Intestinal responsiveness to experimental colitis in young rats is altered by maternal diet
Kevan Jacobson,1
Harmeet Mundra,2 and
Sheila M. Innis2
1Divisions of Gastroenterology and 2Neonatology, Department of Pediatrics and Nutrition Research Program, British Columbia Institute for Children's and Women's Health, University of British Columbia, Vancouver, British Columbia, Canada
Submitted 13 October 2004
; accepted in final form 17 February 2005
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ABSTRACT
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Increasing evidence suggests that fetal and neonatal nutrition impacts later health. Aims of the present study were to determine the effect of maternal dietary fat composition on intestinal phospholipid fatty acids and responsiveness to experimental colitis in suckling rat pups. Female rats were fed isocaloric diets varying only in fat composition throughout gestation and lactation. The oils used were high (8%) in n-3 [canola oil (18:3n-3)], n-6 (72%) [safflower oil (18:2n-6)], or n-9 (78%) [high oleic acid safflower oil (18:1n-9)] fatty acids, n = 6/group. Colitis was induced on postnatal day 15 by intrarectal 2,4-dinitrobenzene sulfonic acid (DNBS) administration with vehicle (50% ethanol) and procedure (0.9% saline) controls. Jejunal and colonic phospholipids and milk fatty acids were determined. The distal colon was assessed for macroscopic damage, histology, and MPO activity. The 18:2n-6 maternal diet increased n-6 fatty acids, whereas the 18:3n-3 diet increased n-3 fatty acids in milk and pup jejunal and colonic phospholipids. Maternal diet, milk, and pup intestinal n-6-to-n-3 fatty acid ratios increased significantly in order: high 18:3n-3 < high 18:1n-9 < high 18:2n-6. DNBS administration in pups in the high 18:2n-6 group led to severe colitis with higher colonic damage scores and MPO activity than in the 18:1n-9 and 18:3n-3 groups. High maternal dietary 18:3n-3 intake was associated with colonic damage scores and MPO activity, which were not significantly different from ethanol controls. We demonstrate that maternal dietary fat influences the composition of intestinal lipids and responsiveness to experimental colitis in nursing offspring.
maternal diet; lipids; suckling pups; inflammatory bowel disease
INFLAMMATORY BOWEL DISEASE (IBD), which includes ulcerative colitis and Crohn's disease, are chronic recurrent intestinal inflammatory disorders of unknown etiology that are characterized by frequent remissions and exacerbation of disease. Incidence of IBD is increasing worldwide, with the highest prevalence rates observed in economically developed countries and in younger age groups (3, 14, 32, 39). The mechanisms responsible for the increase in IBD and for the increasing prevalence in Western countries are unknown; however, a multifactorial basis, including genetic susceptibility and environmental factors, is considered likely (20). Diet and particularly dietary fat is a major modifiable environmental factor known to influence susceptibility to a variety of diseases. The n-6 fatty acid, linoleic acid (18:2n-6), which is the metabolic precursor for synthesis of a range of biologically active compounds (eicosanoids) may be involved, because 18:2n-6 consumption has increased over the last half-century in many Westernized countries (9, 43).
Several studies have begun to examine the effects of dietary fat on the prevalence of IBD (6, 12), and among the Japanese, an increased incidence of Crohn's disease has occurred in association with an increased intake of 18:2n-6 and a relative decrease in intake of the n-3
-linolenic acid (canola oil; 18:3n-3) (42). Consistent with this, the low incidence of IBD among the Inuit has been attributed to their habitual high intake of n-3 fatty acids, particularly eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) from marine foods (6). High dietary intakes of n-3 fatty acids have also shown therapeutic benefit in experimental models of colitis (1, 36, 37, 49) and in several clinical studies including patients with ulcerative colitis and Crohn's disease (4, 7, 18, 45). The absence of significant therapeutic efficacy in some clinical trials of n-3 fatty acids in patients with IBD (31, 33) may be explained by differences in study design, patient selection, and the formulation, dose, and duration of n-3 fatty acids (6).
The preventative and therapeutic efficacy of n-3 fatty acids, however, is believed to involve both the reduction in cell membrane arachidonic acid (20:4n-6) and partial replacement of 20:4n-6 with 20:5n-3 and 22:6n-3 (11). Numerous studies have shown that changes in membrane phospholipid fatty acids affect cell membrane properties including the activity of membrane associated enzymes, ion channels, signal transduction pathways, and synthesis of 20:4n-6- and 20:5n-3-derived eicosanoids (11, 25). In addition, convincing evidence has been published to show that the n-6 and n-3 fatty acid composition of the diet during development influences the composition of membrane phospholipid fatty acids of blood cells, the liver, heart, and brain (10, 23).
It is also known that the composition of maternal dietary fat greatly influences the fatty acid composition of milk (24, 29). Maternal diets high in 20:5n-3 and 22:6n-3 are associated with high levels of 20:5n-3 and 22:6n-3 in milk, whereas diets high in n-6 fatty acids are associated with high levels of n-6 fatty acids (19, 26). Furthermore, the composition of fat fed to animals after weaning influences intestinal membrane phospholipid fatty acids, intestinal transport processes, and possibly early response genes (38, 4648). Despite this, the effect of the fat composition of the milk diet on the developing intestine has received little attention. In the present study, we sought to establish whether the composition of maternal dietary fat during gestation and lactation has functional significance with respect to development of the intestine in the nursing offspring. To the best of our knowledge, this is the first report to demonstrate that the composition of milk fatty acids influences the nursing offspring's susceptibility to chemically induced colitis.
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MATERIALS AND METHODS
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Animals and diets.
Female Sprague-Dawley rats (175200 g) obtained from Charles River laboratories (Wilmington, MA) were housed individually in a temperature-controlled animal facility with a 12:12-h light-dark cycle. Two weeks before mating, rats were randomly assigned to one of three semisynthetic isocaloric diets (n = 6/group) with 40% energy (by weight) as fat (21). The diets differed in unsaturated fatty acids, oleic acid (18:1n-9), 18:2n-6, and 18:3n-3 but not in total fat or macro- or micronutrients. Fat was provided as canola oil high in 18:3n-3, safflower oil high in 18:1n-9, or safflower oil high in 18:2n-6 (Table 1). Each litter was reduced to 10 pups/dam within 24 h of birth. Studies on the nursing pups were conducted on postnatal day 15, at which time no food other than the mother's milk had been consumed. All protocols were approved by the University of British Columbia Committee on Animal Care Ethics Committee.
Tissue preparation and lipid analysis.
On postnatal day 15, the rat pups were anesthetized with isoflurane and killed by cervical dislocation. The small intestine from the level of Treitz ligament to an area just proximal to the ileocecal valve and the large intestine from the cecum to distal rectum were excised and removed. The jejunum (proximal one-third of the small intestinal resection) and the large intestine were rinsed with ice-cold PBS; samples for lipid analysis within a litter were then pooled, frozen in liquid nitrogen, and stored at 70°C until they were analyzed. The respective pooled tissues were homogenized in their entirety, total lipids were extracted, and phospholipid classes were separated by HPLC by using a quaternary solvent system (22). Fatty acids in the recovered phospholipids were converted to their respective methyl esters and separated and quantified by gas liquid chromatography (GLC) (22, 23). Rat milk was collected on postnatal day 12, after the intraperitoneal administration of 0.4 ml oxytocin (10 IE/ml), and the fatty acid composition of rat milk was determined by GLC after direct esterification to prevent loss of more water-soluble medium-chain fatty acids (23).
2,4-Dinitrobenzene sulfonic acid-induced colitis.
On postnatal day 15, pups from each litter were randomly assigned (n = 6/group) to receive 2,4-dinitrobenzene sulfonic acid (DNBS), the vehicle control (50% ethanol), or a procedure control (0.9% saline). DNBS (100 µl of 30 mg/ml 50% ethanol), or an equivalent volume of ethanol or saline was instilled via a polyethylene tube (PE-90; 1.27 OD) inserted 1 cm proximal to the anus (35). Pups were kept in the Trendelenburg position (head down) for 1 min and then placed back in their cages. Twelve hours later, the pups were sedated with isoflurane and killed by cervical dislocation. The inflammatory response was assessed in the distal colon using a macroscopic damage score, a histology score, and through assay of MPO activity.
Macroscopic damage score.
Colonic tissue was excised, cut along the mesenteric border, opened lengthwise, and rinsed with PBS. Two observers blinded to the treatment assigned a macroscopic damage score based on criteria outlined in detail previously (2). Briefly, the damage score consisted of a score for severity and extent of ulceration (010), summed with scores for the absence or presence of diarrhea (0 or 1; diarrhea being defined as loose or watery stool) and adhesions (0, 1, or 2), and the maximum thickness of the wall of the colon (in millimeters). A mean macroscopic damage score and mean ± SE was calculated for each group of mice with <10% scoring variability between observers.
MPO activity.
The colon was excised, and a colonic segment (0.5 cm) was taken from the proximal margin of the maximum macroscopic damage site. A corresponding site was obtained from control animals. MPO activity was assayed (8) as a marker of inflammation (44) within 7 days of tissue collection. MPO activity was defined as the amount of enzyme able to convert 1 µmol H2O2 to H2O/min at 25°C, and was expressed as units per microgram of tissue.
Histological damage score.
The colon was excised, and a colonic segment (0.5 cm) was taken from the proximal margin of the site used for the assessment of MPO activity. A corresponding site was obtained from control animals. The segments of colon were then fixed in 10% neutral buffered formalin for 24 h before routine paraffin sectioning and staining with hematoxylin and eosin. Samples were coded and randomly ordered to prevent observer bias. Tissue cross sections were examined under a Nikon Eclipse E400 light microscope by two independent blinded observers and given a histological damage score using criteria adapted from Galeazzi et al., (16). Briefly, the histological damage score consisted of loss of mucosal architecture (graded 03, for absent, mild to severe), the extent of inflammatory cell infiltrate (graded 03, for absent to transmural), and the presence or absence of epithelialitis and crypt abscess formation (01) and goblet cell depletion (01). In each case, a numerical score was assigned. Three tissue sections from each animal (each separated by at least 500 µm) were assessed by two observers blinded to the treatment and averaged to obtain a mean histological damage score for each group with <5% scoring variability between observers.
Statistical analysis.
The effects of diet and DNBS treatment were analyzed by ANOVA followed by post hoc comparisons using the Tukey's honestly significant difference test to determine significant difference among the means, with the level of statistical significance set at P < 0.05. Results within each litter were pooled, and each litter was considered as n = 1, 10 pups/dam, with n = 6 litters per diet group. All of the statistical procedures were performed using a Statistical Package for the Social Sciences (version 12; SPSS, Chicago, IL). Results shown are expressed as means ± SE.
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RESULTS
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Rat milk fatty acids.
Rats fed the high 18:2n-6 (safflower oil) diet produced milk containing significantly higher 18:2n-6 and 20:4n-6 than rats fed the diets either high 18:1n-9 (high oleic safflower oil) or 18:3n-3 (canola oil) (P < 0.05, Table 2). Rats fed the diet with high 18:3n-3 produced milk with significantly higher 18:3n-3, 20:5n-3, and 22:6n-3 and a significantly lower 18:2n-6-to-18:3n-3 and 20:4n-6-to-20:5n-3 ratio than rats fed the other diets (P < 0.05, Table 2). The differences in the total n-6-to-n-3 fatty acid ratio among the dietary oils were clearly reflected in the difference in the milk, with a significant increase in the n-6-to-n-3 fatty acid ratio among the groups in order: high 18:3n-3 < high 18:1n-9 < high 18:2n-6 (P < 0.05, Table 2).
At 15 days of age, pups in the high 18:2n-6 group had a significantly higher body weight (30.4 ± 0.7 g) than pups in the high 18:1n-9 (22.2 ± 0.4 g) or high 18:3n-3 group (23.5 ± 0.3 g), P < 0.05. There were no statistically significant changes in body weight among the groups after DNBS, ethanol, or saline administration.
Jejunal and colonic phospholipid fatty acids.
Pups in the high 18:2n-6 group had significantly higher 18:2n-6 in their colon phosphatidylcholine (PC) and phosphatidylethanolamine (PE) than pups in the high 18:1n-9 or high 18:3n-3 groups (P < 0.05; Tables 3 and 4). Despite the high 18:2n-6 in milk, the amounts of 20:4n-6 in the colon and jejunal PC and PE were not significantly different among the groups. However, pups in the high 183n:3 group had significantly higher n-3 fatty acids (18:3n-3, 20:5n-3, 22:5n-3, and 22:6n-3) in jejunal and colonic PC and PE than pups in the 18:2n-6 group (P < 0.05, Tables 3 and 4). Of note, the high 18:1n-9 diet, which was low in both 18:2n-6 and 18:3n-3, also resulted in significantly higher 22:6n-3 in the pups' jejunal and colonic PC and PE than in pups in the high 18:2n-6 group. The differences in fatty acid intake from milk were reflected in significantly different 18:2n-6-to-18:3n-3 and 20:4n-6-to-20:5n-3 ratios in the pup intestinal lipids, with consistently lower 18:2n-6-to-18:3n-3 and 20:4n-6-to-20:5n-3 ratios in the jejunal and colon PC and PE of pups in the high 18:3n-3 groups than in the high 18:1n-9 or high 18:2n-6 groups (Tables 3 and 4). As in the diet and milk fat, the n-6-to-n-3 fatty acid ratio in jejunal and colon PC and PE were significantly higher among the groups [in order: high 18:3n-3 < high 18:1n-9 < high 18:2n-6 (P < 0.05, Tables 3 and 4)].
Macroscopic damage score.
Intrarectal administration of DNBS resulted in macroscopic damage associated with diarrhea, shortening and thickening of the colon, and mucosal ulceration (Fig. 1). At 12 h postintrarectal administration of DNBS, macroscopic damage was most marked in pups in the high 18:2n-6 group (P < 0.05, Figs. 1 and 2). Pups in the high 18:2n-6 and high 18:1n-9 group had a 1.6- and 1.76-fold higher damage score, respectively, in response to DNBS than the respective ethanol control (P < 0.05, Fig. 2). In contrast, DNBS treatment in pups in the high 18:3n-3 group had a macroscopic damage score that was not significantly different from their ethanol control group (Figs. 1 and 2). Pups in all diet groups given ethanol had significantly higher macroscopic damage scores compared with those given saline (P < 0.05, Fig. 2).

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Fig. 1. Macroscopic appearance of the colon from pups in the high 18:2n-6 (A) and high 18:3n-3 (B) groups on postnatal day 15, 12 h after intrarectal administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Note the macroscopic damage with shortening and thickening of the colon from a pup suckled by a rat fed high 18:2n-6 compared with the normal-appearing colon of a rat pup that was suckled by a rat fed high 18:3n-3.
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Histological damage score.
Pups in the high 18:2n-6 group had a significantly higher histological damage score after DNBS administration than pups in the high 18:1n-9 or high 18:3n-3 group (P < 0.05, Figs. 3 and 4). Focal epithelial ulceration becoming confluent with superficial fibrinoid necrosis, goblet cell depletion, submucosal hemorrhage, and transmural inflammation with acute and chronic inflammatory cells was found in pups in the high 18:2n-6 group. In contrast, pups in the high 18:1n-9 and high 18:3n-3 diet groups treated with DNBS had histological damage scores that were not significantly different from their respective ethanol controls (Fig. 4). As for the macroscopic damage score, the histological damage scores were higher than respective saline-treated controls (Fig. 4). Pups in the high 18:1n-9 group treated with DNBS had focal epithelial ulceration, submucosal hemorrhage, and a milder infiltrate of acute and chronic inflammatory cells than that observed in the high 18:2n-6 diet group that was limited to the mucosa and submucosa (Figs. 3 and 4). Whereas pups in the high 18:3n-3 diet group given DNBS had an intact epithelium and a slight increase in mononuclear cells in the lamina propria with some extension into the submucosa, with no neutrophils evident (Figs. 3 and 4).

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Fig. 3. Histological appearance of colonic tissue sections (hematoxylin and eosin staining) from pups 12 h postintrarectal administration of DNBS in pups in the high 18:3n-3 (A), high 18:1n-9 (B), or 18:2n-6 (C) groups. The bar represents 50 µm. Note the loss of architecture, epithelial ulceration, goblet cell depletion, and inflammation with acute and chronic inflammatory cells in a representative pup in the high 18:2n-6 group (C). A milder degree of epithelial injury with focal ulceration, and a milder infiltrate of acute and chronic inflammatory cells were present in pups in the high 18:1n-9 (B). Pups in the high 18:3n-3 group (A) showed an intact epithelium and only a slight increase in mononuclear cells.
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MPO activity.
Consistent with the macroscopic damage and histological changes, intrarectal DNBS was associated with significantly higher MPO activity in pups in the high 18:2n-6 group than in pups in the high 18:1n-9 or high 18:3n-3 group (P < 0.05; Fig. 5). MPO activity was also significantly higher in the ethanol-treated pups in the high 18:2n-6 group compared with the high 18:1n-9 and high 18:3n-3 groups (P < 0.05, Fig. 5). Pups in the high 18:1n-9 or high 18:3n-3 diet groups treated with intrarectal DNBS, in contrast, had MPO activity that was not significantly different from their respective ethanol controls (Fig. 5). MPO activity in pups in the high 18:1n-9 group given intrarectal DNBS or ethanol was not significantly different from the activity in pups in the high 18:3n-3 group given the same treatment (Fig. 5). In keeping with previous studies (27), MPO activity in ethanol control pups was significantly different from that observed in saline control pups (P < 0.05, Fig. 5).
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DISCUSSION
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This study used a tightly controlled experimental design with the composition of dietary fat as the only variable, and to our knowledge, provides the first demonstration that maternal dietary fat influences the offspring's responsiveness to experimental colitis. We fed semisynthetic diets that differed in unsaturated, but not saturated fatty acids, with 40% energy from canola oil (8% 18:3n-3), high oleic safflower oil (78% 18:1n-9), or high linoleic safflower oil (72% 18:2n-6). Canola oil and high 18:1n-9 safflower oil were both high in 18:1n-9 and relatively low in 18:2n-6, but differed considerably in 18:3n-3 and in the 18:2n-6-to-18:3n-3 ratio (Refs. 3 and 65, respectively). The high 18:2n-6 safflower oil, on the other hand, was high in 18:2n-6 and low in 18:3n-3 and 18:1n-9 and consequently had a considerably higher 18:2n-6-to-18:3n-3 ratio (360) than the other two dietary oils. Consistent with clinical studies in lactating women (24, 26), the maternal rat diet high in 18:2n-6 resulted in secretion of large amounts of 18:2n-6 in milk, while the diet high in 18:3n-3, on the other hand resulted in higher milk levels of n-3 fatty acids and lower 18:2n-6-to-18:3n-3 and 20:4n-6-to-20:5n-3 ratios.
Our study paradigm allowed us to establish that the maternal diet and consequently the milk diet with n-6 and n-3 fatty acids had marked effects on the developing jejunum and colonic phospholipid fatty acids. However, some differences were found in the responses of the colon and jejunum. For example, the maternal diet high in 18:2n-6 resulted in significantly higher 18:2n-6 in colon but not jejunum PC and PE fatty acids. Possibly this is explained by the higher levels of 18:2n-6 in the jejunum compared with the colon. Clearly evident from our study is that differences in the dietary n-6-to-n-3 fatty acid balance were maintained and transferred through the maternal milk to both the small and large intestinal phospholipids of the developing offspring. The high intake of n-6 fatty acids from milk was not associated with a significant increase in 20:4n-6 in the pup jejunal and colonic PC and PE, but did result in a marked increase in 22:4n-6 and 22:5n-6 in the pup jejunal and colonic PE, although 22:4n-6 and 22:6n-5 were not found in significant amounts in the rat milk. This is reasonably explained by increased desaturation and elongation of n-6 fatty acids in the pups in response to the low n-3 fatty acid supply in the high 18:2n-6 safflower oil group (25).
While the effects of maternal diet, and consequently the milk, were examined on suckling pups, the study did not explore the gestational effects of the maternal diet. Further studies are underway to specifically examine the gestational contribution of the maternal diet.
In keeping with previous observations, the higher weight gain observed in pups suckling from mothers consuming the high 18:2n-6 safflower oil diet was likely due to n-6 fatty acid promotion of adipogenesis during gestation and lactation (13, 34). No evidence of undernutrition was observed in the other two diets groups where the pups had normal healthy appearing coats and no differences in intestinal wall thickness or histology.
A major contribution of our study is the demonstration that maternal dietary fat also modulated the intestinal inflammatory response to chemically induced colitis in offspring not exposed to any diet other than the mother's milk. The DNBS colitis model was chosen because of the rapidity of onset of colitis after intrarectal administration. In addition, the pups were examined 12 h postinstillation of DNBS so as to eliminate the potential confounding effects of reduced suckling associated with colitis and to prevent maternal killing of sick pups. Pups in the high 18:2n-6 diet group demonstrated an exaggerated inflammatory response associated with severe macroscopic and histological damage and elevated MPO activity. In contrast, the diet high in 18:3n-3 and with a low n-6-to-n-3 fatty acid ratio prevented colonic infiltration of neutrophils and abrogated the inflammatory response such that macroscopic and histological damage scores and MPO activity were not different from ethanol-treated control animals. The maternal diet high in 18:1n-9, on the other hand, resulted in macroscopic damage and a histological appearance between that found in the high 18:2n-6 and high 18:3n-3 groups. We interpret these findings to suggest an association between the dietary n-6-to-n-3 fatty acid ratio and consequently, the n-6-to-n-3 fatty acid ratio in colonic phospholipids and the inflammatory response to the colonic insult. However, the absence of differences in the colonic PC and PE 20:4n-6 between pups in the high 18:2n-6 and 18:3n-3 groups suggests that the enhanced susceptibility to chemically induced colitis may involve the significant increase in colonic 18:2n-6 or reduced levels of long-chain n-3 fatty acids, and consequently the high n-6/n-3 fatty acid balance.
Experimental and clinical studies have shown that dietary n-3 fatty acids decrease membrane lipid 20:4n-6 with partial replacement with n-3 fatty acids, which result in decreased synthesis of 20:4n-6-derived eicosanoids and increased synthesis of eicosanoids derived from 20:5n-3 (11, 17, 28, 40). In our study, the colonic 20:5n-3 was significantly higher in pups in the high 18:3n-3 group, while 22:6n-3 was significantly higher in pups in both the high 18:3n-3 and 18:1n-9 groups than in the 18:2n-6 group. Of relevance, 22:6n-3 has recently been shown to be the precursor for 17s-resolvins that have anti-inflammatory properties (41). Possibly, the higher colonic n-3 fatty acids 20:5n-3 and 22:6n-3 abrogated the intestinal inflammatory response, whereas reduced n-3 fatty acids were associated with a potentiation of the inflammatory response.
Intriguingly, 18:3n-3 enrichment of the colonic phospholipids failed to attenuate ethanol-induced colonic damage. Although our study did not address the mechanisms involved in the inflammatory response or the potential different mechanisms involved in ethanol-mediated epithelial injury and in DNBS-induced colitis, it appears that n-3 fatty acids had little effect on the response to the toxic effects of ethanol, but attenuated the inflammatory response associated with the immune-mediated consequences of DNBS. In mature animal models of trinitrobenzene sulfonic acid colitis, the therapeutic effects of n-3 fatty acids have been attributed, at least in part, to suppression of mucosal leukotriene-B4 and prostaglandin E2 production (36, 37).
The effects in our study may reflect direct actions of n-3 fatty acids or may be secondary to suppression of 20:4n-6-derived eicosanoids (17, 36, 37). Consistent with this, the lack of neutrophil infiltration into the colon of pups in the group fed 18:3n-3 suggests that the higher milk and colonic n-3 fatty acids, including 20:5n-3 and 22:6n-3, abrogated the inflammatory response, possibly by attenuating chemotaxis through reduced endothelial cell adherence and directed migration (30). However, others have suggested that n-3 fatty acids may be efficacious in IBD by serving as a free radical scavenger, thereby protecting the mucosa from oxidative cell damage (5, 15).
In conclusion, in the present study, we have demonstrated that maternal dietary fat influences the composition of intestinal phospholipids of the offspring and responsiveness to an inflammatory stimulus. These data support the integral role of maternal diet on the early developmental pattern of the gut; however, further studies are required to determine the durability of these effects. Moreover, such models provide the potential for development of dietary interventions aimed at reducing the risk for development of intestinal inflammatory diseases, such as IBD and eosinophilic gastroenteritis, and exploring the potential for early dietary experience to modify later responsiveness of the intestine to inflammatory insults.
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GRANTS
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This work was supported by a Crohn's Colitis Foundation of Canada Grant (to K. Jacobson) and an unrestricted grant from Mead Johnson to the Nutrition Research Program.
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ACKNOWLEDGMENTS
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K. Jacobson is a CHILD Foundation Clinician Scientist and S. M. Innis is a Michael Smith Foundation for Health Research Scholar. The authors thank Dr. A. B. Thompson for his constructive review of the manuscript.
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FOOTNOTES
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Address for reprint requests and other correspondence: K. Jacobson, Div. of Gastroenterology, BC Children's Hospital, 4480 Oak St., Rm. K4181, Vancouver, BC, Canada V6H 3V4 (e-mail: kjacobson{at}cw.bc.ca)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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