterocyte-binding or transport proteins have been identified as also being important in this process[1]. Gata4 is a zinc-containing transcription factor, expressed in the epithelium of the upper small intestine, and functions to assist in fat and cholesterol absorption[2]. Lipid micelles at the BBM modulate a large number of genes, and this transcriptome responding to dietary lipids has an impact on cell architecture, signaling and metabolism genes[3]. Most lipids are in the enterocyte, and may be bound to the liver and the intestinal fatty acid (FA) binding proteins (L-FABP and I-FABP). L-/I-FABP function to translocate long chain FAs and monoacylglycerol from the BBM to the endoplasmic reticulum (ER). These long FAs are then used in the resynthesis of diacylglycerol and then triacylglycerol.

The absorption of dietary TG in the small intestine is accompanied by a rise of intestinal alkaline phosphatase (IAP) in the serum, and by the secretion of IAP-containing surfactant-like particles (SLPs) from the enterocytes. IAP is a membrane-bound protein that hydrolyses monophosphate esters at high pH optimum, and limits fat absorption by enterocytes by way of its action as a SLP[4]. Translocation of IAP across the enterocyte BBM occurs within 5 min of lipid intake by way of induction of endocytosis via clathrin-coated pits[5]. After fat has been taken up into the enterocyte, IAP is incorporated into membranes surrounding intracellular lipid droplets, and is also incorporated into basolaterally secreted SLPs. IAP is not associated with chylomicron formation, but rather with chylomicron secretion. Serum IAP levels are correlated with levels of apolipoprotein B-48 (apoB48), a protein exclusive to intestinal chylomicrons in humans[6].

After ingestion of a meal rich in TG, the small intestine continues to form very low density lipoprotein (VLDL), but the predominant TG-rich lipoprotein particles secreted in this postprandial condition are the larger chylomicron particles[7]. In the liver, TG is synthesized and packaged with apoB100 to form VLDL particles, whereas chylomicrons produced by the human gut contain apoB48. ApoB48 provides efficient chylomicron formation and lipid absorption. Apolipoprotein A-IV synthesis in the small intestine is regulated by lipid absorption, and plays a role in the regulation of chylomicron assembly and secretion.

Hepatocyte nuclear factor-4α (HNF-4α) is a nuclear receptor that regulates gene expression during enterocyte differentiation. HNF-4α is also involved with the transcription of genes involved in lipid metabolism, such as Apo-IV[8]. In newborn swine intestine, dietary lipid causes ligand-independent transactivation of HNF-4α to induce Apo-A IV and microsomal triglyceride transfer protein (MTP).

The uptake of FAs across the BBM may be partially passive and partially facilitated, mediated by the multiligand scavenger protein CD36. CD36 also participates in the orosensory detection of lipids and the production of the sensation of satiety. Thus, CD36 may play a role in lipid preferences and feeding behaviour[9]. Monoglyceride and free FAs in the cytoplasm reform TG by the successive actions of monoacylglycerol acyltransferase and diacylglycerol acyltransferase at the membrane of the smooth ER. After transfer in the ER lumen, TG droplets associate with primordial lipoprotein comprising apoB48 and phospholipids through the actions of MTP, to form TG-rich lipoproteins (TRL). The lipid droplets fuse with apoB48 plus a resident ER chaperone, MTP. MTP-dependent fusion of lipid droplets with apoB48 in the ER is the crucial restriction point in the formation of chylomicrons. The lipoprotein particle enlarges as more TG is added to the droplet. The maturing lipoprotein particles (prechylomicrons) undergo vectorial vesicular transport through the Golgi membranes. Chylomicrons cross the basolateral membrane (BLM) and into the lacteals.

Glucagon-like peptide-2 (GLP-2) increases lipid absorption, but how does this occur, when enterocytes have no GLP-2 receptors? Perhaps the GLP-2 acts on the enteroendocrine L cells, releasing insulin-like growth factor (IGF-1). GLP-2 increases the glycosylation of CD36 and increases the number of chylomicrons.

After 1 wk of feeding with a high fat diet (HFD) in mice, there is repression of genes involved in FA synthesis, and an increased expression of genes involved n lipoprotein assembly (apoB, MTP, apoA-IV). This process may be coordinated by an increase in the transcription factor SREBP-IC[10]. The number of secreted chylomicrons falls, but there are larger chylomicrons containing increased associated TG, as well as increased amounts and activity of MTP. These changes result in postprandial hypertriglyceridemia, but normal fasting levels of TGs. This postprandial hypertriglyceridemia in the absence of changes in fasting levels may explain some of the risk factors for the development atherosclerosis and cardiovascular diseases.


Dietary and biliary cholesterols are solubilized by bile acid micelles in the upper intestinal lumen. These are large negatively-charged unilamellar vesicles, smaller mixed micelles or monomeric bile acids. Bile acids promote cholesterol absorption and reduce cholesterol synthesis[11].

It is now recognized that intestinal absorption of cholesterol is a complex process, involving both BBM permeation and cotransporters[12,13]. Uptake of cholesterol from the intestinal lumen across the enterocyte BBM is also mediated by at least five proteins: Niemann-Pick C1-like 1 (NPC1L1), the scavenger receptor B-1 (SR-B1), CD36, the ATP-binding cassette protein 5 (ABCG5) and ATP-binding cassette protein 8 (ABCG8) ATP-binding cassette transporters[14,15]. NPC1L1 protein is predominantly expressed in the liver and in the proximal intestine[16]. Modulation of NPC1L1 expression is by cholesterol, as well as by the involvement of several nuclear receptors, such as liver X receptor (LXR), peroxisome proliferator-activated receptor (PPAR)-α, and by sterol regulatory element (SRE) binding proteins (SREBPs). SREBPs are transcription factors which regulate cholesterol synthesis and metabolism[17]. SSEBP-2 activates the NPC1L1 promoter, which has two sterol regulatory elements.

The ATP-binding cassette transporter ABCG1 promotes cholesterol efflux across the BLM and out of the enterocyte. In contrast, ABCG5/G8 facilitates cholesterol efflux back across the enterocyte BBM and into the intestinal lumen[18]. The ATP-binding cassette transporters are target genes of the nuclear receptor LXR. Mice on a high-fat cholesterol free diet have reduced or downregulated NPC1L1, ABCA1, ABCG5, and ABC8, reduced fractional cholesterol absorption, and a posttranslational increase in 3-hydroxy-3methylgluteral-coenzyme A reductase activity. Downregulation of cholesterol transporters is independent of LXR A[19].

NPC1L1 also occurs in intracellular compartments, and is involved as well in the absorption of dietary saturated FAs such as steric and palmitic acids[20]. The drug ezetimibe binds NPC1L1, reduces intestinal absorption of cholesterol as well as saturated FAs, and reduces weight gain in animals fed a diabetogenic diet. In this way, the drug may protect against diet-induced hyperglycemia and insulin resistance[20]. NPC1L1 and the FA translocase (FAT/CD36), as well as scavenger receptor class B type 1 (SR/B1) transporter protein, have been shown to be influenced by 5 mmol/L glucose in the intestinal lumen; enhancing protein expression of NPC1L1 and CD36, decreasing SR/B1 protein, but having no effect on the protein expression of ABCA1 and ABCG8[21]. Higher intraluminal glucose concentration increases 3-hydroxy-3methylglutaryl-coenzyme A reductase activity, increasing the transcription factors LXR-α and LXR-β, PPAR-β and PPAR-γ, as well as SREDP2. Thus, reducing the luminal concentration of glucose will also reduce uptake of cholesterol.

Aging enhances cholesterol absorption by suppressing expression of the sterol efflux transporters ABCG5/G8. In contrast, estrogen enhances cholesterol absorption due to upregulated expression of NPC1l1, ABCG5 and ABCG8[22]. Cholesterol absorption is also enhanced in diabetes; medium levels of glucose concentration in Caco-2 cells in culture increase cholesterol uptake as well as the expression of NPC1L1 and CD36 proteins[21].

Liver FA binding protein (L-FABP) increases FA uptake, intracellular transport, esterification, and oxidation in transfected transformed cells, and gene-ablated mice with no L-FABP show reductions in these steps of FA metabolism[23]. L-FABP may also play a role in hepatic cholesterol metabolism[24].

Phytosterols are cholesterol-like compounds found in plants, which reduce cholesterol absorption and plasma concentrations of low density lipoprotein cholesterol. Natural phytosterol glycosides purified from lecithin are bioactive in humans[25].

Two Na+-coupled (SMIT1 and SMIT2) and one H+-coupled (HMIT) secondary active intestinal transporters for myo-inositol have been identified[26].

One hypothesis suggests that cholesterol is absorbed by an energy independent passive diffusion process regulated via a concentration gradient[14]. The second hypothesis proposes that cholesterol is absorbed through an energy-dependent, protein-mediated process[27].

NPC1L1: NPC1L1 is the main cholesterol transporter in the jejunal BBM[16]. NPC1L1 shares 42% amino acid homology with Niemann-Pick type C1 protein (NPC1), a protein involved in the intracellular transport of cholesterol[28]. Post-translationally, NPC1L1 moves from internal membranes to the mucosal membrane during cellular cholesterol depletion, facilitating absorption[29]. Other studies suggest that NPC1L1 is located at the BBM of enterocytes[30]. NPC1L1 mRNA expression appears to be positively correlated with plasma apoB48 and chylomicron cholesterol content[31].

Scavenger receptor B1: Scavenger receptor B1 (SRB1) is highly expressed in the BBM of the proximal small intestine[32]. Intestinal SRB1 overexpression in transgenic mice has been associated with increased cholesterol absorption[33]. Moreover, antibodies against SRB1 demonstrate abolishment of high affinity binding of cholesterol to BBM vesicles that would normally be observed in NPC111-/- mice[32]. SRB1 may play a role in the initial step of cholesterol absorption by facilitating high affinity cholesterol binding to the mucosal BBM, but alternative cholesterol transporters may compensate for the absence of SRB1 in mediating cholesterol absorption in KO models[32].

FAT/CD36: FAT/CD36 (translocase), a human analogue of SRB1, is expressed along the BBM of the duodenum and jejunum. CD36 deficiency correlates with abnormal lipid processing in enterocytes[14].

ABCG5/8: ABCG5 and ABCG8 are located at the enterocyte BBM[14]. Their expression is greatest in the duodenum and jejunum, where they work in tandem to efflux cholesterol (mainly plant sterols) from the enterocyte back into the lumen for excretion[34]. A negative correlation exists between ABCG5/8 and chylomicron cholesterol content[31]. Mutations of ABCG5 and ABCG8 in humans enhance intestinal cholesterol absorption, and predisposes these individuals to atherosclerosis[35].

ATP-binding cassette protein 1: ATP-binding cassette protein 1 (ABCA1) not only mediates cholesterol efflux from the basolateral surface of enterocytes to high-density lipoprotein[36], but it also contributes to the efflux of cholesterol out of the enterocyte and back into the intestinal lumen[37].

Bile acids

Bile acids are synthesized from cholesterol in the liver, secreted into the bile ducts, stored in the gallbladder, and intermittently released into the duodenum in response to a meal, where bile acids solubilize lipids in the intestinal lumen by formation of micelles[38]. Bile acids dissociate from the lipids which they stabilize prior to the uptake of the lipids across the BBM of the proximal intestine. The bile acids are absorbed passively along the length of the small intestine. In the ileum, enterocyte BBM sodium-dependent bile acid transporters (ASBTs) also mediate bile acid uptake and bile acids are returned to the portal circulation. This is known as the “enterohepatic” circulation of bile acids. ASBT is, in effect, a salvage mechanism for luminal bile acids, providing for maintenance of cholesterol homeostasis, as well as for efficient lipid absorption.

The apical ASBT in the lipid rafts of the ileal BBM functions in concert with hepatic bile acid efflux transporters to regulate hepatic bile acid synthesis from cholesterol. One of the green tea catechins decreases the maximal transport rate (Vmax) of ASBT, without altering its content in the BBM. This reduction in Vmax is achieved by moving the transporter out of the lipid rafts[39]. This suggests a role for lipid rafts in the modulation of the function of this transporter, reducing the size of the bile acid pool, stimulating the hepatic synthesis of bile acids from cholesterol, and thereby reducing the serum concentration of cholesterol.

Initially, ASBT in the enterocyte cytosol undergoes vesicular trafficking to microdomains in the BBM. These ASBT lipid rafts are enriched with sphingolipids and cholesterol. Alterations in cholesterol content of the BBM lead to rapid modulation of the activity of ASBT[40]. Obstructive cholestasis leads to downregulation of ASBT mRNA expression. Thus, luminal bile acid levels may be involved in regulation of ASBT gene regulation[41]. In patients with ileal inflammation, such as Crohn’s disease, reduced bile acid transport may be due to diminished ASBT protein expression, as the result of ASBT inhibition by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter[42].

Once bile acids are in the ileal enterocytes, they bind to ileal bile acid-binding protein (I-BABP). Organic solute transporters (Ost)α and β are located in the BLM of the ileocytes. Ostα/Ostβ expression is induced by bile acids through ligand-dependent transactivation of both Ost genes by the nuclear bile acid receptor/farnesoid X receptor (FXR)[43]. “By coordinated control of Ostα/Ostβ expression, bile acids adjust the rate of efflux from enterocytes in response to changes in intracellular bile acid levels”. Ostα is a seven transmembrane domain protein, and Ostβ is a single transmembrane domain polypeptide. Ostα-Ostβ is the major BLM transporter of bile acids and conjugated steroids in the intestine, as well as in the kidney and liver[44]. Ostα and Ostβ promoters harbor both FXR and liver receptor homolog-1 (LRH-1) elements. FXR and LRH-1 mediate positive- and negative-feedback regulation, respectively[45].

When the BBM uptake of bile acids is impaired, excess bile acids spill into the large intestine, where bile acids stimulate cAMP and cause a secretory diarrhea. The locally-acting steroid budesonide is beneficial for the symptoms of collagenous colitis, which in turn is associated with bile acid malabsorption. This clinical benefit may be due in part to stimulation of bile acid absorption, with decreased bile acids entering the colon, less stimulation of cAMP, and less secretory diarrhea[46].

Glucose-dependent insulinotropic polypeptide (GIP) is a potent insulin secretagogue. GIP is an incretin, a gut factor released after intestinal transport of hexoses, long-chain FAs and TG, and GIP stimulates insulin secretion at physiological concentrations. GIP is secreted by enteroendocrine K cells in the proximal small intestine. Intestinal lymph contains high concentrations of GIP that respond to both enteral carbohydrate and to fat absorption. The combination of glucose and lipid has a potentiating effect on stimulation of GIP secretion in lymph fistula rats[47].

Approximately 25% of individuals with irritable bowel syndrome (IBS) have a previous history of enteric infection, such as with Campylobacter or Salmonella. Persistent chronic diarrhea is more frequently associated with infectious IBS, and bile acid malabsorption may be observed in as many as a third of patients with diarrhea-predominant IBS. In a mouse model of IBS, it was shown that ileal uptake of bile acids was reduced. Surprisingly, this was associated not with a decrease but rather with an unexpected increase in expression of the BBM Na+-dependent bile acid transporter (ASBT)[48].

Bile acids act as detergents to solubilize lipids, but also act as signaling hormones: bile acids activate the G-protein-coupled receptor TGR5, resulting in changes in energy expenditure and glucose homeostasis, as well as having an anti-inflammatory role. Novel patent and selective bile acid derivatives are being developed as TGR5 agonists for possible therapeutic enhancers[49].

Bile acids are synthesized from cholesterol. In the neutral pathway, the rate-limiting enzyme β hydroxylase (Cyp7a7) converts cholesterol to 7-hydroxycholesterol. In the attenuated acidic pathway in mitochondria, sterol 25-hydroxylase or 27-hydroxylase hydroxylates the cholesterol, and a 7β hydroxyl group is added from catalysis by oxysterol 7β hydroxylase (Cyp7b1). The ring structure is then modified, and the side chain is oxidized and shortened, and further hydroxylation occurs to form the primary bile acids, cholic and chenodeoxycholic (chenic) acid. Bile acids regulate their own synthesis by way of negative feedback on the transcription of the rate-limiting enzyme, Cyp7a1. When bile acid concentrations are high, there is activation of the nuclear FXR, which leads to increased transcription of short heterodimeric partner (SHP). Cyp7a1 is activated by the SHP-dependent as well as by the SHP-independent pathway.

The small size of the bile acid pool in neonates is increased as the result of elevated mRNA levels of FXR and SHP, and later by an increase in mRNA and protein levels of Cyp7a1[50]. The increase in Cyp7a1 levels and therefore the increased synthesis of bile acids occurs independently of FXR and SHP, and is not influenced by the administration of sterols[50].


Gangliosides are sialic acid-containing glycosphingolipids which are found in lipid rafts in outer plasma membranes, such as the BBM of the small intestine. The oligosaccharide portion of the ganglioside faces the cell surface, whereas the lymphatic ceramide portion is anchored into the inner (cytosolic side) layer of the BBM. In the rat intestine, 34% of the glycosphingolipids are gangliosides. The amount of ganglioside in the membranes varies along the intestine, being higher distally than proximally. Gangliosides differ depending upon whether ingested in micelles or unilamellar vesicles. GM3 is localized on the BBM whereas GD3 is mainly localized on the BLM. GD3 uptake into Caco-2 cells is greater across BLM than BBM, and gangliosides taken up by the BLM are largely metabolized by these enterocyte-like cells[51]. In contrast, GD3 uptake across the BBM is time- and concentration-dependent, reaches a plateau, and the GD3 is metabolized, stored, or transported out of the cell across the BLM. GD3 is found in milk and colostrum, and feeding GD3 increases its content in the intestinal lipid rafts, and in the blood membrane: the main ganglioside in the BBM is GM3, whereas GD3 is the main ganglioside in the BLM. This raises the possibility of the oral use of gangliosides to modify or to enhance some of their functions, such as regulating cell signaling, protein functions, as well as the recognition of microbes and macromolecules.


SGLT1, the Na+-glucose cotransporter in the enterocyte BBM, is a secondary active transport process which requires a favorable intracellular Na+ gradient. This gradient is provided by Na+-K+-ATPase on the BLM of enterocytes. Constitutive nitric oxide (cNO) has opposite effects on the two primary Na+-absorptive pathways in the mammalian small intestine: reducing cNO inhibits SGLT1 and stimulates the Na+/H+ hydrogen exchanger NHE3[52]. cNO also regulates mucosal blood flow, mucous secretion, and intestinal motility. The glucocorticoid-inducible kinase-1 (SGK1) stimulates SGLT1 as well as NHE3. The effects of glucocorticoid on SGLT1 are fully dependant on SGK1, whereas for NHE3 the effects of glucocorticoids also involve some additional processes[53].

During chronic intestinal inflammation, there is a transcription-mediated decrease in the number of glucose transporters. This is possibly due to altered binding of Sp1 and Hnf1, transcription binding sites for the SGLT1 promoter regions[54].

When glucose is taken by mouth, there is a fast rise in expression of SGLT1. Intestinal sugar uptake is increased in diabetes and in obesity. Roux-en-Y gastric bypass (RYGB) is a successful form of bariatric surgery. RYGB reduces glucose absorption in the Roux limb, as well as in the remaining intestine[55].

Fructose is prevalent in the diet either as a free hexose, as the disaccharide sucrose, and in the polymerized form, fructans. About 50% of adults are unable to absorb a 25 g load of fructose. Fructans are neither hydrolyzed nor absorbed in the small intestine. This osmotic load may alter intestinal motility and change the microbiota by producing a mucosal biofilm. Restricting dietary intake free of fructose and/or fructan has symptomatic benefits in some persons with diarrhea and bloating[56].

The revised SLC Transporter Gene Tables are available online at

Carbohydrate malabsorption, as assessed by hydrogen breath testing, is common in persons with Crohn’s disease (CD) and celiac disease (CeD)[57]. The absolute increase in the rate of fructose malabsorption is about 20% higher in Crohn’s disease, and lactose malabsorption is 30% higher.

The BBM hydrolysis of carbohydrates takes place by the BBM-bound glycoproteins sucrase-isomaltase (SI), maltase-glucoamylase, and lactase-phlorizin hydrolase (LPH). The pro-S1 passes from the ER to the Golgi apparatus. With glycosylation it becomes targeted to the BBM, where it is cleaved by trypsin to form sucrase and isomaltase. Compound heterozygous mutation defects in the protein folding, the direct interaction between sucrase and isomaltase, and an intermolecular chaperone included in the intracellular transport of SI, all have a role in the development of congenital sucrase-isomaltase deficiency[58]. Congenital lactase deficiency results from mutations in the coding region of LPH, with misfolding of LPH which prevents the mutant protein from exiting the ER[59].

Amino acids and proteins

The numerous BBM transporters for amino acids are differentiated functionally by their substrate specificity and driving forces. Neutral amino acids are transported by the system B0+ (Na+-dependent transporter for neutral and cationic amino acids), as well as by the ASC system (Na+-dependent transporter for mid-size neutral amino acids).

Glutamine comprises approximately 20% of the total amino acid content in the human blood stream, and as such is an important amino acid. Glutamine is the preferred substrate for enterocytes, and is also important for mucosal integrity and the intestinal permeability barrier. The Na+-glutamine cotransporter in the BBM of the enterocyte is B0AT1 (SLC6A19)[60]. Glutamine is converted to citrulline in the enterocytes. A citrulline generation test has been developed to assess enterocyte function, and the value of the slope from baseline to peak plasma citrulline concentrations is reduced in persons with celiac disease[61].

Under the influence of cholecystokinin (CCK), bile and pancreatic enzymes are secreted into the duodenal lumen where the pancreatic proteolytic enzymes (trypsin, chymotrypsin, elastase, carboxypeptidase A and carboxypeptidase D) digest proteins and polypeptides into peptides, which are usually 2-6 residues in length. Conjugated bile acids accelerate protein hydrolysis by pancreatic proteases[62].

During chronic intestinal inflammation, there is a decrease in the activity of several transporters such as the short-chain FA-bicarbonate exchanger, H+-dipeptide cotransporter, Na+-amino acid transporter, Na+-glucose cotransporter 1 (SGLT-1), and Na+-bile acid transporter. There may be a decreased number of SGLT -1 transporters in villus cells (lowering the value of the maximal transport rate, Vmax), and decreased affinity of the cotransporter for Na+-neutral amino acid transport (increasing the value of the affinity constant, Km).

For amino acids, the reduction in transport during chronic inflammation arises from a decrease in the affinity of the transport systems, and may be mediated through an increase in leukotriene D4 (an eicosanoid pathway product), which is released in chronic inflammation[63].

The proton-amino acid transporter 1 (PEPT1) transports small neutral amino acids as well as small peptides, through mediation of an inwardly directed H+ gradient across the enterocyte BBM. PEPT1 also transports drugs such as β-lactam and angiotensin-converting enzyme inhibitors. PEPT1 is under diurnal variation, relating to food intake. It is also influenced by transcription factors, such as Sp1, Cdx2, and PPAR-α. Leptin treatment increases enterocyte uptake of di- and tripeptides via the PepT1 transporter, through transcription activation of the MAPK pathway as well as translational activation via ribosomal protein S6[64].

The albumin D site-binding protein (DBP) expression is regulated in a circadian manner by oscillators called “circadian clocks”. These circadian clocks reside in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. This clock system consists of single-cell circadian oscillators that are composed of several clock genes. The expression of DBP is in phase with that of PEPT1. DBP binds to the DBP binding site in the distal promoter region of the PEPT1 gene, and thereby induces transcriptional activity[65].

The SLC6A19 gene encodes the main sodium-independent BBM transporter for neutral amino acids, B0AT1. The expression of B0AT1 requires angiotensin-converting enzyme 2 (ACE2)[66]. It is unknown whether the use of inhibitors of ACE2 in humans alters the protein homeostasis of the body by way of inhibiting the intestinal uptake of neutral amino acids in the small intestine (as well as in the proximal tubule of the kidney).

Small peptides are absorbed predominantly in the proximal small intestine, and free amino acids in the distal intestine. The uptake of sugars is increased by a high carbohydrate diet by upregulation of the Na+-dependent BBM glucose transporter SGLT, and the amino acid alanine also controls its own absorption, through capsaicin-sensitive primary afferent neuronal fibers as well as by the peptide calcitonin gene-related peptide, CGRP[67].

Glutamines become conditionally essential during metabolic stress. Glutamine prevents apoptosis and also plays a role in regulating glucose metabolism. For example, during fasting as well as in diabetes, the intestine by way of its glucose-6 phosphatase (G6Pase) contributes about a quarter of endogenous glucose production through gluconeogenesis.

After a RYGB, used to treat severe obesity, the glucose sensing vagal afferents in the portal vein influence glucose homeostasis. After RYGB, the absorption of glutamine by B0AT is increased in both the biliopancreatic (3.8-fold increase) and the Roux limbs (1.4-fold increase), but not in the common channel. The levels of glutaminase are also increased, but the levels of GEPase (intestinal gluconeogenesis) and PEPCK-C (cytosolic phosphoenolpyruvate carboxykinase, a measure of glutamine metabolism) were not seen to be affected[68].


Biotin is a coenzyme for the “carboxylases” which catalyze essential steps in FA biosynthesis, gluconeogenesis, and catabolism of several amino acids and FAs. Biotin is essential for cellular functions including growth and development. The human intestine utilizes the sodium-dependent multivitamin transporter (hSMVT) for biotin uptake across the enterocyte BBM[69]. The uptake process is adaptively regulated during biotin deficiency, by induction of protein and mRNA levels of hSMVT, mediated by transcriptional regulatory mechanisms.

Two other functionally unrelated nutrients, the water-soluble vitamin pantothenic acid and the metabolically important antioxidant lipoate, share the biotin transport system (hSMVT).


Dietary non-heme ferric (Fe3+) iron in the intestinal lumen is reduced to the ferrous (Fe2+) form by cytochrome b reductase1 (Cybrd1) in the BBM of the mature villus enterocytes of the proximal small intestine. Iron is transported across the BBM by the divalent-metal ion transporter 1 (DMT1). DMT1 is also known as solute carrier family 11, member 2, (SLC11A2). Fe2+ is transported through the cytoplasm of the enterocyte, and is then transferred across the BLM of the enterocyte and into the body by the BLM exporter ferroportin (solute carrier family 40, 1, Slc40a1). There is coordinated expression of ferroportin in enterocytes as well as in tissue macrophages[70].

Ferroxidase (hephaestin) in the BLM promotes the conversion of Fe2+ to Fe3+. Once the Fe3+ is in the vascular system, it binds to transferrin (Tf). There are two mechanisms by which mRNA levels of iron homeostasis-related genes are regulated; firstly, by post-transcriptional mechanisms mediated by the iron response element/iron regulatory protein system, and secondly, by mechanisms related to transcriptional regulation. In peripheral tissues, the Tf-Tf receptor (TfR) system delivers iron in the Tf-Fe loaded TfR by way of endocytosis. Unlike TfR1, TfR2 mRNA does not contain an Fe-responsive element, and TfR2 mRNA expression is not regulated by intracellular Fe levels. Instead, hepatic TfR2 protein is regulated post-translationally by diferric (Fe2+) transferrin. In this way, TfR2 is a sensor of body iron status, and regulates duodenal Fe2+ absorption and liver Fe3+ uptake[71]. Hephaestin expression also occurs in gastric antrum, enteric nervous system and pancreatic β-cells[72].

Fe2+ uptake across the enterocyte BBM responds to body iron stores, whereas transport across the BLM is regulated by the enterocyte iron status. When the enterocyte intracellular ferritin level is increased, iron will be transferred across the BLM and into the portal blood. In addition to a potential cytoplasmic route for iron across the enterocyte, there is evidence of vesicular transport or transcytosis of apotransferrin (apoTf). Approximately half of iron transfer across the enterocyte BLM is by way of apoTf and non-apoTf-dependent vesicular pathways[73].

Factors that affect hepcidin have recently been reviewed and include body iron stores, rate of erythropoiesis, hypoxia and inflammation[74]. The amount of iron absorbed is regulated by the hepatic synthesis of hepcidin. The most common inheritable form of iron overload is an autosomal recessive disorder caused by mutation in the HFE gene, HFE-associated hereditary hemochromatosis (HH). HFE codes for a major histocompatibility complex class I (MHC-I)-like molecule. HFE also needs to be associated with a β 2 microglobulin for its appropriate expression of the cell surface.

HFE modulates the expression of hepcidin in the liver. HFE may influence iron status by acting on hepatocytes and/or Kupffer cells, as well as on duodenocytes[75]. Hepcidin inhibits cellular efflux of iron by binding to and inducing degradation of ferroportin[76]. Hepcidin causes ferroportin on the BLM to be internalized and degraded[77]. In macrophages, hepcidin inhibits iron export by inducing ferroportin degradation, whereas in enterocytes hepcidin inhibits DMT1 transcription and thereby reduces BBM iron uptake[76,78]. Other critical regulators of systemic iron homeostasis are intestinal hypoxia-inducible transcription factors (HIFs)[79]. HIFs (HIF-1 and HIF-2) are critical mediators of cellular adaptation to hypoxia. HIF-2α, but not HIF-1α, promotes iron absorption in mice[80].

The normal decline in intestinal iron absorption which occurs from neonatal to adult animals is due to loss of the iron transporters (particularly ferroportin) from the distal small intestine and colon[81]. Curiously, in iron deficiency there is altered intestinal lipid metabolism resulting in production of biologically active lipid molecules (12-HETE, 13-HODE and 13-HOTE), arising as a result of changes in arachidonate12-lipooxygenase (Alox15)[82]. It is unknown if this has any clinical significance.

The cytochrome b reductase in the BBM of the duodenal enterocytes (Dcyt6) reduces dietary iron from Fe3+ to Fe2+. Fe2+ is transported across the BBM by divalent metal transporter (DMT). The Fe2+ is transported into vesicles containing either ferroportin (FPN1) or hephaestin (Heph). These Fe2+-containing FPN1 and Heph-containing vesicles cross the enterocyte cytoplasm to the BLM. The Heph oxidizes the Fe2+ to Fe3+. Fe3+ binds to transferrin and is released into the circulation[83]. Hepicidin is secreted from the liver in response to the body iron stores: increased body iron stores result in increased hepcidin, decreased FPN1 mRNA expression and increased FPN1 internalization and degradation. The end result of this repositioning of the FPN1 from the BLM is to reduce iron efflux from across the BLM of the duodenocyte, and thereby decrease iron absorption.

Heph, therefore, is a protein in the BLM of the duodenum which has ferroxidase activity to oxidize dietary Fe2+ to Fe3+. Heph is also found by immunocytochemistry to extend from the gastric antrum along the length of the entire GI tract, and to be present in both the submucosa and the myenteric plexi of the entire nervous system[72].

In HH, the variable phenotypic expression of the homozygous HFE C282Y genotype has been attributed to possible disease-modifying genes which affect the iron transporters. In HH “expressors” and “nonexpressors”, there is a significant difference in the expression of DMT1 and DMT1 (IRE), such that HFE C282Y homozygotes without phenotypic expression do not have significantly decreased duodenal gene expression of non-transport genes compared with HH subjects with iron overload[84]. Also, regardless of phenotype, “…there is coordinated regulation between duodenal expression of FPN1 [ferroportin] and DMT1 [divalent metal transporter 1], FPN1 and DCYTB [ferriductase duodenal cytochrome b] and FPN1 and HEPH [ferroxidase hephaestin] and also DCYTB and HEPH…”.


Canonical transient receptor potential (TRPC)1 acts as a calcium channel, with the total calcium effect being mediated by calcium influx through calcium-permeable channels in the plasma membrane, as well as calcium release from intracellular stores such as the ER and cytoplasmic reticulum[85].

Much of our understanding of calcium (Ca2+) absorption has come from studies in animals. Ca2+ enters the enterocyte across the BBM using TRPV6 (aka CAT, or ECAC2), a Ca2+ channel. Intracellular Ca2+ is bound to calbindin-D9K, maintaining a low intracellular concentration of free Ca2+. PMCAI (a Ca2+ ATPase) pumps Ca2+ across the BLM. The major storage form of vitamin D is 25-hydroxy vitamin D (25OHD). In humans, 25OHD is metabolized by the gene product of CYP27B1 [25-hydroxy vitamin D 1α-hydroxylase (1αOHase)] to the biologically active 1α, 25-dihydroxycholecalciferol [1,25(OH)2O3]. 1αOHase forms 25OHD, which increases the transcription of TRPV6, PMCA, and CYP24, thereby enhancing Ca2+ absorption[86].

The active hormonal form of vitamin D is 1.25 dihydroxyvitamin D3 [1,25(OH)2D]. 1,25(OH)2D activates the vitamin D receptor (VDR) which heterodimerizes with the retinoid X receptor to interact on response units such as the apical membrane Ca2+ channel, TRPV6 (the transient receptor potential cation channel, subfamily V, member 6), and the Ca2+ binding protein calcium binding protein D9k (calbindin D9k). VDR and 1,25(OH)2D, acting on TRDV6 and calbindin D9k, maintain high rates of Ca2+ absorption[87].


Copper is a mineral essential for normal growth and development. The level of copper in the body is regulated, because excessive amounts may be toxic. The copper transporter (Ctr1) is copper-specific; its transport function is energy-independent and saturable. Copper efflux from enterocytes across the BLM is mediated by ATP7A. The ability of suckling rat pups to tolerate varying amounts of dietary copper may be due to changes in copper transporters, Ctr1 and ATP7A, facilitated by transcriptional and post translational mechanisms[88].

The Steap proteins on the BBM reduce copper to the cuprous form, which is then transported by Ctr1 across the BBM. In the enterocyte, copper is bound to chaperone Atox1, and reaches ATP7A for export across the BLM[89]. When copper intake is high, Ctr1 is endocytosed into the enterocyte, where there is induction of the copper-binding protein metallothionein, and ATP7A moves to a more basal lateral location. Maturation of small intestinal copper transport occurs by way of increased abundance and local alteration of Ctr1, ATP7A and ATP7B.


The intestinal absorption of zinc is regulated to meet zinc requirements in the body. ZIP4 is a major intestinal zinc transporter; absorptive upregulation of ZIP4 enhances the uptake of zinc from the intestinal lumen, replenishing any deficiency. When the zinc content of the diet is low, there is induction of the transcription factor Kruppel-like factor 4 (KLF4)[90], which leads to increased intestinal zinc uptake, thereby preventing disease manifestations of zinc deficiency such as acrodermatitis enteropathica.


“Intestinal failure” refers to a condition in which inadequate digestion and/or absorption of nutrients leads to malnutrition and/or dehydration. The most common condition resulting in intestinal failure is the short bowel syndrome (SBS). The SBS occurs following massive resection of the small intestine[91]. SBS may be defined anatomically as less than 30% of the normal intestinal length (less than 200 cm in adults). In the United States, the estimated annual prevalence of SBS in patients who have non-malignant intestinal disease, and who require home parenteral nutrition, is at least 4 per 105. The point prevalence is reported to be between 0.6 and 12.7 per 105. The commonest cause of SBS is surgical resection of small intestine for Crohn’s disease. Other common causes include mesenteric infarction, congenital abnormalities, and multiple strictures due to adhesions or abdominal irradiation.

Early in the adaptive response after an intestinal resection, there is an increase in proliferation of intestinal epithelium, with increased depth of crypts, increased villous height, and increased microvillous surface area. The process of adaptation involves the presence of luminal nutrients, gastrointestinal secretions, the mesenchyme, as well as neuronal and hormonal factors. Expansion of the number of intestinal stem cells (ISC) occurs following intestinal resection. This increases the number of intestinal crypts, through the process of intestinal dilation[92]. These ISCs are located deep in the crypts of Lieberkuhn. Isolation of ISCs has been simplified by the use of side population sorting of viable fractions of cell progenitor characteristics[93].

Wnt proteins are regulators of cell proliferation, differentiation and adhesion. Mutation in mice of the adenomatous polyposis coli (APC) gene, together with augmented Wnt signaling in the intestine, results in an enhanced adaptive response to extensive small bowel resection[94]. The increased mucosal surface area occurring following resection is due to sustained increases in crypt depth and villus height. This arises from resetting of proliferative responses, with increases in expression of mRNAs associated with proliferation (c-MYC) and differentiation of goblet cells and Paneth cells[95]. This raises the possibility that early expansion of intestinal secretory lineages within the epithelium may serve to amplify the signal(s) for initiating and sustaining intestinal adaptation. Further proof of concept studies are needed.

The Hedgehog (Hh) signaling pathway plays an important role in epithelial-mesenchymal interactions in gut morphogenesis and in epithelial cell proliferation. Hh proteins are produced in epithelial cells, and interact with underlying mesenchymal/stromal cell receptors. Blocking Hh signaling in the fetus or neonate leads to increased crypt cell proliferation, crypt-villus axis structural abnormalities, and alterations in enterocyte morphology. In Hh antibody-treated mice following intestinal resection, enterocyte migration from the crypt to the villus tip is increased, and apoptosis is also increased[96].

The epidermal growth factor receptor (EGFR) is important in the pathogenesis of intestinal adaptation. This EGFR-mediated induction of enterocyte proliferation requires induced expression of the cyclin-dependent kinase inhibitor p21 to transcribe waf1/cip1, as well as mitogen-activated protein kinase (MAPK)[97]. The cyclin-dependent kinase inhibitor (CDK1) p21waf1/cip1 may be necessary for induction of enterocyte proliferation following initiation of intestinal adaptation[98]. To maintain the new homeostasis achieved with adaptation, the high cell production rate must be matched by an equivalent rate of cell loss. EGFR signaling regulates specific Dcl-2 (Dax and Dcl-w) in the intestinal crypts, and this regulation of Dcl-2 influences apoptosis following extensive small bowel resection[99].

The vascular endothelial growth factor (VEGF) enhances angiogenesis (the growth of new blood vessels from pre-existing blood channels). Angiogenesis is a requirement for successful healing or adaptation. As expected, VEGF is important in the intestinal adaptive response[100].

The bcl-2 family of intracellular proteins has apoptotic properties. An increase in the ratio between pro- and anti-apoptotic members of these pathways occurs after massive small bowel resection, with upregulation of inducers of apoptosis including Fas and TNF-α by way of the death receptor pathway. Angiotensin converting enzyme (ACE) also promotes apoptosis in association with a reduced bax-bcl-2 protein ratio[101]. Thus, ACE may play an important role in epithelial cell adaptive responses.

GLP-2 is released from the ileum and colon in response to nutrients in the intestinal lumen. GLP-2 enhances morphologic and proliferative indices of intestinal adaptation, and this adaptation is inhibited by GLP-2 immunoneutralization[102]. GLP-2 administration enhances intestinal crypt cell proliferation and villus height, and increases expression of glucose transporters. Basal and postprandial GLP-2 levels are correlated with the magnitude of intestinal resection in experimental SBS[103].

A number of hormones and peptides act on the intestinal tract[104]. For example, glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion, pancreatic B-cell proliferation, and reduces lipid absorption, food intake and the rate of gastric emptying[105]. GLP-2 may reduce Ach release from the enteric nervous system, and thereby reduce neuronally evoked intestinal crypt epithelial Cl- secretion[106]. GLP-2 enhances the absorption of sugars and lipids[107] and has a therapeutic potential in patients with the SBS[108].

SBS patients with an end jejunostomy and no colon have limited meal-stimulated GLP-2 secretion. This is due to the removal of GLP-2 secreting L cells which are located primarily in the terminal ileum and colon. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analog, has been administered to enhance the adaptive process in patients with SBS, and to aid intestinal absorption[109]. Thus, there is a therapeutic role for GLP-2 analogs in SBS.

Long-term parenteral nutritional (PN) support may be necessary in persons with SBS. Because of the potential complications of PN, such as infection or cholestatic liver disease, efforts have been undertaken to understand and to improve the intestinal adaptive process, and to thereby enhance nutrient absorption and to possibly reduce the need for PN[110]. The success of surgical procedures designed to optimize intestinal absorptive function, such as bowel tapering or lengthening, has only been modest.

Small intestinal transplantation is an accepted treatment for severe intestinal failure. Over the past 50 years, more than a thousand children have received small bowel transplantation (SBT), alone or with liver and other organs. The one- and five-year graft survival routinely exceeds 90% and 80%, respectively[111]. However, transplantation is usually used only in those persons who have SBS with complications from home PN. With good control of acute rejection and infections, patient and graft survival after small intestinal transplantation is approximately 77% and 65%, respectively. Patient and graft survivals of 60% and 59% are seen in those with combined liver and small bowel transplantation. Unfortunately, almost half of these transplanted patients require enteral nutrition again within two years after transplantation[112]. Thus, small bowel transplantation has its risks and limitations for the SBS patient.

NOD2 is an intercellular microbial sensor present in macrophages, dendritic cells and Paneth cells. NOD2 polymorphisms may be associated with impaired expression of certain Paneth cell-derived antimicrobial peptides. The likelihood of allograft failure is about one hundred-fold higher in small bowel transplantation recipients with mutant NOD2 alleles, as compared with recipients with wild-type NOD2 loci[113].

While intestinal stem cell transplantation may play a role in refractory patients with Crohn’s disease (CD) or celiac disease, the role of stem cells in treatment of other intestinal disorders remains at an early stage of consideration[114,115].

Patients with short bowel syndrome from other non-CD causes were recently reported to develop CD in the residual intestine. The authors suggested that this shortened intestine may be a predisposing factor because of alterations in the motility of the intestine as well as alterations in the intestinal flora[116]. In persons with a short bowel syndrome, continuous tube feeding alone or with oral feeding enhances nutrient absorption, as compared with oral intake alone[117]. “SBS results from surgical resection, congenital defect, a disease-associated loss of absorption and is characterized by the inability to maintain protein-energy, fluid, electrolyte, or micronutrient balances when on a conveniently accepted, normal diet”[118].


Segmentation in the intestine consists of rhythmic contractions of the inner circular muscle and occurs after meals. These rhythmic contractions are regulated by slow waves, with the enteric nervous system (ENS) having a permissive role. These stationary contractions are independent of slow-wave activity, while simultaneously activating surrounding inhibitory motor neurons[119].

The ENS “…coordinates the peristaltic and secretory activity of the gut and is also involved in the regulation of blood flow and modulation of the immune system”[120]. ENS and enteric glial cells (EGCs) are in the submucosal plexus and the myenteric plexus. The ENS is composed of two ganglionated plexuses, the submucosal and the myenteric plexus, as well as the mucosal plexus. This extends within the lamina muscularis mucosae and the lamina propria mucosae beneath the epithelial lining of the intestine. Activation of human submucosal neurons decreases cellular permeability, and also decreases intestinal epithelial cell proliferation. Neurons respond to changes in intracellular calcium levels or to the expression of activation markers such as c-FOS. TTF-β1 mRNA is expressed and TGF-β1 is secreted by EGCs and they have anti-proliferative effects on intestinal epithelial cells[121]. EGCs promote neuronal survival by regulating substrate supply, and thereby help to maintain neuronal homeostasis. EGCs also synthesize cytokines, and in inflammatory conditions may modulate glia proliferation. Glial disruption alters neurochemical coding of the enteric neurons, and leads to dysmotility[122].

A method has been described for isolation and culture of primary enteric neurons. These cell lines have neuronal characteristics similar to those of primary enteric neurons[123]. It is possible to isolate and expand enteric progenitor cells from human adult tissue[120], thereby providing a potential future role for cell-based therapies for disorders of the ENS.

Patients with IBS may have abnormal colonic transit, as well as increased or decreased rectal sensation. The β3-adrenoceptor (β3-AR) is a member of the family of G-protein-coupled receptors. β3-ARs are co-localized with choline acetyltransferase in human neurons in the cholinergic myenteric and submucosal plexus. Selective β3-AR agonists inhibit cholinergic contractions, and enhance the release of somatostatin without altering carbachol-induced contractions. β3-ARs inhibit cholinergic contractions and inhibit spontaneous contraction of the human colon, as well as relaxing pre-contracted colonic longitudinal and circular muscle. Somatostatin may act as an endogenous analgesic substance, and a β-adrenergic agonist may modify visceral sensitivity. Solabegron is a β3-AR agonist which has been studied in healthy human volunteers, where it is well tolerated[124]. This raises the possibility that β3-ARs may be useful for the pain suffered by persons with IBS.

The IGF system influences cell development, growth, and apoptosis. IGF-binding proteins (IGFBP-1 to -6) transport IGFs in the blood. IGFBP-3 to -5 are present in human smooth muscle, and modify the interaction of IGF-I with its receptor, IGF-IR. IGFBP-5 has a role in regulating smooth muscle growth independent of IGF-1, by activating the G protein Gi3[125].

Acetylcholine (Ach) is released from cholinergic neurons in the myenteric plexus, and activates M2 and M3 receptors on the smooth muscles of the gastrointestinal tract. This results in smooth muscle contraction. The M2 and M3 receptors are expressed in the ratio of approximately 75%/25%, respectively, and are coupled to TRPC4 and TRPC6 (transient receptor potential channels), which depolarize the intestinal smooth muscle cells[126]. Cholinergic nerves contain substance P, and there are also nitrergic nerves and nerves which release ATP as well as other mediators in the deep muscular plexus.

Substance P (SP)-mediated sustained contraction of the small intestine is negatively regulated at a pre-synaptic level by the M2 receptor, whereas the atropine-sensitive phasic contraction is positively regulated at the M2 receptor[127]. Cytokines exert differential effects on the muscarinic receptors of intestinal longitudinal smooth muscle[128]. Corticotropin-releasing-factor (CRF) acts through both central and peripheral mechanisms. CRF induces Ca2+ transients in myenteric neurons via a CRF-1 receptor-dependent mechanism[129]. Calcium influx through voltage-operated Ca2+ channels, and in particular the R-type channels, causes the calcium transients necessary for muscle contraction.

Nonselective cationic channels in the smooth muscle cells generate muscarinic receptor-induced nonselective cation currents (MICAT), with increased Ca2+ influx by way of voltage-dependent Ca2+ channels. The Ca2+ leads to smooth muscle contraction, and peristalsis.

The gastrointestinal tract contains most of the serotonin (5-hydroxytryptamine, 5-HT) in the body, where it acts as a neurotransmitter, neuromodulator, and a paracrine factor. 5-HT is produced and released by enterochromaffin cells and by enteric nerves of the intestine. In addition to 5-HT having an effect on motility, it also regulates cell survival and proliferation. The 5-HT2D receptors are expressed on the interstitial cells of Cajal (ICC). Exogenous 5-HT regulates the number of ICC through the 5-HT2B receptor, in part by increasing ICC proliferation[130].

The sensory intrinsic primary afferent neurons (IPANs) from an ENS network modify enteric reflexes, which in turn alter gastrointestinal functions. The sensory terminals of IPANs are close to the enterochromaffin cells, which contain serotonin (5-HT). Extrinsic afferents (vagus and spinal afferents) have similar innervation territories, and both respond to chemical and to mechanical stimulation. In response to mechanical stimuli, extrinsic afferent neurons do not crosstalk with the IPANs. 5-HT activates the extrinsic afferents by a Ca2+-dependent pathway which is different from the N-type Ca2+ channels in IPANs[131].

The topic of the role of the ICC in gastrointestinal motility has been reviewed[132]. It has become controversial with regard to the way nerves transmit their signals to regulate activity of intestinal smooth muscle[133]: the c-kit receptor may be of importance[134]. ICC help in maintaining the gradient of resting membrane potential, rather than by pacing the slow waves or assisting in their propagation[135]. It is by volume transmission rather than wire transmission via the ICC that there is communication between the enteric neuronal varicosities and muscle cells. While the ICC may be impaired in numerous motility disorders, “…a cause-and-effect relationship between ICC impairment and motility dysfunction is not established”. In the small intestine, ICC in the deep muscular plexus mediate neurotransmission, whereas ICC surrounding the myenteric plexus generate slow waves. The slow waves are transferred to the adjacent smooth muscles, and can be recorded as straight “…spontaneous, rhythmic, electrical oscillations of the resting membrane potential”[136].

The ICC occur in the myenteric plexus, within either the circular (CM) or longitudinal (LM) muscles, contributing to pacing these muscle slow waves. ICC also line the septa (ICC-SEP) separating circular muscle bundles, and ICC-SEP form an important conduction pathway for spreading excitation deep into muscle bundles in the human jejunum[137]. The Na+/K+/2Cl- cotransporter (NKCC1) is involved in generation of slow waves in the jejunal musculature. ICC at the deep muscular plexus (ICC-DMP) are closely associated with the enteric nerve endings. Varicosities of nitrergic and other nerves are found on ICC-DMP or on CD34-positive, c-kit-negative fibroblast-like cells. The gap junction coupling is necessary for pacing or nerve transmission to the circuit or muscle of the mouse intestine[138].

The ICC act as pacemakers, producing slow waves of depolarization along the intestinal muscle. A transient outward K+ current may moderate the uptake of the pacemaker potential, resulting in motility arising from the waves of depolarization[139].

Bone morphogenetic protein 2 (BMP-2) is a regulatory molecule which induces the phosphorylation of the Smad1 signaling cascade, and thereby increases the differentiation of the neurons of the ENS[140].

Endogenous adenosine (eADO) is a metabolite of ATP that acts on A1, A2A and A2B receptors on enteric neurons to suppress coordinated responses triggered by immune-histamine H2 receptor activation[141].

Extracellular adenosine levels control adenosine receptor signaling. Enzymes that produce CD73 or degrade adenosine deaminase (adenosine), and thereby alter activity of transport systems in the plasma membrane, influence these extracellular adenosine levels, thereby affecting adenosine receptor signaling, which in turn alters intestinal motility[142]. β-Adrenoceptors are G-protein-coupled receptors which, when activated by an agonist, stimulate adenylyl cyclase to produce the second messenger, cAMP. cAMP activates cAMP-dependent protein kinase (PKA). There is compartmentalization of the process by which these proteins form an interaction.

Caveolae are non-clathrin-coded plasma membrane invaginations which are present in a variety of cells, including monocytes. These caveoli are present in microdomains, also known as lipid rafts, an area of the plasma membrane which is rich in cholesterol and sphingolipid. The caveolae are coated on their cytoplasmic side by caveolins, a family of integral membrane proteins including adenylyl cyclase, which are involved in signal transduction. In knockout mice depleted of caveolin-1, there is reduced PKA activity and thereby reduced function of the β-adrenoceptors[143].

Adenosine is generally accepted to be the ligand for the P1 receptor, and ATP is the ligand for P2 receptors. Adenosine A2A receptors on neuronal cells are excitatory in nature, but A1 receptors in the submucosal plexus have inhibitory actions[144]. In the murine enteric nervous system, adenosine “… suppresses synaptic transmission, efferent function of extrinsic capsaicin-sensitive sensory nerves, mucosal reflexes, neuroeffector transmission, and morphine withdrawal diarrhea”. Purinergic signaling pathways are important in sensory signaling in enterochromaffin cells and secretomotor reflexes in the intestinal tract; purinergic modulation of synaptic transmission also occurs in human intestine[145].

Intestinal motor activity and secretion are linked, and are changed cyclically in a rhythm called the migrating motor complex (MMC). Submucous neurons are both directly and indirectly mechanosensitive, and myenteric neurons can be activated by stretch. There are both rapid and slow components to the potential difference (PD) response to intestinal stretching or distension. The rapid component operates via nicotinic transmission and NK1 receptors; the slow component operates by way of VIP-ergic transmission and involves both NK1 and NK3 receptors[146].

Intestinal inflammation causes hyperplasia of smooth muscle, and this thickening of the smooth muscle layer results in dysmotility. IL-1β is a proinflammatory cytokine which results in production of PGE2 and NO from macrophages within the ileal smooth muscle tissue, and IL-1β acts as an anti-proliferative mediator[147]. Nematode infection in the small intestine induces a smooth muscle hypercontractility that depends on IL-4 and IL-3 (Th-2 cytokines) activation of the signal transducer and activator of transcription (STAT) 6. 5-HT2A is one of the molecules downstream from STAT6 activation that mediates changes in smooth muscle function[148].

Integrins are a family of transmembrane proteins, and the expression of integrins and their preferred ligands is tissue specific. In the small intestine, occupancy of a specific integrin receptor acts in concert with IGF-I-stimulated receptor tyrosine kinase activity on muscle cell growth[149]. Both insulin and IGF-I prevent apoptosis through the activation of phosphatidylinositosol 3-kinase (PIK3-kinase). Through the subsequent activation of the downstream protein serine/3 kinase, Akt IGF-I stimulates proliferation and inhibits apoptosis in intestinal smooth muscle[150].

Mechanisms underlying the sustained tonic contraction of the intestinal smooth muscle include prolonged myosin-like chain phosphorylation, phosphorylation of cytoskeleton filaments and associated proteins, alterations in Ca2+ influx, and increased sensitivity of contractile elements to Ca2+[151]. Muscarinic agonists acting through M3 receptors contract gastrointestinal smooth muscle by a protein kinase C (PKC)-dependent mechanism in the guinea pig ileum; this is thought to be through a novel PKC, PKC-δ[151].

Electrical stimulation may be synchronized with the intrinsic intestinal smooth muscle slow waves [synchronized intestinal electrical stimulation (SIES)]. SIES induces small intestinal contractions during phase I of the MMC in the fed state, and improves postprandial small intestinal hypomotility[152]. SIES remains to be of proven clinical use.

There are olfactory receptors in human mucosal enterochromaffin cells. Odorants present in the luminal environment of the gut may stimulate serotonin release by way of olfactory receptors present in these EC cells[153].

The “ileal break” describes the process by which high concentrations of lipids in the terminal ileum will slow gastric emptying and intestinal transit. High intra-ileal carbohydrate and lipid loads induce phase III motility, probably through release of neurohormonal mediators, glucagon-like peptide (GLP-1) and peptideYY (PYY). Physiological postprandial ileal lipid concentrations inhibit human digestive pancreatic protease and bile acid output, but do not influence intestinal motor activity[154].

Acute radiation exposure of the abdomen is associated with accelerated small intestinal transit through involvement of cholinergic receptors. This raises the possibility that M3 receptors “…may provide specific therapeutic targets in acute radiation enteritis”[155]. The mucosal damage in the small intestine produced by abdominal radiation may occur independently of intestinal dysmotility, and may result in diarrhea and nutrient malabsorption. Interestingly, the high molecular weight polyethylene glycol-based copolymer PEG 15-20 prevents radiation-induced intestinal injury in rats, prevents apoptosis and lethal sepsis due to Pseudomonas aeruginosa in mice, and protects cultured intestinal epithelial cells from apoptosis and microbial adherence, possibly by binding characteristic lipid raft coalescence during the development of intestinal radiation damage[156].

The mechanisms of drug-associated changes in intestinal motility have been reviewed[157]. Chronic intestinal dysmotility or chronic intestinal pseudo-obstruction may be primary, or secondary to disorders such as diabetes mellitus or scleroderma. These disorders may affect isolated components of the GI tract, or the entire GI tract. There may be absence of the phase III component of the MMC, postprandial low amplitude contractions, bursts of sustained uncoordinated phasic contractions, and clusters of contractions. All of these mechanisms contribute to the pathophysiology and the high morbidity of these dysmotility syndromes[158].

Cannabis (CB) and cannabinoid receptors inhibit intestinal motility. The CB1 receptor is present in the central and peripheral nervous system, including the enteric nervous system, as well as in non-neural tissues such as liver and adipose tissue. CB2 receptor expression is present in cells of the immune system as well as in the brain. Lipopolysaccharide (LPS) enhances intestinal transit, and this effect is reversed by cannabinoid CB2 receptor agonists[159].

Lubiprostone is a bicyclic FA compound, a prostone derived from a metabolite of prostaglandin E1. Prostones have highly selective activity on ClC-2 chloride channels, enhancing intestinal fluid secretion, but also accelerating small intestinal and colonic transit[160]. These compounds may be used clinically for the treatment of constipation.

Bowel inflammation may lead to abnormalities in intestinal motor and secretory pattern, through changes in enterochromaffin cell activity, as well as through changes in the excitability of primary afferent neurons of the enteric nervous system. Inflammation at one site of the intestine also alters the cellular components of enteric reflux circuits in non-inflamed regions[161]. Intestinal inflammation is a key event in the pathogenesis of post-operative ileus, and in rats the degree of intestinal paralysis is directly proportional to the degree of intestinal handling and inflammation which occurs at the time of surgery. Intestinal handling triggers mast cell activation and prolongs post-operative ileus[162]. The therapeutic role of this observation in preventing or treating post-operative ileus remains to be proven.

There are three endogenously-produced biologically-active gases, carbon monoxide, hydrogen sulfide and nitric oxide. Methane is also produced by enteric bacteria in one- to two-thirds of humans, and may slow intestinal transit by augmenting small bowel contractile activity[163]. Excess methane production has been recognized in a proportion of persons with constipation-predominant IBS.

Substance P and neurokinin A are the main endogenous tachykinins in the enteric neurons. Stimulation of the NK3R receptor in the GI tract activates protein kinase C, then protein kinase D, leading to noncholinergic slow excitatory postsynaptic potentials in the myenteric intrinsic primary afferent neurons of the guinea pig ileum[164].

The ICC generate pacemaker potentials which drive the electric slow waves that contribute to neuromuscular signaling leading to motor neurotransmission in the GI tract. ICC express receptor tyrosine kinase c-kit. Kit gain-of-function mutations lead to hyperplasia of ICC, with maintenance of both pacemaker function and normal enteric neural responses[165]. This is in contrast to the association between fewer ICC and the development of disturbances in GI motility. Ano1 is part of a family of 10 gene products, and labels ICC around ganglia in the deep muscular plexus[166]. Because Ano1 does not label mast cells, it may prove to be a better marker than c-kit for ICC and for mesenchymal tumors.

C-kit immunohistochemistry is used to diagnose gastrointestinal stromal tumors (GIST), since about 94% of mesenchymal tumors are positive for c-kit receptors. Between 80% and 90% of GIST tumors have gain-of-function mutations in Kit.

Stimulation of the myenteric plexus of the ENS by food in the intestinal lumen or by stretching of the intestine activates mucosal pathways to produce three different types of slow excitatory post-synaptic potentials (EPSPs) which are mediated by tachykinin or purine nucleotide neurons[167]. The predominant cell type in the ENS, the glial cells, provide functional purinergic neuron-glia communication in the ENS[168].

Myofibroblasts are an intermediate cell type between smooth muscle cells and fibroblasts. In persons with Crohn’s disease, there is disruption of the subepithelial myofibroblasts of the epithelial sheath, adding to the suggestion that myofibroblasts may be involved in the pathogenesis of inflammatory bowel disease[169]. This role of myofibroblasts is likely because they serve as a component of the innate immune system, and respond to luminal bacterial adjuvants such as LPS[170].

Manipulation of the intestine rapidly causes activation of the p38 nitrogen-activated protein kinase (MAPK), a stress-activated protein kinase. There is liberation of NO and prostaglandins from the macrophages in the muscularis external to the intestine, and the extravasation of immunocompetent white blood cells[171]. In turn, this leads to postoperative ileus, which can be prevented by giving mice a single preoperative dose of semapimod, which inhibits p38-MAPK and NO production in macrophages. This is an exciting development for its possible future application to humans undergoing abdominal surgery.

An increase in the intracellular concentration of Ca2+ in the smooth muscle of the intestine results from the release of Ca2+ from intracellular stores, as well as from the entry of Ca2+ into the cell through L-type Ca2+ channels. With stretching of the wall of the intestine there develops tension in the plasmalemmal membrane. This tension is transmitted to the mechanosensitive L-type Ca2+ channels, thereby leading to increased intracellular Ca2+ and the possibility for smooth muscle contraction[172].

The peristaltic reflex is mediated by IPANs (intestine sensory efferent neurons), interneurons, as well as excitatory and inhibitory motor neurons. The antipropulsive effect of cannabinoids on the small and large intestine result from the inhibition of the calcitonin gene-related peptide (CGRP)-containing neurons that begin the peristaltic reflex, as well as the inhibition of both the excitatory cholinergic/tachykininergic and inhibitory VIPergic motor neurons responsible for ascending contraction and descending relaxation, respectively[173].

The balance between myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) controls the overall phosphorylation of the 20-kDa regulatory light chains of myosin III. Ca2+-independent contraction of longitudinal ileal smooth muscle is potentiated by a zipper-interacting protein kinase pseudosubstrate peptide[174]. This raises the possibility of developing synthetic peptides from the autoinhibitory region of the smooth muscle myosin light chain kinase to treat hypomotility disorders of the GI tract.


Small bowel cancers represent a heterogenous group of rare tumors, and the prognosis depends upon the cell type. The standardized incidence rate for primary malignant small bowel cancer is 1.2/105 men and 0.8/105 women[175]. The four main histological types are adenocarcinoma (40%), carcinoid (31%), lymphoma (20%) and sarcoma (9%). The five-year survival rate is about 37%, and varies between 57% for neuroendocrine tumors and 18% for sarcomas.

The gastrointestinal tract is the most common extranodal site for non-Hodgkin’s lymphoma (NHL). GI NHL may be primary or secondary, the latter usually representing involvement from diffuse nodal disease. GI NHL used to be increased in the HIV-positive population, but with HAART therapy, GI NHL has virtually disappeared[176]. One intestinal nuclear receptor map has been developed, which “…indicates that the localization pattern of a receptor in normal intestine (signature) predicts the modulation of its expression in tumors”[177].


Imaging techniques for the small intestine include the classic small bowel series, enteroclysis, CT enterography, MR enterography, and more recently capsule endoscopy (CE), push enteroscopy (PE), and double balloon enteroscopy (DBE)[178]. The topic of recent developments in CE has been reviewed[179-182]. Optimal bowel preparation for CE is a PEG solution plus simethicone[183]. Using duodenal histology as the gold standard, the performance characteristics of CE for the diagnosis of celiac disease are: sensitivity 88% (95% CI: 76%-99%), specificity 91% (95% CI: 81%-100%), positive predictive value 97% (95% CI: 90%-100%), negative predictive value 71% (95% CI: 56%-87%), as well as positive and negative likelihood ratios of 9.6 and 0.14, respectively[184]. Of 43 celiac patients, 42% had mucosal changes extending beyond the duodenum, and in 7% the alterations involved the entire small intestine. Interobserver agreement for the diagnosis of celiac disease by CE ranges between 79% and 94%; and κ values range between 0.6 and 0.9. Murray et al[185] reported a sensitivity of CE for the detection of small intestinal mucosal atrophy, as compared with upper endoscopy, to be 92% vs 55% (P = 0.0005), with a specificity of 100%. Other authors have agreed with this high sensitivity of CE (over 90%), but reported a much lower specificity of approximately 64%[186].

The topic of small bowel enteroscopy has been reviewed[187]. CE is contraindicated under a number of circumstances[188]: (1) Swallowing disorder; (2) Known or suspected intestinal obstruction, strictures, or fistulae; (3) Pregnancy; (4) Children less than 10 years old; and (5) Persons with implanted electromedical devices.

In 120 persons on long-term NSAIDs or COX-2 selective agents, CE demonstrated that the 62% with abnormal CE had denuded areas (39%), mucosal breaks (29%), or reddened folds (13%)[189]. CE demonstrated small intestinal polyps in 60% of subjects with familial adenomatous polyposis (FAP) and in 75% of subjects with Peutz-Jeghers Syndrome[190].

A meta-analysis of nine studies compared CE vs other diagnostic methods for Crohn’s disease. The diagnostic yield for CE vs barium radiography was 63% and 23%, respectively. The yield for CE vs ileoscopy was 61% and 46%, respectively, and the yield of CE compared to computed tomography (CT) enterography/CT enteroclysis was 69% and 30%, respectively. A meta-analysis of the yield of CE vs other modality examinations of the small intestine in patients with non-stricturing Crohn’s disease showed that CE was superior to small bowel barium radiography, ileoscopy, CT enterography, CT enteroclysis and PE, as well as small bowel magnetic resonance imaging (MRI)[191]. In patients with previous surgical resection for Crohn’s disease, CE is inferior to ileocolonoscopy, but does detect about two-thirds of lesions outside the reach of the colonoscope[192]. These authors suggest that CE “…cannot systematically replace ileocolonoscopy in the regular management of patients after surgery” (for Crohn’s disease). The CE findings have an impact on patient management: physicians change post-CE diagnostic strategy in 61% of patients[193]. Clearly, CE has proven its diagnostic potential.

There is an incremental diagnostic yield (yield of CE minus yield of comparative modality) of 38% comparing CE to PE, and 22% compared to small bowel MRI. As compared with PE, CE provides superior identification of obscure bleeding sites in the small intestine (50% vs 24%). While CE missed 8% of lesions, these sites were accessible to standard endoscopy; in contrast, PE missed lesions in 26% of patients[194].

DBE may be used from the oral or anal route, or from both. The overall detection rate of small bowel diseases using CE is superior to that with DBE (72% vs 41%, respectively), and is also superior for the detection of small bowel diseases in patients with obscure gastrointestinal bleeding (88% vs 60%, respectively)[195]. In another study, for detection of causes of obscure gastrointestinal bleeding, 80% of small bowel abnormalities were detected by CE vs 60% with DBE[196]. PE may be inferior to push-and-pull enteroscopy to find lesions in patients with suspected small bowel bleeding[197]. DBE performance has also been evaluated in patients with refractory CD who had circumferential, discreet, or confluent ulcerations[196].

When patients with acute intestinal symptoms after allogeneic stem cell transplantation underwent esophagogastroduodenoscopy (EGD) with duodenal biopsies, as well as CE within 24 h of the onset of their symptoms, acute intestinal graft-vs-host disease (GVHD) was diagnosed by EGD with biopsies in 7 out of 13 patients, 3 of whom would have been missed by EGD alone but were detected by CE. In all 7 patients with histologically confirmed acute intestinal GVHD, CE revealed the typical lesions of GVHD[198]. The authors concluded that CE showed comparable sensitivity with EGD plus biopsies, and CE also demonstrated a high negative predictive value for diagnosing acute intestinal GVHD.

After the formation of an ileal pouch anal anastomosis (IPAA) in patients having a colectomy for ulcerative colitis, development of pouchitis is common. It is unknown how frequently lesions occur elsewhere in the small intestine. At small bowel follow-through of persons with pouchitis, 13% showed a focal ectasia of the middle ileum and a stenosis of the pouch, whereas CE performed in patients with chronic pouchitis after IPAA showed diffuse lesions from the duodenum to the ileum in all evaluable patients[199]. These lesions included apthous ulcers, erosions, redness, atrophy, cobblestoning, and deep ulcers or fissures.

A retrospective analysis of the charts of 562 patients who underwent CE at the Mount Sinai Medical Centre (NYC) for a variety of indications showed small bowel tumors in 9%[200]. In a report of the largest series of patients with small bowel tumors detected by CE, half were identified in the jejunum and approximately a quarter were in the ileum or in the mid to distal small bowel[201]. The most common malignant small bowel tumors were adenocarcinoma, carcinoids, melanomas, lymphomas and sarcomas. The most common benign tumors were GIST, hemangiomas, hamartomas, adenomas, and granulation tissue polyps. In a three-center report of Australian experiences with CE, the usefulness of CE was also confirmed, and the authors suggested that “in many patients, detection of a tumor alters management and improves outcomes”[202].

CE found a median of four small bowel polyps greater than 1 cm in size in persons with Peutz-Jeghers syndrome, while barium follow-through detected a median of only one polyp[203]. In persons with known familial adenomatous polyposis (FAP), regular examination of the small intestine for small intestinal tumors is part of the recommended management. CE detected ileal or jejunal polyps in 30% of patients, and all polyps were less than 5 mm in size. Upper gastrointestinal endoscopy detected duodenal polyps in 11 of 23 patients, and only four of these patients were identified as having duodenal polyps on CE. Thus, CE underestimated the number of polyps and did not visualize the ampulla of Vater. This suggests that CE is useful for detection of jejunal and ileal polyps in patients with FAP, but standard forward- and side-viewing endoscopic procedures are advised for detection of duodenal polyps[204].

While duodenal biopsy represents the gold standard for the diagnosis of celiac disease, CE has shown that over a third of celiac patients have mucosal changes extending beyond the duodenum, and in approximately 7% the entire small bowel is involved[184]. As compared with duodenal biopsy for detecting celiac disease, the sensitivity of CE was 88%, specificity 91%, positive predictive value 97%, and negative predictive value 71%.

Although CE provides excellent visualization of the small intestinal epithelium, if a small bowel lesion is identified, it cannot be biopsied. DBE is clinically useful to identify and biopsy such lesions[205-210].

Because of the varying values of the sensitivity and specificity of the various diagnostic methods available to diagnose small bowel disease (such as capsule endoscopy, CT- or MRI- enteroscopy, ileocolonoscopy, small bowel follow-through), it is suggested that except for CE, “…a combination of two of the other available imaging methods is the best diagnostic option for small-bowel Crohn’s disease…”[211,212]. While CE gives a diagnostic yield in about two-thirds of patients with obscure gastrointestinal bleeding, DBE (when used within 1 mo after the last episode of overt bleeding) reveals positive findings in 84% and provides a means to control bleeding in 64%[213].


Meconium ileus occurs in approximately 20% of newborns with cystic fibrosis (CF). The distal intestinal obstruction syndrome (DIOS) occurs in about 25% of CF adults. Mucus accumulation in the CF intestine is partly due to the dehydrated, acidic environment, as well as to the altered glycosylation of mucins. Mucin glycoprotein levels are increased, due to reduced mucus clearance rather than an enhanced synthesis. This is suggested by the lack of increase in the levels of expression of the major intestinal mucin genes (Muc2, Muc3). Interestingly, Muc1 is not a major component of the accumulated mucus of CF mice[214]. Mucin binds bacteria, both by nonspecific trapping as well as by binding to specific glycans, which help to carry bacteria aborally for efficient clearance from the small intestine.

In human CF, there are mutations in the CFTR gene that result in little or no cystic fibrosis transmembrane conductance regulator (CFTR) activity. Some 30%-50% of CF patients have small intestinal bacterial overgrowth (SIBO), thought to be due to slow small intestinal transit[215]. This SIBO may be due to impaired migrating motor complexes, which lead to less removal of mucus and bacteria from the small intestine. Laxatives and N-acetylcysteine (NAC) reduce bacterial overgrowth in the CF intestine of mice, and this eradication is associated with normalized intestinal transit and a reduction in the innate immune response[215].

Exogeneous pancreatic replacement enzyme therapy improves, but does not normalize, steatorrhea in CF patients. In CF mice, the crypt-villus axis height is decreased, there are fewer apoptotic cells in the intestinal crypts; there is also goblet cell hyperplasia and inflammatory cell infiltration[216]. In humans with CF, there is more than just defective lipolytic enzyme activity leading to the malabsorption of lipids. Indeed, there is evidence for abnormal enterocyte intracellular lipid processing in intestinal biopsies from CF subjects, such as decreased lipid esterification and lipid secretion, decreased output of triglyceride-rich lipoproteins, as well as diminished synthesis of apoB48 and apoA-1[217].

Factors that may contribute to the incomplete normalization of fat malabsorption in CF patients who are compliant with their intake of adequate amounts of pancreatic replacement enzymes include the use of outdated or inactivated enzymes, incorrect timing of the intake of the supplements with regards to meals, excessive duodenal acid inactivation of the enzymes, or reduced duodenal and pancreatic bicarbonate secretion leading to high intraduodenal acid concentrations, impaired formation of mixed micelles, altered composition of the BBM [decreased linoleic acid (18:2n-6) and docosahexaenoic acid (26:6n-3), as well as increased arachidonic acid (20:4n-6) and elevated (20:3n-9) to (20:4n-6) ES] with changes in its permeability and absorptive function, impaired esterification of lipids in the enterocytes, reduced apolipoprotein synthesis, chylomicron formation or secretion across the BLM. CFTR knockdown in Caco-2 cells stimulates both the synthesis and transport of fat but not cholesterol[218].

Approaches are needed to prevent the CF-associated increased viscosity of the intestinal luminal contents, and hopefully reduce the frequency of meconium ileus in CF newborns, or DIOS in CF adults. The activation of proteinase-activated receptors on the BLM of enterocytes by EGFR activation, MAP kinase signaling, Ca2+, PKA (and possibly PKC), causes chloride secretion. PKC enhances the activation of PKA, or increases BLM NKCCI, thereby enhancing the phosphorylation of CFTR, and thus Cl- and water secretion. Basolateral PAR2-induced Cl- secretion induces the activation of PKCBI and PKCS via a phospholipase C mechanism, which results in the stimulation of cRaf and ERK 1/2 signaling[219]. Reduction of NHE3-mediated Na+ and water absorption helps to increase the fluidity of the intestinal contents that would otherwise be very thick and dehydrated if NHE3 activity remained normal in the presence of reduced CFTR activity[220]. Lubiprostone activates CIC-2 chloride channels, causing Cl- and water secretion[221].


Peer reviewer: Greger Lindberg, MD, PhD, Department of Gastroenterology and Hepatology, Karolinska University Hospital, K63, SE-14186 Stockholm, Sweden

S- Editor Cheng JX L- Editor Logan S E- Editor Zheng XM

1.  Lammert F, Wang DQ. New insights into the genetic regulation of intestinal cholesterol absorption. Gastroenterology. 2005;129:718-734.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
2.  Battle MA, Bondow BJ, Iverson MA, Adams SJ, Jandacek RJ, Tso P, Duncan SA. GATA4 is essential for jejunal function in mice. Gastroenterology. 2008;135:1676-1686.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 59]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
3.  Béaslas O, Torreilles F, Casellas P, Simon D, Fabre G, Lacasa M, Delers F, Chambaz J, Rousset M, Carrière V. Transcriptome response of enterocytes to dietary lipids: impact on cell architecture, signaling, and metabolism genes. Am J Physiol Gastrointest Liver Physiol. 2008;295:G942-G952.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
4.  Malo MS, Mozumder M, Zhang XB, Biswas S, Chen A, Bai LC, Merchant JL, Hodin RA. Intestinal alkaline phosphatase gene expression is activated by ZBP-89. Am J Physiol Gastrointest Liver Physiol. 2006;290:G737-G746.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 16]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
5.  Hansen GH, Niels-Christiansen LL, Immerdal L, Nystrøm BT, Danielsen EM. Intestinal alkaline phosphatase: selective endocytosis from the enterocyte brush border during fat absorption. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1325-G1332.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 24]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
6.  Nakano T, Inoue I, Koyama I, Kanazawa K, Nakamura K, Narisawa S, Tanaka K, Akita M, Masuyama T, Seo M. Disruption of the murine intestinal alkaline phosphatase gene Akp3 impairs lipid transcytosis and induces visceral fat accumulation and hepatic steatosis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1439-G1449.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 43]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
7.  Lo CM, Nordskog BK, Nauli AM, Zheng S, Vonlehmden SB, Yang Q, Lee D, Swift LL, Davidson NO, Tso P. Why does the gut choose apolipoprotein B48 but not B100 for chylomicron formation? Am J Physiol Gastrointest Liver Physiol. 2008;294:G344-G352.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 44]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
8.  Leng S, Lu S, Yao Y, Kan Z, Morris GS, Stair BR, Cherny MA, Black DD. Hepatocyte nuclear factor-4 mediates apolipoprotein A-IV transcriptional regulation by fatty acid in newborn swine enterocytes. Am J Physiol Gastrointest Liver Physiol. 2007;293:G475-G483.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Newberry EP, Davidson NO. Intestinal lipid absorption, GLP-2, and CD36: still more mysteries to moving fat. Gastroenterology. 2009;137:775-778.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Hernández Vallejo SJ, Alqub M, Luquet S, Cruciani-Guglielmacci C, Delerive P, Lobaccaro JM, Kalopissis AD, Chambaz J, Rousset M, Lacorte JM. Short-term adaptation of postprandial lipoprotein secretion and intestinal gene expression to a high-fat diet. Am J Physiol Gastrointest Liver Physiol. 2009;296:G782-G792.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 37]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
11.  Woollett LA, Wang Y, Buckley DD, Yao L, Chin S, Granholm N, Jones PJ, Setchell KD, Tso P, Heubi JE. Micellar solubilisation of cholesterol is essential for absorption in humans. Gut. 2006;55:197-204.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 48]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
12.  Santosa S, Varady KA, AbuMweis S, Jones PJ. Physiological and therapeutic factors affecting cholesterol metabolism: does a reciprocal relationship between cholesterol absorption and synthesis really exist? Life Sci. 2007;80:505-514.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 55]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
13.  Wang DQ. Regulation of intestinal cholesterol absorption. Annu Rev Physiol. 2007;69:221-248.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 185]  [Cited by in F6Publishing: 153]  [Article Influence: 13.2]  [Reference Citation Analysis (0)]
14.  Hui DY, Labonté ED, Howles PN. Development and physiological regulation of intestinal lipid absorption. III. Intestinal transporters and cholesterol absorption. Am J Physiol Gastrointest Liver Physiol. 2008;294:G839-G843.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Levy E, Spahis S, Sinnett D, Peretti N, Maupas-Schwalm F, Delvin E, Lambert M, Lavoie MA. Intestinal cholesterol transport proteins: an update and beyond. Curr Opin Lipidol. 2007;18:310-318.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 33]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
16.  Altmann SW, Davis HR, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004;303:1201-1204.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1205]  [Cited by in F6Publishing: 959]  [Article Influence: 70.9]  [Reference Citation Analysis (0)]
17.  Alrefai WA, Annaba F, Sarwar Z, Dwivedi A, Saksena S, Singla A, Dudeja PK, Gill RK. Modulation of human Niemann-Pick C1-like 1 gene expression by sterol: Role of sterol regulatory element binding protein 2. Am J Physiol Gastrointest Liver Physiol. 2007;292:G369-G376.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 76]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
18.  van der Velde AE, Vrins CL, van den Oever K, Kunne C, Oude Elferink RP, Kuipers F, Groen AK. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice. Gastroenterology. 2007;133:967-975.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 137]  [Cited by in F6Publishing: 129]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
19.  de Vogel-van den Bosch HM, Bünger M, de Groot PJ, Bosch-Vermeulen H, Hooiveld GJ, Müller M. PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression. BMC Genomics. 2008;9:231.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 41]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
20.  Labonté ED, Camarota LM, Rojas JC, Jandacek RJ, Gilham DE, Davies JP, Ioannou YA, Tso P, Hui DY, Howles PN. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1-/- mice. Am J Physiol Gastrointest Liver Physiol. 2008;295:G776-G783.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 71]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
21.  Ravid Z, Bendayan M, Delvin E, Sane AT, Elchebly M, Lafond J, Lambert M, Mailhot G, Levy E. Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors. Am J Physiol Gastrointest Liver Physiol. 2008;295:G873-G885.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 42]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
22.  Duan LP, Wang HH, Ohashi A, Wang DQ. Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in mice: gender and age effects. Am J Physiol Gastrointest Liver Physiol. 2006;290:G269-G276.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 46]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
23.  Levy E, Ménard D, Delvin E, Montoudis A, Beaulieu JF, Mailhot G, Dubé N, Sinnett D, Seidman E, Bendayan M. Localization, function and regulation of the two intestinal fatty acid-binding protein types. Histochem Cell Biol. 2009;132:351-367.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 40]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
24.  Martin GG, Atshaves BP, Huang H, McIntosh AL, Williams BJ, Pai PJ, Russell DH, Kier AB, Schroeder F. Hepatic phenotype of liver fatty acid binding protein gene-ablated mice. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1053-G1065.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 41]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
25.  Lin X, Ma L, Racette SB, Anderson Spearie CL, Ostlund RE. Phytosterol glycosides reduce cholesterol absorption in humans. Am J Physiol Gastrointest Liver Physiol. 2009;296:G931-G935.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 45]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
26.  Aouameur R, Da Cal S, Bissonnette P, Coady MJ, Lapointe JY. SMIT2 mediates all myo-inositol uptake in apical membranes of rat small intestine. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1300-G1307.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 38]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
27.  Thurnhofer H, Hauser H. Uptake of cholesterol by small intestinal brush border membrane is protein-mediated. Biochemistry. 1990;29:2142-2148.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 74]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
28.  Davies JP, Levy B, Ioannou YA. Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics. 2000;65:137-145.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 158]  [Cited by in F6Publishing: 134]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
29.  Yu L, Bharadwaj S, Brown JM, Ma Y, Du W, Davis MA, Michaely P, Liu P, Willingham MC, Rudel LL. Cholesterol-regulated translocation of NPC1L1 to the cell surface facilitates free cholesterol uptake. J Biol Chem. 2006;281:6616-6624.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 152]  [Cited by in F6Publishing: 55]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
30.  Davis HR, Altmann SW. Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter. Biochim Biophys Acta. 2009;1791:679-683.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
31.  Lally S, Tan CY, Owens D, Tomkin GH. Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann-Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein. Diabetologia. 2006;49:1008-1016.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 68]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
32.  Labonté ED, Howles PN, Granholm NA, Rojas JC, Davies JP, Ioannou YA, Hui DY. Class B type I scavenger receptor is responsible for the high affinity cholesterol binding activity of intestinal brush border membrane vesicles. Biochim Biophys Acta. 2007;1771:1132-1139.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 50]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
33.  Bietrix F, Yan D, Nauze M, Rolland C, Bertrand-Michel J, Coméra C, Schaak S, Barbaras R, Groen AK, Perret B. Accelerated lipid absorption in mice overexpressing intestinal SR-BI. J Biol Chem. 2006;281:7214-7219.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 38]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
34.  Graf GA, Yu L, Li WP, Gerard R, Tuma PL, Cohen JC, Hobbs HH. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem. 2003;278:48275-48282.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 303]  [Cited by in F6Publishing: 127]  [Article Influence: 16.8]  [Reference Citation Analysis (0)]
35.  Tomkin GH. The intestine as a regulator of cholesterol homeostasis in diabetes. Atheroscler Suppl. 2008;9:27-32.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 11]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
36.  Attie AD. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis. Trends Biochem Sci. 2007;32:172-179.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 79]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
37.  Vaisman BL, Lambert G, Amar M, Joyce C, Ito T, Shamburek RD, Cain WJ, Fruchart-Najib J, Neufeld ED, Remaley AT. ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice. J Clin Invest. 2001;108:303-309.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 46]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
38.  Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008;65:2461-2483.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 517]  [Cited by in F6Publishing: 422]  [Article Influence: 39.8]  [Reference Citation Analysis (0)]
39.  Annaba F, Kumar P, Dudeja AK, Saksena S, Gill RK, Alrefai WA. Green tea catechin EGCG inhibits ileal apical sodium bile acid transporter ASBT. Am J Physiol Gastrointest Liver Physiol. 2010;298:G467-G473.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Annaba F, Sarwar Z, Kumar P, Saksena S, Turner JR, Dudeja PK, Gill RK, Alrefai WA. Modulation of ileal bile acid transporter (ASBT) activity by depletion of plasma membrane cholesterol: association with lipid rafts. Am J Physiol Gastrointest Liver Physiol. 2008;294:G489-G497.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 34]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
41.  Hruz P, Zimmermann C, Gutmann H, Degen L, Beuers U, Terracciano L, Drewe J, Beglinger C. Adaptive regulation of the ileal apical sodium dependent bile acid transporter (ASBT) in patients with obstructive cholestasis. Gut. 2006;55:395-402.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 41]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
42.  Neimark E, Chen F, Li X, Magid MS, Alasio TM, Frankenberg T, Sinha J, Dawson PA, Shneider BL. c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter. Gastroenterology. 2006;131:554-567.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 30]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
43.  Landrier JF, Eloranta JJ, Vavricka SR, Kullak-Ublick GA. The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am J Physiol Gastrointest Liver Physiol. 2006;290:G476-G485.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
44.  Ballatori N, Fang F, Christian WV, Li N, Hammond CL. Ostalpha-Ostbeta is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver. Am J Physiol Gastrointest Liver Physiol. 2008;295:G179-G186.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 81]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
45.  Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL, Dawson PA. Regulation of the mouse organic solute transporter alpha-beta, Ostalpha-Ostbeta, by bile acids. Am J Physiol Gastrointest Liver Physiol. 2006;290:G912-G922.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 79]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
46.  Bajor A, Kilander A, Gälman C, Rudling M, Ung KA. Budesonide treatment is associated with increased bile acid absorption in collagenous colitis. Aliment Pharmacol Ther. 2006;24:1643-1649.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 31]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
47.  Lu WJ, Yang Q, Sun W, Woods SC, D'Alessio D, Tso P. The regulation of the lymphatic secretion of glucagon-like peptide-1 (GLP-1) by intestinal absorption of fat and carbohydrate. Am J Physiol Gastrointest Liver Physiol. 2007;293:G963-G971.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 35]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
48.  Kalia N, Hardcastle J, Keating C, Grasa L, Keating C, Pelegrin P, Bardhan KD, Grundy D. Intestinal secretory and absorptive function in Trichinella spiralis mouse model of postinfective gut dysfunction: role of bile acids. Gut. 2008;57:41-49.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 15]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
49.  Sato H, Macchiarulo A, Thomas C, Gioiello A, Une M, Hofmann AF, Saladin R, Schoonjans K, Pellicciari R, Auwerx J. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J Med Chem. 2008;51:1831-1841.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 205]  [Cited by in F6Publishing: 187]  [Article Influence: 15.8]  [Reference Citation Analysis (0)]
50.  Burke KT, Horn PS, Tso P, Heubi JE, Woollett LA. Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increased Cyp7a1 expression levels. Am J Physiol Gastrointest Liver Physiol. 2009;297:G144-G151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 6]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
51.  Schnabl KL, Larcelet M, Thomson AB, Clandinin MT. Uptake and fate of ganglioside GD3 in human intestinal Caco-2 cells. Am J Physiol Gastrointest Liver Physiol. 2009;297:G52-G59.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 12]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
52.  Coon S, Kekuda R, Saha P, Talukder JR, Sundaram U. Constitutive nitric oxide differentially regulates Na-H and Na-glucose cotransport in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1369-G1375.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 11]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
53.  Grahammer F, Henke G, Sandu C, Rexhepaj R, Hussain A, Friedrich B, Risler T, Metzger M, Just L, Skutella T. Intestinal function of gene-targeted mice lacking serum- and glucocorticoid-inducible kinase 1. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1114-G1123.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Kekuda R, Saha P, Sundaram U. Role of Sp1 and HNF1 transcription factors in SGLT1 regulation during chronic intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1354-G1361.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 13]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
55.  Stearns AT, Balakrishnan A, Tavakkolizadeh A. Impact of Roux-en-Y gastric bypass surgery on rat intestinal glucose transport. Am J Physiol Gastrointest Liver Physiol. 2009;297:G950-G957.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 58]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
56.  Shepherd SJ, Gibson PR. Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management. J Am Diet Assoc. 2006;106:1631-1639.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 261]  [Cited by in F6Publishing: 206]  [Article Influence: 17.4]  [Reference Citation Analysis (0)]
57.  Barrett JS, Irving PM, Shepherd SJ, Muir JG, Gibson PR. Comparison of the prevalence of fructose and lactose malabsorption across chronic intestinal disorders. Aliment Pharmacol Ther. 2009;30:165-174.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 74]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
58.  Alfalah M, Keiser M, Leeb T, Zimmer KP, Naim HY. Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-isomaltase deficiency. Gastroenterology. 2009;136:883-892.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
59.  Behrendt M, Keiser M, Hoch M, Naim HY. Impaired trafficking and subcellular localization of a mutant lactase associated with congenital lactase deficiency. Gastroenterology. 2009;136:2295-2303.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 15]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
60.  Talukder JR, Kekuda R, Saha P, Arthur S, Sundaram U. Identification and characterization of rabbit small intestinal villus cell brush border membrane Na-glutamine cotransporter. Am J Physiol Gastrointest Liver Physiol. 2008;295:G7-G15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 14]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
61.  Peters JH, Wierdsma NJ, Teerlink T, van Leeuwen PA, Mulder CJ, van Bodegraven AA. The citrulline generation test: proposal for a new enterocyte function test. Aliment Pharmacol Ther. 2008;27:1300-1310.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 44]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
62.  Gass J, Vora H, Hofmann AF, Gray GM, Khosla C. Enhancement of dietary protein digestion by conjugated bile acids. Gastroenterology. 2007;133:16-23.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Talukder JR, Kekuda R, Saha P, Sundaram U. Mechanism of leukotriene D4 inhibition of Na-alanine cotransport in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2008;295:G1-G6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
64.  Hindlet P, Bado A, Kamenicky P, Deloménie C, Bourasset F, Nazaret C, Farinotti R, Buyse M. Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation. J Biol Chem. 2009;284:6801-6808.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 10]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
65.  Saito H, Terada T, Shimakura J, Katsura T, Inui K. Regulatory mechanism governing the diurnal rhythm of intestinal H+/peptide cotransporter 1 (PEPT1). Am J Physiol Gastrointest Liver Physiol. 2008;295:G395-G402.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Camargo SM, Singer D, Makrides V, Huggel K, Pos KM, Wagner CA, Kuba K, Danilczyk U, Skovby F, Kleta R. Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. Gastroenterology. 2009;136:872-882.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 150]  [Cited by in F6Publishing: 129]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
67.  Mourad FH, Barada KA, Khoury C, Hamdi T, Saadé NE, Nassar CF. Amino acids in the rat intestinal lumen regulate their own absorption from a distant intestinal site. Am J Physiol Gastrointest Liver Physiol. 2009;297:G292-G298.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 8]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
68.  Wolff BS, Meirelles K, Meng Q, Pan M, Cooney RN. Roux-en-Y gastric bypass alters small intestine glutamine transport in the obese Zucker rat. Am J Physiol Gastrointest Liver Physiol. 2009;297:G594-G601.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 16]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
69.  Reidling JC, Nabokina SM, Said HM. Molecular mechanisms involved in the adaptive regulation of human intestinal biotin uptake: A study of the hSMVT system. Am J Physiol Gastrointest Liver Physiol. 2007;292:G275-G281.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 33]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
70.  Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P. Comparative studies of duodenal and macrophage ferroportin proteins. Am J Physiol Gastrointest Liver Physiol. 2006;290:G156-G163.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 76]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
71.  Drake SF, Morgan EH, Herbison CE, Delima R, Graham RM, Chua AC, Leedman PJ, Fleming RE, Bacon BR, Olynyk JK. Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3. Am J Physiol Gastrointest Liver Physiol. 2007;292:G323-G328.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 32]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
72.  Hudson DM, Curtis SB, Smith VC, Griffiths TA, Wong AY, Scudamore CH, Buchan AM, MacGillivray RT. Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic {beta}-cells. Am J Physiol Gastrointest Liver Physiol. 2010;298:G425-G432.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 27]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
73.  Moriya M, Linder MC. Vesicular transport and apotransferrin in intestinal iron absorption, as shown in the Caco-2 cell model. Am J Physiol Gastrointest Liver Physiol. 2006;290:G301-G309.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 24]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
74.  Anderson GJ, Frazer DM, McLaren GD. Iron absorption and metabolism. Curr Opin Gastroenterol. 2009;25:129-135.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 32]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
75.  Fleming RE, Britton RS. Iron Imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol. 2006;290:G590-G594.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 30]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
76.  Ganz T, Nemeth E. Iron imports. IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Mackenzie B, Garrick MD. Iron Imports. II. Iron uptake at the apical membrane in the intestine. Am J Physiol Gastrointest Liver Physiol. 2005;289:G981-G986.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 180]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
78.  Mena NP, Esparza A, Tapia V, Valdés P, Núñez MT. Hepcidin inhibits apical iron uptake in intestinal cells. Am J Physiol Gastrointest Liver Physiol. 2008;294:G192-G198.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 113]  [Cited by in F6Publishing: 103]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
79.  Shah YM, Matsubara T, Ito S, Yim SH, Gonzalez FJ. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9:152-164.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 257]  [Cited by in F6Publishing: 235]  [Article Influence: 21.4]  [Reference Citation Analysis (0)]
80.  Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest. 2009;119:1159-1166.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 309]  [Cited by in F6Publishing: 177]  [Article Influence: 25.8]  [Reference Citation Analysis (0)]
81.  Frazer DM, Wilkins SJ, Anderson GJ. Elevated iron absorption in the neonatal rat reflects high expression of iron transport genes in the distal alimentary tract. Am J Physiol Gastrointest Liver Physiol. 2007;293:G525-G531.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Collins JF, Hu Z, Ranganathan PN, Feng D, Garrick LM, Garrick MD, Browne RW. Induction of arachidonate 12-lipoxygenase (Alox15) in intestine of iron-deficient rats correlates with the production of biologically active lipid mediators. Am J Physiol Gastrointest Liver Physiol. 2008;294:G948-G962.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 32]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
83.  Yeh KY, Yeh M, Mims L, Glass J. Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium. Am J Physiol Gastrointest Liver Physiol. 2009;296:G55-G65.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 41]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
84.  Nelson JE, Mugford VR, Kilcourse E, Wang RS, Kowdley KV. Relationship between gene expression of duodenal iron transporters and iron stores in hemochromatosis subjects. Am J Physiol Gastrointest Liver Physiol. 2010;298:G57-G62.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 9]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
85.  Rao JN, Platoshyn O, Golovina VA, Liu L, Zou T, Marasa BS, Turner DJ, Yuan JX, Wang JY. TRPC1 functions as a store-operated Ca2+ channel in intestinal epithelial cells and regulates early mucosal restitution after wounding. Am J Physiol Gastrointest Liver Physiol. 2006;290:G782-G792.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
86.  Balesaria S, Sangha S, Walters JR. Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1193-G1197.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Xue Y, Fleet JC. Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology. 2009;136:1317-127, 1317-127.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Bauerly KA, Kelleher SL, Lönnerdal B. Effects of copper supplementation on copper absorption, tissue distribution, and copper transporter expression in an infant rat model. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1007-G1014.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 34]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
89.  Lönnerdal B. Intestinal regulation of copper homeostasis: a developmental perspective. Am J Clin Nutr. 2008;88:846S-850S.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Liuzzi JP, Guo L, Chang SM, Cousins RJ. Krüppel-like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2009;296:G517-G523.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 37]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
91.  DiBaise JK, Young RJ, Vanderhoof JA. Intestinal rehabilitation and the short bowel syndrome: part 1. Am J Gastroenterol. 2004;99:1386-1395.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
92.  Dekaney CM, Fong JJ, Rigby RJ, Lund PK, Henning SJ, Helmrath MA. Expansion of intestinal stem cells associated with long-term adaptation following ileocecal resection in mice. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1013-G1022.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 70]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
93.  Gulati AS, Ochsner SA, Henning SJ. Molecular properties of side population-sorted cells from mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2008;294:G286-G294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 23]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
94.  Bernal NP, Stehr W, Zhang Y, Profitt S, Erwin CR, Warner BW. Evidence for active Wnt signaling during postresection intestinal adaptation. J Pediatr Surg. 2005;40:1025-109; discussion 1029.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 24]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
95.  Helmrath MA, Fong JJ, Dekaney CM, Henning SJ. Rapid expansion of intestinal secretory lineages following a massive small bowel resection in mice. Am J Physiol Gastrointest Liver Physiol. 2007;292:G215-G222.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
96.  Tang Y, Swietlicki EA, Jiang S, Buhman KK, Davidson NO, Burkly LC, Levin MS, Rubin DC. Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1280-G1288.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
97.  Sheng G, Bernabe KQ, Guo J, Warner BW. Epidermal growth factor receptor-mediated proliferation of enterocytes requires p21waf1/cip1 expression. Gastroenterology. 2006;131:153-164.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 34]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
98.  Stehr W, Bernal NP, Erwin CR, Bernabe KQ, Guo J, Warner BW. Roles for p21waf1/cip1 and p27kip1 during the adaptation response to massive intestinal resection. Am J Physiol Gastrointest Liver Physiol. 2006;290:G933-G941.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 11]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
99.  Bernal NP, Stehr W, Coyle R, Erwin CR, Warner BW. Epidermal growth factor receptor signaling regulates Bax and Bcl-w expression and apoptotic responses during intestinal adaptation in mice. Gastroenterology. 2006;130:412-423.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
100.  Parvadia JK, Keswani SG, Vaikunth S, Maldonado AR, Marwan A, Stehr W, Erwin C, Uzvolgyi E, Warner BW, Yamano S. Role of VEGF in small bowel adaptation after resection: the adaptive response is angiogenesis dependent. Am J Physiol Gastrointest Liver Physiol. 2007;293:G591-G598.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 22]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
101.  Haxhija EQ, Yang H, Spencer AU, Koga H, Sun X, Teitelbaum DH. Modulation of mouse intestinal epithelial cell turnover in the absence of angiotensin converting enzyme. Am J Physiol Gastrointest Liver Physiol. 2008;295:G88-G98.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 12]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
102.  Perez A, Duxbury M, Rocha FG, Ramsanahie AP, Farivar RS, Varnholt H, Ito H, Wong H, Rounds J, Zinner MJ. Glucagon-like peptide 2 is an endogenous mediator of postresection intestinal adaptation. JPEN J Parenter Enteral Nutr. 2005;29:97-101.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 17]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
103.  Martin GR, Wallace LE, Hartmann B, Holst JJ, Demchyshyn L, Toney K, Sigalet DL. Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2005;288:G431-G438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 82]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
104.  Drozdowski L, Thomson AB. Intestinal hormones and growth factors: effects on the small intestine. World J Gastroenterol. 2009;15:385-406.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 38]  [Cited by in F6Publishing: 34]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
105.  Hira T, Mochida T, Miyashita K, Hara H. GLP-1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats. Am J Physiol Gastrointest Liver Physiol. 2009;297:G663-G671.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 52]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
106.  Baldassano S, Liu S, Qu MH, Mulè F, Wood JD. Glucagon-like peptide-2 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro. Am J Physiol Gastrointest Liver Physiol. 2009;297:G800-G805.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 33]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
107.  Drozdowski L, Iordache C, Clandinin MT, Wild G, Todd Z, Thomson AB. Dexamethasone and GLP-2 given to lactating rat dams influence glucose uptake in suckling and postweanling offspring. JPEN J Parenter Enteral Nutr. 2009;33:433-439.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 4]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
108.  Abbott CA, Yazbeck R, Geier MS, Demuth HU, Howarth GS. Dipeptidyl peptidases and inflammatory bowel disease. Adv Exp Med Biol. 2006;575:155-162.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 7]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
109.  Jeppesen PB, Sanguinetti EL, Buchman A, Howard L, Scolapio JS, Ziegler TR, Gregory J, Tappenden KA, Holst J, Mortensen PB. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54:1224-1231.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 311]  [Cited by in F6Publishing: 254]  [Article Influence: 19.4]  [Reference Citation Analysis (0)]
110.  Weale AR, Edwards AG, Bailey M, Lear PA. Intestinal adaptation after massive intestinal resection. Postgrad Med J. 2005;81:178-184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
111.  Mazariegos GV, Squires RH, Sindhi RK. Current perspectives on pediatric intestinal transplantation. Curr Gastroenterol Rep. 2009;11:226-233.  [PubMed]  [DOI]  [Cited in This Article: ]
112.  Lacaille F, Vass N, Sauvat F, Canioni D, Colomb V, Talbotec C, De Serre NP, Salomon J, Hugot JP, Cézard JP. Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation. Gut. 2008;57:455-461.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 49]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
113.  Fishbein T, Novitskiy G, Mishra L, Matsumoto C, Kaufman S, Goyal S, Shetty K, Johnson L, Lu A, Wang A. NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine. Gut. 2008;57:323-330.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 93]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
114.  Barker N, Clevers H. Tracking down the stem cells of the intestine: strategies to identify adult stem cells. Gastroenterology. 2007;133:1755-1760.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 99]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
115.  Scoville DH, Sato T, He XC, Li L. Current view: intestinal stem cells and signaling. Gastroenterology. 2008;134:849-864.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 292]  [Cited by in F6Publishing: 266]  [Article Influence: 22.5]  [Reference Citation Analysis (0)]
116.  Walzer N, Buchman AL. Development of Crohn's disease in patients with intestinal failure: a role for bacteria? J Clin Gastroenterol. 2010;44:361-363.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
117.  Joly F, Dray X, Corcos O, Barbot L, Kapel N, Messing B. Tube feeding improves intestinal absorption in short bowel syndrome patients. Gastroenterology. 2009;136:824-831.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 47]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
118.  O'Keefe SJ, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short bowel syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol Hepatol. 2006;4:6-10.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 312]  [Cited by in F6Publishing: 223]  [Article Influence: 20.8]  [Reference Citation Analysis (0)]
119.  Gwynne RM, Bornstein JC. Mechanisms underlying nutrient-induced segmentation in isolated guinea pig small intestine. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1162-G1172.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 39]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
120.  Metzger M, Bareiss PM, Danker T, Wagner S, Hennenlotter J, Guenther E, Obermayr F, Stenzl A, Koenigsrainer A, Skutella T. Expansion and differentiation of neural progenitors derived from the human adult enteric nervous system. Gastroenterology. 2009;137:2063-2073.e4.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
121.  Neunlist M, Aubert P, Bonnaud S, Van Landeghem L, Coron E, Wedel T, Naveilhan P, Ruhl A, Lardeux B, Savidge T. Enteric glia inhibit intestinal epithelial cell proliferation partly through a TGF-beta1-dependent pathway. Am J Physiol Gastrointest Liver Physiol. 2007;292:G231-G241.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 84]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
122.  Aubé AC, Cabarrocas J, Bauer J, Philippe D, Aubert P, Doulay F, Liblau R, Galmiche JP, Neunlist M. Changes in enteric neurone phenotype and intestinal functions in a transgenic mouse model of enteric glia disruption. Gut. 2006;55:630-637.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 142]  [Cited by in F6Publishing: 140]  [Article Influence: 8.9]  [Reference Citation Analysis (0)]
123.  Anitha M, Joseph I, Ding X, Torre ER, Sawchuk MA, Mwangi S, Hochman S, Sitaraman SV, Anania F, Srinivasan S. Characterization of fetal and postnatal enteric neuronal cell lines with improvement in intestinal neural function. Gastroenterology. 2008;134:1424-1435.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 40]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
124.  Grudell AB, Camilleri M, Jensen KL, Foxx-Orenstein AE, Burton DD, Ryks MD, Baxter KL, Cox DS, Dukes GE, Kelleher DL. Dose-response effect of a beta3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1114-G1119.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 19]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
125.  Flynn RS, Mahavadi S, Murthy KS, Kellum JM, Kuemmerle JF. Insulin-like growth factor-binding protein-5 stimulates growth of human intestinal muscle cells by activation of G{alpha}i3. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1232-G1238.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
126.  Tsvilovskyy VV, Zholos AV, Aberle T, Philipp SE, Dietrich A, Zhu MX, Birnbaumer L, Freichel M, Flockerzi V. Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. Gastroenterology. 2009;137:1415-1424.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 118]  [Cited by in F6Publishing: 106]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
127.  Takeuchi T, Tanaka K, Nakajima H, Matsui M, Azuma YT. M2 and M3 muscarinic receptors are involved in enteric nerve-mediated contraction of the mouse ileum: Findings obtained with muscarinic-receptor knockout mouse. Am J Physiol Gastrointest Liver Physiol. 2007;292:G154-G164.  [PubMed]  [DOI]  [Cited in This Article: ]
128.  Akiho H, Khan WI, Al-Kaabi A, Blennerhassett P, Deng Y, Collins SM. Cytokine modulation of muscarinic receptors in the murine intestine. Am J Physiol Gastrointest Liver Physiol. 2007;293:G250-G255.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 27]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
129.  Bisschops R, Vanden Berghe P, Sarnelli G, Janssens J, Tack J. CRF-induced calcium signaling in guinea pig small intestine myenteric neurons involves CRF-1 receptors and activation of voltage-sensitive calcium channels. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1252-G1260.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 20]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
130.  Wouters MM, Gibbons SJ, Roeder JL, Distad M, Ou Y, Strege PR, Szurszewski JH, Farrugia G. Exogenous serotonin regulates proliferation of interstitial cells of Cajal in mouse jejunum through 5-HT2B receptors. Gastroenterology. 2007;133:897-906.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 47]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
131.  Mueller MH, Xue B, Glatzle J, Hahn J, Grundy D, Kreis ME. Extrinsic afferent nerve sensitivity and enteric neurotransmission in murine jejunum in vitro. Am J Physiol Gastrointest Liver Physiol. 2009;297:G655-G662.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
132.  Ordög T. Do we need to revise the role of interstitial cells of Cajal in gastrointestinal motility? Am J Physiol Gastrointest Liver Physiol. 2008;294:G368-G371.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
133.  Goyal RK, Chaudhury A. Mounting evidence against the role of ICC in neurotransmission to smooth muscle in the gut. Am J Physiol Gastrointest Liver Physiol. 2010;298:G10-G13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 45]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
134.  Zhang Y, Carmichael SA, Wang XY, Huizinga JD, Paterson WG. Neurotransmission in lower esophageal sphincter of W/Wv mutant mice. Am J Physiol Gastrointest Liver Physiol. 2010;298:G14-G24.  [PubMed]  [DOI]  [Cited in This Article: ]
135.  Sarna SK. Are interstitial cells of Cajal plurifunction cells in the gut? Am J Physiol Gastrointest Liver Physiol. 2008;294:G372-G390.  [PubMed]  [DOI]  [Cited in This Article: ]
136.  Wouters M, De Laet A, Donck LV, Delpire E, van Bogaert PP, Timmermans JP, de Kerchove d'Exaerde A, Smans K, Vanderwinden JM. Subtractive hybridization unravels a role for the ion cotransporter NKCC1 in the murine intestinal pacemaker. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1219-G1227.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 26]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
137.  Lee HT, Hennig GW, Fleming NW, Keef KD, Spencer NJ, Ward SM, Sanders KM, Smith TK. Septal interstitial cells of Cajal conduct pacemaker activity to excite muscle bundles in human jejunum. Gastroenterology. 2007;133:907-917.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 40]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
138.  Daniel EE, Yazbi AE, Mannarino M, Galante G, Boddy G, Livergant J, Oskouei TE. Do gap junctions play a role in nerve transmissions as well as pacing in mouse intestine? Am J Physiol Gastrointest Liver Physiol. 2007;292:G734-G745.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 20]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
139.  Parsons SP, Huizinga JD. Transient outward potassium current in ICC. Am J Physiol Gastrointest Liver Physiol. 2010;298:G456-G466.  [PubMed]  [DOI]  [Cited in This Article: ]
140.  Anitha M, Shahnavaz N, Qayed E, Joseph I, Gossrau G, Mwangi S, Sitaraman SV, Greene JG, Srinivasan S. BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway. Am J Physiol Gastrointest Liver Physiol. 2010;298:G375-G383.  [PubMed]  [DOI]  [Cited in This Article: ]
141.  Bozarov A, Wang YZ, Yu JG, Wunderlich J, Hassanain HH, Alhaj M, Cooke HJ, Grants I, Ren T, Christofi FL. Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1147-G1162.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
142.  El-Yazbi AF, Cho WJ, Schulz R, Daniel EE. Caveolin-1 knockout alters beta-adrenoceptors function in mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2006;291:G1020-G1030.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 11]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
143.  Giron MC, Bin A, Brun P, Etteri S, Bolego C, Florio C, Gaion RM. Cyclic AMP in rat ileum: evidence for the presence of an extracellular cyclic AMP-adenosine pathway. Gastroenterology. 2008;134:1116-1126.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 41]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
144.  Gao N, Hu HZ, Liu S, Gao C, Xia Y, Wood JD. Stimulation of adenosine A1 and A2A receptors by AMP in the submucosal plexus of guinea pig small intestine. Am J Physiol Gastrointest Liver Physiol. 2007;292:G492-G500.  [PubMed]  [DOI]  [Cited in This Article: ]
145.  Wunderlich JE, Needleman BJ, Chen Z, Yu JG, Wang Y, Grants I, Mikami DJ, Melvin WS, Cooke HJ, Christofi FL. Dual purinergic synaptic transmission in the human enteric nervous system. Am J Physiol Gastrointest Liver Physiol. 2008;294:G554-G566.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
146.  Larsson MH, Sapnara M, Thomas EA, Bornstein JC, Lindström E, Svensson DJ, Sjövall H. Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo. Am J Physiol Gastrointest Liver Physiol. 2008;294:G165-G173.  [PubMed]  [DOI]  [Cited in This Article: ]
147.  Ohama T, Hori M, Momotani E, Elorza M, Gerthoffer WT, Ozaki H. IL-1beta inhibits intestinal smooth muscle proliferation in an organ culture system: involvement of COX-2 and iNOS induction in muscularis resident macrophages. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1315-G1322.  [PubMed]  [DOI]  [Cited in This Article: ]
148.  Zhao A, Urban JF, Morimoto M, Elfrey JE, Madden KB, Finkelman FD, Shea-Donohue T. Contribution of 5-HT2A receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility. Gastroenterology. 2006;131:568-578.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 31]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
149.  Kuemmerle JF. Occupation of alphavbeta3-integrin by endogenous ligands modulates IGF-I receptor activation and proliferation of human intestinal smooth muscle. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1194-G1202.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 23]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
150.  Kuemmerle JF. Endogenous IGF-I protects human intestinal smooth muscle cells from apoptosis by regulation of GSK-3 beta activity. Am J Physiol Gastrointest Liver Physiol. 2005;288:G101-G110.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 34]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
151.  Poole DP, Furness JB. PKC delta-isoform translocation and enhancement of tonic contractions of gastrointestinal smooth muscle. Am J Physiol Gastrointest Liver Physiol. 2007;292:G887-G898.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
152.  Yin J, Chen JDz. Excitatory effects of synchronized intestinal electrical stimulation on small intestinal motility in dogs. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1190-G1195.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 16]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
153.  Braun T, Voland P, Kunz L, Prinz C, Gratzl M. Enterochromaffin cells of the human gut: sensors for spices and odorants. Gastroenterology. 2007;132:1890-1901.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 173]  [Cited by in F6Publishing: 152]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
154.  Keller J, Holst JJ, Layer P. Inhibition of human pancreatic and biliary output but not intestinal motility by physiological intraileal lipid loads. Am J Physiol Gastrointest Liver Physiol. 2006;290:G704-G709.  [PubMed]  [DOI]  [Cited in This Article: ]
155.  Frisby CL, Fraser RJ, Schirmer MB, Yeoh EK, Blackshaw LA. Roles of muscarinic receptor subtypes in small intestinal motor dysfunction in acute radiation enteritis. Am J Physiol Gastrointest Liver Physiol. 2007;293:G121-G127.  [PubMed]  [DOI]  [Cited in This Article: ]
156.  Valuckaite V, Zaborina O, Long J, Hauer-Jensen M, Wang J, Holbrook C, Zaborin A, Drabik K, Katdare M, Mauceri H. Oral PEG 15-20 protects the intestine against radiation: role of lipid rafts. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1041-G1052.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
157.  Sarna SK. Molecular, functional, and pharmacological targets for the development of gut promotility drugs. Am J Physiol Gastrointest Liver Physiol. 2006;291:G545-G555.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 24]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
158.  Rosa-E-Silva L, Gerson L, Davila M, Triadafilopoulos G. Clinical, radiologic, and manometric characteristics of chronic intestinal dysmotility: the Stanford experience. Clin Gastroenterol Hepatol. 2006;4:866-873.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
159.  Duncan M, Mouihate A, Mackie K, Keenan CM, Buckley NE, Davison JS, Patel KD, Pittman QJ, Sharkey KA. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats. Am J Physiol Gastrointest Liver Physiol. 2008;295:G78-G87.  [PubMed]  [DOI]  [Cited in This Article: ]
160.  Camilleri M, Bharucha AE, Ueno R, Burton D, Thomforde GM, Baxter K, McKinzie S, Zinsmeister AR. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol. 2006;290:G942-G947.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 141]  [Article Influence: 10.4]  [Reference Citation Analysis (0)]
161.  O'Hara JR, Lomax AE, Mawe GM, Sharkey KA. Ileitis alters neuronal and enteroendocrine signalling in guinea pig distal colon. Gut. 2007;56:186-194.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 43]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
162.  The FO, Bennink RJ, Ankum WM, Buist MR, Busch OR, Gouma DJ, van der Heide S, van den Wijngaard RM, de Jonge WJ, Boeckxstaens GE. Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus. Gut. 2008;57:33-40.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 86]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
163.  Pimentel M, Lin HC, Enayati P, van den Burg B, Lee HR, Chen JH, Park S, Kong Y, Conklin J. Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1089-G1095.  [PubMed]  [DOI]  [Cited in This Article: ]
164.  Poole DP, Amadesi S, Rozengurt E, Thacker M, Bunnett NW, Furness JB. Stimulation of the neurokinin 3 receptor activates protein kinase C epsilon and protein kinase D in enteric neurons. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1245-G1256.  [PubMed]  [DOI]  [Cited in This Article: ]
165.  Kwon JG, Hwang SJ, Hennig GW, Bayguinov Y, McCann C, Chen H, Rossi F, Besmer P, Sanders KM, Ward SM. Changes in the structure and function of ICC networks in ICC hyperplasia and gastrointestinal stromal tumors. Gastroenterology. 2009;136:630-639.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 25]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
166.  Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR, Lorincz A, Pozo MJ, Pasricha PJ, Van de Rijn M, West RB, Sarr MG, Kendrick ML. Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. 2009;296:G1370-G1381.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 257]  [Cited by in F6Publishing: 243]  [Article Influence: 21.4]  [Reference Citation Analysis (0)]
167.  Gwynne RM, Bornstein JC. Electrical stimulation of the mucosa evokes slow EPSPs mediated by NK1 tachykinin receptors and by P2Y1 purinoceptors in different myenteric neurons. Am J Physiol Gastrointest Liver Physiol. 2009;297:G179-G186.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 17]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
168.  Gulbransen BD, Sharkey KA. Purinergic neuron-to-glia signaling in the enteric nervous system. Gastroenterology. 2009;136:1349-1358.  [PubMed]  [DOI]  [Cited in This Article: ]
169.  Francoeur C, Bouatrouss Y, Seltana A, Pinchuk IV, Vachon PH, Powell DW, Sawan B, Seidman EG, Beaulieu JF. Degeneration of the pericryptal myofibroblast sheath by proinflammatory cytokines in inflammatory bowel diseases. Gastroenterology. 2009;136:268-277.e3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 21]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
170.  Walton KL, Holt L, Sartor RB. Lipopolysaccharide activates innate immune responses in murine intestinal myofibroblasts through multiple signaling pathways. Am J Physiol Gastrointest Liver Physiol. 2009;296:G601-G611.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 62]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
171.  Wehner S, Straesser S, Vilz TO, Pantelis D, Sielecki T, de la Cruz VF, Hirner A, Kalff JC. Inhibition of p38 mitogen-activated protein kinase pathway as prophylaxis of postoperative ileus in mice. Gastroenterology. 2009;136:619-629.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 44]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
172.  Kraichely RE, Strege PR, Sarr MG, Kendrick ML, Farrugia G. Lysophosphatidyl choline modulates mechanosensitive L-type Ca2+ current in circular smooth muscle cells from human jejunum. Am J Physiol Gastrointest Liver Physiol. 2009;296:G833-G839.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 18]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
173.  Grider JR, Mahavadi S, Li Y, Qiao LY, Kuemmerle JF, Murthy KS, Martin BR. Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids. Am J Physiol Gastrointest Liver Physiol. 2009;297:G539-G549.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 14]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
174.  Ihara E, Moffat L, Borman MA, Amon JE, Walsh MP, MacDonald JA. Ca2+-independent contraction of longitudinal ileal smooth muscle is potentiated by a zipper-interacting protein kinase pseudosubstrate peptide. Am J Physiol Gastrointest Liver Physiol. 2009;297:G361-G370.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 9]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
175.  Lepage C, Bouvier AM, Manfredi S, Dancourt V, Faivre J. Incidence and management of primary malignant small bowel cancers: a well-defined French population study. Am J Gastroenterol. 2006;101:2826-2832.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 63]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
176.  Andrews CN, John Gill M, Urbanski SJ, Stewart D, Perini R, Beck P. Changing epidemiology and risk factors for gastrointestinal non-Hodgkin's lymphoma in a North American population: population-based study. Am J Gastroenterol. 2008;103:1762-1769.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 18]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
177.  Modica S, Gofflot F, Murzilli S, D'Orazio A, Salvatore L, Pellegrini F, Nicolucci A, Tognoni G, Copetti M, Valanzano R. The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors. Gastroenterology. 2010;138:636-648, 648.e1-12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 55]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
178.  Pennazio M. Enteroscopy and capsule endoscopy. Endoscopy. 2006;38:1079-1086.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 10]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
179.  Galmiche JP, Coron E, Sacher-Huvelin S. Recent developments in capsule endoscopy. Gut. 2008;57:695-703.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 11]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
180.  Makins R, Blanshard C. Guidelines for capsule endoscopy: diagnoses will be missed. Aliment Pharmacol Ther. 2006;24:293-297.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
181.  de' Angelis GL, Fornaroli F, de' Angelis N, Magiteri B, Bizzarri B. Wireless capsule endoscopy for pediatric small-bowel diseases. Am J Gastroenterol. 2007;102:1749-1757; quiz 1748, 1758.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 39]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
182.  Lashner BA. Sensitivity-specificity trade-off for capsule endoscopy in IBD: is it worth it? Am J Gastroenterol. 2006;101:965-966.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
183.  Wei W, Ge ZZ, Lu H, Gao YJ, Hu YB, Xiao SD. Purgative bowel cleansing combined with simethicone improves capsule endoscopy imaging. Am J Gastroenterol. 2008;103:77-82.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 57]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
184.  Rondonotti E, Spada C, Cave D, Pennazio M, Riccioni ME, De Vitis I, Schneider D, Sprujevnik T, Villa F, Langelier J. Video capsule enteroscopy in the diagnosis of celiac disease: a multicenter study. Am J Gastroenterol. 2007;102:1624-1631.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 97]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
185.  Murray JA, Rubio-Tapia A, Van Dyke CT, Brogan DL, Knipschield MA, Lahr B, Rumalla A, Zinsmeister AR, Gostout CJ. Mucosal atrophy in celiac disease: extent of involvement, correlation with clinical presentation, and response to treatment. Clin Gastroenterol Hepatol. 2008;6:186-193; quiz 125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
186.  Biagi F, Rondonotti E, Campanella J, Villa F, Bianchi PI, Klersy C, De Franchis R, Corazza GR. Video capsule endoscopy and histology for small-bowel mucosa evaluation: a comparison performed by blinded observers. Clin Gastroenterol Hepatol. 2006;4:998-1003.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
187.  Semrad CE. Small bowel enteroscopy: territory conquered, future horizons. Curr Opin Gastroenterol. 2009;25:110-115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 3]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
188.  Waterman M, Eliakim R. Capsule enteroscopy of the small intestine. Abdom Imaging. 2009;34:452-458.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 35]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
189.  Maiden L, Thjodleifsson B, Seigal A, Bjarnason II, Scott D, Birgisson S, Bjarnason I. Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol. 2007;5:1040-1045.  [PubMed]  [DOI]  [Cited in This Article: ]
190.  Burke CA, Santisi J, Church J, Levinthal G. The utility of capsule endoscopy small bowel surveillance in patients with polyposis. Am J Gastroenterol. 2005;100:1498-1502.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 135]  [Cited by in F6Publishing: 95]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
191.  Triester SL, Leighton JA, Leontiadis GI, Gurudu SR, Fleischer DE, Hara AK, Heigh RI, Shiff AD, Sharma VK. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn's disease. Am J Gastroenterol. 2006;101:954-964.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 381]  [Cited by in F6Publishing: 322]  [Article Influence: 25.4]  [Reference Citation Analysis (0)]
192.  Bourreille A, Jarry M, D'Halluin PN, Ben-Soussan E, Maunoury V, Bulois P, Sacher-Huvelin S, Vahedy K, Lerebours E, Heresbach D. Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn's disease: a prospective study. Gut. 2006;55:978-983.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 155]  [Cited by in F6Publishing: 123]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
193.  Ahmad NA, Iqbal N, Joyce A. Clinical impact of capsule endoscopy on management of gastrointestinal disorders. Clin Gastroenterol Hepatol. 2008;6:433-437.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 12]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
194.  de Leusse A, Vahedi K, Edery J, Tiah D, Fery-Lemonnier E, Cellier C, Bouhnik Y, Jian R. Capsule endoscopy or push enteroscopy for first-line exploration of obscure gastrointestinal bleeding? Gastroenterology. 2007;132:855-862; quiz 1164-1165.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 72]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
195.  Li XB, Ge ZZ, Dai J, Gao YJ, Liu WZ, Hu YB, Xiao SD. The role of capsule endoscopy combined with double-balloon enteroscopy in diagnosis of small bowel diseases. Chin Med J (Engl). 2007;120:30-35.  [PubMed]  [DOI]  [Cited in This Article: ]
196.  Hadithi M, Al-toma A, Oudejans J, van Bodegraven AA, Mulder CJ, Jacobs M. The value of double-balloon enteroscopy in patients with refractory celiac disease. Am J Gastroenterol. 2007;102:987-996.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
197.  May A, Nachbar L, Schneider M, Ell C. Prospective comparison of push enteroscopy and push-and-pull enteroscopy in patients with suspected small-bowel bleeding. Am J Gastroenterol. 2006;101:2016-2024.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 94]  [Cited by in F6Publishing: 77]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
198.  Neumann S, Schoppmeyer K, Lange T, Wiedmann M, Golsong J, Tannapfel A, Mossner J, Niederwieser D, Caca K. Wireless capsule endoscopy for diagnosis of acute intestinal graft-versus-host disease. Gastrointest Endosc. 2007;65:403-409.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 37]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
199.  Calabrese C, Fabbri A, Gionchetti P, Rizzello F, Morselli C, Liguori G, Poggioli G, Campieri M, Di Febo G. Controlled study using wireless capsule endoscopy for the evaluation of the small intestine in chronic refractory pouchitis. Aliment Pharmacol Ther. 2007;25:1311-1316.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 21]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
200.  Cobrin GM, Pittman RH, Lewis BS. Increased diagnostic yield of small bowel tumors with capsule endoscopy. Cancer. 2006;107:22-27.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 130]  [Cited by in F6Publishing: 89]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
201.  Schwartz GD, Barkin JS. Small-bowel tumors detected by wireless capsule endoscopy. Dig Dis Sci. 2007;52:1026-1030.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 60]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
202.  Bailey AA, Debinski HS, Appleyard MN, Remedios ML, Hooper JE, Walsh AJ, Selby WS. Diagnosis and outcome of small bowel tumors found by capsule endoscopy: a three-center Australian experience. Am J Gastroenterol. 2006;101:2237-2243.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 97]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
203.  Brown G, Fraser C, Schofield G, Taylor S, Bartram C, Phillips R, Saunders B. Video capsule endoscopy in peutz-jeghers syndrome: a blinded comparison with barium follow-through for detection of small-bowel polyps. Endoscopy. 2006;38:385-390.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 60]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
204.  Iaquinto G, Fornasarig M, Quaia M, Giardullo N, D'Onofrio V, Iaquinto S, Di Bella S, Cannizzaro R. Capsule endoscopy is useful and safe for small-bowel surveillance in familial adenomatous polyposis. Gastrointest Endosc. 2008;67:61-67.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 61]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
205.  Yamagami H, Oshitani N, Hosomi S, Suekane T, Kamata N, Sogawa M, Okazaki H, Watanabe K, Tominaga K, Watanabe T. Usefulness of double-balloon endoscopy in the diagnosis of malignant small-bowel tumors. Clin Gastroenterol Hepatol. 2008;6:1202-1205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 10]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
206.  Fry LC, Bellutti M, Neumann H, Malfertheiner P, Monkemuller K. Utility of double-balloon enteroscopy for the evaluation of malabsorption. Dig Dis. 2008;26:134-139.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 19]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
207.  Yano T, Yamamoto H. Vascular, polypoid, and other lesions of the small bowel. Best Pract Res Clin Gastroenterol. 2009;23:61-74.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 6]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
208.  Sunada K, Yamamoto H. Double-balloon endoscopy: past, present, and future. J Gastroenterol. 2009;44:1-12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 35]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
209.  Mönkemüller K, Bellutti M, Fry LC, Malfertheiner P. Enteroscopy. Best Pract Res Clin Gastroenterol. 2008;22:789-811.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 13]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
210.  Ohmiya N, Yano T, Yamamoto H, Arakawa D, Nakamura M, Honda W, Itoh A, Hirooka Y, Niwa Y, Maeda O. Diagnosis and treatment of obscure GI bleeding at double balloon endoscopy. Gastrointest Endosc. 2007;66:S72-S77.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 87]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
211.  Maconi G, Porro GB. Combining two imaging techniques is best to diagnose small-bowel Crohn's disease. Nat Clin Pract Gastroenterol Hepatol. 2009;6:142-143.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 3]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
212.  Solem CA, Loftus EV, Fletcher JG, Baron TH, Gostout CJ, Petersen BT, Tremaine WJ, Egan LJ, Faubion WA, Schroeder KW. Small-bowel imaging in Crohn's disease: a prospective, blinded, 4-way comparison trial. Gastrointest Endosc. 2008;68:255-266.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 239]  [Cited by in F6Publishing: 188]  [Article Influence: 18.4]  [Reference Citation Analysis (0)]
213.  Shinozaki S, Yamamoto H, Yano T, Sunada K, Miyata T, Hayashi Y, Arashiro M, Sugano K. Long-term outcome of patients with obscure gastrointestinal bleeding investigated by double-balloon endoscopy. Clin Gastroenterol Hepatol. 2010;8:151-158.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 60]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
214.  Malmberg EK, Noaksson KA, Phillipson M, Johansson ME, Hinojosa-Kurtzberg M, Holm L, Gendler SJ, Hansson GC. Increased levels of mucins in the cystic fibrosis mouse small intestine, and modulator effects of the Muc1 mucin expression. Am J Physiol Gastrointest Liver Physiol. 2006;291:G203-G210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 44]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
215.  De Lisle RC, Roach E, Jansson K. Effects of laxative and N-acetylcysteine on mucus accumulation, bacterial load, transit, and inflammation in the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2007;293:G577-G584.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 58]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
216.  Canale-Zambrano JC, Poffenberger MC, Cory SM, Humes DG, Haston CK. Intestinal phenotype of variable-weight cystic fibrosis knockout mice. Am J Physiol Gastrointest Liver Physiol. 2007;293:G222-G229.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
217.  Peretti N, Roy CC, Drouin E, Seidman E, Brochu P, Casimir G, Levy E. Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients. Am J Physiol Gastrointest Liver Physiol. 2006;290:G609-G615.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 19]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
218.  Mailhot G, Ravid Z, Barchi S, Moreau A, Rabasa-Lhoret R, Levy E. CFTR knockdown stimulates lipid synthesis and transport in intestinal Caco-2/15 cells. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1239-G1249.  [PubMed]  [DOI]  [Cited in This Article: ]
219.  van der Merwe JQ, Moreau F, MacNaughton WK. Protease-activated receptor-2 stimulates intestinal epithelial chloride transport through activation of PLC and selective PKC isoforms. Am J Physiol Gastrointest Liver Physiol. 2009;296:G1258-G1266.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 11]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
220.  Bradford EM, Sartor MA, Gawenis LR, Clarke LL, Shull GE. Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice. Am J Physiol Gastrointest Liver Physiol. 2009;296:G886-G898.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 36]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
221.  Crowell MD. Lubiprostone: trials and tribulations. Nat Rev Gastroenterol Hepatol. 2009;6:259-260.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 3]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]