Editorial Open Access
Copyright ©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jan 7, 2007; 13(1): 1-7
Published online Jan 7, 2007. doi: 10.3748/wjg.v13.i1.1
Nutritional modulation of the inflammatory response in inflammatory bowel disease- From the molecular to the integrative to the clinical
Gary E Wild, Department of Medicine, Division of Gastroenterology, McGill University, Montreal, Quebec; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
Laurie Drozdowski, Alan BR Thomson, Division of Gastro-enterology, University of Alberta, Edmonton, Alberta, Canada
Carmela Tartaglia, Department of Physiology, McGill University, Montreal, Quebec, Canada
M Tom Clandinin, Department of Agriculture, Foods and Nutrition, University of Alberta, Edmonton, Alberta, Canada
Author contributions: All authors contributed equally to the work.
Correspondence to: Dr. Alan BR Thomson, Zeidler Ledcor Center, 130, University Campus, Edmonton, AB T6G 2X8, Canada. alan.thomson@ualberta.ca
Telephone: +1-780-4926490 Fax: +1-780-4927964
Received: July 30, 2006
Revised: September 7, 2006
Accepted: October 5, 2006
Published online: January 7, 2007

Abstract

Nutrient deficiencies are common in patients with inflammatory bowel disease (IBD). Both total parenteral and enteral nutrition provide important supportive therapy for IBD patients, but in adults these are not useful for primary therapy. Dietary intervention with omega-3 polyunsaturated fatty acids contained in fish oil may be useful for the care of IBD patients, and recent studies have stressed the role of PPAR on NFκB activity on the potential beneficial effect of dietary lipids on intestinal function.

Key Words: Crohn’s disease, Ulcerative colitis, Enteral nutrition, Parenteral nutrition, Glutamine, Fiber, Long chain fatty acids



INTRODUCTION

Inflammatory bowel disease (IBD) is a term used to denote inflammation of the gastrointestinal mucosa of unknown etiology. There are a number of hypotheses pertaining to the development and perpetuation of IBD. Three major theories emerge from the literature. The first implicates a persistent intestinal infection[1-3]; the second proposes that IBD is a consequence of a defective mucosal barrier to luminal antigens[4,5]; and the third suggests a dysregulated host immune response to ubiquitous antigens[4,6]. It is believed that IBD has both genetic and environmental components, and is immunologically mediated[4,7-9]. Data from IBD patients concerning cytokine profiles, permeability defects, response to treatment, and natural history of disease all indicate a heterogeneous group of illnesses that fall under the headings of ulcerative colitis (UC) and Crohn’s disease (CD). Previous epidemiological data covering diet in UC and CD are conflicting, partly due to this heterogeneity of the diseases, difficulty in obtaining reliable data and publication bias such as negative structures of breastfeeding[10].

NUTRITION IN IBD

Specific antibody isotypes to major milk proteins are found in both UC and CD patients. In CD, the antibodies correlate with disease activity[11]. Although ethnic origin[12], and not the IBD disease state, appears to be the main determinant of lactose intolerance, the avoidance of dairy products by IBD patients is extensive[13]. Lack of breast-feeding in infancy has been associated with CD but not UC. In addition, increased carbohydrate consumption has been documented in CD[14]. Others have alluded to a lack of dietary fiber as a predisposing factor for IBD[15]. The development of UC has also been associated with high intakes of monounsaturated fatty acids (MUFA), n6 polyunsaturated fatty acids (n6 PUFA), sulphur-containing diets and vitamin B6[16].

Deficiencies

IBD is associated with a number of nutritional deficiencies including anemia, hypoalbuminemia, hypomagnesia, hypocalcemia and hypophosphatemia, as well as deficiencies in folic acid, niacin, Vitamins A, B12, C, and D as well as deficiencies of iron, zinc, copper[17]. It is not clear if low levels of micronutrients are one of the results of disease or one of primary importance. Plasma antioxidant concentrations are reduced in IBD patients, particularly those with active disease[18]. Antioxidant activity, assessed by measuring selenium concentrations and erythrocyte glutathione peroxidase activity, is inversely correlated with inflammatory biomarkers, including TNFα[19]. Hyperhomocysteinemia is more common in patients with IBD, and is associated with reduced serum, concentrations of vitamin B12, folate and B6[20].

Several mechanisms contribute to the malnutrition observed in IBD patients. Firstly, there is a decrease in the oral intake of nutrients because of abdominal pain and anorexia. Secondly, the mucosal inflammation and associated diarrhea leads to a loss of protein, blood, minerals, electrolytes and trace elements. Thirdly, multiple resections or bacterial overgrowth may have an adverse nutritional effect; and lastly, the pharmacological therapies may also lead to malnutrition. For example, sulfasalazine reduces folic acid absorption, and corticosteroids decrease calcium absorption as well as negatively affecting protein metabolism[21]. Alterations in energy metabolism may result in increased resting energy expenditure and lipid oxidation in IBD patients[22,23]. The consequences of malnutrition are numerous, and include reductions in bone mineral density[24], as well as growth retardation and delayed sexual maturity in children[25]. Osteoporosis may also be implicated as a result of proinflammatory cytokine profiles.

Nutritional therapy can take on a number of forms which include Total Parenteral Nutrition (TPN) and Total Enteral Nutrition (TEN). The diets used are elemental, polymeric, and exclusion diets. Elemental diets contain nutrients reduced to their basic components: amino acids for proteins, glucose for carbohydrates, and short-chain triglycerides for fats. Polymeric formulas contain whole proteins for nitrogen, glucose polymers for carbohydrates and long-chain triglycerides for starch or fat, respectively[17].

Total parenteral nutrition (TPN)

The use of TPN for the management of IBD is based on certain theoretical advantages: bowel rest is beneficial because it diminishes motor and transport function of the diseased bowel[26,27]; a decrease in antigenic stimulation will eliminate the immunologic responses to food, especially in the presence of impaired intestinal permeability[28-30]; TPN fosters protein synthesis in the intestine which leads to cell renewal, healing, and reversal of impaired immunocompetence.

Ostro and co-workers[31] demonstrated remission rates of 63% to 89% with TPN in a large retrospective series of CD patients who were refractory to conventional medical management. However, Matuchansky et al[32] emphasized that there were high relapse rates (40%-62%) after 2 years. It has been suggested that TPN be used only in a nutritionally supportive role[33,34]. In UC, there is no evidence for better outcome with TPN[35,36]. Although remission rates of 9% to 80% have been reported, TPN given to patients with severe colitis appears to only be beneficial as perioperative nutritional support. In patients with mild disease, TPN is more effective but is not better than steroid therapy, and thus the invasiveness and cost of TPN are unjustified. Any benefits associated with TPN may be due to the administration of nutrients, and not bowel rest, as bowel rest alone has no effect on disease activity[37]. Therefore, although TPN has a role in patients with a non-functioning intestine or the short bowel syndrome due to excessive resections, TPN is of limited use as a primary therapy in IBD. This is not intended to be an extensive review of TPN, but it should be cautioned that even in expert centres, TPN is associated with complications such as sepsis and cholestatic liver disease.

Total enteral nutrition (TEN), elemental and defined formula diets

TEN excludes potential toxic dietary factors and antigenic exposure, since there are only amino acids, glucose or oligosaccharides and low lipid content. TEN is not associated with cholestasis, biliary sludge or gallstone formation, as is seen with TPN. Atrophy of the small intestinal mucosa has been observed in animal models receiving long-term TPN, but this atrophy is prevented with TEN. In addition, a 6-wk TPN treatment in dogs resulted in marked reduction in pancreatic weight, a decrease in small intestinal mass, and a decrease in intestinal disaccharidase activity in dogs[38]. For this reason, TEN is preferable to TPN.

The topic of nutrition in GI disorders occurring in IBD has been reviewed recently[39,40]. When compared to TPN, enteral nutrition yielded similar results of preventing and combating malnutrition[35,36,41]. Although Voitk et al[42] proposed that elemental diets may be an effective therapy for IBD, enteral nutrition as a primary therapy has failed to yield consistent results in numerous clinical trials. It is true that a number of trials have shown remission rates in CD patients receiving elemental diets, similar to the rates observed with steroid therapy[43-54]. However, it is noteworthy that significantly better remission rates were observed in patients receiving steroid treatment versus elemental diets when including all the diet group drop outs (i.e., on an intent-to-treat basis). The question remains as to the best way of analyzing the results when a large percentage of patients receiving diet therapy drop out because of unpalatibility or intolerance. Furthermore, some studies have shown no difference with elemental diets when compared to steroid therapy[48,52]. In children, elemental diets were associated with greater linear growth, while in adults these diets preserve nitrogen balance[55,56]. The role of nutritional therapy in the context of pediatric onset illness has been reviewed[57]. Thus, enteral nutrition is easier to use, is less expensive, and is a better alternative to TPN. Unfortunately, its unpalatability limits patient compliance, but with strong encouragement this may be partially overcome.

The fat composition of enteral diets may influence the results which are obtained in the various clinical trials. Elemental diets have a low fat content, while most polymeric diets generally contain more fat including more linoleic acid, which is a precursor for the synthesis of potentially proinflammatory eicosanoids[58].

Defined formula diets are usually more palatable and less expensive than are the elemental diets. While some investigators report no differences between elemental and defined formula diets in patients with acute CD[49,59,60], Giaffer et al[61] found elemental diets to be more effective in active CD. A randomized double-blind trial in Crohn’s patients demonstrated that elemental and polymeric (defined) diets, differing only in their source of nitrogen, were equally effective in reducing the Crohn’s disease activity index (CDAI), and in inducing clinical remission[62]. Although defined formula diets provide less bowel rest, they have the potential advantage of exposing the GI tract to the usual dietary substrates, which allow thereby for the full expression of intestinal, biliary and pancreatic activity[63]. In animal studies, it has also been observed that luminal nutrition has trophic influences on the gut[64].

Is there a beneficial effect of supplementing polymeric formulas with TGF-β1[65]? In pediatric CD, reductions in proinflammatory cytokine concentrations and mRNA, paired with an up-regulation of TGF-β mRNA, was associated with improved macroscopic and microscopic mucosal inflammation. A meta-analysis and a Cochrane review have demonstrated that in adults, corticosteroids are more effective than enteral diet therapy[48-50]. It is unclear what is the role of nutritional therapy in adults with CD[51-53], although there is some evidence in Japan that enteral nutrition enjoys support as primary therapy[53]. In contrast to the generally agreed role in adults of enteral nutrition being useful to improve the patient’s nutritional status as its main benefit, in children with CD enteral nutrition has a much clearer benefit to improve clinical, biochemical and growth parameters[55], and may as well have a steroid sparing effect[56,57].

Glutamine, fiber and fatty acids

Diets high in glutamine, an important source of energy for enterocytes and the preferred fuel of the small intestine[66,67], have been used with variable success. Glutamine probably exerts its trophic effects on the small intestine by increasing protein synthesis, and generating alanine as a substrate for enteric gluconeogenesis[68]. There is evidence that glutamine protects the small intestinal mucosa during critical illness[69,70]. However, oral glutamine supplements do not restore to normal the increased permeability seen in patients with CD, and these supplements do not beneficially affect the patients’ CDAI or C-reactive protein (CRP) levels[71]. Similarly, a randomized controlled trial demonstrated that no benefit was associated with the intake of glutamine-enriched polymeric formulas in children with CD[72].

In animal studies, dietary fiber has been implicated in maintaining the integrity of the intestine, and in preventing the bacterial translocation from the gut to the mesenteric lymph nodes[73,74]. Short chain fatty acids (SCFA, C1 to C6 organic fatty acids), are produced by the fermentation of dietary polysaccharides by the normal anaerobic bacteria in the colon. These SCFA are a source of energy for the colonocytes, in addition to their enhancing sodium and water absorption and promoting blood flow[75,76]. Reduced levels of SCFA, particularly butyrate, and a defect in the oxidation of butyrate by colonocytes, have been proposed as a mechanism in the pathogenesis of IBD[77,78]. Evidence to support this hypothesis includes the observation that the oxidation of 13C-labelled butyrate is lower in patients with active UC as compared to healthy controls[79]. However, Simpson and co-workers failed to demonstrate differences between UC patients and controls in the oxidation of rectally administered 13C-labelled butyrate[80].

TPN supplemented with SCFA enhanced functional adaptation to intestinal resection in rats. It remains to be determined if patients with short bowel syndrome may benefit from SCFA[81].

Butyrate (C4 fatty acid) administered to UC patients resulted in remission rates comparable to corticosteroids and mesalamine[82]. In patients with CD, both intestinal biopsies and lamina propria cells cultured with butyrate had significantly reduced levels of inflammatory cytokines (TNF), possibly due to a reduction in NFκB activation and IκB degradation[83].

Eicosanoids are inflammatory mediators, and have been implicated in the pathogenesis of chronic inflammatory lesions in the bowel. Specimens from patients with IBD show increased eicosanoid formation[84]. High dietary intake of omega-6 polyunsaturated fatty acids (PUFAs), which reduces omega-3 intake, may contribute to IBD development[85]. The benefits of fish oil, which contain n3 fatty acids, have been shown in some inflammatory diseases such as psoriasis and rheumatoid arthritis. Epidemiological observations of the low prevalence of IBD in Japanese and Inuit populations consuming high n3 fatty acid fish provided a rationale for the use of n3 fatty acids in IBD. The n3 fatty acids are believed to compete with n6 fatty acids as precursors of eicosanoid synthesis. The n3 products are series 5 leukotrienes, which have less physiological activity than do the arachidonate- derived series 4 counterparts. Thus, fish oil may have an anti-inflammatory effect.

Rats fed with fish oil which had TNBS-induced inflammatory lesions in the bowel showed less prostaglandin- and leukotriene-mediated immune response[86]. Parenteral lipid emulsions enriched with n3 fatty acids reduce diarrhea, attenuate morphological changes, and decrease colonic concentrations of inflammatory mediators in an animal model of acetic acid induced colitis[87].

Loeschke et al[88] performed a placebo-controlled trial of n3 fatty acids in the prevention of relapse in UC. Patients in remission who received n3 fatty acids experienced fewer relapses than did those receiving placebo. Unfortunately, the beneficial results of this study did not persist throughout the length of the 2 year study, possibly due to decreased compliance over time. In a multicenter placebo controlled relapse prevention trial, Belluzzi et al[89] found a significant reduction in the relapse rate in CD patients given a special formulation designed to allow delayed ileal release of n3 fatty acids. A fish oil diet has been shown to increase eicosapentanoic and docosahexanoic acids in the intestinal mucosal lipids of IBD patients, as well as showing a decrease in arachadonic acid. An increase in the synthesis of leukotriene B5 as well as a 53% decrease of leukotriene B4 was shown in UC patients, whereas the fish oil treatment showed a nonsignificant trend to faster remission[90,91]. Fish oil supplementation results in clinical improvement of active mild to moderate disease, but was not associated with a significant decrease in leukotriene B4 production[84]. Thus, fish oil supplementation of the diet may provide some short-term benefit to patients with CD or UC. The use of probiotics and prebiotics has received much attention; the interested reader is referred to recent reviews in this area[40].

Fatty acids and gene expression

The effect of fatty acids on gene expression was previously thought to result largely from alterations in membrane phospholipids or eicosanoid production. More recently, the discovery of nuclear receptors; such as peroxisome proliferator-activated receptors (PPARs), and their regulation by fatty acids, has changed this view. PPARs are ligand activated transcription factors that upon heterodimerization with the retinoic X receptor (RXR), recognize PPAR response elements in the promoter regions of various genes, and subsequently affect gene transcription. PPARs bind various ligands including nonsteroidal anti-inflammatory drugs (NSAIDS), thiazolidinediones (antidiabetic agents) as well as PUFAs and their metabolites[92-96]. Several subtypes of the receptor have been identified (α,δ,γ) and these are differentially expressed in a variety of tissues. PPARγ is expressed in intestinal tissue, with the highest abundance detected in the colon[97].

PPARγ has been implicated in the regulation of inflammation, and has become a potential therapeutic target in the treatment of inflammatory disorders, including IBD. It has been suggested that patients with UC have a mucosal deficit in PPARγ that may contribute to the development of their disease. Indeed, analysis of mRNA and protein from colonic biopsies shows reduced PPARγ in UC patients when compared to either Crohn’s patients or healthy controls[98].

Using colon cancer lines, it has been shown that PPAR ligands attenuate cytokine gene expression by inhibiting NF-κB via an IκB dependent mechanism[99]. A number of other studies suggest that PPAR activators inhibit COX2 by interference with NF-κB[100-102]. PPARs inhibit the AP-1 signaling pathway[103], and interact with the Jun[104] and STAT signaling pathways[105].

Animal studies support the role of PPAR in intestinal inflammation. Thiazolidinedione ligands for PPAR markedly reduced colonic inflammation in a mouse model of IBD[99]. PPAR+/- and RXR +/- mice display enhanced susceptibility to TNBS-induced colitis[106]. The administration of PPAR and RXR agonists synergistically reduce TNBS-induced colitis, with improved macroscopic and histologic scores, reductions in TNFα and IL-1β mRNA, and decreased NF-κB DNA binding activity.

Although clinical data is limited, the results of an open label study using rosiglitazone, a PPARγ ligand as therapy for UC, showed that 27% of patients achieved remission after 12 wk of therapy[107]. Thus, PPARγ ligands may represent a novel therapy for UC, and double-blind, placebo-controlled, randomized trials are warranted.

Of considerable interest, the ability to modulate PPAR nutritionally has been studied. Dietary PUFA have dramatic effects on gene expression through the regulation of several transcription factors, including PPAR. Fatty acid regulation of PPAR was first noted by Gottlicher et al[108]. A diverse array of fatty acids, eicosanoids, and fatty acid metabolites have been shown to activate PPAR[94-96]. Both PPARα and PPARγ bind mono- and polyunsaturated fatty acids at levels, which are found in human serum[95]. Thus, the anti-inflammatory effects of n3 PUFA may involve PPAR and interference with NFκB, rather than simply alterations in eicosanoid synthesis.

Clinical Implications

It is widely accepted that nutritional deficiencies are common in patients with CD and UC, and these need to be anticipated, identified and treated. There are no specific diets which can be recommended for all patients with IBD; diet therapy needs to be individualized. TPN or TEN may be necessary to restore nutritional balance in selected IBD patients with malnutrition, but in adults these interventions do not provide a primary option to modify disease activity. The omega-3 PUFAs contained in fish oil may reduce disease activity in UC and CD when used in the short term in conjunction with standard medical therapy. Their mechanism of action may be to enhance the activity of the nuclear receptors PPAR (peroxisome proliferator-activated receptors) in the intestine, inhibiting the AP-1 signaling pathway and NF-κB, attenuating proinflammatory cytokine gene expression. Future research will focus on the identification and use of specific dietary lipids to reduce intestinal inflammatory activity and to maintain long-term disease remission.

ACKNOWLEDGMENTS

The authors thank Ms. Lori Ingram for her excellent editorial assistance.

Footnotes

S- Editor Liu Y L- Editor Alpini GD E- Editor Ma WH

References
1.  Liu Y, van Kruiningen HJ, West AB, Cartun RW, Cortot A, Colombel JF. Immunocytochemical evidence of Listeria, Escherichia coli, and Streptococcus antigens in Crohn's disease. Gastroenterology. 1995;108:1396-1404.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 220]  [Cited by in F6Publishing: 237]  [Article Influence: 8.2]  [Reference Citation Analysis (0)]
2.  Sartor R Microbial factors in the pathogenesis of Crohn's disease, ulcerative colitis and experimental intestinal inflammation. Baltimore: Williams & Wilkins 1995; .  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Wakefield AJ, Ekbom A, Dhillon AP, Pittilo RM, Pounder RE. Crohn's disease: pathogenesis and persistent measles virus infection. Gastroenterology. 1995;108:911-916.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 79]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
4.  Sartor RB. Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am. 1995;24:475-507.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Sartor RB. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol. 1997;92:5S-11S.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  MacDermott RP. Alterations in the mucosal immune system in ulcerative colitis and Crohn's disease. Med Clin North Am. 1994;78:1207-1231.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Podolsky DK. Inflammatory bowel disease (1). N Engl J Med. 1991;325:928-937.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 762]  [Cited by in F6Publishing: 768]  [Article Influence: 23.3]  [Reference Citation Analysis (0)]
8.  Podolsky DK. Inflammatory bowel disease (2). N Engl J Med. 1991;325:1008-1016.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 218]  [Cited by in F6Publishing: 229]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
9.  Yang H, Rotter J.  The genetics of inflammatory disease. Baltimore: Williams & Wilkins 1994; .  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Wurzelmann JI, Lyles CM, Sandler RS. Childhood infections and the risk of inflammatory bowel disease. Dig Dis Sci. 1994;39:555-560.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 114]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
11.  Knoflach P, Park BH, Cunningham R, Weiser MM, Albini B. Serum antibodies to cow's milk proteins in ulcerative colitis and Crohn's disease. Gastroenterology. 1987;92:479-485.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  De Palma GD, Catanzano C. Removable self-expanding metal stents: a pilot study for treatment of achalasia of the esophagus. Endoscopy. 1998;30:S95-S96.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 20]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
13.  Bernstein CN, Ament M, Artinian L, Ridgeway J, Shanahan F. Milk tolerance in adults with ulcerative colitis. Am J Gastroenterol. 1994;89:872-877.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Matsui T, Iida M, Fujishima M, Imai K, Yao T. Increased sugar consumption in Japanese patients with Crohn's disease. Gastroenterol Jpn. 1990;25:271.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Kelly DG, Fleming CR. Nutritional considerations in inflammatory bowel diseases. Gastroenterol Clin North Am. 1995;24:597-611.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Geerling BJ, Dagnelie PC, Badart-Smook A, Russel MG, Stockbrügger RW, Brummer RJ. Diet as a risk factor for the development of ulcerative colitis. Am J Gastroenterol. 2000;95:1008-1013.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 112]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
17.  Dudrick SJ, Latifi R, Schrager R. Nutritional management of inflammatory bowel disease. Surg Clin North Am. 1991;71:609-623.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  D'Odorico A, Bortolan S, Cardin R, D'Inca' R, Martines D, Ferronato A, Sturniolo GC. Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease. Scand J Gastroenterol. 2001;36:1289-1294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 127]  [Cited by in F6Publishing: 136]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
19.  Reimund JM, Hirth C, Koehl C, Baumann R, Duclos B. Antioxidant and immune status in active Crohn's disease. A possible relationship. Clin Nutr. 2000;19:43-48.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 52]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
20.  Romagnuolo J, Fedorak RN, Dias VC, Bamforth F, Teltscher M. Hyperhomocysteinemia and inflammatory bowel disease: prevalence and predictors in a cross-sectional study. Am J Gastroenterol. 2001;96:2143-2149.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 76]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
21.  Lewis JD, Fisher RL. Nutrition support in inflammatory bowel disease. Med Clin North Am. 1994;78:1443-1456.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Azcue M, Rashid M, Griffiths A, Pencharz PB. Energy expenditure and body composition in children with Crohn's disease: effect of enteral nutrition and treatment with prednisolone. Gut. 1997;41:203-208.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 119]  [Cited by in F6Publishing: 121]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
23.  Mingrone G, Capristo E, Greco AV, Benedetti G, De Gaetano A, Tataranni PA, Gasbarrini G. Elevated diet-induced thermogenesis and lipid oxidation rate in Crohn disease. Am J Clin Nutr. 1999;69:325-330.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut. 1997;40:228-233.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM. Growth and clinical course of children with Crohn's disease. Gut. 1993;34:939-943.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 178]  [Cited by in F6Publishing: 189]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
26.  Fischer JE, Foster GS, Abel RM, Abbott WM, Ryan JA. Hyperalimentation as primary therapy for inflammatory bowel disease. Am J Surg. 1973;125:165-175.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 109]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
27.  Reilly J, Ryan JA, Strole W, Fischer JE. Hyperalimentation in inflammatory bowel disease. Am J Surg. 1976;131:192-200.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 100]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
28.  Ganem D, Schneider RJ. Hepadnaviridae: The viruses and their replication. Fields Virology. Volume 2. Philadelphia: Lippincott, Williams & Wilkins 2001; 2923-2969.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Jones VA, Dickinson RJ, Workman E, Wilson AJ, Freeman AH, Hunter JO. Crohn's disease: maintenance of remission by diet. Lancet. 1985;2:177-180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 153]  [Cited by in F6Publishing: 151]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
30.  Suzuki I, Kiyono H, Kitamura K, Green DR, McGhee JR. Abrogation of oral tolerance by contrasuppressor T cells suggests the presence of regulatory T-cell networks in the mucosal immune system. Nature. 1986;320:451-454.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 54]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
31.  Ostro MJ, Greenberg GR, Jeejeebhoy KN. Total parenteral nutrition and complete bowel rest in the management of Crohn's disease. JPEN J Parenter Enteral Nutr. 1985;9:280-287.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 97]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
32.  Matuchansky C. Parenteral nutrition in inflammatory bowel disease. Gut. 1986;27 Suppl 1:81-84.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 32]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
33.  Payne-James JJ, Silk DB. Total parenteral nutrition as primary treatment in Crohn's disease--RIP? Gut. 1988;29:1304-1308.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 11]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
34.  Shiloni E, Coronado E, Freund HR. Role of total parenteral nutrition in the treatment of Crohn's disease. Am J Surg. 1989;157:180-185.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 19]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
35.  Dickinson RJ, Ashton MG, Axon AT, Smith RC, Yeung CK, Hill GL. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology. 1980;79:1199-1204.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  McIntyre PB, Powell-Tuck J, Wood SR, Lennard-Jones JE, Lerebours E, Hecketsweiler P, Galmiche JP, Colin R. Controlled trial of bowel rest in the treatment of severe acute colitis. Gut. 1986;27:481-485.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 200]  [Cited by in F6Publishing: 201]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
37.  Greenberg GR, Fleming CR, Jeejeebhoy KN, Rosenberg IH, Sales D, Tremaine WJ. Controlled trial of bowel rest and nutritional support in the management of Crohn's disease. Gut. 1988;29:1309-1315.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 216]  [Cited by in F6Publishing: 219]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
38.  Hughes CA, Bates T, Dowling RH. Cholecystokinin and secretin prevent the intestinal mucosal hypoplasia of total parenteral nutrition in the dog. Gastroenterology. 1978;75:34-41.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Stratton RJ, Smith TR. Role of enteral and parenteral nutrition in the patient with gastrointestinal and liver disease. Best Pract Res Clin Gastroenterol. 2006;20:441-466.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 11]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
40.  O'Sullivan M, O'Morain C. Nutrition in inflammatory bowel disease. Best Pract Res Clin Gastroenterol. 2006;20:561-573.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 84]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
41.  González-Huix F, Fernández-Bañares F, Esteve-Comas M, Abad-Lacruz A, Cabré E, Acero D, Figa M, Guilera M, Humbert P, de León R. Enteral versus parenteral nutrition as adjunct therapy in acute ulcerative colitis. Am J Gastroenterol. 1993;88:227-232.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Voitk AJ, Echave V, Feller JH, Brown RA, Gurd FN. Experience with elemental diet in the treatment of inflammatory bowel disease. Is this primary therapy? Arch Surg. 1973;107:329-333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 153]  [Cited by in F6Publishing: 151]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
43.  Axelsson C, Jarnum S. Assessment of the therapeutic value of an elemental diet in chronic inflammatory bowel disease. Scand J Gastroenterol. 1977;12:89-95.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Lochs H, Steinhardt HJ, Klaus-Wentz B, Zeitz M, Vogelsang H, Sommer H, Fleig WE, Bauer P, Schirrmeister J, Malchow H. Comparison of enteral nutrition and drug treatment in active Crohn's disease. Results of the European Cooperative Crohn's Disease Study. IV. Gastroenterology. 1991;101:881-888.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Malchow H, Steinhardt HJ, Lorenz-Meyer H, Strohm WD, Rasmussen S, Sommer H, Jarnum S, Brandes JW, Leonhardt H, Ewe K. Feasibility and effectiveness of a defined-formula diet regimen in treating active Crohn's disease. European Cooperative Crohn's Disease Study III. Scand J Gastroenterol. 1990;25:235-244.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  O'Brien CJ, Giaffer MH, Cann PA, Holdsworth CD. Elemental diet in steroid-dependent and steroid-refractory Crohn's disease. Am J Gastroenterol. 1991;86:1614-1618.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Okada M, Yao T, Yamamoto T, Takenaka K, Imamura K, Maeda K, Fujita K. Controlled trial comparing an elemental diet with prednisolone in the treatment of active Crohn's disease. Hepatogastroenterology. 1990;37:72-80.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  O'Moráin C, Segal AW, Levi AJ. Elemental diet as primary treatment of acute Crohn's disease: a controlled trial. Br Med J (Clin Res Ed). 1984;288:1859-1862.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 333]  [Cited by in F6Publishing: 346]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
49.  Raouf AH, Hildrey V, Daniel J, Walker RJ, Krasner N, Elias E, Rhodes JM. Enteral feeding as sole treatment for Crohn's disease: controlled trial of whole protein v amino acid based feed and a case study of dietary challenge. Gut. 1991;32:702-707.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 78]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
50.  Rocchio MA, Cha CJ, Haas KF, Randall HT. Use of chemically defined diets in the management of patients with acute inflammatory bowel disease. Am J Surg. 1974;127:469-475.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 54]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
51.  Saverymuttu S, Hodgson HJ, Chadwick VS. Controlled trial comparing prednisolone with an elemental diet plus non-absorbable antibiotics in active Crohn's disease. Gut. 1985;26:994-998.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 113]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
52.  Teahon K, Bjarnason I, Pearson M, Levi AJ. Ten years' experience with an elemental diet in the management of Crohn's disease. Gut. 1990;31:1133-1137.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 113]  [Cited by in F6Publishing: 110]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
53.  Teahon K, Smethurst P, Pearson M, Levi AJ, Bjarnason I. The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease. Gastroenterology. 1991;101:84-89.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Heuschkel RB, Menache CC, Megerian JT, Baird AE. Enteral nutrition and corticosteroids in the treatment of acute Crohn's disease in children. J Pediatr Gastroenterol Nutr. 2000;31:8-15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 304]  [Cited by in F6Publishing: 315]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
55.  Sanderson IR, Boulton P, Menzies I, Walker-Smith JA. Improvement of abnormal lactulose/rhamnose permeability in active Crohn's disease of the small bowel by an elemental diet. Gut. 1987;28:1073-1076.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 133]  [Cited by in F6Publishing: 132]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
56.  Sanderson IR, Udeen S, Davies PS, Savage MO, Walker-Smith JA. Remission induced by an elemental diet in small bowel Crohn's disease. Arch Dis Child. 1987;62:123-127.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 217]  [Cited by in F6Publishing: 191]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
57.  Ruemmele FM, Roy CC, Levy E, Seidman EG. Nutrition as primary therapy in pediatric Crohn's disease: fact or fantasy? J Pediatr. 2000;136:285-291.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 54]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
58.  O'Morain C, O'Sullivan M. Nutritional support in Crohn's disease: current status and future directions. J Gastroenterol. 1995;30 Suppl 8:102-107.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Rigaud D, Cosnes J, Le Quintrec Y, René E, Gendre JP, Mignon M. Controlled trial comparing two types of enteral nutrition in treatment of active Crohn's disease: elemental versus polymeric diet. Gut. 1991;32:1492-1497.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 147]  [Cited by in F6Publishing: 147]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
60.  Royall D, Wolever TM, Jeejeebhoy KN. Evidence for colonic conservation of malabsorbed carbohydrate in short bowel syndrome. Am J Gastroenterol. 1992;87:751-756.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Giaffer MH, North G, Holdsworth CD. Controlled trial of polymeric versus elemental diet in treatment of active Crohn's disease. Lancet. 1990;335:816-819.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 132]  [Cited by in F6Publishing: 125]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
62.  Verma S, Kirkwood B, Brown S, Giaffer MH. Oral nutritional supplementation is effective in the maintenance of remission in Crohn's disease. Dig Liver Dis. 2000;32:769-774.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 73]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
63.  Levine GM, Deren JJ, Steiger E, Zinno R. Role of oral intake in maintenance of gut mass and disaccharide activity. Gastroenterology. 1974;67:975-982.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Weser E, Heller R, Tawil T. Stimulation of mucosal growth in the rat ileum by bile and pancreatic secretions after jejunal resection. Gastroenterology. 1977;73:524-529.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Fell JM, Paintin M, Arnaud-Battandier F, Beattie RM, Hollis A, Kitching P, Donnet-Hughes A, MacDonald TT, Walker-Smith JA. Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn's disease. Aliment Pharmacol Ther. 2000;14:281-289.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 300]  [Cited by in F6Publishing: 267]  [Article Influence: 11.1]  [Reference Citation Analysis (0)]
66.  Souba WW, Smith RJ, Wilmore DW. Glutamine metabolism by the intestinal tract. JPEN J Parenter Enteral Nutr. 1985;9:608-617.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 386]  [Cited by in F6Publishing: 350]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
67.  Windmueller HG, Spaeth AE. Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem. 1974;249:5070-5079.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Higashiguchi T, Hasselgren PO, Wagner K, Fischer JE. Effect of glutamine on protein synthesis in isolated intestinal epithelial cells. JPEN J Parenter Enteral Nutr. 1993;17:307-314.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 72]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
69.  Burke DJ, Alverdy JC, Aoys E, Moss GS. Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg. 1989;124:1396-1399.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 220]  [Cited by in F6Publishing: 229]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
70.  Souba WW, Herskowitz K, Klimberg VS, Salloum RM, Plumley DA, Flynn TC, Copeland EM. The effects of sepsis and endotoxemia on gut glutamine metabolism. Ann Surg. 1990;211:543-549; discussion 543-551;.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 105]  [Cited by in F6Publishing: 113]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
71.  Den Hond E, Hiele M, Peeters M, Ghoos Y, Rutgeerts P. Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn's disease. JPEN J Parenter Enteral Nutr. 1999;23:7-11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 92]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
72.  Akobeng AK, Miller V, Stanton J, Elbadri AM, Thomas AG. Double-blind randomized controlled trial of glutamine-enriched polymeric diet in the treatment of active Crohn's disease. J Pediatr Gastroenterol Nutr. 2000;30:78-84.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 128]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
73.  Jacobs LR, Lupton JR. Effect of dietary fibers on rat large bowel mucosal growth and cell proliferation. Am J Physiol. 1984;246:G378-G385.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Spaeth G, Berg RD, Specian RD, Deitch EA. Food without fiber promotes bacterial translocation from the gut. Surgery. 1990;108:240-246; discussion 246-247;.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Roediger WE, Moore A. Effect of short-chaim fatty acid on sodium absorption in isolated human colon perfused through the vascular bed. Dig Dis Sci. 1981;26:100-106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 127]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
76.  Sakata T. Stimulatory effect of short-chain fatty acids on epithelial cell proliferation in the rat intestine: a possible explanation for trophic effects of fermentable fibre, gut microbes and luminal trophic factors. Br J Nutr. 1987;58:95-103.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 430]  [Cited by in F6Publishing: 433]  [Article Influence: 11.7]  [Reference Citation Analysis (0)]
77.  Roediger WE. The colonic epithelium in ulcerative colitis: an energy-deficiency disease? Lancet. 1980;2:712-715.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 469]  [Cited by in F6Publishing: 436]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
78.  Chapman MA, Grahn MF, Boyle MA, Hutton M, Rogers J, Williams NS. Butyrate oxidation is impaired in the colonic mucosa of sufferers of quiescent ulcerative colitis. Gut. 1994;35:73-76.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 149]  [Cited by in F6Publishing: 169]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
79.  Den Hond E, Hiele M, Evenepoel P, Peeters M, Ghoos Y, Rutgeerts P. In vivo butyrate metabolism and colonic permeability in extensive ulcerative colitis. Gastroenterology. 1998;115:584-590.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 82]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
80.  Simpson EJ, Chapman MA, Dawson J, Berry D, Macdonald IA, Cole A. In vivo measurement of colonic butyrate metabolism in patients with quiescent ulcerative colitis. Gut. 2000;46:73-77.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 54]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
81.  Tappenden KA, Thomson AB, Wild GE, McBurney MI. Short-chain fatty acid-supplemented total parenteral nutrition enhances functional adaptation to intestinal resection in rats. Gastroenterology. 1997;112:792-802.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 104]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
82.  Senagore AJ, MacKeigan JM, Scheider M, Ebrom JS. Short-chain fatty acid enemas: a cost-effective alternative in the treatment of nonspecific proctosigmoiditis. Dis Colon Rectum. 1992;35:923-927.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 72]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
83.  Segain JP, Raingeard de la Blétière D, Bourreille A, Leray V, Gervois N, Rosales C, Ferrier L, Bonnet C, Blottière HM, Galmiche JP. Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease. Gut. 2000;47:397-403.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 886]  [Cited by in F6Publishing: 891]  [Article Influence: 37.1]  [Reference Citation Analysis (0)]
84.  Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992;87:432-437.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Shoda R, Matsueda K, Yamato S, Umeda N. Epidemiologic analysis of Crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. Am J Clin Nutr. 1996;63:741-745.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Vilaseca J, Salas A, Guarner F, Rodríguez R, Martínez M, Malagelada JR. Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis. Gut. 1990;31:539-544.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 140]  [Cited by in F6Publishing: 149]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
87.  Campos FG, Waitzberg DL, Habr-Gama A, Logullo AF, Noronha IL, Jancar S, Torrinhas RS, Fürst P. Impact of parenteral n-3 fatty acids on experimental acute colitis. Br J Nutr. 2002;87 Suppl 1:S83-S88.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 30]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
88.  Loeschke K, Ueberschaer B, Pietsch A, Gruber E, Ewe K, Wiebecke B, Heldwein W, Lorenz R. n-3 fatty acids only delay early relapse of ulcerative colitis in remission. Dig Dis Sci. 1996;41:2087-2094.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 91]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
89.  Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med. 1996;334:1557-1560.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 560]  [Cited by in F6Publishing: 559]  [Article Influence: 20.0]  [Reference Citation Analysis (0)]
90.  Hawthorne AB, Daneshmend TK, Hawkey CJ, Belluzzi A, Everitt SJ, Holmes GK, Malkinson C, Shaheen MZ, Willars JE. Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial. Gut. 1992;33:922-928.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 229]  [Cited by in F6Publishing: 226]  [Article Influence: 7.1]  [Reference Citation Analysis (0)]
91.  Hillier K, Jewell R, Dorrell L, Smith CL. Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease. Gut. 1991;32:1151-1155.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 94]  [Cited by in F6Publishing: 95]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
92.  Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953-12956.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2584]  [Cited by in F6Publishing: 2580]  [Article Influence: 89.0]  [Reference Citation Analysis (0)]
93.  Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997;272:3406-3410.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 842]  [Cited by in F6Publishing: 877]  [Article Influence: 32.5]  [Reference Citation Analysis (0)]
94.  Delerive P, Furman C, Teissier E, Fruchart J, Duriez P, Staels B. Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner. FEBS Lett. 2000;471:34-38.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 154]  [Cited by in F6Publishing: 138]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
95.  Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA. 1997;94:4318-4323.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1627]  [Cited by in F6Publishing: 1587]  [Article Influence: 58.8]  [Reference Citation Analysis (0)]
96.  Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA. 1997;94:4312-4317.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1645]  [Cited by in F6Publishing: 1610]  [Article Influence: 59.6]  [Reference Citation Analysis (0)]
97.  Mansén A, Guardiola-Diaz H, Rafter J, Branting C, Gustafsson JA. Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochem Biophys Res Commun. 1996;222:844-851.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 154]  [Cited by in F6Publishing: 160]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
98.  Desreumaux P, Ernst O, Geboes K, Gambiez L, Berrebi D, Müller-Alouf H, Hafraoui S, Emilie D, Ectors N, Peuchmaur M. Inflammatory alterations in mesenteric adipose tissue in Crohn's disease. Gastroenterology. 1999;117:73-81.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 243]  [Cited by in F6Publishing: 240]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
99.  Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flanigan A, Murthy S, Lazar MA, Wu GD. A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest. 1999;104:383-389.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 597]  [Cited by in F6Publishing: 623]  [Article Influence: 24.9]  [Reference Citation Analysis (0)]
100.  Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W, Glass CK. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA. 1998;95:7614-7619.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 567]  [Cited by in F6Publishing: 586]  [Article Influence: 22.5]  [Reference Citation Analysis (0)]
101.  Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, Delerive P, Fadel A, Chinetti G, Fruchart JC. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature. 1998;393:790-793.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 898]  [Cited by in F6Publishing: 868]  [Article Influence: 33.4]  [Reference Citation Analysis (0)]
102.  Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol. 1999;19:546-551.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 252]  [Cited by in F6Publishing: 251]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
103.  Delerive P, Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, Duriez P, Staels B. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res. 1999;85:394-402.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 345]  [Cited by in F6Publishing: 340]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
104.  Sakai M, Matsushima-Hibiya Y, Nishizawa M, Nishi S. Suppression of rat glutathione transferase P expression by peroxisome proliferators: interaction between Jun and peroxisome proliferator-activated receptor alpha. Cancer Res. 1995;55:5370-5376.  [PubMed]  [DOI]  [Cited in This Article: ]
105.  Zhou YC, Waxman DJ. STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. J Biol Chem. 1999;274:29874-29882.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 63]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
106.  Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P. Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J Exp Med. 2001;193:827-838.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 331]  [Cited by in F6Publishing: 335]  [Article Influence: 14.6]  [Reference Citation Analysis (0)]
107.  Lewis JD, Lichtenstein GR, Stein RB, Deren JJ, Judge TA, Fogt F, Furth EE, Demissie EJ, Hurd LB, Su CG. An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis. Am J Gastroenterol. 2001;96:3323-3328.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Göttlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci USA. 1992;89:4653-4657.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 606]  [Cited by in F6Publishing: 641]  [Article Influence: 20.0]  [Reference Citation Analysis (0)]