Morphological, kinetic, membrane biochemical and genetic aspects of intestinal enteroplasticity

The process of intestinal adaptation （＂enteroplasticity＂） is complex and multifaceted. Although a number of trophic nutrients and non-nutritive factors have been identified in animal studies, successful, reproducible clinical trials in humans are awaited. Understanding mechanisms underlying this adaptive process may direct research toward strategies that maximize intestinal function and impart a true clinical benefit to patients with short bowel syndrome, or to persons in whom nutrient absorption needs to be maximized. In this review, we consider the morphological, kinetic and membrane biochemical aspects of enteroplasticity, focus on the importance of nutritional factors, provide an overview of the many hormones that may alter the adaptive process, and consider some of the possible molecular profiles. While most of the data is derived from rodent studies, wherever possible, the results of human studies of intestinal enteroplasticity are provided.     

Gut hormones, and short bowel role of glucagon-like peptide-2 in adaptation syndrome： The enigmatic the regulation of intestinal

Short bowel syndrome (SBS) refers to the malabsorption of nutrients, water, and essential vitamins as a result of disease or surgical removal of parts of the small intestine. The most common reasons for removing part of the small intestine are due to surgical intervention for the treatment of either Crohn's disease or necrotizing enterocolitis. Intestinal adaptation following resection may take weeks to months to be achieved, thus nutritional support requires a variety of therapeutic measures, which include parenterai nutrition. Improper nutrition management can leave the SBS patient malnourished and/or dehydrated, which can be life threatening. The development of therapeutic strategies that reduce both the complications and medical costs associated with SBS/long-term parenterai nutrition while enhancing the intestinal adaptive response would be valuable. Currently, therapeutic options available for the treatment of SBS are limited. There are many potential stimulators of intestinal adaptation including peptide hormones, growth factors, and neuronally-derived components. Glucagon-like peptide-2 (GLP-2) is one potential treatment for gastrointestinal disorders associated with insufficient mucosal function. A significant body of evidence demonstrates that GLP-2 is a trophic hormone that plays an important role in controlling intestinal adaptation. Recent data from clinical trials demonstrate that GLP-2 is safe, well-tolerated, and promotes intestinal growth in SBS patients. However, the mechanism of action and the localization of the glucagon-like peptide-2 receptor (GLP-2R) remains an enigma. This review summarizes the role of a number of mucosal-derived factors that might be involved with intestinal adaptation processes; however, this discussion primarily examines the physiology, mechanism of action, and utility of GLP-2 in the regulation of intestinal mucosal growth.     

Pleiotropic effects of bombesin and neurotensin on intestinal mucosa： Not just trefoil peptides

Bombesin and neurotensin are neuropeptides which exert a wide spectrum of biological actions on gastrointestinal tissues influencing intestinal growth and adaptation, intestinal motility, blood flow, secretion, nutrient absorption and immune response. Based mainly on their well-established potent enterotrophic effect, numerous experimental studies investigated their potential positive effect on the atrophic or injured intestinal mucosa. These peptides proved to be effective mucosa-healing factors, but the potential molecular and cellular mechanisms for this action remained unresolved. In a recently published study （World J Gastroenterol 2008; 14（8）： 1222-1230）, it was shown that their protective effect on the intestine in experimentally induced inflammatory bowel disease was related to anti-inflammatory, antioxidant and antiapoptotic actions. These results are in close agreement with our previous studies on jaundiced and hepatectomized rats that showed a regulatory effect of bombesin and neurotensin on critical cellular processes such as enterocyte＇ proliferation and death, oxidative stress and redox equilibrium, tight junctions＇ formation and function, and inflammatory response. The pleiotropic effects of bombesin and neurotensin on diverse types of intestinal injury may justify their consideration for clinical trials.     

Hormonal protection in acute pancreatitis by ghrelin,leptin and melatonin

Acute pancreatitis is a nonbacterial disease of the pancreas.The severe form of this ailment is characterized by high mortality.Whether acute pancreatitis develops as the severe type or resolves depends on the intensity of the inflammatory process which is counteracted by the recruitment of innate defense mechanisms.It has been shown that the hormones ghrelin,leptin and melatonin are able to modulate the immune function of the organism and to protect the pancreas against inflammatory damage.Experimental studies have demonstrated that the application of these substances prior to the induction of acute pancreatitis significantly attenuated the intensity of the inflammation and reduced pancreatic tissue damage.The pancreatic protective mechanisms of the above hormones have been related to the mobilization of non-specific immune defense,to the inhibition of nuclear factor kappa B and modulation of cytokine production,to the stimulation of heat shock proteins and changes of apoptotic processes in the acinar cells,as well as to the activation of antioxidant system of the pancreatic tissue.The protective effect ofghrelin seems to be indirect and perhaps dependent on the release of growth hormone and insulin-like growth factor 1.Leptin and ghrelin,but not melatonin,employ sensory nerves in their beneficial action on acute pancreatitis.It is very likely that ghrelin,leptin and melatonin could be implicated in the natural protection of the pancreatic gland against inflammatory damage because the blood levels of these substances increase in the initial phase of pancreatic inflammation.The above hormones could be a part of the innate resistance system which might remove noxious factors and could suppress or attenuate the inflammatory process in the pancreas.     

Effect of prolonged omeprazole administration on segmental intestinal Mg~(2+) absorption in male Sprague-Dawley rats

BACKGROUND The exact mechanism of proton pump inhibitors(PPIs)-induced hypomagnesemia(PPIH) is largely unknown. Previous studies proposed that PPIH is a consequence of intestinal Mg~(2+) malabsorption. However, the mechanism of PPIs-suppressed intestinal Mg~(2+) absorption is under debate.AIM To investigate the effect of 12-wk and 24-wk omeprazole injection on the total,transcellular, and paracellular Mg~(2+) absorption in the duodenum, jejunum, ileum,and colon of male Sprague-Dawley rats.METHODS The rats received 20 mg/kg·d subcutaneous omeprazole injection for 12 or 24 wk.Plasma and urinary Mg~(2+), Ca~(2+), and PO_4~(3-)levels were measured. The plasma concentrations of 1α,25-dihydroxyvitamin D3(1α,25(OH)_2D_3), parathyroid hormone(PTH), fibroblast growth factor 23(FGF-23), epidermal growth factor(EGF), and insulin were also observed. The duodenum, jejunum, ileum, and colon of each rat were mounted onto individual modified Using chamber setups to study the rates of total, transcellular, and paracellular Mg~(2+) absorption simultaneously. The expression of transient receptor potential melastatin 6(TRPM6) and cyclin M4(CNNM4) in the entire intestinal tract was also measured.RESULTS Single-dose omeprazole injection significantly increased the intraluminal p H of the stomach, duodenum, and jejunum. Omeprazole injection for 12 and 24 wk induced hypomagnesemia with reduced urinary Mg~(2+) excretion. The plasma Ca~(2+) was normal but the urinary Ca~(2+) excretion was reduced in rats with PPIH. The plasma and urinary PO_4~(3-)levels increased in PPIH rats. The levels of1α,25(OH)_2D_3 and FGF-23 increased, whereas that of plasma EGF decreased in the omeprazole-treated rats. The rates of the total, transcellular, and paracellular Mg~(2+) absorption was significantly lower in the duodenum, jejunum, ileum, and colon of the rats with PPIH than in those of the control rats. The percent suppression of Mg~(2+) absorption in the duodenum, jejunum, ileum, and colon of the rats with PPIH compared with the control rats was 81.86%, 70.59%, 69.45%,and 39.25%, respectively. Compared with the control rats, the rats with PPIH had significantly higher TRPM6 and CNNM4 expression levels throughout the intestinal tract.CONCLUSION Intestinal Mg~(2+) malabsorption was observed throughout the intestinal tract of rats with PPIH. PPIs mainly suppressed small intestinal Mg~(2+) absorption. Omeprazole exerted no effect on the intraluminal acidic pH in the colon. Thus, the lowest percent suppression of total Mg~(2+) absorption was found in the colon. The expression levels of TRPM6 and CNNM4 increased, indicating the presence of a compensatory response to Mg~(2+) malabsorption in rats with PPIH. Therefore, the small intestine is an appropriate segment that should be modulated to counteract PPIH.     

Intestinal mucosal adaptation

Intestinal failure is a condition characterized by malnutrition and/or dehydration as a result of the inadequate digestion and absorption of nutrients. The most common cause of intestinal failure is short bowel syndrome, which occurs when the functional gut mass is reduced below the level necessary for adequate nutrient and water absorption. This condition may be congenital, or may be acquired as a result of a massive resection of the small bowel. Following resection, the intestine is capable of adaptation in response to enteral nutrients as well as other trophic stimuli. Identifying factors that may enhance the process of intestinal adaptation is an exciting area of research with important potential clinical applications.     

Therapy of gallstone disease: What it was, what it is, what it will be

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors,increasing age,female gender,and metabolic factors.Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones,new perspectives regarding medical therapy of cholelithiasis are currently under discussion,also taking into account the pathogenesis of gallstones,the natural history of the disease and the analysis of the overall costs of therapy.A careful selection of patients may lead to successful nonsurgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones.The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations,suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe),or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis,might be proposed as additional approaches for treating cholesterol gallstones.In this review we discuss old,recent and future perspectives on medical treatment of cholesterol cholelithiasis.     

Current view of the immunopathogenesis in inflammatory bowel disease and its implications for therapy

Although the aetiology of inflammatory bowel disease （IBD） remains unknown, the pathogenesis is gradually being unravelled, seeming to be the result of a combination of environmental, genetic, and immunological factors in which an uncontrolled immune response within the intestinal lumen leads to inflammation in genetically predisposed individuals. Multifactorial evidence suggests that a defect of innate immune response to microbial agents is involved in IBD. This editorial outlines the immunopathogenesis of IBD and their current and future therapy. We present IBD as a result of dysregulated mucosal response in the intestinal wall facilitated by defects in epithelial barrier function and the mucosal immune system with excessive production of cytokines growth factors, adhesion molecules, and reactive oxygen metabolites, resulting in tissue injury. Established and evolving therapies are discussed in the second part of this editorial and at the end of this section we review new therapies to modulate the immune system in patients with IBD.     

Chronic pancreatitis： Maldigestion, intestinal ecology and intestinal inflammation

Exocrine pancreatic insufficiency caused by chronic pancreatitis results from various factors which regulate digestion and absorption of nutrients. Pancreatic function has been extensively studied over the last 40 years, even if some aspects of secretion and gastrointestinal adaptation are not completely understood. The main clinical manifestations of exocrine pancreatic insufficiency are fat malabsorption, known as steatorrhea, which consists of fecal excretion of more than 6 g of fat per day, weight loss, abdominal discomfort and abdominal swelling sensation. Fat malabsorption also results in a deficit of fat-soluble vitamins （A, D, E and K） with consequent clinical manifestations. The relationships between pancreatic maldigestion, intestinal ecology and intestinal inflammation have not received particular attention, even if in clinical practice these mechanisms may be responsible for the low efficacy of pancreatic extracts in abolishing steatorrhea in some patients. The best treatments for pancreatic maldigestion should be re-evaluated, taking into account not only the correction of pancreatic insufficiency using pancreatic extracts and the best duodenal pH to permit optimal efficacy of these extracts, but we also need to consider other therapeutic approaches including the decontamination of intestinal lumen, supplementation of bile acids and, probably, the use of probiotics which may attenuate intestinal inflammation in chronic pancreatitis patients.     

Adenosine： An immune modulator of inflammatory bowel diseases

Inflammatory bowel disease （IBD） is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation.     

Intestinally derived lipids: metabolic regulation and consequences--an overview

Various dietary factors affect postprandial metabolism yet precise mechanisms have not necessarily been pinpointed. The effects of various meal components on postprandial lipemia lead to the following question: do we need a standardized oral lipid tolerance test? A number of transporters, enzymes, receptors and hormones directly influence and act as “gatekeepers” of these processes. Each protein appears to have specific and individual functional roles in the overall process and selected developments in these areas will be reviewed.Within the intestinal cells, FABP2 (fatty acid-binding protein 2) and MTP (microsomal triglyceride transfer protein) are required for the formation of chylomicrons. Niemann-Pick C1-like 1 (NPC1-L1) plays an important role in cholesterol absorption and provides a pharmacological target. Hormones such as GLP1 and GLP2 influence this absorption process. Within the periphery, lipoprotein lipase (LPL) is a key gatekeeper of clearance. Of the massive amounts of fatty acids released by LPL, 36% escape peripheral adipose and muscle uptake and fatty acid overload can result in LPL product inhibition. Acylation stimulating protein (ASP) and insulin are two key hormones in maintaining efficient tissue uptake and re-esterification of fatty acids while TNFα negatively influences this process. In both ASP deficient (C3 KO) and C5L2 KO mice, postprandial lipemia increased with reduced adipose tissue storage. This is compensated by increased energy expenditure and muscle lipid oxidation. Clearance of hepatic remnants is controlled through many factors, including SR-B1 and ABCA1. Intestinal, peripheral and hepatic gatekeepers serve important and individual roles in regulating postprandial lipemia and provide potential targets for regulation.     

Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes

In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon‐like peptide‐1 (GLP‐1) secretion. We evaluated the effects of metformin on serum 3‐O‐methylglucose (3‐OMG; a marker of glucose absorption) and plasma total GLP‐1 concentrations during a standardized intraduodenal infusion of glucose and 3‐OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double‐blind, randomized, crossover design (14 days’ washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3‐OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3‐OMG ( P < .001) and higher plasma total GLP‐1 ( P = .003) concentrations. The increment in plasma GLP‐1 after metformin vs placebo was related to the reduction in serum 3‐OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP‐1 secretion in type 2 diabetes.     

RD Lawrence Lecture 2008 Targeting GLP‐1 release as a potential strategy for the therapy of Type 2 diabetes

Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that play an important role in stimulating postprandial insulin release from pancreatic β‐cells. Agents that either mimic GLP‐1 or prevent its degradation are now available for the treatment of Type 2 diabetes, and strategies to enhance endogenous GLP‐1 release are under assessment. As intestinal peptides have a range of actions, including appetite regulation and coordination of fat metabolism, harnessing the enteric endocrine system is a promising new field for drug development.     

Minireview on regulation of intestinal calcium absorption. Emphasis on molecular mechanisms of transcellular pathway

An overview of current information on the mechanisms by which intestinal calcium absorption occurs is described in this article. Both paracellular and transcellular pathways are analyzed. Special emphasis focuses on molecules participating in the latter pathway, such as TRPV5 and TRPV6 channels, located in the apical region of the enterocytes, CB(9k) and CB(28k), presumably involved in the cation movement from the apical to the basolateral pole of the cell, and PMCA(1b) and Na(+)/Ca(2+) exchanger, proteins that extrude Ca(2+) from the cells. Current concepts on the relative importance of paracellular and transcellular calcium transport and the vitamin D dependence of each pathway are referred and analyzed showing the contrasting views on this issue. More detailed information is given regarding the stimulatory effect of vitamin D on intestinal Ca(2+) absorption either in animal models or in the human intestine. The possible mechanisms triggered by hormones such as PTH, calcitonin, estrogen, thyroid hormone, glucocorticoids and different nutritional factors on intestinal calcium absorption are also reviewed. Finally, the influence of physiological conditions such as growth, pregnancy, lactation and aging on intestinal calcium absorption are discussed.     

Nutrition and bone health in the elderly

The interface between nutrition and bone health in the elderly includes factors that affect bone formation and remodeling. Insulin-like growth factor-I is a circulating and skeletal growth factor influenced by nutritional status and is important for osteoblast differentiation. It is necessary, although not sufficient, for periosteal apposition and longitudinal growth as well as skeletal maintenance with age. Decreased protein intake, with or without vitamin D deficiency in the elderly, reduces serum IGF-I, changes local IGF-I expression, and leads to lower rates of bone formation and decreased calcium absorption. Aging also decreases systemic hormones, such as DHEA, testosterone, and estrogen, as well as growth hormone, all of which negatively influence IGF-I. In the end, age-related changes in circulating and skeletal IGF-I resulting from heritable factors, environmental determinants, and inflammatory components lead to qualitative skeletal alterations that result in bone fragility. Nutritional supplementation, particularly with calcium and vitamin D, provides some hope for maintaining skeletal integrity and preventing fractures.     

Effect of intestinal ischemia-reperfusion on expressions of endogenous basic fibroblast growth factor and transforming growth factor betain lung and its relation with lung repair

AIM:To study the changes of endogenous transforming growth factor beta(TGFbeta) and basic fibroblast growth factor (bFGF) in lung following intestinal ischemia and reperfusion injury and their effects on lung injury and repair.METHODS:Sixty Wistar rats were divided into five groups, which underwent sham-operation, ischemia (45 minutes), and reperfusion (6, 24 and 48 hours, respectively) after ischemia (45 minutes). Immunohistochemical method was used to observe the localization and amounts of both growth factors.RESULTS:Positive signals of both growth factors could be found in normal lung, mainly in alveolar cells and endothelial cells of vein. After ischemia and reperfusion insult, expressions of both growth factors were increased and their amounts at 6 hours were larger than those of normal control or of 24 and 48 hours after insult.CONCLUSION:The endogenous bFGF and TGF beta expression appears to be upregulated in the lung following intestinal ischemia and reperfusion, suggesting that both growth factors may be involved in the process of lung injury and repair.     

Mucosal repair and growth factors: recombinant human hepatocyte growth factor as an innovative therapy for inflammatory bowel disease

The repair of intestinal mucosal injuries is a tightly regulated process involving epithelial restitution, cell proliferation and maturation, and the dedifferentiation of epithelial cells. Deeper injuries also require additional repair mechanisms, including inflammatory processes, angiogenesis, and extracellular-matrix deposition. Once intestinal mucosal injury occurs, numerous growth factors and cytokines, including hepatocyte growth factor (HGF), keratinocyte growth factor, endothelial growth factor, epidermal growth factor, transforming growth factor-β1, intestinal trefoil factor, interleukin (IL)-1, and IL-2, are induced in both the intestinal lumen and submucosa, and these factors cooperatively stimulate epithelial mucosal repair. HGF, a major agent promoting hepatocyte proliferation, also modulates intestinal epithelial cell proliferation and migration, leading to the acceleration of intestinal mucosal repair. Additionally, the proteolytic activation of HGF, which is mediated by HGF activator, is essential for the regeneration of injured intestinal mucosa. Recently, several studies have shown that the administration of recombinant human HGF or HGF gene therapy abrogates disease severity in several animal models of inflammatory bowel disease (IBD). Recombinant human HGF will soon be available for administration to patients with fulminant hepatic failure. Although additional preclinical biological studies are required, HGF has the potential to be an important new treatment modality promoting intestinal mucosal repair in patients with IBD.     

Intestinal Ca~(2+) absorption revisited: A molecular and clinical approach

Ca~(2+) has an important role in the maintenance of the skeleton and is involved in the main physiological processes. Its homeostasis is controlled by the intestine,kidney, bone and parathyroid glands. The intestinal Ca~(2+) absorption occurs mainly via the paracellular and the transcellular pathways. The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors. Fibroblast growth factor 23(FGF-23) is a strong antagonist of vitamin D action. Part of the intestinal Ca~(2+) movement seems to be vitamin D independent.Intestinal Ca~(2+) absorption changes according to different physiological conditions.It is promoted under high Ca~(2+) demands such as growth, pregnancy, lactation,dietary Ca~(2+) deficiency and high physical activity. In contrast, the intestinal Ca~(2+)transport decreases with aging. Oxidative stress inhibits the intestinal Ca~(2+)absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process. Several pathologies such as celiac disease, inflammatory bowel diseases, Turner syndrome and others occur with inhibition of intestinal Ca~(2+) absorption, some hypercalciurias show Ca~(2+)hyperabsorption, most of these alterations are related to the vitamin D endocrine system. Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca~(2+) absorption.