Intestinal Mucosal Surface Area Research Articles

Methionine dietary supplementation potentiates ionizing radiation-induced gastrointestinal syndrome.

Methionine is an essential amino acid needed for a variety of processes in living organisms. Ionizing radiation depletes tissue methionine concentrations and leads to the loss of DNA methylation and decreased synthesis of glutathione. In this study, we aimed to investigate the effects of methionine dietary supplementation in CBA/CaJ mice after exposure to doses ranging from 3 to 8.5 Gy of 137Cs of total body irradiation. We report that mice fed a methionine-supplemented diet (MSD; 19.5 vs. 6.5 mg/kg in a methionine-adequate diet, MAD) developed acute radiation toxicity at doses as low as 3 Gy. Partial body irradiation performed with hindlimb shielding resulted in a 50% mortality rate in MSD-fed mice exposed to 8.5 Gy, suggesting prevalence of radiation-induced gastrointestinal syndrome in the development of acute radiation toxicity. Analysis of the intestinal microbiome demonstrated shifts in the gut ecology, observed along with the development of leaky gut syndrome and bacterial translocation into the liver. Normal gut physiology impairment was facilitated by alterations in the one-carbon metabolism pathway and was exhibited as decreases in circulating citrulline levels mirrored by decreased intestinal mucosal surface area and the number of surviving crypts. In conclusion, we demonstrate that a relevant excess of methionine dietary intake exacerbates the detrimental effects of exposure to ionizing radiation in the small intestine.NEW & NOTEWORTHY Methionine supplementation, instead of an anticipated health-promoting effect, sensitizes mice to gastrointestinal radiation syndrome. Mechanistically, excess of methionine negatively affects intestinal ecology, leading to a cascade of physiological, biochemical, and molecular alterations that impair normal gut response to a clinically relevant genotoxic stressor. These findings speak toward increasing the role of registered dietitians during cancer therapy and the necessity of a solid scientific background behind the sales of dietary supplements and claims regarding their benefits.

The 5-HT4 Receptor Agonist Prucalopride Stimulates Mucosal Growth and Enhances Carbohydrate Absorption in the Ileum of the Mouse

BackgroundEnteric serotonin may function as a mucosal growth factor. Previous work demonstrated increased crypt cell proliferation and intestinal mucosal surface area with potentiation of serotonin. While an indirect mechanism was postulated to explain these effects, the presence of 5-HT4 receptors on enterocytes raises the possibility of a direct action of serotonin. We hypothesized that a 5-HT4 specific agonist, prucalopride, would stimulate intestinal mucosal growth and enhance absorptive function in the murine small intestine. MethodsAdult wild-type mice were treated parenterally with prucalopride for 14 days via surgically implanted osmotic pumps. In vivo d-xylose absorption was assessed by oral gavage and serum d-xylose measurements. On day 14, glucose absorption was assessed by instilling a glucose solution into isolated segments of small intestine. The bowel was harvested and examined for morphologic parameters and crypt cell proliferation. ResultsVillus height, crypt depth, and crypt proliferation were significantly increased in the distal small bowel of prucalopride-treated mice compared with control animals. Crypt depth was also increased in the proximal and middle small intestine in treated mice. There was no difference in d-xylose absorption throughout the study period; however, glucose absorption was significantly increased in the distal small intestine of prucalopride-treated mice. ConclusionParenteral administration of the 5-HT4 receptor specific agonist, prucalopride, results in morphologic and functional changes in the murine small intestine that are most prominent in the distal small bowel. While further studies are necessary to delineate the mechanism, it is plausible that the effects are mediated by 5-HT4 receptors on enterocytes.

Improved capacity to evaluate changes in intestinal mucosal surface area using mathematical modeling.

Quantification of intestinal mucosal growth typically relies on morphometric parameters, commonly villus height, as a surrogate for presumed changes in mucosal surface area (MSA). We hypothesized that using mathematical modeling based on multiple unique measurements would improve discrimination of the effects of interventions on MSA compared to standard measures. To determine the ability of mathematical modeling to resolve differences in MSA, a mouse model with enhanced serotonin (5HT) signaling known to stimulate mucosal growth was used. 5-HT signaling is potentiated by targeting the serotonin reuptake transporter (SERT) molecule. Selective serotonin reuptake inhibitor-treated wild-type (WT-SSRI), SERT-knockout (SERTKO), and wild-type C57Bl/6 (WT) mice were used. Distal ileal sections were H&E-stained. Villus height (VH), width (VW), crypt width (CW), and bowel diameter were used to calculate surface area enlargement factor (SEF) and MSA. VH alone for SERTKO and SSRI was significantly increased compared to WT, without a difference between SERTKO and WT-SSRI. VW and CW were significantly decreased for both SERTKO and WT-SSRI compared to WT, and VW for WT-SSRI was also decreased compared to SERTKO. These changes increased SEF and MSA for SERTKO and WT-SSRI compared to WT. Additionally, SEF and MSA were significantly increased for WT-SSRI compared to SERTKO. Mathematical modeling provides a valuable tool for differentiating changes in intestinal MSA. This more comprehensive assessment of surface area does not appear to correlate linearly with standard morphometric measures and represents a more comprehensive method for discriminating between therapies aimed at increasing functional intestinal mucosa.

Oral Interleukin 11 as a Countermeasure to Lethal Total-Body Irradiation in a Murine Model

Countermeasures against radiation are critically needed. Ideally, these measures would be easy to store, easy to administer and have minimal toxicity. We used oral delivery of interleukin 11 (IL11) in mice exposed to lethal doses of total-body irradiation (TBI). Animals were given IL11 by gavage at various daily doses beginning 24 h after TBI, which continued for 5 days. At a TBI of 9.0 Gy, mice treated with IL11 had a 70% survival at 30 days compared with control group survival of 25% (P = 0.035). At 10.0 Gy, treated animals had 50% survival at 30 days compared with no survivors in the control group. Treated animals had significant improvement in intestinal mucosal surface area and crypt survival. In addition bacterial translocation of coliform bacteria was significantly less in the treated animals. Systemic absorption of IL11 was low in treated animals and effects on the hematopoietic cells were not seen. Serum citrulline levels rebounded significantly faster after irradiation in the IL11 treated animals, indicating quicker recovery of small intestine health. These data suggest that IL11 given orally protects the intestinal mucosa from radiation damage and that this compound is beneficial as a mitigating agent even when started 24 h after radiation exposure.

IGF-2 mediates intestinal mucosal hyperplasia in retinoblastoma protein (Rb)-deficient mice

PurposeWe have previously demonstrated a hyperplastic phenotype when Rb expression was disrupted within the intestinal epithelium. These findings mimic resection-induced adaptation suggesting a possible mechanistic role for Rb during adaptation. The purpose of the present study was to elucidate a mechanism for how Rb deficiency induces intestinal hyperplasia. MethodsEnterocytes isolated from intestine-specific Rb knockout mice (Rb-IKO) underwent a microarray to elucidate their gene expression profile. IGF2 expression was significantly elevated, which was subsequently confirmed by RT-PCR and in situ mRNA hybridization. Mice with deficient expression of IGF2 or its receptor IGF1R were therefore crossed with Rb-IKO mice to determine the significance of IGF2 in mediating the Rb-IKO intestinal phenotype. ResultsExpression of IGF2 was significantly elevated in villus enterocytes of Rb-IKO mice. The mucosal hyperplasia in Rb-IKO mice was reversed when either IGF2 or IGF1R expression was genetically disrupted in Rb-IKO mice. ConclusionIGF-2 expression is significantly elevated in villus enterocytes and is required for the hyperplastic intestinal mucosal phenotype of Rb-IKO mice. The trophic effects of IGF2 require intact IGF1R signaling within the intestinal epithelium. These findings reveal novel regulatory roles for Rb in expanding intestinal mucosal surface area.

High-fat nutrition for short gut syndrome: Another indication for the Atkin’s diet?

High-fat nutrition for short gut syndrome: Another indication for the Atkin’s diet?

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome.

Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 microg.kg(-1).h(-1) GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals (P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression (P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.

Epidermal growth factor is critical for intestinal adaptation following small bowel resection

The loss of small intestinal mucosal surface area is a relatively common clinical situation seen in both the pediatric and adult population. The most frequent causes include mesenteric ischemia, trauma, inflammatory bowel disease, necrotizing enterocolitis, and volvulus. Following surgical resection, the remnant intestine compensates or adapts to the loss of native bowel by increasing its absorptive surface area and functional capacity. Unfortunately, many patients fail to adapt adequately, and are relegated to lifelong intravenous nutrition. Research into intestinal adaptation following small bowel resection (SBR) has evolved only recently from the gross and microscopic level to the biochemical and genetic level. As understanding of this process has increased, numerous therapeutic strategies to augment adaptation have been proposed. Epidermal growth factor (EGF) is an endogenous peptide that is secreted into the gastrointestinal tract and able to influence gut ontogeny, as well as mucosal healing. Early studies have demonstrated its ability to augment the adaptive process. Focusing on a murine model of massive intestinal loss, the morphological, structural, biochemical, and genetic changes that occur during the intestinal adaptive process will be reviewed. The role of EGF and its receptor as critical mediators of the adaptive process will be discussed. Additionally, the ability of EGF to augment intestinal proliferation and diminish programmed cell death (apoptosis) following SBR will be examined. Enhancing adaptation in a controlled manner may allow patients to transition off parenteral nutrition to enteral feeding and, thereby, normalize their lifestyle. Microsc. Res. Tech. 51:138–148, 2000. © 2000 Wiley-Liss, Inc.

Epidermal growth factor is critical for intestinal adaptation following small bowel resection

The loss of small intestinal mucosal surface area is a relatively common clinical situation seen in both the pediatric and adult population. The most frequent causes include mesenteric ischemia, trauma, inflammatory bowel disease, necrotizing enterocolitis, and volvulus. Following surgical resection, the remnant intestine compensates or adapts to the loss of native bowel by increasing its absorptive surface area and functional capacity. Unfortunately, many patients fail to adapt adequately, and are relegated to lifelong intravenous nutrition. Research into intestinal adaptation following small bowel resection (SBR) has evolved only recently from the gross and microscopic level to the biochemical and genetic level. As understanding of this process has increased, numerous therapeutic strategies to augment adaptation have been proposed. Epidermal growth factor (EGF) is an endogenous peptide that is secreted into the gastrointestinal tract and able to influence gut ontogeny, as well as mucosal healing. Early studies have demonstrated its ability to augment the adaptive process. Focusing on a murine model of massive intestinal loss, the morphological, structural, biochemical, and genetic changes that occur during the intestinal adaptive process will be reviewed. The role of EGF and its receptor as critical mediators of the adaptive process will be discussed. Additionally, the ability of EGF to augment intestinal proliferation and diminish programmed cell death (apoptosis) following SBR will be examined. Enhancing adaptation in a controlled manner may allow patients to transition off parenteral nutrition to enteral feeding and, thereby, normalize their lifestyle.

A high cholesterol diet blocks the effect of calcium channel blockers on the uptake of sugars in rabbit intestine

Two classes of calcium channel blockers, nisoldipine (NIS) and verapamil (VER), alter the intestinal uptake of sugars, and varying the lipid composition of the diet also modifies intestinal transport function. This study was undertaken in adult male New Zealand rabbits to assess the effect of 3 weeks of dosing with NIS (1 mg.kg-1.day-1) or VER (4 mg.kg-1.day-1) on the in vitro jejunal uptake of D-galactose and L- or D-glucose. The value of the maximal transport rate of D-galactose (Vmax) increased with NIS and VER, compared with control vehicle. The value of the apparent Michaelis constant (K(m)) rose with NIS and fell with VER, and the value of the passive permeability coefficient (Pd) estimated from the uptake of L-glucose fell with NIS and rose with VER. These effects of NIS and VER on Vmax, K(m), and Pd were prevented by feeding a high cholesterol (2.8%) supplemented chow diet (HCD), as compared with chow alone. These effects were not due to any change in the animal's weight gain or intestinal mucosal surface area. The acute exposure of the jejunal tissue in vitro to varying concentrations of NIS but not VER reduced the uptake of D-glucose but had no effect on basal short circuit current (Isc) in either chow or HCD. Isc stimulated with glucose or theophylline was less in chow-fed rabbits compared with HCD-fed rabbits given NIS or VER. Thus, the active transport of sugars by the sodium-dependent transporter in the brush-border membrane, SGLT1, and the passive uptake by the paracellular route are variably influenced by these two classes of calcium channel blockers, and this effect is modified by the cholesterol content of the diet.

Differential and interactive effects of calcium channel blockers and cholesterol content of the diet on jejunal uptake of lipids in rabbits.

The present study was undertaken to determine the effects of two classes of calcium channel blockers (CCB), nisoldipine (N) and verapamil (V), on the jejunal uptake of lipids in rabbits. The uptake of cholesterol and long-chain fatty acids into rabbit jejunum was examined after 6 and 36 min of exposure to N or V in vitro ("acute" studies), and after 3-wk feeding of N or V ("chronic" studies). Animals were fed either a low (0.08%) cholesterol diet (LCD) or a high (2.8%) cholesterol diet (HCD), with or without N or V added. Acute in vitro exposure of the jejunum to N or V did not affect the uptake of cholesterol or palmitic acid in rabbits fed LCD or HCD. The effect of N or V feeding depended upon the cholesterol content of the diet; adding N or V to LCD increased cholesterol uptake while adding N or V to HCD enhanced or lowered cholesterol uptake, respectively. Both N and V increased the uptake of stearic acid in LCD. N in HCD had no effect on fatty acid uptake, whereas V lowered the uptake of stearic and linoleic acids and increased the uptake of oleic acid. These changes in lipid uptake were not due to variation in the animals' food intake, body weight gain, or intestinal mucosal surface area. The chronic administration of N or V results in an intestinal adaptative process that alters the jejunal uptake of lipids, the direction of which is influenced by the class of CCB, and by the cholesterol content of the diet. (ABSTRACT TRUNCATED AT 250 WORDS)

Two weeks of oral synthetic E2 prostaglandin (Enprostil) improves the intestinal morphological but not the absorptive response in the rat to abdominal irradiation.

Enprostil, a synthetic E2 prostaglandin, was administered in a dose of 5 micrograms/kg body weight by gastric tube to rats for 14 days following abdominal irradiation with a single dose of 600 cGy from a 137Cs source. Enprostil prevented the body weight loss and the reduced food intake observed in irradiated animals given placebo, and also prevented the irradiation-associated decline in the mucosal weight and surface area of the ileum. Enprostil given to nonirradiated animals reduced the maximal transport rate (Vmax) and the apparent Michaelis constant (Km*) for the ileal uptake of D-glucose, but did not prevent the irradiation-associated decline in the ileal uptake of glucose. Thus, there is a dissociation of the effects of Enprostil on the morphological and the absorptive properties of the intestine. It is concluded that a 2-week course of a daily oral dose of E2 prostaglandin begun shortly after a single exposure to nonlethal abdominal irradiation prevents the radiation-associated reduction in the intestinal mucosal surface area and the animal's body weight, but does not prevent the malabsorption of glucose.

Rechallenge Following an Early Life Exposure to a High‐Cholesterol Diet Enhances Diet‐Associated Alterations in Intestinal Permeability

Summary:This study was undertaken to test the hypothesis that the intestinal transport response to a highcholesterol (2%) diet (HCD) is influenced by prior exposure to HCD at an earlier age. Uptake was assessed using an in vitro technique, and rabbits were fed one of four dietary regimens: chow for 20 weeks, chow for 14 weeks followed by HCD for 6 weeks, chow for 2 weeks followed by 4 weeks HCD followed by chow for 14 weeks, or 2 weeks chow followed by 4 weeks HCD followed by 8 weeks chow and then 6 further weeks with HCD. The passive jejunal uptake of octanoic, lauric, cholic, and taurocholic acids was greater in animals previously exposed at an earlier age to HCD, as compared with those first exposed to HCD at a later age. Furthermore, the effect of HCD on the passive permeability properties of the intestine lasted for as long as 14 weeks after the animals were switched from HCD back to chow. These alterations in permeability properties occurred in the absence of changes in the intestinal mucosal surface area and were not explained by differences in the rabbits' body weight gain, food consumption, or mucosal surface area of the jejunum or ileum. Thus, (a) early changes in animals' dietary content of cholesterol may have prolonged effects on intestinal transport function, and (b) this early feeding experience with cholesterol may alter the adaptive pattern of the intestine when animals are exposed to a dietary cholesterol challenge at a later age.

Rechallenge Following an Early Life Exposure to a High-Cholesterol Diet Enhances Diet-Associated Alterations in Intestinal Permeability

This study was undertaken to test the hypothesis that the intestinal transport response to a high-cholesterol (2%) diet (HCD) is influenced by prior exposure to HCD at an earlier age. Uptake was assessed using an in vitro technique, and rabbits were fed one of four dietary regimens: chow for 20 weeks, chow for 14 weeks followed by HCD for 6 weeks, chow for 2 weeks followed by 4 weeks HCD followed by chow for 14 weeks, or 2 weeks chow followed by 4 weeks HCD followed by 8 weeks chow and then 6 further weeks with HCD. The passive jejunal uptake of octanoic, lauric, cholic, and taurocholic acids was greater in animals previously exposed at an earlier age to HCD, as compared with those first exposed to HCD at a later age. Furthermore, the effect of HCD on the passive permeability properties of the intestine lasted for as long as 14 weeks after the animals were switched from HCD back to chow. These alterations in permeability properties occurred in the absence of changes in the intestinal mucosal surface area and were not explained by differences in the rabbits' body weight gain, food consumption, or mucosal surface area of the jejunum or ileum. Thus, (a) early changes in animals' dietary content of cholesterol may have prolonged effects on intestinal transport function, and (b) this early feeding experience with cholesterol may alter the adaptive pattern of the intestine when animals are exposed to a dietary cholesterol challenge at a later age.

Saturated fatty acid diet prevents radiation-associated decline in intestinal uptake.

Adult female Sprague-Dawley rats were fed isocaloric semipurified diets containing a high content of either polyunsaturated (P) or saturated (S) fatty acids; these diets were nutritionally adequate, providing for all known essential nutrient requirements. On day 3 after beginning S or P, one group of animals was exposed to a single 6-Gy dose of abdominal radiation, and the other half was sham irradiated. S or P diets were continued for a further 14 days. Brush-border membrane purification and sucrase-specific activities were unaffected by diet or by abdominal irradiation. In rats fed P, irradiation was associated with an increase in jejunal brush-border membrane total phospholipid and the ratio of phospholipid to cholesterol; these changes were not observed in animals fed S. In irradiated rats, ileal brush-border membrane phospholipid per cholesterol was high in animals fed S compared with P. In irradiated animals fed P, there was reduced jejunal and ileal uptake of several medium- and long-chain saturated and unsaturated fatty acids and cholesterol, and the ileal uptake of higher concentrations of glucose was reduced in irradiated animals fed P. In contrast, lipid uptake was similar in control and irradiated animals fed S except for cholesterol uptake, which was reduced. Ileal uptake of higher concentrations of glucose was increased in irradiated animals fed S. Quantitative autoradiography failed to demonstrate any change in the distribution of leucine or lysine transport sites along the villus 1 or 2 wk after abdominal irradiation or in response to feeding S or P. Also, these differences in transport achieved by feeding S to radiated animals were not explained by variations in the animals' food consumption or intestinal mucosal surface area. Thus the use of short-term feeding with a saturated fatty acid diet in the prevention of acute irradiation damage to the intestine warrants further investigation in humans.

The development of the small intestine.

The remarkable degree of coordination between the development of various aspects of gastrointestinal function suggests that the process may be triggered by a single or a few central mechanisms, such as weaning and (or) hormones. Precocious development of enzyme and transport function can be induced by exogenous thyroxine and corticosteroids, while thyroidectomy and adrenalectomy abolish the normal pattern of postnatal development. These hormones may have a primary or a permissive role. Activation of the dormant hormonal mechanism could be controlled by a genetically coded biologic clock, such as chronologic age, or by a biological signal such as body size and oral intake. Generally speaking, shortly after birth, there are increases in the intestinal mucosal surface area, brush border membrane enzymes, and carrier-mediated transport. These adaptive changes occur as a result of the genetic endowment of the animal, but may be modified by environmental factors, particularly nutrient intake.