![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
From the Division of Gastroenterology, Department of Medicine; and Department of Pathology, State University of New York Health Science Center, Syracuse, NY 13210
5To whom correspondence should be addressed at Division of Gastroenterology, University Hospital, 750 East Adams St., Syracuse, NY 13210. E-mail address: LevineR@mailbox.HSCSYR.EDU.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
KEY WORDS: • nucleotides • rats • colitis • myeloperoxidase • interleukin-1ß
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). Although
the intestine can synthesize NT from amino acids and other precursors
and are thus not essential nutrients, NT synthesis appears to be
limited and dependent on an exogenous supply of NT (LeLeiko et al. 1983
and LeLeiko et al. 1987
).
Because the de novo synthesis is metabolically costly, a dietary source
of NT may optimize the function of rapidly dividing tissues like the
intestine, especially during periods of food deprivation or stress.
Beneficial effects of dietary NT on intestinal injury were also
demonstrated in animals. Studies showed that dietary NT and nucleosides
augmented maturation and growth rates in rats (Uuay et al. 1990
) and, in experimental chronic diarrhea (Nunez et al. 1990
), improved gut morphology. Restriction of dietary NT
decreased intestinal mucosal height, brush border enzymatic activities,
intestinal thickness, and fractional synthesis of protein in small
intestine and liver (Lopez-Navarro et al. 1996
,
Ortega et al. 1995
). Furthermore, NT supplementation
enhanced proliferation and differentiation of human and normal rat
small intestinal epithelial cell line in culture under normal and
nutritional stress-related conditions (He et al. 1993
).
Crohn's disease and ulcerative colitis are major inflammatory bowel
diseases in humans. The etiology of inflammatory bowel disease remains
unknown. It can be surmised that in Crohn's disease and/or ulcerative
colitis, dietary NT may become conditionally essential nutrients for
maintenance of gut integrity. Recent studies have suggested that
nutritional supplementation in the form of enteral diets may prove
useful as adjunctive or primary therapy for patients with inflammatory
bowel disease (O'Morain 1990
, Seidman et al. 1991
).
Colitis induced by various agents has been used as an experimental
model to study the pathogenesis of inflammatory bowel disease
(Sartor 1991
). We showed previously that enteral
(Sukumar et al. 1997
) and parenteral (Veerabagu et al. 1996
) administration of NT to rats with
indomethacin-induced ulcerative ileitis-accelerated ulcer
healing. It seems that dietary NT may become conditionally essential
nutrients for maintenance of small intestinal rather than large
intestinal morphology and function under such conditions, as described
by Leleiko et al. (1979)
. In the present study, we
evaluated whether or not enteral feeding of NT could similarly affect
colitis using a dextran sulfate sodium (DSS)-induced colitis model in
rats.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
All experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, published by the U.S. Public Health Service. The studies were approved by the Committee for the Humane Use of Animals at the SUNY Health Science Center at Syracuse. Specific pathogen-free male Sprague-Dawley rats (180–200 g) were obtained from Taconic Sprague-Dawley, Inc. (Indianapolis, IN) and were housed in individual microisolator cages.
Study design and diets.
The animals were maintained on a 12-h dark-light cycle and allowed
free access to pelleted nonpurified diet (Formulab #5008; Purina Mills,
Inc., Richmond, IN) and tap water under conditions of controlled
temperatures (25 ± 2°C). They were adapted for 2 to 5 d
prior to initiation of the experimental protocol. One rat in each group
died during DSS treatment. The remaining animals analyzed (n
= 11 in each group) were randomly assigned to either a control
group receiving a modified AIN-76A diet, or experimental group
receiving same diet supplemented with yeast RNA (1 g/100 g diet)
containing 90–92% NT and 5–6% water. The experimental and control
diets were approximately isonitrogenous and isocaloric. The modified
AIN-76A diet was virtually free of NT (NF) (AIN, 1977
).
This modification of AIN-76A diet was designed with a series of
TD95126-TD95130 by Harlan Tekiad (Madison, WI). The custom research
diet TD95130 was used in this study. The casein (ALACID710) is
manufactured by New Zealand Milk Products (Hawera, New Zealand). Some
nucleic acids could be contributed by residual lactobacilli. The amount
is estimated at 0.3–3.0 mg/100 g. The added NT accounted for no more
than 3% of nitrogen in the diet. Adult rats generally ate 12–15 g of
diet per day. Diets were obtained from Novartis Nutrition Corporation
(Minneapolis, MN).
Induction of colitis.
After two d of prefeeding with NF or NT diets, colitis was induced by free access of food and 40 g/L of DSS (MW 40,000–50,000; United States Biochemical Corp., Cleveland, OH) in drinking water for 3 d, followed by tap water and continuation of the NF or NT diets until killing at 7 or 12 d. In a separate group of experiments, rats receiving the NF (n = 11) or NT (n = 6) diet for 14 d were used as control without DSS (untreated group). All rats were given free access to food and water. Body weights and food intake were measured daily. For DSS-treated groups, volume of DSS (40 g/L) in drinking water also was measured for 3 d. Rats were observed twice daily for their physical symptoms.
Assessment of colonic damage.
Rats were killed using a mixture of ketamine and acepromazine anesthesia (143 mg/kg and 0.71 mg/kg, respectively) by i.p. injection. The abdominal cavity was opened by a midline incision, and the colon from the colocecal junction to the anal verge removed. The colon was then flushed with phosphate-buffered saline, opened longitudinally for morphologic studies. Gross morphological changes were noted in the distal colon, but could not be scored because of the diffuse nature of the lesions. The length of the colon was measured.
Tissue was obtained from each colon as distal, middle, and proximal at
2, 6, and 10 cm beyond the anus, respectively, for histological
analyses. The specimen was then fixed in 10% buffered formalin
solution. The cut specimen was dehydrated in ethanol, embedded in
paraffin wax, sectioned, and stained with hematoxylin and eosin.
Microscopic sections were analyzed by two investigators blinded to the
treatment groups, and a modified grading system was used to assign a
histological score (Dieleman et al. 1996
). The score
included extent of ulceration, expressed as percentage of mucosa
involved, degree of inflammation, scored according to number of
neutrophils per microscopic field, and extent of necrosis and
regeneration scored as mild, moderate, or severe and focal, multifocal,
or complete, respectively.
Colonic myeloperoxidase (MPO) activity.
Colonic MPO activity, simultaneous with colonic histology procurement,
was determined by the method of Grisham et al. (1990)
. A
small portion of distal colon (~100 mg wet weight) was removed about
2 cm beyond the anus for assay of MPO activity. One unit of activity
was defined as the amount of enzyme present that produces a change in
absorbance per min of 1.0 at 37°C in the final reaction volume
containing sodium acetate. In a separate series of experiments, rats
from NF or NT groups were killed at 7 and 12 d, and colons were
retrieved and divided into three equal segments. Each section was
weighed and measured for MPO activity.
Interleukin 1ß (IL-1ß) in rectal dialysate and plasma.
In a separate series of experiments, rats from NF, NT (n
= 12 in each group) and NF untreated (n = 6)
groups were studied at days 0, 4, 7, and 12 for IL-1ß in rectal
dialysate (Stenson et al. 1992
) and plasma only at
12 d (Veerabagu et al. 1996a
). Dialysis tubing (12
kDa molecular weight cutoff) was filled with 200 µL of 120 mmol/L of
NaCl, 30 mmol/L of KHCO3, and 3 g/L of fatty acid-free
bovine serum albumin, inserted into the distal 2 cm of the rat colon
manually, and left in place for 1 h. Rats were anesthetized during
this period using one-third of the original dose of anesthesia
mixture by i.p. Immediately after removal of dialysis tubing, the
dialysate was centrifuged at 8000 x g using Centricon
30 filter (30 kDa molecular weight cut off) for 15 min to remove blood
contamination and clear supernatant was frozen at -20°C. Fifty µL
of dialysate was used for assay employing the Quantikine mouse IL-1ß
kit (R&D Systems, Inc., Minneapolis, MN).
Plasma was separated from heparinized blood that was collected from the heart at the time of killing, by centrifuging at 300–400 x g for 20 min at 4°C. The supernatant clear plasma was stored at -70°C until estimation of IL-1ß within 1 wk.
Statistical analysis.
Data were analyzed by a Student's t-test for paired experimental studies, or by one-way ANOVA followed by Student Newman-Keuls test for multiple comparisons, or by two-way ANOVA, performed to test the effect of treatment and duration (7 and 12 d), where a significant effect was detected (Statview, 4.5 version; Abacus Concepts, Inc., Berkeley, CA). A post-hoc analysis (Fisher PLSD test) was conducted to identify the difference among the groups. The results were expressed as the mean ± SEM. A P value of <0.05 was considered significant.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
All DSS-treated rats showed signs of systemic illness
(Cooper et al. 1993
, Okayasu et al. 1990
), such as ruffled fur and lethargy. There were no
significant differences between the NF and NT untreated groups with
respect to their body weight and food intake (data not shown).
Furthermore, in DSS-treated rats, there were no significant
differences between NF and NT groups in terms of body weight
(Fig. 1
)or food intake (Fig. 2
).There were no differences in the volume of DSS-containing drinking
water that was consumed by rats in NF or NT groups during the
experimental period (Fig. 2
panel insert). Although diarrhea was worse
in the NT group, grossly bloody diarrhea was noted in 4 of 11 rats in
NF group compared to 2 of 11 in NT group. Macroscopically, the exposed
colonic mucosa showed areas of hyperemia, hemorrhage, and necrosis in
the distal segment. The middle and the proximal segments appeared
uninvolved macroscopically.
|
|
).
|
On d 7 in the distal 2.0-cm segment of colon of DSS-treated rats from both NF and NT groups, confluent areas of erosions were seen with near-complete loss of epithelium, extensive crypt distortion and inflammatory infiltration, constituting neutrophils, eosinophils, and mononuclear cells. The infiltrate involved mainly the mucosa and submucosa. Focal re-epithelialization of erosions was seen in some sections in both NF and NT groups. On d 12, microscopic erosions were minimal and more focal, and a less-extensive inflammatory infiltrate was seen, mainly involving the mucosa. Regenerative epithelium was present showing re-epithelialization of erosions.
No significant difference in the extent of ulcers and total
histological scores were found between the NF and NT groups at 7 or
12 d, although the means at 7 d for inflammation, necrosis,
and total score tended to differ (P < 0.084,
P < 0.095, and P < 0.085,
respectively, Table 1
). There was a significant decrease in total
scores in both NF and NT groups at 12 d compared to 7 d,
suggesting healing of colitis by 12 d.
Histological scores were virtually zero in the middle and proximal sections of the colon in the DSS-untreated NF and NT groups at 7 and 12 d, suggesting very little inflammation. No ulcerations or histological damage were seen in the colon of these groups.
MPO activity.
MPO activity was significantly higher in the distal segment of the
colon in the NT compared with the NF group at 7 and 12 d. MPO
activity in the NT and NF groups was also significantly higher
(P < 0.05) at 7 and 12 d, compared to both the
untreated groups. MPO activity decreased from 7 to 12 d in both
the NF and NT groups, suggesting a lesser degree of inflammation
(Fig. 3
).In a separate group of experiments (data not shown), the middle and
proximal colonic MPO activities at 7 and 12 d did not differ in
the NT and NF groups with or without DSS treatment, suggesting minimal
or no inflammation in these parts of the colon.
|
IL-1ß concentration in rectal dialysates was significantly higher at
7 d in both NF and NT groups compared to their respective
counterparts at 0 and 4 d (Fig. 4
).However, there was no significant differences between NF and NT groups
at 7 d. The IL-1ß secretion was significantly elevated at
12 d in the NT compared to NF group as well as relative to 0 and
4 d. These data suggest persistent inflammation in the NT but not
in the NF group at 12 d. In the untreated NF group (Fig. 4)
, there
was no change in IL-1ß concentration during the 0, 4, 7, and 12 d experimental periods. We did not perform control studies in the
untreated NT group, since the NF-untreated group failed to show any
alteration in IL-1ß secretion. Plasma IL-1ß was undetectable.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, who observed that dietary NT
aggravated colonic damage and inflammation in trinitrobenzene sulfonic
acid (TNBS)-induced colitis in rats. In our study there was a strong
trend toward microscopic damage, as determined by the histological
scores, in the NT compared to NF groups during the acute or healing
phases. However, at 7 and 12 d MPO activity was significantly
greater in the NT compared to the NF group, suggesting that there was a
higher degree of inflammation in rats receiving NT.
MPO is considered to be a marker of tissue inflammation and has been
used as a quantitative index of inflammation in several tissues,
including the intestine, despite recognition that it is not specific
only to neutrophils (Yamada et al. 1992
), and can be
released by cells such as eosinophils, monocytes and to a lesser
extent, macrophages. The latter might explain the discrepancy in our
observation since we found MPO activity still elevated significantly at
12 d in the NT group, yet large numbers of neutrophils were not as
apparent as we had observed at 7 d.
Significant elevation of IL-1ß concentration in distal colon at
7 d in both NF and NT groups, compared to 0 and 4 d, suggests
acute inflammation in DSS-treated rats. IL-1ß secretion remained
elevated at 12 d in the NT but not NF group, implicating ongoing
inflammation in the NT group. Numerous studies uniformly found enhanced
expression of IL-1ß in inflammatory bowel disease (Brynskov et al. 1992
, Mahida et al. 1989
, Youngman et al. 1993
). This pro-inflammatory cytokine may be critical
for amplification of mucosal inflammation. The approximate 6-fold
greater IL-1ß concentration at 12 d in the NT compared to the NF
group is consistent with the significant elevation of MPO activity
observed at 12 d in the NT group.
DSS- and TNBS-induced colitis vary in their pathogenesis. The
former presumably has a direct toxic effect on the colonic epithelial
cells (Dieleman et al. 1994
) while the latter may be
immune system-mediated (Sartor 1991
). However, a
recent study showed that TNBS-induced colitis is also associated
with marked defects in epithelial barrier and transport functions,
besides being mediated by the immune system, and that tissue mast cells
may contribute to its pathogenesis (Stein et al. 1998
).
Surprisingly from our observation and that of Adjei et al. (1996)
, enteral NT supplementation aggravates distal colitis in
both DSS and TNBS models, although the mode of induction of colitis by
the two agents is presumably different. Dietary NT appear to modulate
the immune system. An NF diet previously showed a decrease or
suppression of a variety of T-cell-mediated immune responses
(Van Buren et al. 1983
). Furthermore, the effects of
this diet were reversed by NT supplementation, suggesting that the
latter may upregulate immune function (Carver and Walker 1995
, Sanderson and Walker 1991
). Our data lead
us to speculate that NT, besides enhancing the T-cell immune
response, also has a generalized effect on the immune system.
NT may modify the composition of intestinal microflora favorably by
increasing the bifidobacteria compared to enterobacteria (Gil et al. 1986
). The former are thought to restrict the growth of
pathogenic bacteria. Therefore, conceivably NT may preferentially
accelerate healing in the ileum where the bacterial population is less
than in the colon. However, a clinical study in infants failed to show
a beneficial effect of NT on intestinal bacterial flora (Balmer et al. 1994
).
When compared with the colon, which has excess NT synthesis, de novo
synthesis of purines in the small intestine is low (LeLeiko et al. 1979
). There is little expression of the enzyme glutamine
phosphoribosoamidotransferase, the key enzyme in de novo purine
synthesis in the small intestine when compared with either liver or the
large intestine (LeLeiko et al. 1987
). Conversely, there
is increased expression of the hypoxanthine guanine phosphoribosyl
transferase, a salvage enzyme in small intestine, when compared with
either liver or colon. LeLeiko et al. (1987)
further
demonstrated that a significant decrease in total RNA and protein in
rat small intestine and colon results from feeding purine- and
pyrimidine-free diets, similar to that occurring after
intraperitoneal injection of 6-mercaptopurine. Both diets and
6-mercaptopurine selectively decreased intestinal mRNA transcripts of
hypoxanthine gaunine phosphoribosyl transferase and adenine
phosphosylribotransferase, key enzymes in purine salvage. Therefore, we
speculate that in inflammatory bowel disease, where immune responses
could be contributing to its pathogenesis, NT may have an
immunomodulating effect upgrading inflammation, thus aggravating
colitis.
In conclusion, our data suggest that dietary NT supplementation
augments DSS-induced colitis. We are unable to explain the opposite
effects of NT supplementation in experimental indomethacin-induced
ileitis and DSS-induced colitis. Future studies should address
possible mechanisms of dietary NT supplementation in other genetic
experimental inflammatory bowel disease models, including tissue
expression of intestinal cytokines under varying treatments, as
reported in DSS-induced colitis (Mitsuyama et al. 1998
, Murthy et al. 1998
).
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 Presented in part at the annual Meeting of the
American Gastroenterological Association, May 18, 1998, New Orleans, LA
[Sukumar, P., Loo, A., Adolphe, R., Nandi, J., Oler, A., and Levine,
R. A. (1998), Dietary nucleotides augment rat colonic
myeloperoxidase and interleukin-1ß in rectal dialysate in dextran
sulfate-induced colitis. Gastroenterology 114:A1094].
3 Current address: 15616 Copperfield, Darnestown,
MD 20874-3631.
4 Current address: Bristol-Myers, Squibb
Pharmaceutical Research Institute, Neuroscience Drug Discovery
Department, 5 Research Parkway, Wallingford, CT 06492.
6 Abbreviations used: DSS, dextran sulfate sodium;
IL-1ß, interleukin-1ß; MPO, myeloperoxidase; NF, nucleotide-free;
NT, nucleotides; TNBS, trinitrobenzene sulfonic acid.
Manuscript received November 30, 1998. Initial review completed January 26, 1999. Revision accepted April 2, 1999.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1.
Adjei A. A., Morioka T., Ameho C. K., Yamauchi K., Kulkarni A. D., Al-Mansouri H.M.S., Kawajiri A., Yamamoto S. Nucleoside-nucleotide-free diet protects rat colonic mucosa from damage by trinitrobenzene sulfonic acid. Gut 1996;39:428-433
2. AIN. Report of AIN Committee on Diets for Experimental Animals Ad Hoc Committee on Standards for Nutritional Studies. J. Nutr. 1977;107:1340-1348
3. Balmer S. E., Hanvey L. S., Wharton B. A. Diet and faecal flora in the newborn: nucleotides. Arch. Dis. Child. 1994;70:F137-F140
4. Brynskov J., Tvede N., Andersen L. B., Vilien M. Increased concentration of interleukin 1-ß, interleukin-2 and soluble interleukin-2 receptors in endoscopical mucosal biopsy specimens with active inflammatory bowel disease. Gut 1992;3:55-58
5. Carver J. D., Walker W. A. The role of nucleotide in human nutrition. J. Nutr. Biochem. 1995;6:58-72
6. Cooper H. S., Murthy S.N.S., Shah R. S., Sedergran D.J.L. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Invest. 1993;69:238-249[Medline]
7.
Dieleman L. A., Elson C. O., Tennyson G. S., Beagley K. W. Kinetics of cytokine expression during healing of acute colitis in mice. Am. J. Physiol. 1996;271:G130-G136
8. Dieleman L. A., Ridwan B. V., Tennyson G. S., Beagley K. W., Bucy R. P., Elson C. O. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 1994;107:1643-1652[Medline]
9. Gil A., Corral E., Martinez A., Molina J. A. Effects of the addition of nucleotides to an adapted milk formula on the microbial pattern of feces in at term newborn infants. J. Clin. Nutr. Gastroenterol. 1986;1:127-232
10. Grishman M. B., Benoit J. N., Granger D. N. Assessment of leucocyte involvement during ischaemia and reperfusion of intestine. Methods Enzymol 1990;186:729-742[Medline]
11. He Y., Chu S. W., Walker W. A. Nucleotide supplements after proliferation and differentiation of cultured human (Caco-2) and rat (IEC-6) intestinal epithelial cells. J. Nutr. 1993;123:1017-1027
12. LeLeiko N. S., Bronstein A. D., Baliga B. S., Munro H. N. De novo purine nucleotide synthesis in the rat small and large intestine: effect of dietary protein and purines. J. Pediatr. Gastroenterol. Nutr. 1983;2:313-319[Medline]
13. LeLeiko N. S., Bronstein A. D., Munro H. N. RNA synthesis in the small intestine. Utilization of luminal purines. Gastroenterology 1979;76:1183(abs)
14. LeLeiko N. S., Martin B. A., Walsh M. J., Kaslow P., Rabinowitz S., Sterling K. Tissue-specific gene expression results from a purine- and pyrimidine-free diet and 6-mercaptopurine in the rat small intestine and colon. Gastroenterology 1987;93:1014-1020[Medline]
15. Lopez-Navarro A. T., Ortega M. A., Peragon J., Bueno J. D., Gil A., Sanchez-Pozo A. Deprivation of dietary nucleotides decreases protein synthesis in the liver and small intestine in rats. Gastroenterology 1996;110:1760-1769[Medline]
16.
Mahida Y. R., Wu K., Jewell D. P. Enhanced production of interleukin 1-ß by mononuclear cells isolated from mucosa with active ulcerative colitis and Crohn's disease. Gut 1989;30:835-838
17. Mitsuyama K., Ide M., Nishiyama T., Tomiyasu N., Shirachi A., Saiki T., Tateishi H., Toyonaga A., Kurimoto M., Okamura H., Tanikawa K. Role of interleukin-18 in a murine model of dextran sulfate sodium-induced colitis. Gastroenterology 1998;114:A1040(abs)
18. Murthy S., Yoshitake H., Flanigan A. The response of IL-1ß-converting enzyme (ICE)-deficient mice to dextran sulfate (DSS). Gastroenterology 1998;114:A1047(abs)
19. Nunez M. C., Ayudarte M. V., Morales D., Suarez M. D., Gil A. Effect of dietary nucleotides on intestinal repair in rats with experimental chronic diarrhea. JPEN 1990;14:598-604[Abstract]
20. Okayasu I., Hatakeyama S., Yamada M., Ohkusa T., Inagaki Y., Nakaya R. Novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 1990;98:694-702[Medline]
21. O'Morain C. A. Does nutritional therapy in inflammatory bowel disease have a primary or an adjunctive role?. Scand. J. Gastroenterol. 1990;25(suppl 172):29-34[Medline]
22. Ortega M. A., Gil A., Sanchez-Pozo A. Maturation status of small intestine epithelium in rats deprived of dietary nucleotides. Life Sci 1995;56:1623-1630[Medline]
23. Raul F., Goda T., Gosse F., Koldovsky O. Short-term effect of a high protein, low carbohydrate diet on aminopeptidase in adult rat jejunoileum. Biochem. J. 1987;247:401-405[Medline]
24. Sanderson I. R., Walker W. A. Nutrition and immunity. Current Opinion in Gastroenterology 1991;7:463-470
25. Sartor R. B. Animal models of intestinal inflammation. Relevance to inflammatory bowel disease. MacDermott R. P. Stenson W. F. eds. Inflammatory Bowel Disease 1991:337-353 New York Elsevier.
26. Seidman E., LeLeiko N., Ament M., Berman W., Caplan D., Evans J., Kocoshis S., Lake A., Motil K., Sutphen J., Thomas D. Nutritional issues in pediatric inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 1991;12:424-438[Medline]
27.
Stein J., Ries J., Barrett K. E. Disruption of intestinal barrier function associated with experimental colitis: possible role of mast cells. Am. J. Physiol. 1998;274:G203-G209
28. Stenson W. F., Cort D., Rodgers J., Burakoff R., DeSchryver-Kecskemeti K., Gramlich T. L., Beeken W. Dietary supplementation with fish oil in ulcerative colitis. Ann. Int. Med. 1992;116:609-614
29. Sukumar P., Loo A. T., Magur E., Nandi J., Oler A., Levine R. A. Dietary supplementation of nucleotides and arginine promotes healing of small bowel ulcers in experimental ulcerative ileitis. Dig. Dis. Sci. 1997;42:1530-1536[Medline]
30. Uuay R., Stringel G., Thomas R., Quan R. Effect of dietary nucleosides on growth and maturation of the developing gut in the rat. J. Parent. Ent. Nutr. 1990;10:497-503
31. Van Buren C. T., Kulkarni A. D., Schandle V. B., Rudolph F. B. The influence of dietary nucleotides on cell mediated immunity. Transplantation 1983;36:350-352[Medline]
32. Veerabagu M. P., Meguid M. M., Oler A., Levine R. A. Intravenous nucleosides and a nucleotide promote healing of small bowel ulcers in experimental enterocolitis. Dig. Dis. Sci. 1996;41:1452-1457[Medline]
33. Veerabagu M. P., Opara E. I., Meguid M. M., Nandi J., Oler A., Holtzapple P. G., Levine R. A. Mode of food intake reduction in Lewis rats with indomethacin-induced ulcerative ileitis. Physiol. Behav. 1996;60:381-387[Medline]
34. Yamada T., Marshall S., Specian R. D., Grisham M. B. Comparative analysis of two models of colitis in rats. Gastroenterology 1992;102:1524-1534[Medline]
35. Youngman K. R., Simon P. L., West G. A. Localization of intestinal interleukin 1 activity and protein and gene expression of lamina propria cells. Gastroenterology 1993;104:749-758[Medline]
This article has been cited by other articles:
|
|
 |
|
  A Belo, T Marchbank, A Fitzgerald, S Ghosh, and R J Playford Gastroprotective effects of oral nucleotide administration Gut, February 1, 2006; 55(2): 165 - 171. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
P < 0.05 for 4 vs. 12 d in NT
group, 
P < 0.05 for NT vs. NF group at
12 d.