Proglucagon-Derived Peptides in Intestinal Epithelial Proliferation

Proglucagon-derived peptides have been implicated in the control of intestinal mucosal cell division. To investigate the actions of these peptides on intestinal cell proliferation, different doses of enteroglucagon, oxyntomodulin, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) were tested in male Wistar rats maintained on total parenteral nutrition. Crypt cell proliferation was assessed by the analysis of arrested metaphases in microdissected crypts. Enteroglucagon and oxyntomodulin had no effect on intestinal weight or cell proliferation. GLP-1 had a slight effect on stomach and small intestinal weights and on epithelial cell proliferation in the small and large intestines. GLP-2 infusion dose-dependently increased the weights of the stomach, small intestine, colon, and cecum and increased crypt cell proliferation in the small and large intestines of parenterally fed rats. In orally fed animals, GLP-2 increased intestinal weight but had little effect on proliferation. Therefore, of the proglucagon-derived peptides, GLP-2 appears to be a major mediator of intestinal epithelial proliferation.     

Effects of amidated gastrin and glycine-extended gastrin on cell proliferation and crypt fission in parenterally and orally fed rats

BACKGROUND/AIMS: It has been suggested that processing variants of gastrin, such as glycine-extended gastrin (G17-Gly), are enterotrophic to the colon. METHODS: Cell proliferation and crypt branching were studied in total parenteral nutrition (TPN) and orally fed rats after infusion of G17-Gly or gastrin-17. RESULTS: Gastrin produced an increase in the weight of the stomach and small intestine and a marked proliferative action on the proximal small intestine, which diminished distally. No proliferative effects of gastrin were seen in the colon. G17-Gly was associated with a small, but significant, increase in colonic weight but had little effect on cell proliferation, except in the gastric fundus. In the distal colon, G17-Gly was associated with a significant decrease in proliferation. Neither agent affected crypt branching in the small intestine or colon, but both proliferation and branching were significantly decreased by TPN. CONCLUSION: Gastrin was trophic to the stomach and the proximal small intestine but not the colon. G17-Gly had only modest proliferative actions on the intestinal epithelium in this study.     

Effects of urogastrone-epidermal growth factor on intestinal brush border enzymes and mitotic activity.

The wet weight of the stomach, small intestine, caecum, and colon were significantly reduced (p less than 0.001) in intravenously fed rats compared with orally fed controls. Human epidermal growth factor (urogastrone) reversed this atrophy. Detailed analysis of the small intestine showed a similar effect on intestinal crypt cell population, mitoses per crypt, and protein content. Brush border gamma glutamyltransferase and alpha glucosidase activities were reduced by up to 50% throughout the small intestine of the animals fed intravenously. The specific activities (mU/mg protein) were unchanged, as a concomitant decrease in the tissue weight and protein content also occurred. Intestinal brush border enzyme activities in the rats treated with urogastrone-epidermal growth factor were restored to those seen in the orally fed rats except for alpha glucosidase activity in the proximal gut. In addition, the specific activity of gamma glutamyltransferase was highly significantly increased (p less than 0.01) in all regions of the small intestine. Thus, although urogastrone administration prevents the decrease in brush border enzyme activity seen after the removal of luminal nutrition, the response seems to differ depending on the intestinal location, with the specific activities of some enzymes being higher than those seen in orally fed rats. Urogastrone-epidermal growth factor can thus significantly increase the functional ability of the intestine in addition to its trophic effects.     

重组生长激素与谷氨酰胺协同促进短肠大鼠小肠的代偿

目的　研究添加生长激素(rhGH)及谷氨酰胺(Gln)的肠外营养(PN)对短肠大鼠残存小肠代偿的作用及机制。方法　按2×2析因实验方案,将SD大鼠随机分成STD、Gln、rhGH及rhGH+Gln组,建立PN短肠动物模型。PN6d后行小肠黏膜形态学检查,并行细胞增殖核心抗原(PCNA)测定、原位末端标记(TUNEL)染色及胰岛素样生长因子-1(IGF-1)mRNA的Northernb1ot测定。结果　rhGH+Gln组残余小肠黏膜形态学上呈显著代偿表现。析因分析表明,rhGH与Gln间存在协同作用(P＜0.01)。其PCNA表达显著高于rhGH、Gln与STD组,分别为24.95±3.93、19.28±3.25、17.27±3.38与8.37±2.23(P＜0.01);凋亡指数显著降低,分别为5.68±2.07、8.06±2.33、10.00±2.24及22.32±3.84(P＜0.01);小肠IGF-1mRNA表达在rhGH+Gln组显著高于rhGH、Gln及STD组,分别为0.73±0.05、0.62±0.04、0.51±0.04及0.41±0.22(P＜0.05)。结论　rhGH与Gln通过促进肠黏膜上皮细胞增生与抑制其凋亡,协同促进短肠大鼠残存小肠代偿,小肠IGF-1在二者协同作用的发挥中起重要的介导作用。     

Starvation, leptin and epithelial cell proliferation in the gastrointestinal tract of the mouse

BACKGROUND/AIMS: Leptin, the ob/ob gene product, is a recently discovered peptide hormone, secreted by adipocytes, which can act as a satiety factor to regulate food intake. Its levels thus will be related to the presence of food in the lumen of the gut, and food intake is one of the most potent stimuli for intestinal epithelial cell proliferation. Leptin has a variety of other actions and the aim of this study was to see if one of these was to stimulate mucosal growth. METHODS: Three groups of mice were fed ad libitum, starved for 48 h or starved for 48 h and given twice-daily intraperitoneal injections of recombinant leptin (1 microg/g). RESULTS: Starvation led to a 20% decrease in body weight and a similar decrease in the weights of the intestines. Starvation also markedly inhibited intestinal epithelial cell proliferation. Leptin had little effect on the small intestine and did not stimulate proliferation. However, in the hind gut it was associated with small but significant decreases in caecal weight, distal colon mitotic counts (p = 0.036) and in colonic crypt area (approximately 20%, p<0.001). CONCLUSION: Leptin did not stimulate intestinal cell proliferation, however it did have a paradoxical inhibitory action on the caecum and colon.     

Luminal and metabolic regulation of jejunal amino acid absorption in the rat

Studies were carried out to determine the role of luminal amino acids and metabolic balance in in vivo amino acid absorption. Previous in vitro studies have shown that adaptation of amino acid transport is a complex phenomenon. In the first series of experiments, parenterally nourished rats received a 7-day jejunal infusion of either 3% aspartic acid, glutamine, lysine, valine, or mixed amino acids. A single-pass perfusion was performed to determine the effects of infusates on 5 mM valine, aspartic acid, and lysine absorption. Compared with controls receiving luminal saline, prior glutamine infusion increased valine absorption; prior valine, glutamine, and aspartic acid infusion significantly increased aspartic acid absorption; and prior valine and lysine infusion significantly increased lysine absorption. The mixed amino acid solution had no effect. The effects of metabolic balance were examined by comparing fasted rats with parenterally fed and orally fed rats. Within 24 h fasting significantly increased valine and aspartic acid absorption, despite a significant decrease in intestinal mass.     

Indomethacin inhibits cell proliferation and increases cell losses in rat gastrointestinal epithelium

Gastrointestinal cell proliferation was estimated in histological sections of rats treated with low and high doses of parenteral indomethacin for 3 to 60 days. Mitoses were arrested with vincristine and cells in S phase were labeled with tritiated thymidine. Short-term, low-dose treatments reduced the mitotic activity in the oxyntic and small intestinal epithelium, whereas moderate doses restored the mitotic index and high doses increased the proliferative activity and produced epithelial hyperplasia. Long-term, low-dose treatments increased cell proliferation in the small intestine and reduced the number of villous cells. Indomethacin did not affect the proliferative response elicited by refeeding in the oxyntic mucosa, but the simultaneous administration of prostaglandin E₂ analog increased the number of arrested mitoses. The turnover of labeled cells was accelerated by indomethacin, particularly in the small intestine. These findings indicate that prostaglandins are regulators of the cell kinetics of the gastrointestinal epithelium but, at the same time, they disclose the presence of trophic mechanisms that are independent of the synthesis of endogenous prostaglandins.     

Effect of the dietary fibre content of lifelong diet on colonic cellular proliferation in the rat.

The effect of the fibre content of lifelong (18 months) diets on proximal and distal colonic cellular proliferation and short chain fatty acid (SCFA) content was investigated in 40 rats. Rats were fed a low fibre diet (17 g/kg non-starch polysaccharides NSP) or the stock diet (133 g/kg NSP). The higher fibre fed rats had increased caecal and colonic total contents (p < 0.001) and SCFAs than the low fibre fed rats (caecal SCFAs: higher fibre rats 96.4 (6.8) mumol/g wet weight v low fibre 22.7 (3.0): p < 0.001, colonic SCFAs: higher fibre 52.3 (3.1) mumol/g wet weight v low fibre 6.9 (2.2) mumol/g wet weight: p < 0.001). Cellular proliferation was increased in the proximal colon (bromodeoxyuridine labelling index, higher fibre 9.3 v low fibre 8.4 p < 0.05; flow cytometry, % cells in S phase higher fibre diet 7.9 v low fibre 6.9; p < 0.01) and there was a shift of proliferating cells to a higher region in each crypt. There was no significant difference in the percentage of cells in S phase in the distal colon of rats in both diet groups. The proliferative zone, however, was expanded in the distal colon of the higher fibre diet fed rats. This study indicates that long term higher fibre intake in rats is associated with a modest increase in cellular proliferation in the proximal colon but not the distal colon.     

Effects of an elemental diet, inert bulk and different types of dietary fibre on the response of the intestinal epithelium to refeeding in the rat and relationship to plasma gastrin, enteroglucagon, and PYY concentrations.

Refeeding starved rats with an elemental diet resulted in a marked increase in crypt cell production rate (CCPR) in the proximal small intestine but not in the distal regions of the gut. Little effect on CCPR was noted when inert bulk (kaolin) was added to the elemental diet. Addition of a poorly fermentable dietary fibre (purified wood cellulose) had little effect on intestinal epithelial cell proliferation except in the distal colon where it significantly increased CCPR. A more readily fermentable fibre (purified wheat bran) caused a large proliferative response in the proximal, mid, and distal colon and in the distal small intestine. A gel forming fibre only significantly stimulated proliferation in the distal colon; the rats in this group, however, did not eat all the food given. There was no significant correlation between CCPR and plasma gastrin concentrations, but plasma enteroglucagon concentrations were significantly correlated with CCPR in almost all the sites studied. Plasma PYY concentrations also showed some correlation with CCPR, especially in the colon. Thus while inert bulk cannot stimulate colonic epithelial cell proliferation fermentable fibre is capable of stimulating proliferation in the colon, and especially in the distal colon: it can also stimulate proliferation in the distal small intestine and it is likely that plasma enteroglucagon may have a role to play in this process.     

Two-month glucocorticoid treatment increases proliferation in the stomach and large intestine of rats

BACKGROUND/AIMS: It has been shown that acute or short-term treatments with glucocorticoids lead to a marked decrease in proliferation in the stomach and large intestine. The effects of more prolonged glucocorticoid treatment on cell renewal in these organs are not known. The present work was therefore undertaken to examine the proliferative activity in the stomach and colon during 2 months of glucocorticoid treatment in comparison with shorter treatments. METHODS: Rats were treated with either the glucocorticoid triamcinolone acetonide or vehicle for 63, 33 or 3 days. Proliferation was assessed in the glandular epithelium of the fundal part of the stomach and in the epithelium of the colonic crypts using three criteria: the mitotic index; the bromodeoxyuridine labelling index, and the proliferating cell nuclear antigen-labelling index (percentage of mitotic or labelled cells). RESULTS: Treatment with glucocorticoid for 63 days resulted in a very significant increase in all proliferative parameters tested in the gastric mucosa and the colonic crypts. On the contrary, treatments with glucocorticoid for 3 or 33 days had a marked inhibitory influence on proliferation in these tissues. CONCLUSION: As opposed to treatments for 3 or 33 days, glucocorticoid treatment for 2 months leads to an increase in the number of cycling cells in the gastric and colonic mucosae.     

Effect of L-glutamine and n-butyrate on the restitution of rat colonic mucosa after acid induced injury.

BACKGROUND: L-glutamine and n-butyrate are important nutrients for colonocytes affecting both their structure and function. The effect of these epithelial substrates on resealing of rat distal colon after acid induced injury was studied. METHODS: Isolated colonic mucosa of 32 rats was mounted in Ussing chambers and exposed to Krebs-Ringer solution for four hours. Epithelial injury was induced by short-term exposure to luminal hydrochloric acid and resealing was studied with or without added glutamine or butyrate. RESULTS: Glutamine (luminal and serosal) reduced tissue conductance, mannitol and lactulose permeability, and permeation of enteropathogenic Escherichia coli. Glutamine (serosal) diminished conductance and mannitol permeability. Both interventions stimulated bromodeoxyuridine incorporation in nuclei of colonocytes. Luminal butyrate had no measurable effect on these parameters. CONCLUSIONS: These data suggest that L-glutamine stimulates repair mechanisms of rat colonic mucosa after acid injury. This effect on the gut barrier is associated with a stimulation of crypt cell proliferation. The addition of glutamine to parenteral solutions may be beneficial for patients under intensive care whose intestinal barrier is weakened in the course of sepsis and trauma.     

Chronic Lipid Hydroperoxide Stress Suppresses Mucosal Proliferation in Rat Intestine: Potentiation of Ornithine Decarboxylase Activity by Epidermal Growth Factor

We recently demonstrated that chronic exposure of rat intestine to sublethal levels of peroxidized lipids suppresses ornithine decarboxylase (ODC) activity, consistent with attenuated intestinal proliferation. The current study was designed to better understand the influence of exogenous epidermal growth factor (EGF) on intestinal proliferation in normal intestine and intestine that was challenged by oxidative stress induced by dietary consumption of peroxidized lipids. Male Sprague-Dawley rats (250-300 g) were fed standard chow (control) or peroxidized lipid chow for 4 weeks. EGF was injected intraperitoneally at a dose of 40 microg/kg. Intestinal proliferation was evaluated by ODC activity in fed or fasted states and at specified times during the circadian phase. Chronic peroxide consumption significantly attenuated ODC activities in association with increased tissue peroxide content. The suppressed ODC activities were restored to control values by EGF in the small intestine; in the colon, EGF increased ODC activity threefold over control rats given EGF. This elevated colonic ODC activity was correlated with decreased tissue GSSG and an increased GSH/GSSG ratio. These results show that EGF administration reverses the suppression of intestinal ODC activities induced by chronic peroxidized lipid intake. In contrast, EGF significantly elevates proliferative activity in the peroxide-stressed colon. This exaggerated proliferation may contribute to a better understanding of colonic susceptibility to oxidant-induced malignant transformation.     

The maximal activity of phosphate-dependent glutaminase and glutamine metabolism in the colon and the small intestine of streptozotocin-diabetic rats

Summary The effects of short- and long-term diabetes on the maximal activities of phosphate-dependent glutaminase and glutamine metabolism were studied in the colon and the small intestine of streptozotocin-diabetic rats. The maximal activity of colonic phosphate-dependent glutaminase was decreased [44% in mucosal scrapings (p<0.01); 29% in whole colon (p<0.001)] or unchanged in short- or long-term diabetes respectively. That of the small intestine was increased in both short- (110%) and long-term (200%–500%) diabetes; insulin treatment corrected this increase. Acute insulin-deficiency (using anti-insulin serum) resulted in the increase (18%, p<0.05) of the activity of only intestinal glutaminase. Chemically-induced acidosis and alkalosis decreased (46%, p<0.001) and increased (24%, p<0.001), respectively, the activity of intestinal glutaminase, but had no effect on the colonic enzyme. Changes in glutaminase of the enlarged colon and small intestine were only detectable when activities were measured in whole organ. Arteriovenous-difference measurements showed diminished metabolism of plasma glutamine by the gut which correlated with the duration of the state of diabetes, and was accompanied by enhanced release by skeletal muscle and increased uptake by both kidney and liver. It is concluded that insulin is directly or indirectly involved in the regulation of glutamine metabolism of the gut.     

Morphometry and cell proliferation in endoscopic biopsies: evaluation of a technique

A simple method for the quantification of intestinal epithelial cell proliferation in humans was evaluated. Endoscopic biopsy specimens were stained and microdissected, and the number of mitoses per gland or crypt was determined, as was the area of these units. The technique could readily be applied to tissue from the stomach, small intestine colon, and rectum. The number of mitoses and the size of the proliferative compartments increased caudally from the stomach to the cecum in humans. There was a good correlation between area and mitoses per gland or per crypt (r = 0.89; P less than 0.001), confirming the general equivalence between proliferative rate and compartment size. The method was validated by comparing microdissection-derived data with data previously obtained as part of an autoradiography-based study in the dog. This showed that similar differences in proliferation and crypt cell mass could be obtained but in less than one sixth of the time taken to score autoradiographs. It is concluded that this method for the estimation of gastrointestinal epithelial proliferation correlates well with other well-established techniques, confers speed as well as accuracy, has an all encompassing denominator, and can thus avoid many of the problems associated with the quantification of tissue sections.     

Effects of Yersinia enterocolitica infection on rabbit intestinal and colonic goblet cells and mucin: morphometrics, histochemistry, and biochemistry.

The effects of Yersinia enterocolitica on intestinal goblet cells were investigated in New Zealand white rabbits. Animals infected with Y enterocolitica were compared with weight matched and pair fed controls. Goblet cell hyperplasia developed in the distal small intestine of infected rabbits on day 1, in the mid small intestine on day 3, and in the upper small intestine on day 6. In all regions hyperplasia persisted throughout the 14 day study. The degree of hyperplasia was greater in the distal small intestine than the upper and mid regions. Goblet cells in the proximal colon of infected animals seemed to respond as those in the distal small intestine. Thus goblet cell hyperplasia developed more rapidly and to a greater extent in the ileocaecal region where mucosal injury was most severe. These changes resulted directly from Y enterocolitica infection since goblet cell numbers did not increase in pair fed controls. Histochemically, goblet cell mucins from infected rabbits were unchanged at either six or 14 days. Biochemical analysis, however, established that purified mucins from animals on day 6 after infection were less sialylated (in the small intestine) and more sulphated (in the small intestine and proximal colon). In addition, mucins from the distal small intestine and the proximal colon seemed to contain fewer but longer oligosaccharide chains.     

Changes in intestinal tunica muscularis following dietary fiber feeding in rats

The morphological changes in the intestinal tunica muscularis induced by prolonged dietary fiber intake were determined in rat small intestine and colon with the aid of computerized image analysis. Thirty male Sprague-Dawley rats were fed either a fiber free, 15% cellulose or 15% pectin diet for 8 weeks. Intestine length was measured and stained cross sections of the jejunum, ileum, and colon were quantitated using image analysis. In the distal colon, muscle cell size was also determined. Despite lower weight gain in the pectin fed rats, both the small intestine and colon length were significantly increased. Cellulose feeding had a lesser effect on intestine length. Pectin fed rats had significantly increased relative tunica muscularis area (37.2±2.2 mm²) in ileum cross sections when compared to control (24.3±1.8 mm²) and cellulose fed rats (26.1±1.1 mm²). In the mid-colon, the tunica muscularis area was found to be pectin > cellulose > control (33.5±2.2; 29.7±1.7; 25.8±1.5 respectively) with significant differences reached between pectin and control rats. In jejunal samples, no differences were observed among the groups. Circular smooth muscle cell size in the distal colon was significantly increased following cellulose feeding but was less pronounced in the case of pectin. We conclude that fiber supplementation leads to morphological changes in the rat intestine including changes in length and tunica muscularis volume.Support for this research was partially provided by: The Ben Gurion Fund for the Encouragement of Research Histadrut—The General Federation of Labor in Israel.     

Recombinant human growth hormone and glutamine synergistically improve the adaptation of the remnant small intestine in rats with short bowel syndrome

OBJECTIVE : To study the effects and the underlying mechanism of recombinant human growth hormone (rhGH) and glutamine (Gln) on the adaptation of the remnant small intestine in parenterally nourished, short bowel syndrome (SBS) rats. METHOD : Four parenteral nutrition (PN) treatment groups of SBS rats were randomly arranged in a 2 × 2 factorial design as follows: (i) STD (standard PN) group (–rhGH, –Gln); (ii) Gln group (–rhGH, +Gln); (iii) rhGH group (+rhGH, –Gln); and (iv) rhGH + Gln group (+rhGH, +Gln). Morphological changes of the intestinal mucosa were investigated and the expression of proliferating cell nuclear antigen (PCNA) and the occurrence of apoptosis were observed by immunohistochemical staining and terminal deoxynucleotidyl transfer‐mediated dUTP‐biotin nick end‐labeling (TUNEL) methods. The level of intestinal insulin‐like growth factor‐1 (IGF‐1) mRNA was determined by northern blotting. RESULTS : The mucosal thickness, villous height, crypt depth and villous surface area of the remnant small intestine in the rhGH + Gln group were increased significantly as compared with the other three experimental groups, and there were synergistic effects between rhGH and Gln (P < 0.01). The expression of PCNA was higher in the rhGH + Gln group than in the rhGH, Gln and STD groups (24.95 ± 3.93 vs 19.28 ± 3.25, 17.27 ± 3.38, and 8.37 ± 2.23 positive cells per crypt of Lieberkuhn, respectively; P < 0.01) but the rate of apoptosis was lower in the rhGH + Gln group than in the rhGH, Gln and STD groups (5.68 ± 2.07 vs 8.06 ± 2.33, 10.00 ± 2.24 and 22.32 ± 3.84 positive cells per 100 cells, respectively; P < 0.01). The intestinal IGF‐1 mRNA was also expressed at a higher level in the rhGH + Gln group than in the rhGH, Gln and STD groups (0.73 ± 0.05 vs 0.62 ± 0.04 vs 0.51 ± 0.04 and 0.41 ± 0.22, respectively; P < 0.05). CONCLUSION : The synergistic combination of rhGH and Gln can significantly improve the adaptation of the remnant small intestine in parenterally fed SBS rats. An increase in cell proliferation and a decrease in cell apoptosis are both responsible for the intestinal adaptation. An increase in local IGF‐1 plays an important role in this process.     

The effects of and interactions between fermentable dietary fiber and lipid in germfree and conventional mice

Dietary fiber can stimulate intestinal epithelial cell proliferation. The aim of this study was to resolve the different roles of fermentation and intraluminal viscosity on this trophic action and to investigate reported interactions between fiber and dietary fat. Conventional and germfree mice were fed guar gum in combination with low- or high-lipid diets for 2 weeks, and crypt cell production rates were determined. Guar gum significantly stimulated proliferation in the small intestine, especially when combined with fat. Lipid itself also stimulated proliferation in the small intestine and had a direct trophic effect in the cecum and colon of the germfree mice. Fiber markedly stimulated proliferation in the cecum and colon but only in the conventional group. Interactions between lipid and bacteria and between guar gum and bacteria were also observed in the small intestine. Guar gum has a trophic effect in the small bowel, probably related to viscosity, in addition to its fermentation-related actions in the colon. Positive interaction with lipid may be associated with delayed absorption. Lipid also has its own direct actions on small bowel mucosal proliferation, which are attenuated by the presence of bacteria.     

Regional blood flow and the localisation of lymphoblasts in the small intestine of the mouse: effect of an elemental diet

To test the hypothesis that food antigens influence the in vivo migration of lymphoblasts to the small intestine, the effect of an elemental diet (Vivonex) on the distribution of lymphoblasts within the small intestine of mice has been examined. Viable lymphoblasts from the mesenteric nodes of conventionally fed animals were labelled in vitro and given intravenously to recipient mice fed either a standard diet or elemental diet. The localisation of these cells within the small intestine was altered in the animals fed the elemental diet but only in the distal half of the small intestine. The relationship of the localisation of blast cells to the delivery of cardiac output along the small intestine was examined by assessing cell localisation in conjunction with the distribution of an isotopic indicator (86RbC1). The results show that the pattern of localisation of lymphoblasts within the small intestine is related to the probability that they will be delivered to different regions by the blood stream. Therefore, the alterations in blast localisation in the small intestine of animals of the elemental diet can be viewed as a consequence of changes in the perfusion of the distal small intestine. These results do not support the concept that antigens directly influence the efficiency with which blast cells migrate into the intestinal mucosa.     

Lipid accumulation in jejunal and colonic mucosa following chronic cholestyramine (Questran) feeding

The hypolipidemic agent, cholestyramine (Questran), when fed to rats inhibits intestinal absorption of cholesterol and triglycerides and causes significant epithelial cell damage in both small and large intestine. In this study, we report significant accumulation of lipids in the mucosal layer of both jejunum and colon in rats administered 2% cholestyramine for a four-week period, when compared to a control group maintained on regular chow. The total lipid increment with cholestyramine was 4.7-fold in the jejunum and 3.7-fold in the colon. The triglyceride fraction increased substantially in the small but not the large intestine. Relative phospholipid levels decreased in the treated jejunum but not in the colon. The biochemical data were reflected in morphological evidence of lipid-laden enterocytes obtained by light and transmission electron microscopy. Since cholestyramine has been shown to sequester 99.8% of micellar phospholipidin vitro, it is concluded that the presence of cholestyramine in the intestinal lumen may interefere with phospholipid availability for chylomicron synthesis and serosal lipid exit from the epithelium. This unusual deposition of lipid within the mucosal layer may also be correlated with the known cocarcinogenic effect of this resin in experimentally induced intestinal cancer.Supported by USDA grants 82CRCR 1071 and 82 CRCR 1001.