Article

Formulation of the Total Western Diet (TWD) as a Basal Diet for Rodent Cancer Studies

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Abstract

Rodent cancer studies typically use defined diets with nutrient profiles optimized for rodent health. However, a defined rodent diet that represents typical American nutrition in all aspects, including calorie sources and macro- and micronutrient composition, is not yet available. Thus, a nutrient density approach was used to formulate the new Total Western Diet (TWD) based on NHANES data for macro- and micronutrient intakes. The TWD has fewer calories from protein and carbohydrate sources and twice that from fat as compared to the AIN-93 diet. The new diet contains more saturated and monounsaturated fats, less polyunsaturated fat, fewer complex carbohydrates, and twice the level of simple sugars. The TWD includes less calcium, copper, folate, thiamin, and vitamins B(6), B(12), D, and E, but much more sodium. This newly devised diet that better represents typical American nutrition will be highly useful for studies employing animal models of human disease, including cancer.

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... To address this question, we conducted studies using a rodent Total Western Diet (TWD) formulated using the 50th percentile daily intake levels for macro and micronutrients from the National Health and Nutrition Examination Survey (NHANES) which has fewer calories from protein and carbohydrates, double the fat including more saturated and monounsaturated fats, less polyunsaturated fat, and fewer complex carbohydrates, and two times the level of simple sugars compared to the AIN-93 G diet (30) that was supplemented with different levels of RPS. The TWD has been compared to the AIN-76A or AIN-93 diet in several studies. ...
... Breeding pairs were fed rodent chow (Teklad 2020X, Frederick, MD). After weaning, mice were placed on the TWD (Supplementary Table 1, Envigo, Madison, WI) (30). After feeding mice with the TWD for 6 weeks, mice were divided into four dietary treatment groups: (1) TWD, (2) TWD supplemented with 2% w/w RPS (Ingredion, Westchester, IL), (3) TWD supplemented with 5% w/w RPS, or (4) TWD supplemented with 10% w/w RPS for an additional 3 weeks. ...
... Typically, potato starch is 50-70% RS2. In this study, the RPS levels chosen are approximately equivalent to a human consuming between 5 and 30 g (maximum range) of RS/day based on the nutrient density calculations used in formulating the TWD (energy density 4.4 kcal/g) (30), the NHANES 50th percentile caloric intake of 2,070 kcal/day, and potato starch typically containing 50-70% RS2. Body weights and food consumption were recorded weekly. ...
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Article
Several studies indicate that the four major types of resistant starch (RS1-4) are fermented in the cecum and colon to produce short-chain fatty acids (SCFAs) and can alter the microbiome and host physiology. However, nearly all these studies were conducted in rodents fed with a diet that does not approximate what is typically consumed by humans. To address this, mice were fed a Total Western Diet (TWD) based on National Health and Nutrition Examination Survey (NHANES) data that mimics the macro and micronutrient composition of a typical American diet for 6 weeks and then supplemented with 0, 2, 5, or 10% of the RS2, resistant potato starch (RPS), for an additional 3 weeks. The cecal microbiome was analyzed by 16S sequencing. The alpha-diversity of the microbiome decreased with increasing consumption of RPS while a beta-diversity plot showed four discreet groupings based on the RPS level in the diet. The relative abundance of various genera was altered by feeding increasing levels of RPS. In particular, the genus Lachnospiraceae NK4A136 group was markedly increased. Cecal, proximal, and distal colon tissue mRNA abundance was analyzed by RNASeq. The cecal mRNA abundance principal component analysis showed clear segregation of the four dietary groups whose separation decreased in the proximal and distal colon. Differential expression of the genes was highest in the cecum, but substantially decreased in the proximal colon (PC) and distal colon (DC). Most differentially expressed genes were unique to each tissue with little overlap in between. The pattern of the observed gene expression suggests that RPS, likely through metabolic changes secondary to differences in microbial composition, appears to prime the host to respond to a range of pathogens, including viruses, bacteria, and parasites. In summary, consumption of dietary RPS led to significant changes to the microbiome and gene expression in the cecum and to a lesser extent in the proximal and distal colon.
... Importantly, none of the approaches described above for modeling typical Western nutrition appropriately considered the contribution of suboptimal micronutrient intakes in their disease models. To address this research gap, our research team developed the new total Western diet (TWD) for rodents with energy and nutrient profiles that emulate a typical Western diet using available U.S. nutrient intake survey data [23]. Briefly, the amount of each macro-and micronutrient in the AIN93G basal diet, a diet routinely used in cancer studies today, was adjusted to match 50th percentile intakes for Americans as reported in NHANES survey data. ...
... The chronic intestinal inflammation that 5000 2011 5000 2011 5000 5000 2011 Phosphorus 3000 2757 3000 2757 3000 2757 2757 Sodium 1019 7078 1019 7078 1019 7078 7078 Potassium 3600 5333 3600 5333 3600 5333 5333 Magnesium 507 589 507 589 507 589 589 Iron 35 31 35 31 35 31 31 Zinc 30 25 30 25 30 25 Abbreviations: AIN American Institution of Nutrition, TWD total Western diet, DIO diet-induced obesity, VMM vitamin-and mineral-modified diet; MM macronutrient-modified diet; TWD + CaVD total Western diet with restored calcium and vitamin D; TWD + MD total Western diet with restored methyl donor micronutrients B 2 , B 6 , B 12 , choline and folate. Notes: Composition of the TWD was published previously [23]. No data are available in NHANES for chloride, manganese, iodine, pantothenic acid, biotin, or ultra-trace minerals. ...
... We hypothesized that exposure to the TWD would promote colon tumorigenesis, and that this effect would be mediated, at least in part, by the micronutrient faction of the diet. Experimental diets included (1) AIN93G, the standard basal diet routinely employed in rodent studies (AIN); (2) the total Western diet (TWD), as described in Hintze, et al. [23]; (3) a macronutrient-modified diet (MM), which was modeled after the 50th percentile of NHANES intakes (as with TWD), yet contained the same vitamin and mineral content as the AIN93G diet; (4) a vitamin-and mineral-modified diet (VMM), which was modeled after the 50th percentile of NHANES intakes for vitamins and minerals (as with TWD), yet contained the same macronutrient content as the AIN93G diet; and (5) a commercial diet-induced obesity diet (DIO) that contained 45% of energy as fat (primarily lard) and matched the AIN93G for micronutrient content. At 5 weeks of age, male C57BL/6J mice were assigned to diet groups using a random block design to equalize group body weight at the start of the study (n = 20 per diet group) ( Figure S1). ...
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Article
Consumption of a Western type diet is a known risk factor for colorectal cancer. Our group previously developed the total Western diet (TWD) for rodents with energy and nutrient profiles that emulate a typical Western diet. In this study, we tested the hypothesis that consumption of the TWD would enhance colitis, delay recovery from gut injury and promote colon tumorigenesis. In multiple experiments using the azoxymethane + dextran sodium sulfate or ApcMin/+ mouse models of colitis-associated colorectal carcinogenesis (CAC), we determined that mice fed TWD experienced more severe and more prolonged colitis compared to their counterparts fed the standard AIN93G diet, ultimately leading to markedly enhanced colon tumorigenesis. Additionally, this increased tumor response was attributed to the micronutrient fraction of the TWD, and restoration of calcium and vitamin D to standard amounts ameliorated the tumor-promoting effects of TWD. Finally, exposure to the TWD elicited large scale, dynamic changes in mRNA signatures of colon mucosa associated with interferon (IFN) response, inflammation, innate immunity, adaptive immunity, and antigen processing pathways, among others. Taken together, these observations indicate that consumption of the TWD markedly enhanced colitis, delayed recovery from gut injury, and enhanced colon tumorigenesis likely via extensive changes in expression of immune-related genes in the colon mucosa.
... K 12 22 20 Biotin 15 27 25 Pantothenate 30 57 51 Calcium 20 37 33 Phosphorus 23 43 38 Magnesium 79 146 132 Iron 23 42 38 Zinc 109 201 181 Copper 15 27 25 Selenium 36 67 60 Potassium 232 429 386 Sodium 296 548 493 Manganese 23 42 38 Iodine 99 183 164 Molybdenum 30 55 49 body size scaling was computed assuming a human weight of 60 kg, mouse weight of 20 g and scaled to the ¾ power. Human nutrient recommendations are in the format of g/day while mice recommendations are in the format of mg/kg diet, therefore to convert between these formats, a daily mouse intake of 2.5 g was assumed [24] 2 Nutrient density scaling was calculated by dividing the mass of human recommendation by a daily energy intake of 2079 kcal [10] in order to determine mass of nutrient/kcal. This was then translated to the mouse requirement (mg/kg diet) assuming a mouse food intake 2.5 g/day and an energy intake 9.5 kcal/day [24]. ...
... Human nutrient recommendations are in the format of g/day while mice recommendations are in the format of mg/kg diet, therefore to convert between these formats, a daily mouse intake of 2.5 g was assumed [24] 2 Nutrient density scaling was calculated by dividing the mass of human recommendation by a daily energy intake of 2079 kcal [10] in order to determine mass of nutrient/kcal. This was then translated to the mouse requirement (mg/kg diet) assuming a mouse food intake 2.5 g/day and an energy intake 9.5 kcal/day [24]. 3 Body surface area scaling computed using the equation: Mouse Equivalent Dose (mg/BW) = human dose (mg/BW) X (human Km,37)/(mouse Km, 3) [18]. ...
... Values were computed assuming a human weight of 60 kg, mouse weight of 20 g. Human nutrient recommendations are in the format of g/day while mice recommendations are in the format of mg/kg diet, therefore to convert between these formats, a daily mouse intake of 2.5 g was assumed [24] In general, when metabolic body size scaling is compared to the body surface area or the nutrient density approach, a lower concentration of micronutrients is calculated. As the data demonstrates in Table 1, one could make the case for using any of these methods. ...
Article
Background: Rodent models have been an invaluable resource for biomedical research and have been instrumental for countless advances in our understanding of biology and human disease. However, inherent to using these models is the issue of translatability of research findings to human populations. Some differences between humans and rodents can never be reconciled because of key differences in physiology. However, rodent models have evolved over time through innovations in genetics and standardized animal diets, resulting in reduced variability across experiments. Developing animal diets that more closely emulate what humans eat will help increase the translational fidelity of animal models to human populations. This review will focus on the role of basal laboratory diets for improving animal models. Keywords: laboratory rodent diets, total Western Diet, allometric scaling, nutrient density scaling
... However, most of these simple high-fat diets do not emulate the macro-and micronutrient profile typical of the Western dietary pattern, and thus they are generally not relevant for at-risk human populations. To address this issue, Hintze total Western diet (TWD) for rodents by translating the 50th percentile of micro-and macronutrient intakes reported in the National Health and Nutrition Examination Survey (NHANES) using an energy density approach [29,30]. ...
... No. TD.06415) that contained 45% of energy as lard; and (3) the total Western diet (TWD) (Cat. No. TD.110424), which models typical U.S. nutrient intakes on an energy density basis, as described previously [29]. Diet formulations are provided in Table S2. ...
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Article
The Western dietary pattern can alter the gut microbiome and cause obesity and metabolic disorders. To examine the interactions between diet, the microbiome, and obesity, we transplanted gut microbiota from lean or obese human donors into mice fed one of three diets for 22 weeks: (1) a control AIN93G diet; (2) the total Western diet (TWD), which mimics the American diet; or (3) a 45% high-fat diet-induced obesity (DIO) diet. We hypothesized that a fecal microbiome transfer (FMT) from obese donors would lead to an obese phenotype and aberrant glucose metabolism in recipient mice that would be exacerbated by consumption of the TWD or DIO diets. Prior to the FMT, the native microbiome was depleted using an established broad-spectrum antibiotic protocol. Interestingly, the human donor body type microbiome did not significantly affect final body weight or body composition in mice fed any of the experimental diets. Beta diversity analysis and linear discriminant analysis with effect size (LEfSe) showed that mice that received an FMT from obese donors had a significantly different microbiome compared to mice that received an FMT from lean donors. However, after 22 weeks, diet influenced the microbiome composition irrespective of donor body type, suggesting that diet is a key variable in the shaping of the gut microbiome after FMT.
... The following study design is based upon the reported anti-inflammatory properties of walnuts [11][12][13]. Using a preclinical mouse model of UC, we have examined the potential health benefits of whole walnuts added to a Total Western Diet (TWD) [14] on the extent of intestinal injury following exposure of mice to the ulcerogenic agent, DSS. We have examined how walnut consumption, starting prior to DSS exposure and continuing throughout the entire disease course, may influence the extent of intestinal inflammation during both the acute and recovery phases of the experimentally-induced disease. ...
... C57BL/6 (B6) mice were fed the TWD ( [14]: Envigo, Madison, WI, USA) supplemented with freshly ground whole walnuts throughout the entire experimental period. Fixed amounts of the diet were given each week based on an average daily food intake of 3.5 g/day/mouse. ...
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Article
Walnuts contain a complex array of natural compounds and phytochemicals that exhibit a wide range of health benefits, including protection against inflammation and colon cancer. In this study, we assess the effects of dietary supplementation with walnuts on colonic mucosal injury induced in mice by the ulcerogenic agent, dextran sodium sulfate (DSS). C57Bl/6J mice were started on the Total Western Diet supplemented with freshly-ground whole walnuts (0, 3.5, 7 and 14% g/kg) 2 weeks prior to a 5-day DSS treatment and walnut diets were continued throughout the entire experimental period. Mice were examined at 2 days or 10 days after withdrawal of DSS. In a separate study, a discovery-based metabolite profiling analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on fecal samples and colonic mucosa following two weeks of walnut supplementation. Dietary walnut supplementation showed significant effects in the 10-day post-DSS recovery-phase study, in which the extent of ulceration was significantly reduced (7.5% vs. 0.3%, p < 0.05) with 14% walnuts. In the metabolite-profiling analysis, walnuts caused a significant increase in several polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and 9-oxo-10(E),12(E)-octadecadienoic acid (9-oxoODA), as well as kynurenic acid. In colon tissue samples, walnuts caused a significant increase in the levels of S-adenosylhomocysteine (SAH) and betaine, important components of fatty acid β-oxidation. These metabolite changes may contribute in part to the observed protection against DSS-induced inflammatory tissue injury.
... To address this question, we used a Western diet (WD) containing less fat than routinely used in a HFD (35% kcal from fat for WD vs. 60% kcal from fat for HFD) that has been designed to represent the typical Western dietary practices in all aspects, including caloric value and macro-and micronutrient composition (Hintze et al., 2012). With this diet, our goal was to assess enteric neuronal damage and determine how LPS and saturated FFA contribute to this disorder. ...
... Female Germ-Free (GF) wild-type (WT) C57BL/6 mice maintained under GF conditions in the Georgia State University gnobiotic facility using Park Bioservices isolators were fed for 6 weeks. The WD was designed as described by Hintze et al. (2012), RD is the control of WD. Diet compositions provided by the manufacturer (Table 1) suggest that the relative palmitate content in WD and RD is ß4:1. ...
Article
Key points: A high-fat diet (60% kcal from fat) is associated with motility disorders inducing constipation and loss of nitrergic myenteric neurons in the proximal colon. Gut microbiota dysbiosis, which occurs in response to HFD, contributes to endotoxaemia. High levels of lipopolysaccharide lead to apoptosis in cultured myenteric neurons that express Toll-like receptor 4 (TLR4). Consumption of a Western diet (WD) (35% kcal from fat) for 6 weeks leads to gut microbiota dysbiosis associated with altered bacterial metabolites and increased levels of plasma free fatty acids. These disorders precede the nitrergic myenteric cell loss observed in the proximal colon. Mice lacking TLR4 did not exhibit WD-induced myenteric cell loss and dysmotility. Lipopolysaccharide-induced in vitro enteric neurodegeneration requires the presence of palmitate and may be a result of enhanced NO production. The present study highlights the critical role of plasma saturated free fatty acids that are abundant in the WD with respect to driving enteric neuropathy and colonic dysmotility. Abstract: The consumption of a high-fat diet (HFD) is associated with myenteric neurodegeneration, which in turn is associated with delayed colonic transit and constipation. We examined the hypothesis that an inherent increase in plasma free fatty acids (FFA) in the HFD together with an HFD-induced alteration in gut microbiota contributes to the pathophysiology of these disorders. C57BL/6 mice were fed a Western diet (WD) (35% kcal from fat enriched in palmitate) or a purified regular diet (16.9% kcal from fat) for 3, 6, 9 and 12 weeks. Gut microbiota dysbiosis was investigated by fecal lipopolysaccharide (LPS) measurement and metabolomics (linear trap quadrupole-Fourier transform mass spectrometer) analysis. Plasma FFA and LPS levels were assessed, in addition to colonic and ileal nitrergic myenteric neuron quantifications and motility. Compared to regular diet-fed control mice, WD-fed mice gained significantly more weight without blood glucose alteration. Dysbiosis was exhibited after 6 weeks of feeding, as reflected by increased fecal LPS and bacterial metabolites and concomitant higher plasma FFA. The numbers of nitrergic myenteric neurons were reduced in the proximal colon after 9 and 12 weeks of WD and this was also associated with delayed colonic transit. WD-fed Toll-like receptor 4 (TLR4)-/-mice did not exhibit myenteric cell loss or dysmotility. Finally, LPS (0.5-2 ng·ml-1) and palmitate (20 and 30 μm) acted synergistically to induce neuronal cell death in vitro, which was prevented by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. In conclusion, WD-feeding results in increased levels of FFA and microbiota that, even in absence of hyperglycaemia or overt endotoxaemia, synergistically induce TLR4-mediated neurodegeneration and dysmotility.
... The selection of HFD, therefore, deserves further discussion. The HFD used in these experiments approximates a "Western diet", which, according to reports from the National Health and Nutrition Examination Survey (NHANES), is around 35% fat by energy content and 23% by simple carbohydrates such as sucrose [137,138]. Whereas diet duration did not vary, the composition was chosen to parallel human dietary patterns and thus included a high sucrose component of around 21% by energy content. Additionally, we wanted to examine how our results compared to other HFD RPE/choroid transcription data in mice with intact gut microbiota. ...
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Article
Relationships between retinal disease, diet, and the gut microbiome have started to emerge. In particular, high-fat diets (HFDs) are associated with the prevalence and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR). These effects are thought to be partly mediated by the gut microbiome, which modulates interactions between diet and host homeostasis. Nevertheless, the effects of HFDs on the retina and adjacent retinal pigment epithelium (RPE) and choroid at the transcriptional level, independent of gut microbiota, are not well-understood. In this study, we performed the high-throughput RNA-sequencing of germ-free (GF) mice to explore the transcriptional changes induced by HFD in the RPE/choroid. After filtering and cleaning the data, 649 differentially expressed genes (DEGs) were identified, with 616 genes transcriptionally upregulated and 33 genes downregulated by HFD compared to a normal diet (ND). Enrichment analysis for gene ontology (GO) using the DEGs was performed to analyze over-represented biological processes in the RPE/choroid of GF-HFD mice relative to GF-ND mice. GO analysis revealed the upregulation of processes related to angiogenesis, immune response, and the inflammatory response. Additionally, molecular functions that were altered involved extracellular matrix (ECM) binding, ECM structural constituents, and heparin binding. This study demonstrates novel data showing that HFDs can alter RPE/choroid tissue transcription in the absence of the gut microbiome.
... This study was a collaborative opportunity with an experimental design focused on investigating liver and gut pathology in the Iberian pig model; our muscle studies were thus limited by the original study design in terms of diet, duration, and sample size. In practice, the hypercaloric "Western-style" diet varies widely, and no single experimental diet can represent the full spectrum of hypercaloric diets as they vary among humans or within an individual over time [70]. Because the pigs were housed in pairs controlled for sex and the pens constituted the experimental unit, we were unable to test for differences between sexes. ...
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Article
Non-alcoholic fatty liver disease (NAFLD) is a serious metabolic condition affecting millions of people worldwide. A "Western-style diet" has been shown to induce pediatric NAFLD with the potential disruption of skeletal muscle composition and metabolism. To determine the in vivo effect of a "Western-style diet" on pediatric skeletal muscle fiber type and fuel utilization, 28 juvenile Iberian pigs were fed either a control diet (CON) or a high-fructose, high-fat diet (HFF), with or without probiotic supplementation, for 10 weeks. The HFF diets increased the total triacylglycerol content of muscle tissue but decreased intramyocellular lipid (IMCL) content and the number of type I (slow oxidative) muscle fibers. HFF diets induced autophagy as assessed by LC3I and LC3II, and inflammation, as assessed by IL-1α. No differences in body composition were observed, and there was no change in insulin sensitivity, but HFF diets increased several plasma acylcarnitines and decreased expression of lipid oxidation regulators PGC1α and CPT1, suggesting disruption of skeletal muscle metabolism. Our results show that an HFF diet fed to juvenile Iberian pigs produces a less oxidative skeletal muscle phenotype, similar to a detraining effect, and reduces the capacity to use lipid as fuel, even in the absence of insulin resistance and obesity.
... Many studies that compare health impacts of dairy proteins to those of soy often do so in the context of feeding a high-fat diet [18,19,25,26]. For example, milk-derived saturated fats were shown to promote colitis and microbial dysbiosis in an IL-10 −/− mouse model fed a high-fat diet that provided 37% of calories as fat [25]. ...
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Article
Various proteins or protein fractions reportedly positively affect gastrointestinal integrity and inflammation in diets providing >45% energy as fat. This study tested whether benefits were seen in diets providing 30% of energy as fat. Purified diets (PD) with isolated soy protein (ISP), dried whole milk powder (DWMP), milk fat globule membrane (MFGM), or milk protein concentrate (MPC) as protein sources were fed to C57BL/6J mice (n = 15/diet group) for 13 weeks. MFGM-fed mice were heaviest (p < 0.005) but remained within breeder norms. Growth rates and gut motility were similar for all PD-fed mice. FITC-dextran assessed gut permeability was lowest in DWMP and MFGM (p = 0.054); overall, plasma endotoxin and unprovoked circulating cytokines indicated a non-inflammatory state for all PD-fed mice. Despite differences in cecal butyrate and intestinal gene expression, all PDs supported gastrointestinal health. Whole milk provided more positive effects compared to its fractions. However, ISP-fed mice showed a >370%, (p < 0.006) increase in colonic myeloperoxidase activity indicative of tissue neutrophil infiltration. Surprisingly, FITC-dextran and endotoxin outcomes were many folds better in PD-fed mice than mice (strain, vendor, age and sex matched) fed a “chow-type” nutritionally adequate non-PD. Additional variables within a diet’s matrix appear to affect routine indicators or gastrointestinal health.
... no. TD.160422; formulation previously published [28]) to emulate the Western dietary pattern (Table S1). The energy densities of these diets differ, with AIN93G (AIN) at 3.8 kcal/g and the TWD at 4.4 kcal/g. ...
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Article
Previous work by our group using a mouse model of inflammation-associated colorectal cancer (CAC) showed that the total Western diet (TWD) promoted colon tumor development. Others have also shown that vancomycin-mediated changes to the gut microbiome increased colorectal cancer (CRC). Therefore, the objective of this study was to determine the impact of vancomycin on colon tumorigenesis in the context of a standard mouse diet or the TWD. A 2 × 2 factorial design was used, in which C57Bl/6J mice were fed either the standard AIN93G diet or TWD and with vancomycin in the drinking water or not. While both the TWD and vancomycin treatments independently increased parameters associated with gut inflammation and tumorigenesis compared to AIN93G and plain water controls, mice fed the TWD and treated with vancomycin had significantly increased tumor multiplicity and burden relative to all other treatments. Vancomycin treatment significantly decreased alpha diversity and changed the abundance of several taxa at the phylum, family, and genus levels. Conversely, basal diet had relatively minor effects on the gut microbiome composition. These results support our previous research that the TWD promotes colon tumorigenesis and suggest that vancomycin-induced changes to the gut microbiome are associated with higher tumor rates.
... There are two approaches for establishing obesity models: One is the use of a highlard-and-sucrose content diet named the "Western diet", while the other one is the use of a diet with low amounts of calcium, vitamin D3, and other nutrient profiles that emulate a typical Western diet named the "stress diet", using the available U.S. nutrient intake survey data [93]. ...
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Article
Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis.
... Epidemiological studies have consistently shown a positive association between a Western dietary pattern and colorectal cancer risk [2,3]. The TWD is a rodent diet that closely mimics the macronutrient and micronutrient composition of the average American diet [12]. By using a highly relevant background diet, the TWD, and a foodborne carcinogen, PhIP, the present study greatly reduces the translational gap between humans and experimental animals. ...
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Article
Western-style diets (WD) are associated with greater risk of colon cancer. Exposure to 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), a food-borne carcinogen, is linked to increased colon cancer risk. In contrast, intake of apiaceous and cruciferous vegetables (APIs and CRUs) is associated with reduced risk. Here we evaluated effects of a WD alone or a WD containing API or CRU, relative to a purified diet (basal), on colon cancer risk in mice. All diets were fed at one of two concentrations of PhIP (100 or 400 ppm). The activity of the hepatic PhIP-activating enzyme, cytochrome P450 (CYP) 1A2, was examined at week 4 and colonic precancerous lesions (aberrant crypt foci, ACF) were enumerated at week 12. In low PhIP-fed groups, CYP1A2 activity was greater for CRU than all other groups, which did not differ from one another. WD had a significantly greater effect on the formation of ACF than the basal diet. In groups fed API or CRU, the ACF number was reduced to the level observed in the basal diet-fed group. In high PhIP-fed groups, all WD-based diets had greater CYP1A2 activity than the basal diet-fed group. Surprisingly, the basal diet group had more ACF than the WD group, and API and CRU groups did not differ from the WD alone group. Thus, at the lower dose of PhIP, the WD increased colon cancer risk in mice, compared to a purified diet, and APIs and CRUs reduced the risk of the WD. However, at the higher dose of PhIP, the enhancement of colon cancer risk by the WD was not evident, nor was the chemopreventive effect of these vegetables.
... The majority of TBI and nutrition studies are focused on acute severe brain injury; while in an outpatient setting, few studies that assess the nutritional status of central nervous system injury. Vitamins, minerals, and essential fatty acids intake were failed to meet the RDA of spinal cord injured patients [66][67][68][69]. Bioactive Vitamin D3 is a powerful modulator of the immune response [70][71][72][73][74] and it is one of the major regulatory hormones of the entire immune system [75]. ...
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Research
Background: Vitamin D insufficiency has been shown to be prevalent in modern society. It has been associated with worsening outcomes in critically ill patients. However, its effect on critically injured trauma patients is unknown. We hypothesize that Vitamin D insufficiency is an independent risk factor for increased in-hospital mortality in critically injured trauma patients (CITPs) requiring admission to the intensive care unit (ICU). Methods: This cross-section study includes 21 trauma brain patients transferred from ICU at Hamad general hospital to the rehabilitation unit at Rumailah hospital in the state of Qatar between August 2014 and June 2015, and 21 control healthy adults. Serum vitamin D3 levels were measured upon rehabilitation unit admission. Patients were stratified into sufficient group (≥ 27 ng/ml), insufficient group (14-26 ng/ml) and severely insufficient (< 14 ng/ml) group. The secondary measure was the prevalence of vitamin D insufficiency/deficiency. Vitamin D dietary intake was assessed using 24-recall and analyzed by an electronic software program (Super tracker). Adequacy/inadequacy was assessed by comparing the actual intake with the Recommended Dietary Allowance (RDA). Results: In total, 23.8% of patients had vitamin D deficiency and an additional 66.7% were insufficient with only 9.5 % being normal Figure1. Patients with vitamin D deficiency were significantly younger than depleted group (P < 0.05). Patients with vitamin D insufficiency also had a higher BMI compared with patients in the other two groups. Insufficient intake of vitamin D (82.7%) after TBI was significantly greater than would be expected in the controls (4.7%) (P< 0.05), as well as it was significantly lower than RDA. Conclusion: Insufficient vitamin D dietary intake combined with low 25-hydroxy-Vitamin D3 levels may be an independent risk factor for worse clinical outcomes, increased length of stay and affect patient quality of life. For optimal brain function, a plentiful supply of vitamins, minerals, antioxidants, and fatty acids are required by using food plans and targeted supplementation.
... To better parallel human food consumption in rodent feeding studies, the total Western diet (TWD) was formulated to emulate typical American intakes of macro-and micro-nutrients on an energy density basis for rodents [32,33]. The TWD is based on 50 th percentile intakes reported in the Centers for Disease Control National Health and Nutrition Examination Survey (NHANES) for 2007-2008, which were adjusted for differences in caloric intake. ...
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Article
Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet.
... Mice then were inoculated with human microbiota from either lean or obese donors. Mice were fed either the standard AIN93G diet; the total Western diet, which is a basal diet that models typical micro-and macronutrient intakes based on National Health and Nutrition Examination Survey (NHANES) data [17]; or a diet-induced obesity diet (diet with 45% of energy as fat). Interestingly, after 22 weeks, diet had the largest impact on the microbiota composition and body weight gain, although some notable, significant differences remained among mice that received the microbiota of different donor types. ...
Article
Animal models of chronic disease are continuously being refined and have evolved with the goal of increasing the translation of results to human populations. Examples of this progress include transgenic models and germ-free animals conventionalized with human microbiota. The gut microbiome is involved in the etiology of several chronic diseases. Therefore, consideration of the experimental conditions that may affect the gut microbiome in pre-clinical disease is very important. Of note, diet plays a large role in shaping the gut microbiome and can be a source of variation between animal models and human populations. Traditionally, nutrition researchers have focused on manipulating the macronutrient profile of experimental diets to model diseases such as metabolic syndrome. However, other dietary components found in human foods, but not in animal diets, can have sizable effects on the composition and metabolic capacity of the gut microbiome and, as a consequence, manifestation of the chronic disease being modeled. The purpose of this review is to describe how food matrix food components, including diverse fiber sources, oxidation products from cooking, and dietary fat emulsifiers shape the composition of the gut microbiome and influence gut health.
... The diet is high in calories, saturated fat, added sugar, and sodium and low in many essential nutrients including vitamin D, calcium, and dietary fiber [11,12]. Excess energy intake has led to a growing prevalence of not only obesity, but also other obesity-related chronic diseases such as cardiovascular disease (CVD) and cancer [11,13,14]. The western-style diet may account for the steady increase in the prevalence of various chronic diseases such as obesity and dyslipidemia in Korea [15]. ...
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Article
Purpose This study was to see the effects of a balanced Korean diet (BKD) on metabolic risk factors in overweight or obese Korean adults, comparing with those of a typical American diet (TAD) and a diet recommended by the 2010 Dietary Guidelines for Americans (2010DGA). Methods The study was designed as a randomized crossover controlled trial, in which 61 overweight or obese volunteers were divided into six groups and each consumed the BKD, 2010DGA, and TAD in a random order for 4 weeks separated by 2-week washout intervals. Anthropometric indices, blood pressure, blood lipid content, fasting blood glucose, and blood insulin level were measured at the beginning and end of each diet period. Results A total of 54 participants completed the trial. The BKD caused more significant reductions of body mass index (BMI) (p < 0.001), body fat percent (p < 0.001), blood total cholesterol (p < 0.001), and low-density lipoprotein (LDL) cholesterol (p = 0.007) compared with the 2010DGA or TAD (all p values for differences between diets < 0.05). All three diets significantly lowered blood triglyceride levels (p < 0.05). The BKD decreased high-density lipoprotein (HDL) cholesterol (p = 0.001) and increased fasting blood glucose (p = 0.018), whereas TAD and 2010DGA increased HDL cholesterol and did not affect blood glucose levels. Furthermore, the BKD significantly decreased the proportion of individuals with elevated total cholesterol (p < 0.001) and LDL cholesterol (p < 0.01), whereas the 2010DGA significantly reduced the number of obese individuals (p < 0.05), and the TAD decreased the number of participants with elevated triglyceride levels (p < 0.05), but increased that of those with elevated LDL cholesterol (p < 0.05). Conclusions The Korean diet based on dietary guidelines improved metabolic risk factors such as BMI, body fat percent, and blood lipid profiles in overweight or obese Korean adults. These results provide evidence to recommend the Korean diet for preventing various metabolic diseases. Clinical trial registration The trial was registered at the Clinical Research Information Service (CRIS) in Korea, the primary registry of the World Health Organization (WHO) international clinical trial registry platform, under number KCT0002437.
... The control group had a standard maintenance diet which is considered the optimal diet for experimental rodents [60]. The nutrition content in TWD provided the median values from National Health and Nutrition Examination Survey (NHANES) [61], which attempts to represent the overall typical/average diet quality in the US. A second study using a diet designed to represent an adjustment to the NHANES data which tend to provide overly optimistic (i.e., healthy) estimates of the typical US diet (due to report bias). ...
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Article
The current systematic review considered research published within the 10 years preceding June 2019, dealing with the topic of obesity and pain. Within the context of the complex biological and behavioral interrelationships among these phenomena, we sought to identify gaps in the literature and to highlight key targets for future transdisciplinary research. The overarching inclusion criteria were that the included studies could directly contribute to our understanding of these complex phenomena. We searched PubMed/Medline/Cochrane databases dating back 10 years, using the primary search terms “obesity” and “pain,” and for a secondary search we used the search terms “pain” and “diet quality.” Included studies (n = 70) are primarily human; however, some animal studies were included to enhance understanding of related basic biological phenomena and/or where human data were absent or significantly limited. Our overall conclusions highlight (1) the mechanisms of obesity-related pain (i.e., mechanical, behavioral, and physiological) and potential biological and behavioral contributors (e.g., gender, distribution of body fat, and dietary factors), (2) the requirement for accurate and reliable objective measurement, (3) the need to integrate biological and behavioral contributors into comprehensive, well-controlled prospective study designs.
... The Western diet was based on NHANES data for macronutrient and micronutrient intake of typical Americans (Supplementary Table 1, available at Carcinogenesis online) (10). All the diets were customdesigned by Envigo (Madison, WI) by modifying the macronutrient composition of the Western diet and keeping the micronutrients the same (Figures 1A and 4A, Supplementary Tables 1-2, available at Carcinogenesis online). ...
Article
In previous studies, we found that low-carbohydrate (CHO) diets reduced the incidence of tumors in mice genetically predisposed to cancer. However, because >90% of human cancers arise via carcinogen-induced somatic mutations, we investigated, herein, the role that different types and levels of CHO, protein and lipid play in lung cancer induced by the tobacco-specific carcinogen, nicotine-derived nitrosamine ketone (NNK) in A/J mice. We found lowering CHO levels significantly reduced lung nodules and blood glucose levels. We also found that soy protein was superior to casein and that coconut oil was ineffective at reducing lung nodules. Diets containing amylose or inulin (at 15% of total calories), soy protein (at 35%) and fat (at 50%, 30% being fish oil) were the most effective at reducing lung nodules. These fish oil-containing diets increased plasma levels of the ketone body, β-hydroxybutyrate, while reducing both insulin and 8-isoprostane in plasma and bronchoalveolar interleukin-12 and lung PGE2 levels. After only 2 weeks on this diet, the levels of γ-H2AX were significantly reduced, 24 hours after NNK treatment. Housing these mice in two-tiered rat cages with exercise wheels led to similar mouse weights on the different diets, whereas keeping mice in standard mouse cages led to both significant weight differences between the low-CHO, soy protein, fish oil diet and Western diet and substantially more lung nodules than in the two-tiered cages. Our results suggest that low-CHO, soy protein, fish oil-containing diets, together with exercise, may reduce the incidence of lung cancer.
... LV dysfunction was achieved using a higher-fat diet-one that is similar in fat content to a standard WD. 21 Mice that were fed this diet for 40 weeks (compared to NC with 10% fat) showed increased body weight and liver weight, fasting hyperglycemia, and impaired glucose tolerance. WD-fed mice tended to exhibit impaired rates of LV pressure development (+dP/dt) and impaired rates of LV pressure decline (-dP/dt) compared to mice fed NC. ...
Article
Diabetes mellitus is associated with increased risk of heart failure. It has been previously demonstrated in mice that a single injection of adeno-associated virus 8 encoding urocortin 2 (AAV8.UCn2) increases glucose disposal in models of insulin resistance and improves the function of the failing heart. The present study tested the hypothesis that UCn2 gene transfer would reduce diabetes-related left ventricular (LV) dysfunction. Eight-week-old C57BL6 male mice were fed a Western diet (WD; 45% fat, 35% carbohydrate) for 40 weeks. At week 30, they received saline or AAV8.UCn2 (2 × 1013 genome copies/kg) via intravenous injection. Ten weeks after gene transfer, fasting blood glucose, glucose tolerance, and cardiac function were measured via echocardiography and in vivo measurement of LV contractile function, and the results were compared to those of mice fed normal chow (NC; 10% fat; 70% carbohydrate). The contents of key LV signaling proteins were also measured to probe mechanisms. WD increased 12 h fasting glucose (WD: 190 ± 11 mg/dL, n = 8; NC: 105 ± 12 mg/dL, n = 7; p = 0.0004). WD tended to reduce LV peak +dP/dt (p = 0.08) and LV peak -dP/dt (p = 0.05). LV ejection fraction was unchanged. Among WD-fed mice, UCn2 gene transfer reduced 12 h fasting glucose (WD-UCn2: 149 ± 6 mg/dL, n = 8; WD-Saline: 190 ± 11 mg/dL, n = 8; p = 0.012), increased LV peak +dP/dt (p < 0.001) and LV peak -dP/dt (p = 0.013), and reduced Tau (p < 0.02), indicating beneficial effects on systolic and diastolic LV function. In addition, among WD-fed mice, UCn2 gene transfer increased LV ejection fraction (p < 0.005) and the velocity of circumferential fiber shortening (p = 0.0005). Finally, a reduction was seen in fatty infiltration of the liver in WD-fed mice that had received UCn2 gene transfer. LV samples from WD-UCn2 mice showed increased phosphorylation of the protein kinase A catalytic domain (p = 0.03). In conclusion, UCn2 gene transfer increased LV systolic and diastolic function and reduced blood glucose in mice with diabetes-related LV dysfunction, indicating that UCn2 gene transfer may be of potential therapeutic benefit.
... To more closely model human intakes, we developed the TWD for rodents with energy and nutrient profiles that emulate a typical Western diet with the use of NHANES data. The TWD was formulated by using a nutrient density approach, described in detail elsewhere (45). Briefly, the amount of each macro-and micronutrient in the AIN93G basal diet, a diet routinely used in cancer studies today, was adjusted to match 50th-percentile intakes for Americans, as reported in NHANES data. ...
Article
Rodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.
... Spinal cord injured patients have revealed that patients often fail to meet the RDAs for multiple vitamins, minerals, and essential fatty acids as reported by multiple studies. [Hintze KJ, et al., 2012, Levine AM et al.,1992, Perret C, Stoffel-Kurt N, 2011, Walters JL, et al., 2009 Several authors have discussed the nutritional needs of the brain at both macro-and micro-levels [Bourre JM (a), 2006, Bourre JM (b) 2006, Morley JE, 2010] stressing the need for nutrient-dense diets that supply ample levels of vitamins, minerals, antioxidants, and essential fatty acids. ...
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Abstract Traumatic Brain Injury (TBI), also known as acquired brain injury or concussion is one of the most serious and challenging health problems worldwide. Emerging economies such as Oman and Qatar have high rates of traumatic brain injury due to road traffic accidents. The incidence of TBI is alarming in Oman (300-400 per 100,000 of the population), which means between 7,500 and 10,000 Omanis suffer a traumatic brain injury (TBI) each year. Previous studies have focused on pharmacological intervention. There is no study, to our knowledge, on the nutritional, biochemical and behavioral status in TBI patients of Oman and Qatar. Despite this extraordinary incidence, little is known about the nutritional and behavioral complications followed TBI. The aims of this study were to assess the nutritional status and nutritional adequacy of traumatic brain injury in Oman. In Oman, this study was conducted in Khoula Hospital (national trauma center) – Muscat – Oman from February 2014 to February 2015 among consecutive patient with TBI. In Qatar, this study was conducted among attendees admitted to the national trauma center, Rumailah Hospital, Hamad Medical Corporation- Doha, Qatar from August 2014 to June 2015. Healthy volunteers were recruited as controls. All participants were signed letter of consent and the study was approved by Institutional Review Boards of both countries. Demographic variables, anthropometric measurements (weight, height, body mass index, skinfold thickness were measured) using standard protocols for such population with myriad complications. Dietary intake was assessed by using 24 – Hour Recall Method and it was analyzed electronically using a computer program (super- tracker) to assess the adequacy/inadequacy of macronutrients and micrinutrients. Behavioural and biochemical entities also measured. The results showed that the cohort with TBI from both countries tend to exhibit nutritional imbalance, including deficient in energy, carbohydrate, protein, micronutrients and fiber respectively. Further, the TBI group exhibited altered cognitive functioning such as memory impairment and behavioral problem such as lack of initiative when compared with healthy control volunteers. Elevated oxidative stress and less antioxidant status also found in both countries TBI population enrolled in our study. This study indicates that TBI in Oman and Qatar are at risk of developing malnutrition, neurobehavioural complication and deranged biochemical profile. These factors are likely to impede their road to regain premorbid self. Future studies should focus on intervention to reverse malnutrition, neurobehavioural complications and its accompanying pathological processes. Keywords: Traumatic Brain Injury, biochemicals, behavioral, Nutrition Adequacy, Nutrition Assessment, Malnutrition
... Previously, we showed that a Total Western Diet (TWD) increased inflammatory cytokines and recovery time following injury (Totsch et al., 2016). The TWD contains median values of nutrients based on the National Health and Nutrition Examination Survey (Hintze et al., 2012). However, Americans at greatest risk for chronic conditions likely consume a poor-quality diet. ...
... Background eucaloric diets (D071005004 and D071005 005; Research Diets Inc., New Brunswick, NJ, USA) were patterned after a typical Western diet (50% kcals carbohydrate, 34% kcals fat, 16% kcals protein; Table 1), with similar micronutrient composition when allometrically scaled based on energy. [20][21][22] Zyflamend extract (0.192%, w/w), solubilized in olive oil, was added to the diet of the experimental group after 1 week on the control diet and maintained on this diet for four additional weeks. The levels of Zyflamend were equivalent to humans consuming *3 one-gram capsules per day. ...
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Article
Zyflamend is a highly controlled blend of 10 herbal extracts that synergistically impact multiple cell signaling pathways with anticancer and anti-inflammatory properties. More recently, its effects were shown to also modify cellular energetics, for example, activation of fatty acid oxidation and inhibition of lipogenesis. However, its general metabolic effects in vivo have yet to be explored. The objective of this study was to characterize the tissue specific metabolomes in response to supplementation of Zyflamend in mice, with a comparison of equivalent metabolomics data generated in plasma from humans supplemented with Zyflamend. Because Zyflamend has been shown to activate AMPK, the "energy sensor" of the cell, in vitro, the effects of Zyflamend on adiposity were also tested in the murine model. C57BL/6 mice were fed diets that mimicked the macro- and micronutrient composition of the U.S. diet with and without Zyflamend supplementation at human equivalent doses. Untargeted metabolomics was performed in liver, skeletal muscle, adipose, and plasma from mice consuming Zyflamend and in plasma from humans supplemented with Zyflamend at an equivalent dose. Adiposity in mice was significantly reduced in the Zyflamend-treated animals (compared with controls) without affecting body weight or weight gain. Based on KEGG pathway enrichment, purine and pyrimidine metabolism (potential regulators of AMPK) were particularly responsive to Zyflamend across all tissues, but only in mice. Consistent with the metabolomics data, Zyflamend activated AMPK and inhibited acetyl CoA-carboxylase in adipose tissue, key regulators of lipogenesis. Zyflamend reduces adipose tissue in mice through a mechanism that likely involves the activation of AMPK.
... The SAD differs from commercially available high-fat diets in that it contains a human-relevant omega-6 to omega-3 PUFA ratio of 16:1 [36], has refined white flour (Gold Medal, General Mills, Minneapolis, MN), sugar and added trans fatty acids to mimic human intake [37]. These changes were chosen to make the diet more translatable to poor quality human diets, but based on the available Total Western Diet [38]. The SAD is composed of 16.7% protein (15.4% kcal), 52.9% carbohydrates (49.0% ...
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Article
Background and aims: Obesity is a significant health concern in the Western world and the presence of comorbid conditions suggests an interaction. The overlapping distributions of chronic pain populations and obesity suggests that an interaction may exist. Poor quality diet (high carbohydrates, saturated fats, omega-6 polyunsaturated fatty acids) can lead to increased adiposity which can activate immune cells independent of the activating effect of the diet components themselves. This dual action can contribute to chronic inflammation that may alter susceptibility to chronic pain and prolong recovery from injury. However, traditional examinations of diet focus on high-fat diets that often contain a single source of fat, that is not reflective of an American diet. Thus, we examined the impact of a novel human-relevant (high-carbohydrate) American diet on measures of pain and inflammation in rats, as well as the effect on recovery and immune cell activation. Methods: We developed a novel, human-relevant Standard American Diet (SAD) to better model the kilocalorie levels and nutrient sources in an American population. Male and female rats were fed the SAD over the course of 20 weeks prior to persistent inflammatory pain induction with Complete Freund's Adjuvant (CFA). Mechanical and thermal sensitivity were measured weekly. Spontaneous pain, open field locomotion and blood glucose levels were measured during diet consumption. Body composition was assessed at 20 weeks. Following full recovery from CFA-induced hypersensitivity, blood was analyzed for inflammatory mediators and spinal cords were immunohistochemically processed for microglial markers. Results: Chronic consumption of the SAD increased fat mass, decreased lean mass and reduce bone mineral density. SAD-fed rats had increased leptin levels and pro-inflammatory cytokines in peripheral blood serum. Following CFA administration, mechanical sensitivity was assessed and recovery was delayed significantly in SAD-fed animals. Sex differences in the impact of the SAD were also observed. The SAD increased body weight and common T-cell related inflammatory mediators in female, but not male, animals. In males, the SAD had a greater effect on bone mineral density and body composition. Long-term consumption of the SAD resulted in elevated microglial staining in the dorsal horn of the spinal cord, but no sex differences were observed. Conclusions: We demonstrate the negative effects of an American diet on physiology, behavior and recovery from injury. SAD consumption elevated pro-inflammatory mediators and increased microglial activation in the spinal cord. While there were sex differences in weight gain and inflammation, both sexes showed prolonged recovery from injury. Implications: These data suggest that poor quality diet may increase susceptibility to chronic pain due to persistent peripheral and central immune system activation. Furthermore, consumption of a diet that is high in carbohydrates and omega-6 polyunsaturated fatty acid is likely to lead to protracted recovery following trauma or surgical procedures. These data suggest that recovery of a number of patients eating a poor quality diet may be expedited with a change in diet to one that is healthier.
... To address this resource gap, our group developed the new total Western diet (TWD) for rodents with energy and nutrient profiles that emulate a typical Western diet using available U.S. survey data (NHANES) (Hintze et al., 2012). Briefly, the amount of each macro-and micronutrient in the AIN93G basal diet, a diet routinely used in cancer studies today, was adjusted to match 50 th percentile intakes for Americans as reported in NHANES survey data. ...
Article
Cancer is a leading cause of death worldwide. The Western dietary pattern is an established risk factor for many cancers, particularly for colorectal cancer (CRC). The Western diet is typified by the high consumption of red and processed meats, high fat foods, sugary foods and refined grains, whereas a more prudent diet replaces these foods with whole grains, fruits and vegetables, many of which are rich in dietary bioactives known to reduce cancer risk. Agricultural production of many of the foods common to the Western diet is also estimated to have a high environmental impact. Thus, diet modification to reduce cancer risk by consumption of more fruits and vegetables would also be considered a more environmentally sustainable diet. This review summarizes the impact of dietary bioactives on gastrointestinal health, with a focus on the role of the gut microbiome and intestinal inflammation in colorectal carcinogenesis. Four dietary bioactives with purported anti-cancer activities are discussed, including catechins (green tea), anthocyanins (red/blue berries), proanthocyanidins (cocoa) and isoflavones (soy), with special consideration given to evidence for their interaction with the gut microbiome. The review concludes with a proposed model for investigating the impact of dietary bioactives for prevention of colon cancer that incorporates the Western nutritional pattern and considers the role of human gut microbiota in pre-clinical studies.
... The LF diet consisted of 5.5% energy from soybean oil and 4.5% from lard. The HF diets consisted of approximately 10.5% energy from soybean oil, 9.6% of energy from butter, 7.6% energy from lard, 12.0% energy from shortening and 4.3% energy from beef tallow [34,40]. Thus, the HF diets were rich in fat with the proportion of the sources of fat mimicking an American-type diet [34]. ...
... To accomplish this, the Total Western Diet (TWD) was used modeled on the National Health and Nutrition Examination Survey (NHANES). 14 The TWD contains the median values of a number of micronutrients and macronutrients from NHANES, and we believe more accurately represents the diet quality of many Americans compared with the standard HFD. ...
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Article
Unlabelled: Obesity and chronic pain are often comorbid and their rates are increasing. It is unknown whether increased pain is caused by greater weight or poor diet quality or both. Therefore, we utilized a Total Western Diet (TWD) to investigate the functional and physiologic consequences of nutritionally poor diet in mice. For 13 weeks on the commercially available TWD, based on the National Health and Nutrition Examination Survey, thresholds of TWD-fed mice significantly increased in both thermal and mechanical tests. Quantitative magnetic resonance imaging revealed a significant increase in fat mass with a concomitant decrease in lean mass in the TWD-fed mice. In addition, there were significant increases in levels of serum leptin and inflammatory cytokines. After chronic pain induction using complete Freund's adjuvant, hypersensitivity was more pronounced and significantly prolonged in the TWD-fed mice. Therefore, prolonged exposure to poor diet quality resulted in altered acute nociceptive sensitivity, systemic inflammation, and persistent pain after inflammatory pain induction. Perspective: These results highlight the negative effects of poor diet quality with respect to recovery from hypersensitivity and susceptibility to chronic pain. A complete understanding of the impact of diet can aid in treatment and recovery dynamics in human clinical patients.
... The purpose of Experiment 2 was to assess whether stimulus control by food deprivation cues would be diminished by chronic exposure to a diet high in saturated fat and processed sugars. This diet was selected because it is similar in macronutrient content to the human "western diet" so named because of its widespread consumption in western and westernized societies (e.g., Hintze, Benninghoff, & Ward, 2012). If intake of a western-style diet (WD) impairs the ability of interoceptive state cues to control appetitive responding, and the function of those state cues is to modulate the ability of external food cues to evoke eating and appetitive behavior, then this impairment may be one mechanism by which consuming a WD makes it difficult to resist responding to environmental food cues in an obesogenic environment. ...
... We propose that this CARD9 deficiency may allow laboratory investigation of this important clinical phenomenon without confounding effects of gender-biased diet and lifestyle. Intriguingly, CARD9 has an established role in Candida response (15,22), and simple sugars, prevalent in Western diets, can increase the presence of intestinal Candida (23,24). Although this is just one of many microbes that may enhance CARD9dependent inflammation, it is an attractive hypothesis that Candida species promote male-specific colorectal cancer associated with Western diets. ...
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Article
CARD9 functions in different inflammation pathways to elicit reponses to microbial signals and is known to impact intestinal inflammation. Examining the APCmin mouse model of intestinal tumorigenesis and using stringently controlled, sex- and age-matched pairs of CARD9-competent and -deficient mice, we have found that CARD9 has a restricted but strong effect on tumorigenesis in the large intestine. We have found that CARD9 reduces viability specifically in males and promotes tumorigenesis specifically in large intestine of these male mice. To our knowledge, this is the first gene ablation in APCmin mice solely affecting colon tumors in male subjects and, as such, may have significant clinical implications. Additional data suggest correlative disruption of plasma cytokine expression and immune infiltration of the tumors. We speculate that known sex-specific differences in human colorectal cancer (CRC) may involve inflammation, particularly CARD9-dependent inflammation. Copyright © 2015, American Association for Cancer Research.
Article
We recently showed that a low carbohydrate (CHO) diet containing soy protein and fish oil dramatically reduces lung nodules in a mouse model of lung cancer when compared to a Western diet. To explore the universality of this finding, we herein compared this low CHO diet to a Western diet on in preventing breast and prostate cancer using a mouse model that expresses the SV40 large T antigen specifically in breast epithelia in females and prostate epithelia in males. We found that breast cancer was significantly reduced with this low CHO diet and this correlated with a reduction in plasma levels of glucose, insulin, IL-6, TNFα and PGE2. This also corresponded with a reduction in the Ki67 proliferation index within breast tumors. On the other hand, this low CHO diet did not reduce the incidence of prostate cancer in the male mice. Although it reduced both blood glucose and insulin to the same extent as in the female mice, there was no reduction in plasma IL-6, TNFα or PGE2 levels, nor in the Ki67 proliferation index in prostate lesions. Based on immunohistochemistry studies with antibodies to PFKFB3, CPT1a and FAS, it is likely that this difference in response of the two cancer types to this low CHO diet reflects differences in the glucose dependence of breast and prostate cancer, with the former being highly dependent on glucose for energy and the latter being more dependent on fatty acids.
Article
The composition and metabolic activity of the microbiome affect many aspects of health, and there is current interest in dietary constituents that may affect this system. The purpose of this study was to evaluate the effects of a mix of probiotics, a mix of prebiotics and a bioactive protein fraction on the microbiome, when fed to mice alone and in combination at physiologically relevant doses. Mice were fed the total western diet (TWD) supplemented with prebiotics, probiotics, and bioactive proteins individually and in combination for four weeks. Subsequently, effects on the composition of gut microbiome, gut short-chain fatty acid (SCFAs) concentration, gut inflammation and integrity of the mucosal barrier were measured. Ruminococcus gnavus was increased in mice gut microbiome after feeding prebiotics. Bifidobacterium longum was increased after feeding probiotics. The treatments significantly affected beta-diversity with minor treatment effects on cecal or fecal SCFAs levels, and the treatments did not affect gut inflammation as measured by fecal calprotectin.
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Asthma is a chronic airway inflammatory disease that affects approximately 300 million people worldwide, causing a substantial healthcare burden. Although there is a large degree of heterogeneity in the inflammatory response of asthmatics, a subset of patients are characterized by type-2 inflammation, which is in part mediated by T H 2 cells in both the upper and lower airways. Asthma prevalence is increased in low-socioeconomic-status populations, where disparities in health behavior exist, including a shift toward a western diet characterized by low dietary fiber. Gut microbes metabolize fiber into short chain fatty acids that can reduce type-2 inflammation in peripheral organs, such as the airways. We hypothesized that soluble fiber can reduce ovalbumin (OVA)-induced upper airway inflammation in the context of the unified airway hypothesis, in mice maintained on ingredient-matched western (WD) and control diets (CD) through production of short chain fatty acids. Our results show that soluble fiber reduces IL-4 and IL-13 gene expression (p<0.05, Mann Whitney) in the sinonasal cavity of CD-fed mice, but this effect was lost in WD-fed mice. This loss of protection in WD-fed mice parallels compositional changes of the cecal and fecal microbiota. Mice fed a soluble fiber supplement while being maintained on a WD had altered microbial communities characterized by lower abundance of fiber fermentering bacteria. This work can be used to develop effective microbiome-based therapeutics as a low-cost method to reduce asthma morbidity. IMPORTANCE Previous research has supported that western-style diets, typically high-fat and low-fiber, are associated with changes in the gut microbiome and increased inflammation. Western diets are accessible and prominent in low-socioeconomic-status populations, where asthma rates are highest; however, there has yet to be a low-cost asthma therapeutic. For the first time, we investigated whether supplementation with a physiologically relevant quantity of soluble corn fiber can reduce allergic airway inflammation. Our study supports that soluble corn fiber supplementation is associated with compositional shifts of the gut microbiota and reduced airway inflammation, promoting the use of fiber as a low-cost microbiome modifying therapy to reduce asthma-associated inflammation. However, soluble corn fiber in conjunction with a western diet resulted in an alternate gut microbiome composition and loss of protection against allergic airway inflammation. These findings further support the importance of the gut microbiota in host health.
Article
The clinical spectra of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) intersect to form a scantily defined overlap syndrome, termed pre-IBD. We show that increased Enterobacteriaceae and reduced Clostridia abundance distinguish the fecal microbiota of pre-IBD patients from IBS patients. A history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD. Exposing mice to these risk factors resulted in conditions resembling pre-IBD and impaired mitochondrial bioenergetics in the colonic epithelium, which triggered dysbiosis. Restoring mitochondrial bioenergetics in the colonic epithelium with 5-amino salicylic acid, a PPAR-γ (peroxisome proliferator–activated receptor gamma) agonist that stimulates mitochondrial activity, ameliorated pre-IBD symptoms. As with patients, mice with pre-IBD exhibited notable expansions of Enterobacteriaceae that exacerbated low-grade mucosal inflammation, suggesting that remediating dysbiosis can alleviate inflammation. Thus, environmental risk factors cooperate to impair epithelial mitochondrial bioenergetics, thereby triggering microbiota disruptions that exacerbate inflammation and distinguish pre-IBD from IBS.
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There is limited understanding of how walnut consumption inhibits the development of colorectal cancer(CRC). A possible mechanism may involve alterations to the gut microbiota. In this study, the effects of walnut on gut microbiota was tested in a mouse tumor bioassay using the colonotropic carcinogen, azoxymethane (AOM) added to the Total Western Diet (TWD). 16S rRNA pyrosequencing identified 3 enterotype-like clusters (E1, E2, E3) in this murine model. E1, E2 and E3 are associated with AOM exposure, walnut consumption and TWD diet, respectively. E2 and E3 showed distinct taxonomic and functional characteristics, while E1 represented an intermediate state. At the family level, E1 and E3 were both enriched with Bacteroidaceae, but driven by two different OTUs (OTU-2 for E1, OTU-4 for E3). E2 was overrepresented with Porphyromonadaceae and Lachnospiraceae, with OTU-3 (family Porphyromonadaceae) as the 'driver' OTU for this cluster. Functionally, E3 is overrepresented with genes of glycan biosynthesis and metabolism, xenobiotic metabolism and lipid metabolism. E2 is enriched with genes associated with cell motility, replication and repair, and amino acid metabolism. Longitudinally, E2 represents the gut microbial status of early life in these mice. In comparison with E1 and E3, E2 is associated with a moderate lower tumor burden (p=0.12). Our results suggest that walnuts may reduce the risk of CRC within a Western diet by altering the gut microbiota. Our findings provide further evidence that CRC risk is potentially modifiable by diet via alterations to the microbiota.
Article
Fetal accretion for DHA is high during late pregnancy due to the brain growth spurt. Prior evidence suggests that DHA is mobilized from maternal liver and adipose to meet fetal accretion and physiological requirements. However, changes in the DHA levels of various maternal tissues throughout pregnancy and into lactation of mothers on diets with and without dietary DHA, and with a background dietary fatty acid profile that resembles human intake has not been examined. Sprague Dawley rats were fed a total western diet with (TWD +) or without DHA (TWD-) along with a commercial rodent chow control (Chow) throughout pregnancy and postpartum. The fatty acid compositions of adipose, brain, heart, liver, erythrocytes, and plasma were determined before pregnancy, at 15 and 20 days of pregnancy, and 7 days postpartum. The placenta, fetuses, and pups were also examined when available. Maternal DHA concentrations were increased in plasma at 20 days pregnancy in all the diets with TWD + > Chow > TWD-. Maternal DHA concentrations in the TWD- group were lower in adipose throughout pregnancy as compared with the other diets. At postpartum, DHA concentrations decreased below baseline levels in the heart of the TWD- and Chow dams and the liver of the TWD- dams. Whole body DHA concentrations of the fetuses did not differ but there was evidence of decreased DHA in the whole body and tissues of the TWD- and Chow 7d old pups. In conclusion, it appears that in this rodent model of pregnancy, maternal adaptations were made to meet fetal DHA requirements, but they may compromise maternal DHA status and the ability to deliver DHA during lactation.
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Scope: In pre-clinical studies investigating bioactive components, the efficacy of the bioactive is likely influenced by the basal diet provided to rodents. In this study, we hypothesized that a model bioactive, green tea extract (GTE), would have different effects on colon carcinogenesis, body composition, and lipid metabolism in mice fed a basal diet formulated to promote animal health and growth (AIN93G) as compared to a Western diet that emulates typical American intakes of micro- and macronutrients, the total Western diet (TWD). Methods and results: Mice were fed either AIN93G or TWD, with or without GTE added to drinking water for 18 weeks. Aberrant crypt foci (ACF) in azoxymethane-initiated mice was nearly three times greater in mice fed TWD compared to AIN93G. Consumption of GTE suppressed ACF development only in mice fed the TWD. Similarly, supplementation with GTE suppressed weight gain and fasted glucose only in mice fed TWD, while GTE suppressed fat mass in mice fed either diet. Irrespective of diet, GTE supplementation increased cecum weight and decreased cecal SCFA concentration. Conclusion: Collectively, these observations indicate that the TWD influences the bioactivity of GTE in rodent models of obesity, metabolism, and carcinogenesis. This article is protected by copyright. All rights reserved.
Article
In this study, we determined the impact of the total Western diet (TWD) for rodents and its macro- and micronutrient components on weight gain and biomarkers of metabolic function in mice compared to a 45% fat diet-induced obesity (DIO) diet and the standard AIN93G diet. We hypothesized that mice fed the TWD would have increased body fat with indicators of metabolic syndrome similar to mice consuming the DIO diet. As expected, DIO-fed mice acquired a metabolic syndrome phenotype typified by increased energy intake, increased body weight gain, increased fat mass, higher fasting glucose, impaired glucose tolerance, and higher plasma leptin relative to the AIN93G diet. Mice fed a macronutrient-modified (MM) diet (with standard vitamin and mineral composition) had a similar response, albeit to a lesser degree than mice fed the DIO diet. Mice fed a vitamin- and mineral-modified diet (with standard macronutrient composition) were not different from mice fed the AIN93G diet. Surprisingly, the TWD (with modified macronutrients, vitamins and minerals) did not significantly affect any of these parameters, despite the fact that the TWD macronutrient profile was identical to the MM diet. These data suggest that, in the context of the TWD, vitamin and mineral intakes in mice that reflect a Western dietary pattern inhibit the hyperphagia and resulting increased weight gain associated with the higher fat content of the TWD. In conclusion, these observations underscore the need to consider the influence of micronutrient intakes in pre-clinical models of obesity and metabolic syndrome.
Article
Walnuts are comprised of a complex array of biologically active constituents with individual cancer-protective properties. Here, we assessed the potential benefit of whole walnut consumption in a mouse tumor bioassay using azoxymethane (AOM). In study 1, a modest reduction (1.3-fold) in tumor numbers was observed in mice fed a standard diet (AIN-76A) containing 9.4% walnuts (15% of total fat). In Study 2, the effects of walnut supplementation were tested in the Total Western Diet (TWD). There was a significant reduction (2.3-fold; p<0.02) in tumor numbers in male mice fed TWD containing 7% walnuts (10.5% of total fat). Higher concentrations of walnuts lacked inhibitory effects, particularly in female mice, indicating there may be optimal levels of dietary walnut intake for cancer prevention. Since components of the Mediterranean diet have been shown to affect the gut microbiome, the effects of walnuts were therefore tested in fecal samples using 16S rRNA gene sequencing. Carcinogen treatment reduced the diversity and richness of the gut microbiome, especially in male mice, which exhibited lower variability and greater sensitivity to environmental changes. Analysis of individual operational taxonomic units (OTUs) identified specific groups of bacteria associated with carcinogen exposure, walnut consumption and/or both variables. Correlation analysis also identified specific OTU-clades that were strongly associated with the presence and number of tumors. Taken together, our results indicate that walnuts afford partial protection to the colon against a potent carcinogenic insult, and this may be due in part to walnut-induced changes to the gut microbiome.
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Unlabelled: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). Up to a third of NAFLD subjects are at risk for developing nonalcoholic steatohepatitis (NASH). Many rodent models fail to replicate both MetS and NASH. The purpose of this study was to develop a reliable mouse model of NASH and MetS using a diet containing cholesterol, saturated fat and carbohydrate that is reflective of Western diets of North Americans. Experimental design: We used adult male C57BL/6 J 4- to 5-week-old mice and administered a solid diet containing 0.2% cholesterol, 45% of its calories from fat, with 30% of the fat in the form of partially hydrogenated vegetable oil. We also provided carbohydrate largely as high-fructose corn syrup equivalent in water. In a separate cohort, we gave the identical diet in the absence of cholesterol. Glucose and insulin tolerance testing was conducted throughout the feeding period. The feeding was conducted for 16 weeks, and the mice were sacrificed for histological analysis, markers of MetS, liver inflammation, circulating lipids, as well as liver staining for fibrosis and alpha smooth muscle actin (α-SMA). Results: We found that cholesterol significantly increased serum leptin, interleukin-6, liver weight and liver weight/body weight ratio, fibrosis and liver α-SMA. Conclusions: Mice administered a diet accurately reflecting patterns associated with humans afflicted with MetS can reliably replicate features of MetS, NASH and significant liver fibrosis. The model we describe significantly reduces the time by several months for development of stage 3 hepatic fibrosis.
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To evaluate dietary adequacy of patients presenting for evaluation at an outpatient traumatic brain injury (TBI) clinic. We identified 14 key micronutrients with defined dietary intake reference ranges that are considered important for brain health. Adult patients completed the Brief NutritionQuest Food Frequency Questionnaire (FFQ) to calculate estimated nutrient intake. Medical records were abstracted for diagnoses, body mass index, and neurobehavioral subscale scores. Nutrients were assessed individually and were also summarized into a summary score. Associations between individual nutrients, summary nutrient intake, and neurobehavioral scores were assessed. A total of 39 FFQs were completed by subjects, and 25 (64%) had recorded neurobehavioral scores. No subjects met the recommended dietary allowances (RDAs) for all 14 micronutrients. Ten (26%) met the RDAs for 6 or fewer nutrients, and 10 met the RDAs for 11-12 nutrients. Of 12 nutrients with sufficient sample size for analysis, 11 (92%) were associated with worse mean somatic scores, 9 (75%) were associated with worse cognitive scores, and 8 (67%) were linked with worse affective scores for those with the lowest nutrient intake compared with those who had the highest intake. However, only four nutrients were statistically associated with the somatic mean score: folate (P = 0.010), magnesium (P = 0.082), vitamin C (P = 0.021), and vitamin K (P = 0.024). None were linked with cognitive or affective scores. Diets failing to meet RDAs for important brain nutrients were common in an outpatient TBI clinic, with the worst mean neurobehavioral scores for those patients not meeting the estimated average requirements.
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For sixteen years, the American institute of Nutrition Rodent Diets, AIN-76 and AIN-76A, have been used extensively around the world. Because of numerous nutritional and technical problems encountered with the diet during this period, it was revised. Two new formulations were derived: AIN-93G for growth, pregnancy and lactation, and AIN-93M for adult maintenance. Some major differences in the new formulation of AIN-93G compared with AIN-76A are as follows: 7 g soybean oil/100 g diet was substituted for 5 g corn oil/ 100 g diet to increase the amount of linolenic acid; cornstarch was substituted for sucrose; the amount of phosphorus was reduced to help eliminate the problem of kidney calcification in female rats; L-cystine was substituted for DL-methionine as the amino acid supplement for casein, known to be deficient in the sulfur amino acids; manganese concentration was lowered to one-fifth the amount in the old diet; the amounts of vitamin E, vitamin K and vitamin B-12 were increased; and molybdenum, silicon, fluoride, nickel, boron, lithium and vanadium were added to the mineral mix. For the AIN-93M maintenance diet, the amount of fat was lowered to 40 g/kg diet from 70 g/kg diet, and the amount of casein to 140 g/kg from 200 g/kg in the AIN-93G diet. Because of a better balance of essential nutrients, the AIN-93 diets may prove to be a better choice than AIN-76A for long-term as well as short-term studies with laboratory rodents.
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Mounting evidence indicates that vitamin B(6), a coenzyme involved in nearly 100 enzymatic reactions, may reduce the risk of colorectal cancer. To conduct a systematic review with meta-analysis of prospective studies assessing the association of vitamin B(6) intake or blood levels of pyridoxal 5'-phosphate (PLP; the active form of vitamin B(6)) with risk of colorectal cancer. Relevant studies were identified by a search of MEDLINE and EMBASE databases to February 2010, with no restrictions. We also reviewed reference lists from retrieved articles. We included prospective studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the association between vitamin B(6) intake or blood PLP levels and the risk of colorectal, colon, or rectal cancer. Two authors independently extracted data and assessed study quality. Study-specific RRs were pooled using a random-effects model. Nine studies on vitamin B(6) intake and 4 studies on blood PLP levels were included in the meta-analysis. The pooled RRs of colorectal cancer for the highest vs lowest category of vitamin B(6) intake and blood PLP levels were 0.90 (95% CI, 0.75-1.07) and 0.52 (95% CI, 0.38-0.71), respectively. There was heterogeneity among studies of vitamin B(6) intake (P = .01) but not among studies of blood PLP levels (P = .95). Omitting 1 study that contributed substantially to the heterogeneity among studies of vitamin B(6) intake yielded a pooled RR of 0.80 (95% CI, 0.69-0.92). The risk of colorectal cancer decreased by 49% for every 100-pmol/mL increase (approximately 2 SDs) in blood PLP levels (RR, 0.51; 95% CI, 0.38-0.69). Vitamin B(6) intake and blood PLP levels were inversely associated with the risk of colorectal cancer in this meta-analysis.
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Epidemiological studies report that high sucrose consumption is associated with increased risk of colon cancer. One hypothesis is that this association is mediated by elevated circulatory insulin and IGF levels promoting intestinal proliferation. To test this hypothesis, APC(Min) mice and their wild type littermates were fed, starting at 4 wk of age, sucrose or cornstarch as the sole carbohydrate source in the absence or presence of low levels of dietary sulindac for 10 or 16 wk, respectively. APC(Min) mice fed sucrose had an increased tumor number in the proximal third of the small intestine in both studies and a higher incidence of papillary colon tumors in the 16-wk feeding study (P < or = 0.05). Mice fed sucrose (relative to cornstarch) had higher body weights and greater Ki67-labeling indexes in colonic epithelium than mice fed cornstarch in both feeding studies (P < or = 0.05). Furthermore, mice fed sucrose had higher serum glucose and liver IGF-I mRNA concentrations (P < or = 0.05) and tended to have higher serum insulin levels (P = 0.08). These results support the hypothesis that high dietary sucrose intake promotes intestinal proliferation and tumorigenesis by increasing circulating levels of insulin and IGF-I.
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Colorectal cancer is the second cause of morbidity and death in Italy. Genetic and environmental factors, i.e. inappropriate nutrition, are strongly involved in the aetiology of colon cancer. In the present review the authors analyze the possible mechanisms by which certain nutritive factors may interfere with the complex process of carcinogenesis. The authors identify studies by a literature search of Medline from January 1, 1970, through December 31, 2006. The mechanism of every protective compound is detailed, in particular the impact of antioxidant vitamins and minerals on tumor development. At present, the data suggest that vegetables are associated with lower risk and that their fbre content alone does not account for this association. Further, meat consumption is associated with an increased risk but this, too, is not explained solely by its fat content. Several microconstituents of the diet may be associated with reduced risk, including folate, methionine, calcium and vitamin D. Short chain fatty acids also contribute to colonic health. Nevertheless agricultural products contain several dangerous pesticides. Mutagenic compounds, particularly heterocyclic amines, produced when protein is cooked, plausibly explain the meat association. Healthy nutrition is a necessary but not sufficient condition for colon cancer prevention: accepted the feasibility of an accurate control on every patient's diet, fequently the difficulty encountered in nutritional chemoprevention is to establish individual metabolic profiles.
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Prospective cohort studies suggest that higher intakes of dairy products, in particular milk, are associated with a decreased risk of colorectal cancer (CRC). In Western populations, dairy products are major contributors to dietary Ca, which may have chemopreventive effects in the colon. The pooling of data from prospective studies suggests a significant protective effect of Ca on CRC risk. Randomised controlled trials with Ca supplements have been conducted with both colorectal adenoma and CRC as endpoints. Results suggest that Ca supplementation at a level of 1000-2000 mg/d reduces adenoma recurrence in individuals with a previous adenoma but has no effect on CRC incidence. There is evidence that the risk reduction from dairy foods may not be solely due to their high Ca content. Dairy products contain other potential chemopreventive components such as vitamin D, butyric acid, conjugated linoleic acid, sphingolipids, and probiotic bacteria in fermented products such as yoghurt. The present review will focus on the epidemiological evidence (and in particular prospective cohort studies) investigating the relationship between dairy product consumption and risk of CRC. An outline of the proposed mechanisms responsible for the protective effect of both Ca and other potential chemopreventive components in dairy products will also be presented.
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We reported previously that a new Western-style diet (NWD) for 18 months, consisting of elevated lipids and decreased calcium, vitamin D and methyl-donor nutrients, induced colonic tumors in normal C57Bl/6 mice [Newmark, H.L. et al. (2001) A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis, 22, 1871-1875], suggesting a new mouse model for human sporadic colon cancer. Here, we have extended this study during a longer feeding period of 2 years wherein tumor formation, tumor inhibition by addition of dietary calcium and vitamin D and their effects on gene expression were determined. We also similarly tested individual supplements of methyl donor (transfer) nutrients (folic acid, choline, methionine and dietary fiber), but these had no significant effect on colonic tumor incidence or multiplicity, whereas supplementation with combined calcium and vitamin D produced significant decrease in both colon tumor incidence and multiplicity, during 2 years of feeding. No visible colonic tumors were found at 6 months, very few at 12 months, more at 18 months and significantly at 24 months. In a related study of gene changes of the mouse colonic mucosa at 6 months of feeding taken from this study, long before any tumors were visibly detectable, indicated altered profiles of gene expression linked to later risk of dietary initiation of colon tumor formation. This type of early genetic altered profile, an indication of increased risk of later colonic tumor development, may become a useful tool for prediction of colon tumor risk while the colon grossly still appears histologically and physiologically normal.
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Significant differences in colon cancer incidence worldwide have led to the hypothesis that this variation can be explained largely by environmental, notably dietary influences. Although a positive correlation between dietary fat intake and incidence is suggested from some human epidemiological and rodent carcinogenesis studies, a direct association remains contentious. Using a spontaneous mouse tumor model of multiple intestinal neoplasia, we demonstrate that there is a generalized increase in tumor counts, in both the large and small bowel with higher dietary fat [standard (3%) fat versus high (15%) fat diet (mean +/- SD) 1.59 +/- 1.46 vs. 3.85 +/- 2.37 P < 0.001 and 21.36 +/- 7.4 vs. 31.3 +/- 9.7, respectively, P < 0.001]. Increasing dietary fat also increases polyp size in the small bowel. These changes appear independent of total calorific intake as assessed by body weights. Halving the crude fiber intake together with an increase in dietary fat from 3% to 10% did not have as marked an effect on tumor counts as an increase of fat alone to 15%, which also decreased survival (P < 0.05). These results demonstrate that increasing dietary fat intake from weaning can have a significant adverse effect on polyp numbers in mice genetically predisposed to intestinal tumor development. A further understanding of the biology of this interaction may provide novel strategies aimed at both colonic polyp prevention and treatment.
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Collectively, the evidence from epidemiologic, animal and human studies strongly suggests that folate status modulates the risk of developing cancers in selected tissues, the most notable of which is the colorectum. Folate depletion appears to enhance carcinogenesis whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. The means by which this modulation of cancer risk is mediated is not known with certainty, but there are several plausible mechanisms which have been described. Folate plays a major role in the formation of S-adenosylmethionine, the universal methyl donor, as well as in the formation of purine and thymidine synthesis for DNA and RNA. Therefore, most mechanistic studies performed to date have focused on alterations in DNA methylation, disruption of DNA integrity and disruption of DNA repair, all of which have been observed with folate depletion. These aberrations in DNA are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes. Recently, the role of a common polymorphism of the methylenetetrahydrofolate reductase gene has been highlighted as well. This review presents those mechanisms which are the most likely candidates to explain folate's effects and it proposes an integrated scheme to explain how these mechanisms might interact.
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In countries with a westernised lifestyle about half of all deaths are caused by circulatory disease and a quarter by cancer. Cancer is an important problem in both public health and political terms worldwide, irrespective of a country's development. The most recent estimates of the global cancer burden suggest that there were 8.1 million new cases, excluding non-melanoma skin cancer, worldwide in 1990. About 10 million new cases are now diagnosed each year. The numbers of new cases of colorectal cancer worldwide has increased rapidly since 1975 Estimated incidence of colorectal cancer in United Kingdom, by age and sex, 1995Colorectal cancer is the fourth commonest form of cancer occurring worldwide, with an estimated 783 000 new cases diagnosed in 1990, the most recent year for which international estimates are available. It affects men and women almost equally, with about 401 000 new cases in men annually and 381 000 in women. The number of new cases of colorectal cancer worldwide has been increasing rapidly since 1975 (when it was 500 000).Worldwide, colorectal cancer represents 9.4% of all incident cancer in men and 10.1% in women. Colorectal cancer, however, is not equally common throughout the world. If the westernised countries (North America; those in northern, southern, and western Europe; Australasia; and New Zealand) are combined, colorectal cancer represents 12.6% of all incident cancer in westernised countries in men and 14.1% in women. Elsewhere colorectal cancer represents 7.7% and 7.9% of all incident cases in men and women respectively.International comparison of five year relative survival for colon and rectal cancer in adults aged 15-99 at diagnosis (based on Coleman et al, Cancer survival trends in England and Wales, 1971-1975; Berrino et al, Survival of cancer patients in Europe: the EUROCARE-2 study; and Surveillance Epidemiology and End Results …
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Epidemiological studies and laboratory animal model assays suggest that a high intake of dietary fat promotes colorectal cancer. Several in vivo and in vitro studies support the hypothesis that omega-6 fatty acids promote colon tumorigenesis, whereas omega-3 fatty acids lack promoting activity. Fat intake in the United States traditionally includes high amounts (30% of total caloric intake) of saturated fat rather than omega-6 fatty acids. Therefore, the present study was designed to compare the modulatory effects of a high-fat diet containing mixed lipids (HFML), a diet rich in saturated fatty acids (the average American diet), a diet with fish oil (HFFO) that is rich in omega-3 fatty acids, and a low-fat corn oil diet (LFCO) on the formation of chemically induced colonic aberrant crypt foci (ACF) and tumors, cyclooxygenase (COX)-2 activity, and apoptosis during experimental colon carcinogenesis. At 5 weeks of age, groups of male F344 rats were fed a 5% corn oil diet (LFCO). At 7 weeks of age, rats intended for carcinogen treatment received s.c. injections of azoxymethane at a dose level of 15 mg/kg of body weight once weekly for 2 weeks. Beginning 1 day after the carcinogen treatment, groups of rats were then maintained on experimental diets containing 20% HFML or 20% HFFO. Rats were killed at 8, 23, or 38 weeks after azoxymethane treatment. Colonic ACF and tumors were evaluated histopathologically, and apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated nick end labeling method. Colonic mucosae and tumor samples harvested at week 38 were analyzed for COX-2 synthetic activity and expression. The rats fed the HFML diet showed significantly increased total colonic ACF (P < 0.001-0.0001) with a multiplicity of > or = 4 aberrant crypts/focus (P < 0.0001) compared with the effects of the HFFO or LFCO diets at week 8, 23, and 38. Interestingly, there was a 2- to 3-fold increase (> or = 4) in multicrypt foci in rats given the HFML diet as compared with such foci in rats fed the HFFO or LFCO diets. By week 23, the HFML diet had significantly increased the incidence of colonic tumors (30-60%) and their multiplicity (100-141%) when compared with the effects of the LFCO or HFFO diets. At week 38, the HFML diet had induced 100% colon tumor incidence and a 4-fold multiplicity of adenocarcinomas compared with the LFCO and HFFO diets. At weeks 23 and 38, a significantly lower percentage of apoptotic colonic epithelial cells were observed in the tumors of animals fed the HFML diet as compared with those fed the HFFO diet. The HFML diet caused significantly increased levels of COX-2 activity in colon tumors (P < 0.05-0.01), and these tumors had enhanced levels of COX-2 expression as compared with those in assays with LFCO or HFFO diets. These observations demonstrate for the first time that HFML diets containing high levels of saturated fatty acids (such as those in Western diets) promote colon carcinogenesis. Although the mechanisms involved in colon tumor promotion by a HFML diet are not fully known, our results indicate that the modulation of eicosanoid production via the influence on COX activity and the suppression of apoptosis may play a key role in HFML diet-induced colon tumorigenesis.
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Decreased dietary intakes of calcium, vitamin D and folic acid have been suggested as risk factors for human colon cancer. We previously fed a Western-style diet (WD) containing reduced calcium, vitamin D and increased fat content to normal C57/Bl6 mice: hyperproliferation, hyperplasia and whole crypt dysplasias developed in the colon following WD administration. Utilizing the same diet, we now also decreased the levels of several nutrients that are required for biochemical reactions involving methyl group inadequacy, i.e. folic acid, methionine, choline and vitamin B(12). Dietary levels of these nutrients were reduced to nutrient-density levels approximating those consumed by large segments of human Western populations. This further modification of the WD resulted in adenoma and carcinoma development in normal mouse colon (P < 0.04 compared with AIN-76A diet). The results indicate, for the first time, that a semi-purified rodent diet designed to mimic the human Western diet can induce colonic tumors in normal mice without carcinogen exposure.
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Collectively, the evidence from epidemiologic, animal and human studies strongly suggests that folate status modulates the risk of developing cancers in selected tissues, the most notable of which is the colorectum. Folate depletion appears to enhance carcinogenesis whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. The means by which this modulation of cancer risk is mediated is not known with certainty, but there are several plausible mechanisms which have been described. Folate plays a major role in the formation of S-adenosylmethionine, the universal methyl donor, as well as in the formation of purine and thymidine synthesis for DNA and RNA. Therefore, most mechanistic studies performed to date have focused on alterations in DNA methylation, disruption of DNA integrity and disruption of DNA repair, all of which have been observed with folate depletion. These aberrations in DNA are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes. Recently, the role of a common polymorphism of the methylenetetrahydrofolate reductase gene has been highlighted as well. This review presents those mechanisms which are the most likely candidates to explain folate's effects and it proposes an integrated scheme to explain how these mechanisms might interact.
Book
This book reviews epidemiological and other knowledge about cancer to provide an overview of what is known, what is not known, and where important knowledge should be sought about practicable means of avoiding cancer. Although the perspective offered will be of interest to specialists in cancer research or regulation, no specialist knowledge by the reader is assumed, so students of many subjects will enjoy the clarity of thought and style which it offers.
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Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are standardized by age to the 2000 United States standard million population. A total of 1,479,350 new cancer cases and 562,340 deaths from cancer are projected to occur in the United States in 2009. Overall cancer incidence rates decreased in the most recent time period in both men (1.8% per year from 2001 to 2005) and women (0.6% per year from 1998 to 2005), largely because of decreases in the three major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and in two major cancer sites in women (breast and colorectum). Overall cancer death rates decreased in men by 19.2% between 1990 and 2005, with decreases in lung (37%), prostate (24%), and colorectal (17%) cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2005 decreased by 11.4%, with decreases in breast (37%) and colorectal (24%) cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates has resulted in the avoidance of about 650,000 deaths from cancer over the 15-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
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apoE-deficient mice have been created by homologous recombination in ES cells. On a low fat, low cholesterol chow diet these animals have plasma cholesterol levels of 494 mg/dl compared with 60 mg/dl in control animals, and when challenged with a high fat Western-type diet, these animals have plasma cholesterol levels of 1821 mg/dl compared with 132 mg/dl in controls. This marked hypercholesterolemia is primarily due to elevated levels of very low and intermediate density lipoproteins. At 10 weeks of age, apoE-deficient mice have already developed atherosclerotic lesions in the aorta and coronary and pulmonary arteries. apoE-deficient mice are a promising small animal model to help understand the role of apoE in vivo and the genetic and environmental determinants of atherosclerosis.
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In a previous study colonic hyperplasia and hyperproliferation were induced in mice and rats by a nutritional-stress diet, based on the AIN-76A semisynthetic diet modified to contain four suggested high-risk components of the human Western-style diet: increased fat and phosphate and decreased calcium and vitamin D contents. In this study the effect of raising calcium alone to near the median level (0.22 mg/kcal) and to a high level (1.3 mg/kcal), comparable to adult human dietary intake, was tested in mice and rats while retaining the three other high-risk components. With median calcium intake the nutritional-stress diet induced hyperproliferation of epithelial cells in colonic crypts, with increased numbers of proliferating cells in crypt columns in sigmoid colon of mice (P less than 0.001) and rats (P = 0.02) and in the ascending colon of mice (P = 0.01). With high calcium intake, hyperproliferation was reduced almost to control amounts in the presence of unchanged fat, phosphate, and vitamin D.
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We studied the effects of specific nutritional modifications on colonic epithelial cell proliferation in mice and rats. The nutritional stress diet developed for this study was based on the AIN (American Institute of Nutrition)-76A semisynthetic diet, modified to contain four suggested risk factors of the human Western-style diet: increased fat and phosphate and decreased calcium and vitamin D content. We fed diets to mice and rats for 12 weeks beginning at 3 weeks of age. Hyperplasia developed in both sigmoid and ascending colon of mice and rats with lengthening of colonic crypts. Hyperproliferation developed in the sigmoid colon of mice and rats, and in the ascending colon of rats, with increased [3H]thymidine-labeling of epithelial cells. Thus, in colonic mucosa, the nutritional stress diet, which included risk factors of a Western-style diet, induced changes that occur in carcinogen-induced rodent models and in humans who are at increased risk for colonic neoplasia. [J Natl Cance0r Inst 82:491-196, 1990]
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Nutritional deficiencies or imbalances are suspected contributory factors to several types of human cancers, and perhaps other human diseases related to long-term metabolic derangements. In order to study these more effectively in laboratory animals, it is suggested that the laboratory diets more closely mimic the nutrient density of suspect human diets. Toxicology and carcinogenic data obtained in animal study using diets based on human nutrient density might be more readily applicable in relation to humans.
Article
Evidence that the various common types of cancer are largely avoidable diseases is reviewed. Life-style and other environmental factors are divided into a dozen categories, and for each category the evidence relating those particular factors to cancer onset rates is summarized. Where possible, an estimate is made of the percentage of current U.S. cancer mortality that might have been caused or avoided by that category of factors. These estimates are based chiefly on evidence from epidemiology, as the available evidence from animal and other laboratory studies cannot provide reliable human risk assessments. By far the largest reliably known percentage is the 30% of current U.S. cancer deaths that are due to tobacco, although it is possible that some nutritional factor(s) may eventually be found to be of comparable importance. The percentage of U.S. cancer deaths that are due to tobacco is still increasing, and must be expected to continue to increase for some years yet due to the delayed effects of the adoption of cigarettes in earlier decades. Trends in mortality and in onset rates for many separate types of cancer are studied in detail in appendixes to this paper. Biases in the available data on registration of new cases produce apparent trends in cancer incidence which are spurious. Biases also produce spurious trends in cancer incidence which are spurious. Biases also produce spurious trends in cancer death certification rates, especially among old people. In (and before) middle age, where the biases are smaller, there appear to be a few real increases and a few real decreases in mortality from some particular types of cancer, but there is no evidence of any generalized increase other than that due to tobacco. Moderate increases or decreases due to some new agent(s) or habit(s) might of course be overlooked in such large-scale analyses. But, such analyses do suggest that, apart from cancer of the respiratory tract, the types of cancer that are currently common are not peculiarly modern diseases and are likely to depend chiefly on some long-established factor(s). (A prospective study utilizing both questionnaires and stored blood and other biological materials might help elucidate these factors.) The proportion of current U.S. cancer deaths attributed to occupational factors is provisionally estimated as 4% (lung cancer being the major contributor to this). This is far smaller than has recently been suggested by various U.S. Government agencies. The matter could be resolved directly by a "case-control" study of lung cancer two or three times larger than the recently completed U.S. National Bladder Cancer Study but similar to it in methodology and unit costs; there are also other reasons for such a study. A fuller summary of conclusions and recommendations comprises the final section of this report.
Article
In this study we evaluated the effect of dietary administration of a high-fat, low-fiber diet (HRD) supplemented with Vitamin E, beta-carotene or folic acid and wheat bran on the growth of pre-existing aberrant crypt foci (ACF) that had been induced in Fischer-344 rats exposed to azoxymethane (AOM) and a HRD for 10 weeks. The rats (25 rats/dietary group) were fed a HRD for 2 weeks and were then given 2 subcutaneous injections of AOM (15 mg/kg body weight) while the rats continued on the HRD. After 6 weeks, rats were either maintained on the HRD (control) or crossed over to a HRD containing non-toxic levels of either Vitamin E, beta-carotene, folic acid or wheat bran. At 10, 14 and 18 weeks after the initiation of the experiment, 5 rats from each group were killed and the number of aberrant crypt foci (ACF) with different multiplicities were compared between groups. The dietary intervention was continued for 30 weeks to determine whether the inhibitory effect on the growth of ACF influenced the subsequent development of colonic tumors. The results revealed that vitamin E and beta-carotene caused a significant decrease in the number of ACF of different multiplicities when compared to the effect of the HRD alone. The decrease in the number of ACF due to folic acid and wheat bran appeared to be much smaller and in most cases was not significant. However, there was also a significant decrease in the incidence of colonic tumors and tumor multiplicity in both the vitamin E and beta-carotene groups that was not seen in the control group. The reports clearly demonstrates the ability of vitamin E and beta-carotene to inhibit the growth of colonic ACF, even in the presence of the strong promoting effect of high levels of dietary fat, using a post-initiation experimental design.
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Dietary deficiency of labile methyl donors (choline and methionine) increases spontaneous and chemically induced hepatocarcinogenesis in rats. Chemical carcinogenesis in the colon, mammary gland, esophagus, and pancreas also may be increased. The mechanism of the dietary effect is not known but may be related to reduced methylation of DNA and RNA, hyperplasia of target cells, increased peroxidative damage, and altered carcinogen or promoter metabolism. Folate deficiency also is associated with increased carcinogenesis, an effect that may be mediated through participation in methyl metabolism; this has been less extensively studied. Deficiency of these three nutrients also may play a role in the elevated cancer risk in humans that is associated with ethanol intake.
Article
The effect of a high vitamin E diet on the early stages of colon carcinogenesis and on the proliferative indexes in the colon and in the prostate glands was investigated in rats. F344 male rats were injected with azoxymethane (AOM, 15 mg/kg sc). One week later, animals were randomly allocated into two dietary groups (n = 8 rats/group): normal vitamin E (50 IU/kg diet) and high vitamin E (200 IU/kg diet). The basal diet was the AIN-76 diet modified to contain high corn oil (23% wt/wt). After eight weeks of feeding, concentrations of vitamin E in plasma, liver, and prostate were analyzed. Enumeration of aberrant crypt foci (ACF) in colons and proliferative indexes of colons and prostate glands were determined. The total number of ACF and the average number of aberrant crypts (AC) per focus were similar in both dietary groups. ACF were classified as small (1-3 crypts/focus), medium (4-6 crypts/focus), or large (> or = 7 crypts/focus). Only the ACF in the small category showed a significant treatment effect, with values being lower in the high vitamin E group than in the control group (p < or = 0.05). No significant difference was observed in colonic proliferative indexes assessed by enumeration of metaphase cells, S phase cells, or cells exhibiting proliferative cell nuclear antigen (PCNA). The PCNA labeling index in the prostate glands and the activity of prostatic acid phosphatase in plasma were higher in high vitamin E-fed rats (p < or = 0.05) than in control animals. The present study demonstrates that additional vitamin E does not inhibit the induction and growth of ACF; also it enhances the proliferative status of the prostate glands.
Article
Aberrant crypt foci (ACF) are preneoplastic lesions for colon cancer. Altered amounts of copper-zinc (CuZnSOD) and manganese (MnSOD) superoxide dismutases have been implicated in multistage carcinogesis of both rodents and humans. Dietary factors are potential modulators of both CuZnSOD and MnSOD activity. The purpose of this study was to investigate the interactive effects of dietary copper, manganese, and iron on 3,2'-dimethyl-4-aminobiphenyl (DMABP)-induced ACF and superoxide dismutase activities in weanling rats fed low or adequate copper (0.8 or 5.1 microg Cu/g diet), low or adequate manganese (0.6 or 17 microg Mn/g diet), and adequate or high iron (37 or 140 microg Fe/g diet). Twelve rats were allowed free access to each of these eight diets for 3.5 wk prior to DMABP administration and for an additional 8 wk after the first DMABP injection. Rats fed low dietary copper had 105% (P < 0.0001) higher formation of DMABP-induced ACF than those fed adequate dietary copper. Rats ingesting low rather than adequate dietary manganese had 23% higher formation of ACF, and rats ingesting high rather than adequate dietary iron had 18% higher formation of ACF. Heart total superoxide dismutase activity was significantly correlated with the number of ACF (r = -0.43, P < 0.0001) in rats administered DMABP. These results suggest that dietary alterations that affect superoxide dismutase activity may affect cancer susceptibility.
Article
A deficiency of any of the micronutrients: folic acid, Vitamin B12, Vitamin B6, niacin, Vitamin C, Vitamin E, iron, or zinc, mimics radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both. For example, the percentage of the US population that has a low intake (<50% of the RDA) for each of these eight micronutrients ranges from 2 to >20%. A level of folate deficiency causing chromosome breaks was present in approximately 10% of the US population, and in a much higher percentage of the poor. Folate deficiency causes extensive incorporation of uracil into human DNA (4 million/cell), leading to chromosomal breaks. This mechanism is the likely cause of the increased colon cancer risk associated with low folate intake. Some evidence, and mechanistic considerations, suggest that Vitamin B12 (14% US elderly) and B6 (10% of US) deficiencies also cause high uracil and chromosome breaks. Micronutrient deficiency may explain, in good part, why the quarter of the population that eats the fewest fruits and vegetables (five portions a day is advised) has about double the cancer rate for most types of cancer when compared to the quarter with the highest intake. For example, 80% of American children and adolescents and 68% of adults do not eat five portions a day. Common micronutrient deficiencies are likely to damage DNA by the same mechanism as radiation and many chemicals, appear to be orders of magnitude more important, and should be compared for perspective. Remedying micronutrient deficiencies should lead to a major improvement in health and an increase in longevity at low cost.
Article
The aim of the present study was to investigate the enhancing effect of dietary sugar on the development of aberrant crypt foci (ACF) in male F344 rats initiated with azoxymethane (AOM). The potential role of sugar as either a co-initiator or a promoter was investigated by giving diets high in sucrose and dextrin (61%) during either the pre-initiation, the initiation, and/or the post-initiation stage of the ACF development. The colonic cell proliferation, activity of colonic phase II enzymes, and a biomarker of lipid peroxidation were additionally examined in order to obtain information on the specific mechanisms involved in the suggested effect of sucrose and dextrin on ACF development. The number of large sized and the total number of ACF were significantly increased by feeding sucrose and dextrin in the post-initiation period. No positive association between colonic cell proliferation and ACF was seen. The level of oxidative stress in the cytosol from the proximal colon and colonic glutathione transferase and quinone reductase was not affected by the sugar treatments. The overall results from this study show that sucrose and dextrin enhance the number of preneoplastic lesions in AOM-initiated rats, and act primarily as promoters in the development of ACF.
Article
Male ICR mice were examined for the effect of vitamin B-6 [pyridoxine (PN) HCl] on azoxymethane-induced colon tumorigenesis. Mice were fed the diets containing 1, 7, 14 or 35 mg PN HCl/kg for 22 wk, and given a weekly injection of azoxymethane (5 mg/kg body) for the initial 10 wk. Compared with the 1 mg PN HCl/kg diet, 7, 14 and 35 mg PN HCl/kg diets significantly suppressed the incidence and number of colon tumors, colon cell proliferation and expressions of c-myc and c-fos proteins. For some variables, 14 and 35 mg PN HCl/kg diets were more effective than the 7 mg/kg diet. Supplemental vitamin B-6 had no influence on the number of colon apoptotic cells. The results suggest that elevating dietary vitamin B-6 suppresses colon tumorigenesis by reducing cell proliferation.
Article
Folate is involved in the synthesis of nucleotides and amino acid metabolism such as methylation of homocysteine to methionine. Methionine is activated by adenosine triphosphate (ATP) to produce S-adenosylmethionine (SAM), the primary intracellular methyl donor. Thus, folate is essential for the synthesis, methylation, and repair of DNA. With regard to its biochemical function it has been hypothesized that a diminished folate status may contribute to carcinogenesis by alteration of gene expression and increased DNA damage. Animal and human studies support this hypothesis, particularly with respect to colorectal cancer. Epidemiological evidence for the association between folate status and cancer was first observed among ulcerative colitis patients. Several case-control studies demonstrated reduction in colorectal cancer risk with better folate status. Two large, prospective cohort studies support the concept that high folate intake is protective against colon cancer. In contrast to colorectal cancer, the potential association of folate status and risk has been less investigated in breast cancer. Recently, convincing epidemiological data establishing a positive effect of folate status on breast cancer risk were published. This review summarizes the epidemiological evidence for the association between folate status and colorectal and breast cancer risk. In addition, a short overview is given on the discussed mechanism(s) by which folate might be involved in carcinogenesis.
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Previous studies have show that changes in protein kinase C (PKC) isoform expression may be related to increased susceptibility of copper-deficient rats to aberrant crypt formation. The purpose of this study was to determine whether dietary copper would affect azoxymethane-induced intestinal tumor formation and PKC isozyme expression in normal colonic mucosa and tumor samples. Eighty weanling Fischer-344 rats were randomly assigned to diets that contained either 0.8 or 5.3 microg Cu/g diet. After 24 and 31 d of diet consumption, 30 rats/diet were administered azoxymethane (15 mg/kg i.p.) and 10 rats/diet were administered saline. Rats continued to consume their respective diets for an additional 38 wk. Rats injected with azoxymethane and fed the low copper diet had a significantly (P < 0.0001) greater small intestinal and total tumor incidence compared with rats fed adequate dietary copper. However, dietary copper did not affect colon tumor incidence. Low dietary copper significantly (P < 0.004) decreased PKC alpha protein expression in normal but not in tumor tissue. In contrast, low dietary copper did not affect PKC delta or zeta protein expression in either the normal or tumor tissue. PKC alpha and delta protein and mRNA expression were lower in tumor tissue than in normal tissue. These results along with previous observations suggest that dietary copper-mediated changes in PKC alpha, delta and zeta protein expression are not as important for colon tumor promotion/progression as they are for tumor initiation.
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Recently we reported that the supplementation of vitamin B6 to low vitamin B6 diet caused suppression in colon tumorigenesis and cell proliferation of azoxymethane-treated mice in a dose-dependent manner among 1, 7, and 14 mg pyridoxine HCl/kg diet (J. Nutr. 131: 2204-2207, 2001). To examine the mechanism of the anticolon tumor effect of vitamin B6, male ICR mice were fed the diet containing 1, 7, 14, and 35 mg pyridoxine HCl/kg diet for 22 wk and simultaneously given a weekly injection of azoxymethane for an initial 10 wk. The supplementation of vitamin B6 to a low vitamin B6 diet (1 mg pyridoxine HCl/kg) suppressed the levels of colonic 8-hydroxyguanosine and 4-hydroxynonenal and inducible nitric oxide synthase protein. The results suggest that the preventive effect of vitamin B6 against colon tumorigenesis is at least in part mediated by reducing oxidative stress and nitric oxide production.
Article
DNA methylation at cytosines in CpG dinucleotides can lead to changes in gene expression and function without altering the primary sequence of the DNA. Methylation can be affected by dietary levels of methyl-donor components, such as folic acid. This may be an important mechanism for environmentally induced changes in gene expression. Recent literature supports a role for DNA-methylation changes in a number of adult-onset disorders and during development. These changes may be significant for better understanding certain birth defects (e.g., neural tube defects) and the long-term consequences of early environmental influences on gene expression (metabolic programming). Optimal "methylation diets" should be investigated as part of the prevention and treatment of all these conditions, as well as in disorders such as Rett syndrome, whose primary defects may lie in DNA methylation-dependent gene regulation.
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Many micronutrients and vitamins are critical for DNA synthesis/repair and maintenance of DNA methylation patterns. Folate has been most extensively investigated in this regard because of its unique function as methyl donor for nucleotide synthesis and biological methylation. Cell culture and animal and human studies showed that deficiency of folate induces disruption of DNA as well as alterations in DNA methylation status. Animal models of methyl deficiency demonstrated an even stronger cause-and-effect relationship than did studies using a folate-deficient diet alone. Such observations imply that the adverse effects of inadequate folate status on DNA metabolism are mostly due to the impairment of methyl supply. Recently, an interaction was observed between folate status and a common mutation in the gene encoding for methylenetetrahydrofolate reductase, an essential enzyme in one-carbon metabolism, in determining genomic DNA methylation. This finding suggests that the interaction between a nutritional status with a genetic polymorphism can modulate gene expression through DNA methylation, especially when such polymorphism limits the methyl supply. DNA methylation, both genome-wide and gene-specific, is of particular interest for the study of cancer, aging and other conditions related to cell-cycle regulation and tissue-specific differentiation, because it affects gene expression without permanent alterations in DNA sequence such as mutations or allele deletions. Understanding the patterns of DNA methylation through the interaction with nutrients is fundamental, not only to provide pathophysiological explanations for the development of certain diseases, but also to improve the knowledge of possible prevention strategies by modifying a nutritional status in at-risk populations.
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Potential chemopreventive agents for colorectal cancer are assessed in rodents. We speculated that the magnitude of the effect is meaningful and ranked all published agents according to their potency. Data were gathered systematically from 137 articles with the aberrant crypt foci (ACF) end point and from 146 articles with the tumor end point. The potency of each agent to reduce the number of ACF is listed in one table and the potency of each agent to reduce the tumor incidence in another table. Both tables are shown in this review and on a website with sorting abilities (http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html). Potency was estimated as the ratio of the value in control rats to the value in treated rats. From each article, only the most potent agent was kept, except in articles reporting the effect of more than seven agents. Among the 186 agents in the ACF table, the median agent reduced the number of ACF by one-half. The most potent agents to reduce azoxymethane-induced ACF were Pluronic, polyethylene glycol, perilla oil with beta-carotene, and sulindac sulfide. Among the 160 agents in the tumor table, the median agent reduced the tumor incidence in rats by one-half. The most potent agents to reduce the incidence of azoxymethane-induced tumors were celecoxib, a protease inhibitor from soy, difluoromethylornithine with piroxicam, polyethylene glycol, and a thiosulfonate. For the 57 agents present in both tables, a significant correlation (r) was found between the potencies against ACF and tumors (r = 0.45, P < 0.001); without celecoxib, a major outlying point in the correlation, r = 0.68 (P < 0.001, n = 56). In conclusion, this review gathers most known chemopreventive agents, ranks the most promising agents against colon carcinogenesis in rats or mice, and further supports the use of ACF as a surrogate end point for tumors in rats.
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We evaluated the effects of diet on intestinal tumorigenesis in male Apc(Min) mice by comparing AIN-76A diet fed ad libitum (CON); calorie intake restricted by 40% of the CON (CR); diet high in olive oil and supplemented with freeze-dried fruit and vegetable extracts (OFV); and diet high in total fat (HF). Compared with CON, the frequency of intestinal polyps was reduced by 57% by CR (P < 0.001) and by 33% OFV diet (P = 0.04). Both effective interventions reduced total body weight, lean mass, and fat mass and increased daily urinary corticosterone output, but only CR reduced serum insulin-like growth factor I and leptin. We conclude that dietary interventions can partially offset genetic susceptibility to intestinal carcinogenesis.
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Thiamin deficiency leads to the endogenous formation of genotoxic alpha-oxoaldehydes (glyoxals). To evaluate whether marginal deficiency poses a carcinogenesis risk we fed rats AIN-76A sucrose-based diets containing thiamin at 4.9 (control), 1.6 or 1.0 mg/kg diet and examined their colons after 160 days. Reduced thiamin increased aberrant crypt foci (ACF) from 1.14+/-0.46 to 3.70+/-1.17 and 2.60+/-1.02 ACF/colon in the absence of exogenous carcinogen or of symptoms of beriberi. Since typical Western diets can provide marginal levels of thiamin with high levels of simple sugars, individuals could be exposed to an increased risk of colon and perhaps other cancers.
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The incidence of colon cancer in industrialised countries has increased since the early 1970s. It is estimated that more than one-third of cases are associated with factors related to a Western diet. Both the type and amount of dietary fats consumed have been implicated in colon cancer aetiology. Recent studies have demonstrated that n-3 polyunsaturated fatty acids (PUFAs), commonly found in fish oil (FO), could prevent colon cancer development. Evidences show that n-3 PUFAs act at different stages of cancer development and through several mechanisms including the modulation of arachidonic acid-derived prostaglandin synthesis, and Ras protein and protein kinase C expression and activity. As a result, n-3 PUFAs limit tumour cell proliferation, increase apoptotic potential along the crypt axis, promote cell differentiation and possibly limit angiogenesis. The modulatory actions of n-3 PUFAs on the immune system and their anti-inflammatory effects might also play a role in reducing colon carcinogenesis. There remains, nevertheless, some ambiguity over the safety of n-3 PUFAs with respect to secondary tumour formation. However, it appears that n-3 PUFAs may be of use in colon cancer prevention.
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One possible dietary factor that may increase susceptibility to colon cancer is inadequate copper intake. The objective of this study was to investigate the effects of low and adequate copper intakes on copper nutriture and putative risk factors for colon cancer susceptibility in healthy men. Seventeen healthy free-living nonsmoking men aged 21-52 y completed a 13-wk controlled feeding study in a randomized crossover design. The basal diet contained 0.59 mg Cu/13.65 MJ. After a 1-wk equilibration period in which the men consumed the basal diet supplemented with 1.0 mg Cu/d, they were randomly assigned to receive either the basal diet or the basal diet supplemented with 2 mg Cu/d for 6 wk. After the first dietary period, the men immediately began to consume the other level of Cu for the last 6 wk. They collected their feces during the equilibration period and during the last 2 wk of the two dietary periods for free radical and fecal water analysis. Low dietary copper significantly (P < 0.01) increased fecal free radical production and fecal water alkaline phosphatase activity. Low dietary copper significantly (P < 0.0001) decreased fecal water copper concentrations but did not affect fecal water volume, pH, iron or zinc concentrations. In contrast to the fecal analysis, hematological indicators of copper status were not significantly affected by the dietary treatments. These results suggest that low dietary copper adversely affects fecal free radical production and fecal water alkaline phosphatase activity, which are putative risk factors for colon cancer.
Article
Folate and folic acid are forms of the B vitamin that are involved in the synthesis, repair, and functioning of DNA and are required for the production and maintenance of cells. Low levels of folate have been associated with several forms of cancer, including colon cancer. Aberrant crypt foci (ACF), identified as putative precursor lesions in the development of colon cancer, have been induced by the drinking water disinfection by-product, tribromomethane (TBM). To investigate whether ACF induced by TBM could be promoted by a diet devoid of dietary folate, male F344/N rats were exposed to 500 mg/l of TBM in drinking water and fed either a normal or no folate diet (NFD) for 26 weeks. At the conclusion of the study, colons were excised and examined for ACF. Rats exposed to TBM and fed a NFD, evident by significantly reduced serum folate concentrations and elevated serum homocysteine levels, had significant increases of ACF when compared to rats exposed to TBM and fed a normal diet. This study highlights the important role that diet, especially folate intake, represents in protecting the colon against TBM-induced ACF.
Article
Previously we reported that dietary supplemental vitamin B6 (B6) reduced colon tumorigenesis and cell proliferation in mice receiving azoxymethane (AOM) for 22 weeks. This study was conducted to examine the influence of short-term consumption (5 weeks) of diets containing graded levels of B6 and fat on colonic cell proliferation in mice with or without receiving AOM. In experiment 1, mice were fed the 10% corn oil diet containing 1, 7, 14, 35 or 70 mg pyridoxine HCl/kg, and received weekly injections of AOM for the initial 3 weeks. In experiment 2, mice were fed 5 or 20% corn oil diet containing 1, 7, 14 or 35 mg pyridoxine HCl/kg, and received weekly injections of AOM or saline for the initial 3 weeks. In experiment 1, supplemental B6 caused a dose-dependent reduction of colon aberrant crypt foci and cell proliferation (BrdU-labeling index) among the 1-14 mg pyridoxine HCl/kg. There was no influence of B6 on these parameters among 14-70 mg pyridoxine HCl/kg. Immunohistochemical analysis of apoptosis labeling by TUNEL method indicated no influence of dietary B6 on colon apoptosis. In experiment 2, supplemental B6 significantly reduced colon cell proliferation regardless of AOM injection. This inhibitory effect on cell proliferation was markedly enhanced by a high-fat diet, but slightly affected by AOM treatment. The results suggest that dietary supplemental B6 inhibits colon cell proliferation from the early stage of colon carcinogenesis, and a high-fat diet markedly enhances the inhibitory effect.
Article
Tumours in rodent and human colon share many histological and genetic features. To know if rodent models of colon carcinogenesis are good predictors of chemopreventive efficacy in humans, we conducted a meta-analysis of aspirin, beta-carotene, calcium, and wheat bran studies. Controlled intervention studies of adenoma recurrence in human volunteers were compared with chemoprevention studies of carcinogen-induced tumours in rats, and of polyps in Min (Apc(+/-)) mice: 6714 volunteers, 3911 rats and 458 mice were included in the meta-analyses. Difference between models was small since most global relative risks were between 0.76 and 1.00. A closer look showed that carcinogen-induced rat studies matched human trials for aspirin, calcium, carotene, and were compatible for wheat bran. Min mice results were compatible with human results for aspirin, but discordant for calcium and wheat bran (no carotene study). These few results suggest that rodent models roughly predict effect in humans, but the prediction is not accurate for all agents. Based on three cases only, the carcinogen-induced rat model seems better than the Min mouse model. However, rodent studies are useful to screen potential chemopreventive agents, and to study mechanisms of carcinogenesis and chemoprevention.
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Since vitamin B12 serves as a cofactor in the synthesis of methyl precursors for biological methylation and enables methylfolate to be recycled for nucleotide synthesis, B12 deficiency has been known to induce hyperhomocysteinemia and inad