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Journal of the American College of Nutrition, Vol. 23, No. 3, 220-226 (2004)
Published by the American College of Nutrition

Original Research

Efficacy of a Transforming Growth Factor ß2 Containing Nutritional Support Formula in a Murine Model of Inflammatory Bowel Disease

Helieh S. Oz, DVM, PhD, Mukunda Ray, MD, PhD, Theresa S. Chen, PhD and Craig J. McClain, MD

Department of Medicine, Section of Gastroenterology/Nutrition, Rush University Medical Center, Chicago, Illinois (H.S.O.), Louisville, Kentucky
Department of Pathology (M.R.), Louisville, Kentucky
Department of Pharmacology/Toxicology (T.S.C., C.J.M.), Louisville, Kentucky
University of Louisville Medical School, VAMC (C.J.M.), Louisville, Kentucky

Address reprint requests to: Helieh S. Oz, DVM, PhD, Assistant Professor of Medicine, Director, Animal Studies Program in Digestive Diseases, Department of Medicine, Section of Gastroenterology/Nutrition Rush University Medical Center, Suite 206, 1725 W Harrison, Chicago, IL 60612. E-mail: helieh_oz{at}rush.edu


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: Dietary, environmental and genetic events may influence host susceptibility to inflammatory bowel diseases (IBD). Transforming growth factor ß2 (TGF-ß2), a multifunctional polypeptide (cytokine) present in human and bovine milk, plays a critical role in the development of tolerance, the prevention of autoimmunity, and in anti-inflammatory responses. TGF-ß2 is a potent inhibitor of intestinal epithelial cell (IEC) growth and stimulates IEC differentiation. The objective of this study was to determine whether a diet containing TGF-ß2 modulates intestinal injury and immune responses in an Interleukin-10 knockout (IL-10–/–) mouse model of IBD.

Methods: Five-week-old IL-10–/– mice (in BALB/c background) reared in our transgenic facility were fed either an enteral diet (Diet-A) containing TGF-ß2 or a control enteral diet (Diet-B) not rich in TGF-ß2. Mice were weighed weekly, monitored for illness and euthanized after eight weeks on the diet.

Results: Final weights were 28 ± 1.2 g (58.2% gain) for Diet-A mice and 23 ± 1.6 g (32.9% gain) for Diet-B mice (p = 0.0194). The hematocrits were 48.3% for Diet-A compared to 42% for Diet-B mice (p = 0.0021). Mice on Diet-A had significantly lower serum TNF-{alpha} concentrations. Forty-four percent of mice on Diet-B developed severe diarrhea and rectal prolapse compared with none on Diet-A. Evaluation of intestinal pathology (score 0–4) revealed that animals fed Diet-A had a score of 2.1 ± 0.4 compared to 3.2 ± 0.36 in the Diet-B group (p = 0.040). The acute phase protein, serum amyloid A (SAA), was 3.8 times higher in the Diet-B group (p = 0.0038).

Conclusions: IL-10–/– mice fed a TGF-ß2 containing diet gained more weight, did not develop diarrhea or prolapse, had lower pathological scores, and lower SAAs. These data further support the use of TGF-ß2 containing enteral diets as one mode of therapy for Crohn’s disease.

Key words: IBD, Crohn’s disease, TGF-ß2, enterocolitis


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
Crohn’s disease is a chronic idiopathic inflammatory disease of the gastrointestinal tract. Major factors such as dietary, environmental and genetic events may lead to host susceptibility to inflammatory bowel diseases (IBD). The current medical management of Crohn’s disease generally consists of anti-inflammatory and immunosuppressive agents. Despite medical intervention, many patients remain refractory. Patients with chronic conditions such as Crohn’s disease commonly use complementary and alternative medicine (CAM) and/or dietary supplements [1–5]. Enteral feeding may induce remission in Crohn’s, but relapse is frequent [6].

Transforming growth factor ß2 (TGF-ß2) is a multifunctional polypeptide that is present in human and bovine milk. TGF-ß2 plays a critical role in the development of tolerance, the prevention of autoimmunity, and in anti-inflammatory responses [7–9]. TGF-ß is a potent inhibitor of intestinal epithelial cell (IEC) growth and stimulates IEC differentiation [10]. Increased intestinal permeability [11–12] and abnormal expression of pro-inflammatory cytokines such as TNF-{alpha}, IL-1 and IFN-{gamma} are key elements in the pathophysiology of Crohn’s disease [13]. TGF-ß2 suppresses IFN-{gamma} and IL-1 at the level of transcription and is considered a critical anti-inflammatory cytokine [14]. Children with active intestinal Crohn’s disease were treated with CT3211 (an oral polymeric diet which is rich in TGF-ß2, Table 1) as the sole source of nutrition for eight weeks. This was associated with mucosal healing and a down-regulation of mucosal pro-inflammatory cytokine mRNA in both the terminal ileum (IL-1 and IFN-{gamma}) and colon (IL-1 and IL-8) [15]. The known anti-inflammatory effects of TGF-ß2 and the beneficial effects of CT3211 in a pilot human IBD study prompted a more controlled and mechanistic evaluation of this product in a well-defined murine model that mimics Crohn’s disease.


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  		Table 1. Diet-A Composition

 
Specifically, we examined whether the enteral formula ModulenTM (rich in TGF-ß2) could attenuate local and systemic inflammation in an animal model of enterocolitis compared to treatment with a standard enteral formula.


   MATERIAL AND METHODS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
ModulenTM was provided by Nestle’ USA (Glendale, CA). All other chemicals were purchased from Sigma Aldrich (St Louis, MO).

Animals
This study was approved and performed in accordance with the guidelines for Institutional Animal Care and Use Committee (IACUC), and the University of Louisville (UL) Research Resource Facility, Louisville, KY, which is certified by the American Association of Accreditation of Laboratory Animal Care.

IL-10 Deficient Mouse Model of IBD
IL-10–/– mice were raised in our transgenic facility under bacteria and pathogen-free conditions in ventilated microisolators with HEPA-filtrated air. Animals were handled in a biosafety cabinet with HEPA-filter and supplied with autoclaved food, water and bedding. Mice were weaned at three weeks of age and at four weeks moved to a conventional animal room and housed in the filter top cages. Cages were seeded with feces from IL-10+/+ (BALB/c) wildtype mice to assure rapid colonization with gut flora, thus provoking intestinal inflammation. The IL-10–/– BALB/c mice develop enterocolitis when exposed to normal gut flora [16]. Animals were divided into two groups of nine mice each.

Group A were fed Diet-A (ModulenTM) and Group B were fed Diet-B (similar enteral diet, but not rich in TGFß2). Mice consumed an average 200 g of diet/kg of body weight per day. The amount of TGF-ß2 in the Diet-A was about 2 µg/g of protein and negligible in the Diet-B. Animals were checked daily for physical appearance, food consumption, consistency of feces, diarrhea or prolapse. Mice were provided with clean diet and water ad libitum. Animals’ weights were recorded weekly. Mice were euthanized after eight weeks on the diets (earlier for severe cases of diarrhea and/or rectal prolapse). Animals were anesthetized by halothane inhalation. Blood was collected via heart puncture for subsequent determinations of antioxidants, cytokines and hematocrit. The liver, spleen, heart, small and large intestine were excised. The small and large intestines were removed and perfused with phosphate buffered saline (PBS), pH 7.4. A small cuff of the proximal and distal colon (within 1 cm from rectum) was cut and fixed in 10% buffered formalin. The rest of the large and a portion of the small intestine (ileum) were dissected, flash frozen in liquid nitrogen, and the tissue stored at –80°C.

Histology
The formalin fixed and paraffin embedded sections were stained with routine hematoxylin and eosin (H & E) and evaluated by standard light microscopy for the presence of lesions in the colon. The severity of colitis was graded and scored semiquantitatively on scale 0–4. All slides were evaluated in a blinded fashion by two of the authors (M. Ray, GI pathologist and H. Oz). The scores were based on histological changes assigning a numeric value (0 to 4) to the specimens based on the following criteria:

0) Normal with no detectable gross lesions. Mucosa appeared normal; no inflammatory cells on microscopy.

1) Few focal inflammatory cells; mononuclear cell inflammatory cells in lamina propria, crypt hyperplasia.

2) Mild inflammation, small multifocal mononuclear infiltrate with few neutrophils and epithelial cell hyperplasia.

3) Moderate inflammation, large multifocal monocytes, neutrophils infiltration, crypt abscess, and epithelial hyperplasia.

4) Severe diffuse infiltration of mononuclear cell, many neutrophils, transmural inflammation, decreased mucin and crypt abscess.

Immunoassays
Serum concentration of amyloid A (SAA) was determined using an enzyme-linked immunosorbent assay (ELISA) according to manufacturer (Cytoscreen M SAA, Biosource, Camarillo, CA), and tumor necrosis factor-{alpha} (TNF-{alpha}), IL-12 (p70), interferon-{gamma} (IFN-{gamma}) were detected with Quantikine M kits (R&D System, Minneapolis, MN).

Tissue and Blood Preparation for Antioxidants
Blood samples were collected in heparinized tubes, and a 20% homogenate in 5% metaphosphoric acid was prepared. After standing for 30 minutes, the homogenate was centrifuged for 10 minutes (10,000 g) and the acid-soluble fraction was collected for measurement of sulfhydryl and disulfide compounds. Tissue homogenates (10%, w/v) were prepared in 5% (w/v) metaphosphoric acid, using all-glass Tenbroeck homogenizers and kept on ice. After standing for 20–40 minutes, the homogenates were centrifuged for one minute (10,000 g) and the acid soluble fractions collected for measurement of free thiol-disulfides.

Glutathione (GSH), other thiols (SH) and disulfides (SS): Reduced GSH, GSH disulfide (GSSG), cysteine and cystine were simultaneously quantified by high performance liquid chromatography with dual electrochemical detection (HPLC-DEC) according to the method of Richie and Lang [17] with slight modification [18].

In brief, 20-µL samples were injected onto a 250 x 4.6 mm, 5 µm, C-18 column (Val-U-Pak HP, fully endcapped ODS, 5 µm, 250 x 4.6 mm; Chrom Tech Inc., Apple Valley, MN). Samples (20 µL) were injected onto the column and eluted isocratically with a mobile phase consisting of 0.1 M monochloroacetic acid, 2 mM heptane sulfonic acid, and 2% acetonitrile at pH 2.8 and delivered at a flow rate of 1 mL/min. The compounds were detected in the eluant with a Bioanalytical Systems model LC4B dual electrochemical detector using two Au-Hg electrodes in series with potentials of –1.2 V and 0.15 V for the upstream and downstream electrodes, respectively. Current (nA) was measured at the downstream electrode. Analytes were quantified from peak area measurements using authentic external standards.

Statistical Analysis
All results are expressed as mean ± SEM unless otherwise stated. Data were evaluated using the Student’s t test or analysis of variance followed by the Tukey-Kramer test using GraphPad Instat Version 3 for Window, GraphPad software, San Diego, CA. Statistical significance was set at p < 0.05.


   RESULTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
Final weights were 28 ± 1.2 g (58.2% gain) for Diet-A mice and 23 ± 1.6 g (32.9% gain) for Diet-B mice (p = 0.0194). Fig. 1 shows the weight gain/loss over time in these animals. About 44% of animals on Diet-B developed severe diarrhea and or prolapse compared to none in Diet-A. The hematocrit was significantly higher in Diet-A animals compared to Diet-B mice (48.3% and 42%, respectively) (p = 0.0021). Mice on Diet-B had significantly higher (p = 0.040) pathological scores compared to Diet-A (Diet-A 2.1 ± 0.4 compared to 3.2 ± 0.36 in Diet B). Fig. 2 shows representative histological sections stained with H & E demonstrating severity of colon lesions in Diet-B compared to Diet-A, with greater inflammation in the Diet-B group. The acute phase protein, serum amyloid A (SAA) was 3.8 times higher for mice on Diet-B compared to those on Diet-A, thus documenting the systemic anti-inflammatory effects of the diet (p = 0.0038). Serum IL-12 and IFN-{gamma} were numerically decreased with the TGF-ß2 containing diet, but the differences did not reach statistical significance. Serum TNF-{alpha} (Fig. 3) was significantly lower for mice on Diet-A compared to Diet-B, (p = 0.0387). No differences were noted in the major antioxidant GSH (blood or intestine) or in cysteine (intestine) concentrations in the two animal groups (Table 2).



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  		Fig. 1. Average Body weight (gram) for the mice on Diet-A compared to Diet-B (mean ± SEM).

 


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  		Fig. 2. Representative colon sections from animals on Diet-A and Diet-B stained with hematoxylin and eosin (H & E) showing mild inflammatory cell infiltration in animals on Diet-A compared to severe transmural inflammatory cell infiltrate with desquamated epithelial cells and ulcer formation in colon in animals on Diet-B.

 


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  		Fig. 3. Average serum concentration of cytokines, TNF-{alpha}, IL-12 p70 and IFN-{gamma} in Diet-A compared to Diet-B mice (mean ± SEM).

 

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  		Table 2. Effect of Diet-A and Diet-B on the Body Weight, Serum Amyloid A (SAA), Colon and Blood Antioxidants (GSH) and CYSH (GSH Precursor)

 

   DISCUSSION
 
Malnutrition is a frequent complication of inflammatory bowel disease, especially Crohn’s disease [19]. The etiologies of malnutrition are diverse and include decreased nutrition intake, malabsorption, excessive losses, increased requirements and iatrogenic factors. Enteral nutritional support has been extensively used in Crohn’s disease in an attempt to improve nutritional status and to attenuate disease activity. There are studies demonstrating the efficacy of enteral nutritional support in improving nutritional status, especially in children with growth retardation [20–24]. Indeed, one of the documented benefits of enteral nutritional support is improvement in growth retardation in children with Crohn’s disease [20]. Data concerning efficacy of enteral nutritional support in attenuating disease activity are more disparate. Studies in adults suggest that enteral support is helpful but not as effective as steroids in inducing remission [25]. On the other hand, a recent meta-analysis of enteral nutritional support in children suggests that enteral nutrition is just as efficacious as steroids in remission induction [26]. Problems in evaluating many of these studies relate to product compliance, different types of products utilized and the study end points. A recent study by Fell and co-workers [15] used this enteral solution rich in TGF-ß2 to treat 29 consecutive children with active intestinal Crohn’s disease. The product, CT3211, was used as the sole source of nutrition. Patients were assessed clinically, endoscopically, and cytokine measurements were made in both the blood and intestinal tissue. At eight weeks, 79% of children were in complete remission. There was a significant decrease in serum TNF-{alpha} levels and in the intestinal pro-inflammatory cytokines. Furthermore, over a 10-month follow-up, there was only a 39% relapse rate in those who had achieved clinical remission. This was an open-label, non-randomized study, however; controlled followed up studies are required.

TGF-ß is necessary for the maintenance of normal immune regulation [7–9]. Indeed TGF-ß was first described as the most potent endogenous immunosuppressive factor (similar to cyclosporin) in the immune system [27]. Under physiological conditions, this cytokine enhances immune defense mechanisms by preventing destruction of the intestinal mucosa. TGF-ß is important in immune tolerance. TGF-ß is involved in reducing T cells apoptosis, therefore generating long-term memory T cells [9]. TGF-ß suppresses certain inflammatory cytokines such as IFN-{gamma} and IL-1 at level of transcription and is considered a critical anti-inflammatory cytokine [14].

Under physiological conditions, there is a constant stimulation and interaction of antigens with immune cells and maintenance of homeostasis between the pro- and anti-inflammatory factors in the gastrointestinal tract. In Crohn’s disease there is abnormal biological activity of cytokines present in the intestinal mucosa, which is postulated to lead to many of the metabolic abnormalities and intestinal injury [13]. Deficiency or reduced activity of suppressive cytokines such as TGF-ß may be one important factor in Crohn’s pathogenesis [28–29].

The inter-relationship between the anti-inflammatory cytokines TGF-ß and IL-10 has been studied in the regulation of the Th1-mediated inflammation occurring in the trinitrobenzene sulfonic acid (TNBS) model of colitis [30]. Feeding of trinitrophenol-haptenated colonic protein to mice induced CD4+ regulatory T cells that conferred protection from induction of TNBS-colitis, and this protection correlated with cells producing TGF-ß, and not IL-10. Administration of either anti-TGF-ß or anti-IL-10 abolished this protection. Anti-TGF-ß administration prevented TGF-ß secretion, but left IL-10 secretion intact, whereas anti-IL-10 administration prevented both TGF-ß and IL-10 secretion. Thus, it appears that the protective effect of IL-10 is an indirect consequence of its effect on TGF-ß secretion. The investigators conducted adoptive transfer studies and showed that anti-IL-10 administration had no effect on induction of TGF-ß-producing T cells in donor mice. However, it did inhibit their subsequent expansion in recipient mice, probably by regulating the magnitude of the Th-1 T cell response, which would otherwise inhibit the TGF-ß response. Therefore, these studies suggest that TGF-ß production is a primary mechanism of counter Th-1 T cell-mediated mucosal inflammation and that IL-10 appears to be a secondary factor that facilitates TGF-ß production.

Over the past decade many animal models of inflammatory bowel disease have been developed [31]. In this study, we utilized the IL-10–/– mouse model that spontaneously develops intestinal inflammation that is discontinuous, transmural and involves both large and small intestine (analogous to Crohn’s disease). It is characterized by dysregulated and uncontrolled production of pro-inflammatory cytokines. IL-10 is an essential anti-inflammatory cytokine that suppresses production of multiple inflammatory cytokines by macrophages, T-cells, dendritic cells and natural killer cells. IL-10–/– mice require normal enteric flora to trigger the intestinal inflammatory response, with animals raised under germ-free conditions being protected from intestinal disease. This is consistent with the concept that human inflammatory bowel disease occurs in a genetically susceptible host because of dysregulated immune response to gut-derived antigens.

Our studies evaluated the clinical, histological and biochemical response to consumption of an enteral diet containing TGF-ß2. Clinically, mice on the Diet-A (rich in TGF-ß2) had no diarrhea, rectal prolapse or GI bleeding in contrast to mice on Diet-B. Mice on Diet-A also had significantly better weight gain and higher hematocrits (the average hematocrit for the BALB/C background mice is about 47–50%). However, Diet-A did not alter GSH status. In general, IL-10–/– mice with more disease activity had poor weight gain and greater disease activity associated with more bleeding from GI. Thus, Diet-A significantly improved the clinical parameters evaluated. Moreover, mice receiving Diet-A had significantly improved pathology scores compared to mice on Diet-B (2.01 ± 0.4 vs. 3.2 + 0.36). Lastly, mice receiving Diet-A had significantly lower serum amyloid A levels (an indicator of systemic inflammation) and significantly lower serum TNF concentrations. Thus, Diet-A not only decreased intestinal injury but also decreased markers of systemic inflammation and cytokine production.

A theoretical concern with a diet rich in TGF-ß is the potential risk for intestinal fibrosis. As well as having anti-inflammatory activities, TGF-ß2 plays a well-documented role in fibrosis [7]. Therefore, it is possible that diets rich in TGF-ß2 could potentially enhance stricture formation in inflammatory bowel disease. This was clearly not the situation in this animal model. Indeed, animals receiving Diet-A had visually and microscopically much less disease than those receiving Diet-B, with no evidence of stricture formation. In this situation, it appears that the anti-inflammatory effects of TGF-ß2 dominated over fibrotic effects. Analogous situations are described in other animal model systems. For example, a single intramuscular injection of plasmid DNA encoding TGF-ß1 in animals developing granulomatous hepatitis caused a paradoxically marked decrease in liver fibrosis [32]. This unexpected decrease in fibrosis caused by high circulating TGF-ß appeared to be due to decrease in hepatic inflammation, pro-inflammatory cytokines (TNF-{alpha}, IL-1ß, INF-{gamma}) CXC and CC chemokine production.

This study does not define conclusively whether it is the TGF-ß2 or some other salutary effect of Diet-A that induces beneficial effects in human and in this experimental animal model of IBD. In our model system, it would have been necessary to use neutralizing TGF-ß2 antibodies to unequivocally answer that question, and this would have been prohibitively expensive in a long-term animal feeding study.


   CONCLUSIONS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 CONCLUSIONS
ACKNOWLEDGMENTS
 REFERENCES
 
IL-10–/– mice maintained on a TGF-ß2-containing diet (Diet-A) gained more weight, did not develop prolapse or diarrhea, had lower pathological scores, and lower SAA concentrations. Moreover, no intestinal stricturing or fibrosis was seen in the mice fed the TGF-ß2 containing diet. The TGF-ß2 containing diets may be of clinical benefit in Crohn’s disease management. This study provides the scientific rationale for further human studies.


   ACKNOWLEDGMENTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 CONCLUSIONS
 ACKNOWLEDGMENTS
REFERENCES
 
ModulenTM was provided by Nestle’ USA. Dr. DM Rennick provided the IL-10 deficient mouse-breeding colony. We appreciate the nutritional input from Laura Czerkies, consulting dietitian.


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
This research was supported by the National Institutes of Health grants AA01762, AA10496, Jewish Hospital Foundation and the Department of Veterans Affairs and an unrestricted educational gift from Nestle’ USA.

Received April 11, 2003. Accepted November 20, 2003.


   REFERENCES
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 

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