Nutritional Aspects of Pediatric Gastrointestinal Diseases.

In the last decade, the role of nutritional management in pediatric gastrointestinal diseases has gained increasing popularity. Disease-specific diets have been introduced as conventional treatments by international guidelines. Patients tend to more willingly accept food-based therapies than drugs because of their relatively "harmless" nature. Apart from a diet's therapeutic role, nutritional support is crucial in maintaining growth and improving clinical outcomes in pediatric patients. Despite the absence of classical "side effects", however, it should be emphasized that any dietary modification might have negative consequences on children's growth and development. Hence, expert supervision is always advised, in order to support adequate nutritional requirements. Unfortunately, the media provide an inaccurate perception of the role of diet for gastrointestinal diseases, leading to misconceptions by patients or their caregivers that tends to overestimate the beneficial role of diets and underestimate the potential adverse effects. Moreover, not only patients, but also healthcare professionals, have a number of misconceptions about the nutritional benefits of diet modification on gastrointestinal diseases. The aim of this review is to highlight the role of diet in pediatric gastrointestinal diseases, to detect misconceptions and to give a practical guide for physicians on the basis of current scientific evidence.

Interactive effect of 2 dietary calcium and phytase levels on broilers challenged with subclinical necrotic enteritis: part 1-broiler performance, gut lesions and pH, bacterial counts, and apparent ileal digestibility.

This study investigated the hypothesis that high dietary calcium (Ca) would stimulate necrotic enteritis (NE) and reduce performance, gut health, and nutrient digestibility, and if increased, phytase would reduce NE. Ross 308 male broilers (n = 768) were randomly distributed to 8 treatments in a factorial arrangement. Factors were NE challenge (no or yes), phytase level (500 or 1,500 FTU/kg using 500 FTU/kg matrix values), and Ca level (0.6 or 1.0% starter, 0.5 or 0.9% grower, 0.4 or 0.8% finisher) with the same level of available P (0.40 S, 0.35 G, and 0.35 F). There were 48 pens, 16 birds per pen and 6 replications. Half of the birds were challenged with Eimeria spp on day 9 and 108 CFU per mL of Clostridium perfringens strain EHE-NE18 on day 14 and 15. Gain was higher in birds fed high phytase on day 14 (P < 0.01), day 21 (P < 0.01), day 28 (P < 0.01), and day 35 (P < 0.01). Birds fed high phytase had greater livability on day 21 (P < 0.01). Ca was more digestible in high-Ca diets on day 16, and an NE × Ca interaction (P < 0.05) showed this effect to be more pronounced in unchallenged than in challenged birds. A challenge × Ca interaction for apparent ileal digestibility (AID) of crude protein (CP) (P < 0.05) indicated lower AID of CP in challenged birds fed high Ca. The challenge decreased AID of Ca (P < 0.01). Ca level had no impact on C. perfringens count, but it decreased Lactobacillus (P < 0.05) and Bifidobacteria (P < 0.05) populations in the ceca. High dietary Ca decreased feed conversion ratio. Overall (42 D), the highest WG was observed in unchallenged birds fed high Ca and high phytase with the lowest WG observed in NE-challenged birds fed low Ca and low phytase. The results suggest that full matrix values for high doses of phytase may be appropriate during NE challenge.

Animal Models of Undernutrition and Enteropathy as Tools for Assessment of Nutritional Intervention.

: Undernutrition is a major public health problem leading to 1 in 5 of all deaths in children under 5 years. Undernutrition leads to growth stunting and/or wasting and is often associated with environmental enteric dysfunction (EED). EED mechanisms leading to growth failure include intestinal hyperpermeability, villus blunting, malabsorption and gut inflammation. As non-invasive methods for investigating gut function in undernourished children are limited, pre-clinical models are relevant to elucidating the pathophysiological processes involved in undernutrition and EED, and to identifying novel therapeutic strategies. In many published models, undernutrition was induced using protein or micronutrient deficient diets, but these experimental models were not associated with EED. Enteropathy models mainly used gastrointestinal injury triggers. These models are presented in this review. We found only a few studies investigating the combination of undernutrition and enteropathy. This highlights the need for further developments to establish an experimental model reproducing the impact of undernutrition and enteropathy on growth, intestinal hyperpermeability and inflammation, that could be suitable for preclinical evaluation of innovative therapeutic intervention.

Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorders (EGID) are a group of disorders characterized by pathologic eosinophilic infiltration of the esophagus, stomach, small intestine, or colon leading to organ dysfunction and clinical symptoms (J Pediatr Gastroenterol Nutr; Spergel et al., 52: 300-306, 2011). These disorders include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), eosinophilic enteritis (EE), and eosinophilic colitis (EC). Symptoms are dependent not only on the location (organ) as well as extent (layer invasion of the bowel wall). Common symptoms of EoE include dysphagia and food impaction in adults and heartburn, abdominal pain, and vomiting in children. Common symptoms of the other EGIDs include abdominal pain, nausea, vomiting, early satiety, diarrhea, and weight loss. These disorders are considered immune-mediated chronic inflammatory disorders with strong links to food allergen triggers. Treatment strategies focus on either medical or dietary therapy. These options include not only controlling symptoms and bowel inflammation but also on identifying potential food triggers. This chapter will focus on the clinical presentation, pathophysiology, and treatment of these increasingly recognized disorders.

Capsaicin-induced satiety is associated with gastrointestinal distress but not with the release of satiety hormones.

BACKGROUND: Capsaicin, which is the major pungent principle in chili peppers, is able to induce satiety and reduce caloric intake. The exact mechanism behind this satiating effect is still unknown. We hypothesized that capsaicin induces satiety through the release of gastrointestinal peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), from enteroendocrine cells in the small intestine. OBJECTIVE: We investigate the effects of an intraduodenal capsaicin infusion (1.5 mg pure capsaicin) in healthy volunteers on hunger, satiety, and gastrointestinal symptoms and the release of GLP-1 and PYY. DESIGN: Thirteen participants (7 women) [mean ± SEM age: 21.5 ± 0.6 y; body mass index (in kg/m(2)): 22.8 ± 0.6] participated in this single-blind, randomized, placebo-controlled crossover study with 2 different treatments. During test days, an intraduodenal infusion of either capsaicin or a placebo (physiologic saline) was performed with the use of a nasoduodenal catheter over a period of 30 min. Visual analog scale scores were used to measure hunger, satiety, and gastrointestinal symptoms. Blood samples were drawn at regular intervals for GLP-1 and PYY. Gallbladder volumes were measured with the use of real-time ultrasonography. RESULTS: The intraduodenal capsaicin infusion significantly increased satiety (P-treatment effect < 0.05) but also resulted in an increase in the gastrointestinal symptoms pain (P-treatment × time interaction < 0.0005), burning sensation (P-treatment × time interaction < 0.0001), nausea (P-treatment × time interaction < 0.05), and bloating (P-treatment × time interaction < 0.001) compared with the effects of the placebo infusion. Satiety scores had a positive correlation with all gastrointestinal symptoms. No differences in GLP-1 and PYY concentrations and gallbladder volumes were observed after the capsaicin infusion compared with after the placebo infusion. CONCLUSIONS: An intraduodenal infusion of capsaicin significantly increases satiety but does not affect plasma concentrations of GLP-1 and PYY. Rather, the effect on satiety seems related to gastrointestinal stress as shown by the associations with pain, burning sensation, nausea, and bloating scores. This trial was registered at clinicaltrials.gov as NCT01667523.

Dietary calcium, phosphorus, and phytase effects on bird performance, intestinal morphology, mineral digestibility, and bone ash during a natural necrotic enteritis episode.

The objective of this study was to evaluate the effects of dietary Ca, P, and phytase on performance, intestinal morphology, bone ash, and Ca and P digestibility during a necrotic enteritis (NE) outbreak. The 35-d trial was designed as a 2 × 2 × 2 factorial, which included 2 Ca levels (0.6 and 0.9%), 2 P levels (0.3 and 0.45%), and 2 levels of phytase [0 and 1,000 phytase units (FTU)/kg]. Birds were placed on litter from a previous flock that exhibited clinical signs of NE. Birds and feed were weighed on d 12, 19, and 35, and BW gain, feed intake, and feed conversion were calculated. Mortality was recorded daily, and gastrointestinal pH was measured. Tibias and ileal digesta were also collected. Birds began exhibiting clinical signs of NE on d 9, and NE-associated mortality persisted until d 26. Dietary Ca supplemented at 0.9% or inclusion of 1,000 FTU/kg of phytase significantly increased mortality compared with 0.6% Ca or 0 FTU/kg of phytase, respectively. From d 0 to 12, birds fed 0.9% Ca and 0.45% available P with phytase had greater BW gain compared with birds fed 0.6% Ca, 0.45% available P, and phytase. From d 0 to 19, birds fed diets with 0.9% Ca and 0.3% available P had decreased feed intake and improved feed conversion compared with birds fed 0.9% Ca and 0.45% available P. Calcium at 0.9% increased gizzard (d 19) and jejunum (d 12) pH. Phytase supplementation significantly increased Ca digestibility regardless of Ca and P levels of the diets. In addition, diets containing 0.6% Ca and 1,000 FTU/kg of phytase resulted in a significant increase in P digestibility. The results suggest that dietary Ca level may influence NE-associated mortality. In addition, bird performance was affected by interactions of Ca, P, and phytase during the exposure to Clostridium perfringens and the subsequent NE outbreak. Results showed improvements in bird performance when birds were fed 0.6% Ca and 0.3% P in diets supplemented with phytase, which was likely consequent to the influence of Ca in NE pathogenesis.

Adenosine A2A receptor contributes to the anti-inflammatory effect of the fixed herbal combination STW 5 (Iberogast®) in rat small intestinal preparations.

STW 5 (Iberogast®), an established herbal combination, was effective in randomized, double blind clinical studies in functional dyspepsia and irritable bowel syndrome. Since STW 5 was found to influence intestinal motility and has anti-inflammatory properties, this study investigated the expression of adenosine receptors and characterized their role in the control of the anti-inflammatory action of STW 5 and its fresh plant component STW 6 in inflammation-disturbed rat small intestinal preparations. The inflammation was induced by intraluminal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 0.01 M). The effects of coincubation with selective receptor agonists and antagonists, STW 5, STW 6, or combinations of these compounds on acetylcholine (ACh)-evoked contraction of ileum/jejunum preparations were tested. Adenosine receptor mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR). In untreated preparations, RT-PCR revealed the presence of all adenosine receptor subtypes. Suppressed expression was detected for all subtypes in inflamed tissues, except for A(2B)R mRNA, which was unaffected. STW 5 reversed these effects and enhanced A(2A)R expression above control levels. Radioligand binding assays confirm the affinity of STW 5 to the A(2A)R, and the A(2A)R antagonist was able to prevent the effect of STW 5 on TNBS-induced attenuation of the ACh contraction. Our findings provide evidence that STW 5, but not STW 6 interacts with A(2A)R, which is involved in the anti-inflammatory action of STW 5. STW 6 did not contribute to adenosine A(2A)R-mediated anti-inflammatory effect of STW 5. Other signaling pathways could be involved in the mechanism of action of STW 6.

Measurement of small intestinal damage.

Many animal models have been devised for investigating the pathogenesis of intestinal lesions and for screening drugs for the treatment of intestinal ulcers in humans. Recently, particular attention has been focused on NSAID-induced intestinal lesions as a result of the development of the capsule endoscope and double-balloon endoscope. Ischemic enteritis, one of the most dramatic abdominal emergencies, is known to cause severe damage to the small intestine by a significant decrease of arterial blood flow in the small intestine. In this unit, two animal models for small intestinal damage induced by NSAIDs or intestinal ischemia are described. Also included are methods for lesion induction and evaluation of the damage as well as the measurement of pathogenic functional and biochemical changes.

Cholecystokinin.

PURPOSE OF REVIEW: The hormone cholecystokinin was discovered in 1928 because of its ability to induce gallbladder contraction. Since then, cholecystokinin has been shown to possess multiple functions in the gastrointestinal tract and brain. This review discusses several significant developments in cholecystokinin biology that show how it plays a role in gastrointestinal diseases, including control of appetite. RECENT FINDINGS: Cholecystokinin was shown to induce satiety by interacting through CCK-1 receptors located in specialized regions of the hindbrain. Cholecystokinin also inhibits expression of orexigenic peptides in the hypothalamus and prevents stimulation of specialized neurons by ghrelin. In the pancreas, cholecystokinin increased the proliferation of insulin-producing beta cells and reduced insulin-induced hyperphagia. Elevated cholecystokinin levels decreased appetite and reduced intestinal inflammation caused by parasites and bacterial toxins. SUMMARY: Understanding the mechanisms by which cholecystokinin regulates orexigenic pathways in the body may lead to strategies for controlling appetite-related disorders such as obesity and bulimia. The reduction of intestinal inflammation by dietary fats (by elevating cholecystokinin) suggests that the hormone plays an integrated role in regulating the ingestion and digestion of food that may be relevant to inflammatory diseases of the gastrointestinal tract.

The involvement of nitric oxide in the enhanced expression of mu-opioid receptors during intestinal inflammation in mice.

Intestinal inflammation enhances the potency of mu-opioid receptor (MOR) agonists inhibiting gastrointestinal transit and increases the expression of MOR in mice intestine. The precise mechanisms implicated in the increased expression of MOR during intestinal inflammation are not known. The aim of the study is to evaluate if nitric oxide released during intestinal inflammation could modulate MOR gene expression and affect gastrointestinal transit. Intestinal inflammation was induced by the intragastric administration of croton oil. In CD-1 mice, with and without inflammation, we evaluated the anti-transit effects of morphine in animals treated with NOS inhibitors (L-NAME and L-NIL) and the intestinal levels of iNOS enzyme mRNA. The anti-transit effects of morphine and the expression of MOR mRNA in the gut of wild-type (WT) and iNOS-/- mice were also assessed. Gastrointestinal transit was measured with charcoal meal and mRNA levels determined by real-time PCR. In CD-1 mice, inflammation induced a 10-fold increase (P<0.0001) in iNOS mRNA levels in the gut. The absence of iNOS gene and treatment of CD-1 mice with L-NAME or L-NIL abolished the increased antitransit effects of morphine observed during inflammation. Moreover, although the basal levels of MOR mRNA were similar in WT and iNOS animals (-/-), intestinal inflammation only increased the MOR expression in the gut of WT (P<0.01) but not in iNOS-/- mice. The results suggest that nitric oxide derived from the increased expression of iNOS is implicated in the enhanced effects of morphine and in the upregulation of MOR gene transcription observed during intestinal inflammation.

Intestinal inflammation enhances the inhibitory effects of opioids on intestinal permeability in mice.

The inhibitory effects of central and peripherally acting opioid agonists on intestinal permeability (PER) were evaluated during acute and chronic intestinal inflammation in mice. Inflammation was induced by the intragastric (p.o.) administration of one (acute) or two (chronic) doses of croton oil (CO), whereas controls received saline (SS). Intestinal PER was assessed by the blood-to-lumen transfer of 51Cr-ethylenediaminetetraacetate (51Cr-EDTA). CO significantly increased PER during acute (2.5 times) and chronic (3.2 times) inflammation. The potency of s.c. morphine-inhibiting PER was enhanced 3.8 and 8.7 times in acute and chronic CO, whereas that of s.c. fentanyl was increased 2.0 and 4.3 times, respectively, compared with SS. Similarly, s.c. [D-Pen(2,5)]-enkephalin was 4.7 and 11.1 times more potent during acute and chronic CO, and the E(max) values of the dose-response curves increased 35% during inflammation. The potency of s.c. U50,488H was 5.6 (acute) and 6.7 times (chronic) greater compared with SS. All effects were reversed by specific antagonists. The i.p. administration of beta-funaltrexamine differentially blocked morphine effects during acute and chronic CO, suggesting that the effects are mediated by different populations of functional mu-opioid receptors (OR). The increase in potencies of s.c. PL017 and ICI-204,448 during CO were comparable to those observed with fentanyl and U50,488H and their effects were antagonized by s.c. naloxone methiodide. Moreover, the potency of the agonists during inflammation was unaltered when administered i.c.v. The results show that intestinal inflammation enhances the effects of delta- > mu- > kappa-opioid agonists on PER by activation of peripheral OR.

Antisense oligodeoxynucleotides to mu- and delta-opioid receptor mRNA block the enhanced effects of opioids during intestinal inflammation.

Intestinal inflammation enhances the inhibitory effects of mu- and delta-opioids in the gut, possibly related to an increased receptor expression. We evaluated the effects of opioids after intraperitoneal administration of antisense oligodeoxynucleotides to mu- and/or delta-opioid receptor mRNA. Inflammation was induced in mice by intragastric administration of croton oil; gastrointestinal transit was assessed with charcoal and permeability with [51Cr]etylenediaminetetraacetate ([51Cr]EDTA). Baseline values were unaltered after antisense oligodeoxynucleotides. In controls, antisense oligodeoxynucleotides to mu-opioid receptor mRNA decreased the antitransit effects of morphine (27%) and [N-MePhe3D-Pro4]morphiceptin (PL017) (26%), and the reduction was significantly greater during inflammation (50% and 47%). A similar effect was observed on permeability (control: 41-21% decrease; inflamed: 66-45%). In both assays, antisense oligodeoxynucleotides to delta-opioid receptor mRNA also reduced the effects of [D-Pen2,5]enkephalin (DPDPE) in a higher percentage during inflammation (43-32% controls, 60-49% inflamed). We show that antisense oligodeoxynucleotides to mu- and/or delta-opioid receptor mRNA are efficiently blocking the intestinal effects of opioids during inflammation, suggesting that an increased transcription of these receptors in the gut mediates the enhanced effects of opioids during inflammation.

Supplemental dietary arginine accelerates intestinal mucosal regeneration and enhances bacterial clearance following radiation enteritis in rats.

BACKGROUND: Arginine is a dibasic amino acid with significant metabolic and immunologic, effects especially in trauma and stress situations. Arginine supplementation has been shown to promote wound healing and improve immune system. We designed a study to evaluate the effects of supplemental dietary arginine on intestinal mucosal recovery and bacterial translocation and bacterial clearance after induction of radiation injury in rats. METHODS: Twenty-one male Sprague-Dawley rats were subjected to a single dose of 1100 rads of abdominal X radiation. Rats were divided into three groups; the first group received diet enriched with 2% arginine, the second group with 4% arginine, and the third group with isonitrogenous 4% glycine. Rats were sacrificed 7 days after the radiation. Blood was drawn for arginine levels and mesenteric lymph nodes were harvested for quantitative aerobic and anaerobic cultures. Segments of ileum and jejunum were evaluated for villous height, number of villi per centimeter of intestine, and the number of mucous cells per villous. RESULTS AND CONCLUSIONS: Arginine is absorbed reliably from the gut following oral administration. Dietary 4% arginine supplementation enhanced bacterial clearance from mesenteric lymph nodes compared to 2% arginine and 4% glycine supplemented diet following radiation enteritis in rats. Four percent arginine resulted in clear improvement in intestinal mucosal recovery when compared to 2% arginine and 4% glycine after abdominal irradiation in rats.

Peripheral effects of opioids in a model of intestinal inflammation in mice.

The study evaluates the peripheral component of the antitransit effects of opioids during acute intestinal inflammation induced by the intragastric administration of croton oil (CO) in mice. Gastrointestinal transit was measured 3 h after CO or saline (SS) administration with a charcoal meal. In both groups, the effects of mixed (morphine, fentanyl, U-50488H) and peripherally acting (N-methylmorphine, PL017, ICI-204448) opioids and their antagonism by naloxone and naloxone methiodide were established. During inflammation, the potencies of morphine and N-methylmorphine increased 3 times, and those of fentanyl and PL017, 1.9 times. The effects were reversed by naloxone (0.1 mg/kg) and naloxone methiodide (0.3 mg/kg). No dose-response relationships could be elicited with U-50488H or ICI-204448, and their antitransit effects were analogous in SS- and CO-treated animals. These results show that during inflammation the enhanced antitransit effects of opioids are primarily mediated by interaction with opioid receptors located at peripheral sites. In addition, inflammation of the gut seems to induce a sensitization of mu-but not kappa-opioid receptors.

The inhibitory effects of alpha(2)-adrenoceptor agonists on gastrointestinal transit during croton oil-induced intestinal inflammation.

1. The peripheral effects of alpha(2)-adrenoceptor agonists were investigated in a model of intestinal inflammation induced by intragastric administration of croton oil (CO). Our hypothesis was that inflammation would 'sensitize' adrenoceptors in peripheral and/or central terminals of myenteric and submucous plexus neurones, and enhance systemic effects of alpha(2)-adrenoceptor agonists. 2. Male swiss CD-1 mice, received intragastrically CO (0.05 ml), castor oil (CA, 0.1 ml) or saline (SS) 3 h before the study: gastrointestinal transit (GIT) was evaluated 20 min afterwards with a charcoal meal. The presence of inflammation was assessed by electron microscopy. 3. The intragastric administration of CA or CO caused an increase in GIT and weight loss, but only CO induced an inflammatory response. Both clonidine (imidazoline1/alpha(2)-agonist) and UK-14304 (alpha(2)-agonist) produced dose-related inhibitions of GIT in all groups. During inflammatory diarrhoea (CO), potencies of systemic (s.c.) clonidine and UK-14304 were significantly increased 3.5 and 2.1 times, respectively, while potencies remained unaltered in the presence of diarrhoea without inflammation (CA). The effects were reversed by administration (s.c.) of receptor-specific adrenoceptor antagonists, but not by naloxone. 4. Clonidine was 8.3 (SS) and 2.8 (CO) times more potent when administered intracerebroventricularly (i.c.v.), than when administered s.c. Inflammation of the gut did not alter the potency of i.c.v. clonidine, demonstrating that enhanced effects of s.c. clonidine are mediated by peripheral receptors. During inflammation, i.c.v. efaroxan did not antagonize low doses of s.c. clonidine (ED20 and ED50S), but partially reversed ED80S, further supporting the peripheral effects of the agonists in CO treated animals. 5. The results demonstrate that inflammation of the gut enhances the potency of alpha(2)-adrenoceptor agonists by a peripheral mechanism. The results also suggest that the inflammatory response induces an up-regulation or sensitization of alpha(2)-adrenoceptors and/or imidazoline receptors.