Synergy between medical and nutrient therapies: George Washington meets Rodney Dangerfield.

Although medical therapies are widely accepted by health practitioners, sometimes without adequate testing, nutritional therapy is frequently looked upon uniformly as without merit. There are many reasons for this attitude. However, a substantial body of literature has accumulated that objectively demonstrates the value of adding nutritional therapy to the prevention or treatment of some diseases or specific risk factors for diseases. Examples of successful nutrition therapy that can be combined with medical management include treatment of hypertension, hyperlipidemia, intermittent claudication, osteoporosis, respiratory distress syndrome, and arthritis.

Comparison of dietary assessment methods in a low-fat dietary intervention program.

The food frequency questionnaire (FFQ) is commonly utilized for assessment of dietary fat intake, but its validity among individuals following a low-fat diet is unclear. We evaluated the agreement of nutrient estimates derived from FFQ, 24-h recall, and 3-day food records obtained from 104 participants in a randomized trial of a low-fat dietary intervention for women at elevated breast cancer risk. Comparisons were made for total calories, percent calories from fat, and total fat after 1 yr. Correlation was assessed using standard methods based on a null hypothesis of no agreement between instruments as well as by a methodology based on a null hypothesis that the instruments should be in agreement. With the use of standard methods, FFQ estimates for women on the low-fat diet were significantly correlated to records only for percent calories from fat (r = 0.39), whereas recall and record estimates were significantly correlated for all three dietary variables. Using the new method, we found no significant correlation between FFQ and either recalls or records for women following a low-fat diet but significant correlation between recall and record estimates for total calories (r = 0.67). Traditional correlation testing may overestimate the extent of agreement in dietary instruments among women on a low-fat diet. We found empirical support for the nontraditional method.

Are dietary fiber-induced alterations in colonic epithelial cell proliferation predictive of fiber's effect on colon cancer?

Alterations in cell proliferation of the colon have been observed as a result of changes in amount and type of dietary fiber and in relation to risk of developing colon cancer. Although some human observational and intervention studies contribute to the database, most information results from experiments on rodents. Because of numerous contradictory reports linking dietary fiber, cell proliferation, and colon cancer, we undertook a critical review of existing methods in an attempt to explain the inconsistencies. Although there may be some individual types of dietary fiber that protect against chemically induced colon cancer, dietary fiber as a single entity does not appear to afford any consistent protection. Because of significant differences in experimental protocols among laboratories, it is not yet possible to state with certainty that increases in cell proliferation, induced by fiber consumption, are predictive of increased tumorigenesis. Much of what has been observed and interpreted as elevation of risk may simply be normal homeostatic changes in cell proliferation. Even though fermentation to short-chain fatty acids is a mechanistically attractive hypothesis to explain why fiber modulates cytokinetics, data do not consistently support short-chain fatty acids as biological intermediates in risk of colon cancer. The state of the art in this field has not yet progressed to the point where a clear effect of dietary fiber on cytokinetics and colon carcinogenesis can be assessed with any degree of certainty. Additional markers of apoptosis, differentiation, and cell-cell communication may be required for a more accurate analysis of the relation among fiber, cytokinetics, and colon cancer.

Increased tight junctional permeability is associated with the development of colon cancer.

Epithelial tissues act as barriers between two fluid compartments, and the epithelial barrier function is provided by the epithelial cells and the tight junctions (TJs) that connect them. We have shown previously that chronic treatment of a cultured epithelial monolayer with phorbol ester tumor promoters induces an increase in transepithelial paracellular permeability and produces tumor-like polyps, suggesting an association between TJ permeability and tumor formation. In this study, we analyzed the association between TJ permeability and formation of tumors in vivo. The permeability of the TJs was assessed in normal human and rat colon epithelia and in colon tumors by measuring the transepithelial electrical resistance, the paracellular flux rate of D-[(14)C]mannitol and the electron microscopic evaluation of the penetration of the electron dense dye ruthenium red across the TJs. By these criteria, the TJs of human colon tumors, including carcinomas and adenomatous polyps, and the TJs of 1,2-dimethylhydrazine (DMH)-induced rat colon tumors were leakier than the TJs of normal colon. Treatment of rats with the carcinogen DMH induced a progressive increase in the number of aberrant colonic crypts, considered the putative pre-neoplastic colonic phenotype while increasing TJ permeability of the colon epithelium prior to the development of tumors. These results showed that increased TJ permeability of the colon epithelium and consequently a decrease in epithelial barrier function precede the development of colon tumors.

Nutritional regulation of gastrointestinal growth.

Nutrition can control gastrointestinal (GI) tract growth at many stages of development. Fetal growth of the GI tract can be inhibited by restriction of the maternal diet, decrease of blood supply to the placenta, or partial obstruction of amniotic fluid swallowing. In most species there is an immature appearance of the GI mucosa that is characterized by large, long villi extending into the proximal colon. This pattern usually changes around the time of weaning and can be modified by manipulation of the diet. While total nutrition has a profound effect on GI development, there are specific nutrients that influence the epithelium during adult life. In the small intestine, glutamine has the most important effects and this amino acid is now considered conditionally essential. In the colon, dietary fiber has the strongest influence on mucosal structure and turnover. While it has been assumed that concentrations of bile acids and/or short chain fatty acids are the mediating factors, there is substantial evidence that mitigates against this conclusion. A better understanding of the molecular changes accompanying alterations in GI growth may lead to more comprehensive strategies for improving intestinal function and decreasing the risk of colon cancer.

Lectin may contribute to the atherogenicity of peanut oil.

Peanut oil is unexpectedly atherogenic for rats, rabbits, and primates. The lesions it produces are more fibrous than fatty. The mechanism underlying the atherogenicity of peanut oil has been elusive. Randomization of peanut oil reduces significantly its atherogenic properties, but native and randomized peanut oils have similar rates of lipolysis, and rats fed the two oils absorb and transport lipids in a similar fashion. Peanut oil differs from other oils in having a relatively high lectin content, and the randomization process markedly reduces the lectin content as well. The biologically active lectin of peanut oil has an affinity for glycoproteins found specifically on arterial smooth muscle cells. Peanut lectin has been shown to stimulate growth of smooth muscle and pulmonary arterial cells. Vigorous washing of peanut oil reduces its lectin content by 46%. Compared to rabbits fed cholesterol and peanut oil, rabbits fed cholesterol and washed peanut oil exhibited less severe atherosclerosis in the aortic arch (by 9%) and in the thoracic aorta (by 31%). The data suggest that peanut oils' endogenous lectin may contribute significantly to its atherogenic properties.

Early atherosclerotic plaques in the aorta following cytomegalovirus infection of mice.

We show here that BALB/c mice inoculated with murine cytomegalovirus (MCMV) express viral antigens in the endothelial and smooth muscle cells of the aortic wall, and that accumulation of inflammatory cells in the aortic lumen, similar to that seen in early atherosclerotic lesions in humans, colocalizes with the site of virus antigen expression. Immunosuppression of the mice at the time of virus infection increased the expression of viral antigens and the size of early atherosclerotic lesions in the intima. The percentage of the low-density lipoprotein cholesterol (LDL-C), the major lipid contributor to atherosclerotic plaques, was significantly increased in the serum of MCMV-infected mice, whether or not the mice were fed a high cholesterol diet. Human cytomegalovirus (HCMV) significantly increased the esterified cholesterol component of the total cholesterol in a human arterial smooth muscle cell line infected in vitro with HCMV. These results suggest that CMV infection is involved in two of the major mechanisms that lead to development of atherosclerosis, i.e., immune injury and high LDL-C.

Fatty acids and colon cancer in experimental models.

Experimental models have several advantages in the study of colon cancer. They can be used to tightly control diet, examine putative intermediate markers, test hypotheses about mechanisms of carcinogenesis, and quantify development of tumors in a short time. Dietary issues that have been studied in animal models but are unresolved include the concept of the effects of total fat compared with energy intake, composition of the basal diet, linoleic acid requirements, and interactions of fat with other nutrients. Intermediate markers that have been probed in animal or in vitro studies include cytokinetics, aberrant crypt foci, eicosanoids and hydroxyoctadecadienoic acids, ornithine decarboxylase, tyrosine kinase, protein kinase C, and gene expression. Colon cancer is studied in animals primarily with use of chemicals that are relatively specific inducers of these tumors, but transplantable models and transgenic animals are also used. Total dietary fat is generally thought to affect colon tumorigenesis, but there does not appear to be any specific fatty acid that promotes the development of colon cancer. Several studies indicate that n-3 fatty acids from marine sources alter a variety of biological intermediates and inhibit colonic tumorigenesis; this is probably mediated via the eicosanoid pathway. Although there are undoubtedly multiple cellular changes elicited by certain fatty acids, our current knowledge of this area suggests that specific fatty acid metabolites or their targets are the likely mediators in this sequence.

Interaction of fiber and energy registration in experimental colon carcinogens.

Male, F344 rats were fed ad libitum diets in which the fiber was either 10% wheat bran or 4% cellulose. The diets contained equivalent amounts of fiber. Other groups were fed wheat bran or cellulose-containing diets which were pair fed to the controls to provide 10, 20, or 30% energy restriction (ER). Colon cancer was induced by five weekly feedings of DMH. After 28 weeks, colon tumor incidence in the ad libitum fed groups was: cellulose 70%, wheat bran 42%. At 10, 20, or 30% ER tumor incidence was 46, 29, and 21% in rats fed cellulose and 17, 17, and 21% in those fed wheat bran, respectively. The data confirm the greater protective action of wheat bran compared to cellulose.

Fiber and cancer protection--mechanisms.

There is no reason to believe that a single lumenal or tissue factor will hold the key to understanding the of dietary fiber's effect on reducing the risk of colon cancer. In fact, the data suggest that multiple, interacting factors will be revealed. After years of research, it appears that the bile acid hypothesis is not nearly as strong as first envisaged. Additionally, the theory that SCFA protect against colon cancer has little clinical or experimental support. There is no doubt that identification of genetic alterations, and their controlling factors, will play a major role in our understanding of this issue. The appeal of the original fiber hypothesis has not diminished but simply requires updating based on discoveries made since it was first proposed. It is this author's opinion that dietary fiber will likely be found to modulate human colon cancer and the mechanisms of its beneficial effect will probably be through multiple actions within the lumen and at the level of the target tissue. Based on our current knowledge of the pathogenesis of colon cancer we cannot make definitive statements about what percentage of colon cancer might be prevented by a specific type or amount of dietary fiber but it is reasonable to conclude that consumption of fiber-rich diets is associated with reduced risk of colon cancer. It is quite plausible that the combination of dietary fiber, or its metabolites, in conjunction with other phytochemicals may be necessary to realize inhibition of the tumorigenic process.

Effect of sesame oil on serum and liver lipid profiles in the rat.

In our previous study (Satchithanandam, S., Reicks, M., Calvert, R.J., Cassidy, M.M. and Kritchevsky, D. (1993) J. Nutr. 123, 1852-1858), we found that the absorption of lymphatic cholesterol by rats fed diets containing 24% sesame oil was about 50% less than that by rats fed the control diet containing no sesame oil. The effect of sesame oil on serum cholesterol levels was not determined at that time. In the present study, three groups of male Wistar rats (75-100 g) were fed a control diet or a diet containing 12 or 24% sesame oil. To increase serum cholesterol levels, 1% cholesterol and 0.5% cholic acid were added to each diet. After rats were fed for 4 weeks, total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride levels were measured in the serum. Liver weight and cholesterol and triglyceride levels were determined. Liver cholesterol levels were significantly lower in rats fed the 24% sesame oil diet, and the liver lipid level was significantly higher in the 24% sesame oil-fed group, compared with levels in the group fed the control diet. Liver weights and esterified cholesterol and liver triglyceride levels were not significantly different among the groups. Levels of serum total cholesterol and LDL-cholesterol were significantly lower in rats fed the 24% sesame oil diet, compared with levels in the control group. Serum triglyceride and HDL-cholesterol levels did not differ significantly among the groups. The mechanism by which a diet containing 24% sesame oil reduces levels of serum and liver cholesterol, liver LDL cholesterol, and liver lipids is not known. However, the high degree of unsaturation (85%) of sesame oil and the presence of linoleic acid may be important factors.

Glutamine reduces bacterial translocation after small bowel transplantation in cyclosporine-treated rats.

Bacterial translocation (BT) of enteric organisms is a major cause of sepsis in patients undergoing small bowel transplantation (SBT). Cyclosporine (CsA) may be toxic to intestinal epithelium and increase the risk of BT. Glutamine (Gln) is the preferred enterocyte fuel and maintains graft epithelial integrity in experimental SBT. This study determined the effects of CsA on mucosal structure and function of transplanted intestinal isograft and examined whether Gln-enriched diet reversed CsA-induced intestinal toxicity. Thirty-three adult Lewis rats underwent resection of the distal 60% of small bowel and received an orthotopic jejunal isograft. Rats received either elemental diet with 2% Gln or the same diet with balanced nonessential amino acids (non-Gln) by gastrostomy for 10 days. CsA (15 mg/kg, im) or olive oil was injected daily. Rats were assigned to four groups: non-Gln with vehicle, non-Gln with CsA, Gln with vehicle, and Gln with CsA. Mucosal villous height, surface area, crypt depth, 14C glucose absorption, BT to mesenteric lymph nodes (MLN), and body weight change were evaluated. The non-Gln with CsA group had the highest incidence of BT (P < 0.001). Gln groups had significantly decreased BT (P < 0.01) and increased crypt depth and villous surface area (P < 0.01) when compared to non-Gln groups. Body weight significantly decreased in CsA groups when compared to non-CsA groups (P < 0.01). These results indicate at CsA significantly decreased body weight and increased BT without decreasing mucosal structure and glucose absorption of intestinal isografts.(ABSTRACT TRUNCATED AT 250 WORDS)

Pectin improves colonic function in rat short bowel syndrome.

Short bowel syndrome is characterized by weight loss, diarrhea, and malabsorption. Pectin, a highly fermentable fiber, improves small and large bowel mucosal structure, prolongs intestinal transit, and decreases diarrhea. This study determined if the addition of citrus pectin to an enteral liquid diet (LD) improved structure and absorptive function in the rat jejunum and colon following massive intestinal resection. Twenty-one male Sprague-Dawley rats underwent placement of gastrostomy tube for isocaloric, isonitrogenous feeding and either 60% small bowel and cecal resection or small bowel transection with anastomosis. Animals in each group were then randomly and equally assigned to receive either LD (Enercal Plus, Wyeth) or LD supplemented with 2% citrus pectin for 7 days. Study variables included body weight change, percentage of stool solidity, jejunal villous height (JVH) and crypt depth, colonic crypt depth (CCD), and colonic short-chain fatty acid content (SCFA). Jejunal [14C]glucose absorption and colonic [3H]H2O absorption were measured by a dual in vivo perfusion assay. Resection significantly (P < 0.05) decreased body weight, stool solidity, and colonic SCFA content; enlarged structure (JVH, CCD); and increased absorptive function in the remaining bowel. Pectin significantly decreased (P < 0.05) body weight loss, increased (P < 0.05) stool solidity, and improved (P = 0.05) colonic water absorption following resection without significantly altering mucosal structure. It is concluded that pectin improves colonic absorptive function following massive bowel resection in the rat.

Fiber: effect on bacterial translocation and intestinal mucin content.

Total parenteral nutrition (TPN) and elemental diet (ED) produce intestinal atrophy and increase bacterial translocation (BT) to mesenteric lymph nodes. The increased rate of BT may be due to alterations in mucosal structure, enzyme activity, or mucin content. Fiber improves intestinal structure and function in rats and may reduce the rate of BT. This study determined whether the addition of fiber to TPN or ED would maintain intestinal integrity and decrease BT to the mesenteric lymph nodes. Fifty-six adult male Sprague-Dawley rats underwent placement of jugular catheters and were assigned to one of five dietary groups: TPN, TPN+oral oat fiber (TPNF) 2 g/day, ED, ED+oral oat fiber (EDF) 2 g/day, or AIN-76 (control); they were pair-fed for 7 days. On day 8 the mesenteric lymph nodes were removed for bacterial cultures; and jejunal mucosal weight, DNA, protein, alkaline phosphatase, maltase, and jejunal mucin content were measured. Enteral nutrition significantly decreased BT when compared to parenteral feeding, and fiber significantly decreased BT when administered to rats receiving TPN or ED. Improvements in intestinal mucosal structure were not consistently associated with decreased rates of BT. Additionally, BT occurred independently of jejunal mucin concentration. Mechanisms other than maintenance of mucosal structure or mucin content are important in the mediation of fiber-induced decreased BT in rats receiving TPN or ED.