Antioxidant foods and ingredients are an important component of the food industry. In the past, antioxidants were used primarily to control oxidation and retard spoilage, but today many are used ...because of putative health benefits. However, the traditional message that oxidative stress, which involves the production of reactive oxygen species (ROS), is the basis for chronic diseases and aging is being reexamined. Accumulating evidence suggests that ROS exert essential metabolic functions and that removal of too many ROS can upset cell signaling pathways and actually increase the risk of chronic disease. It is imperative that the food industry be aware of progress in this field to present the science relative to foods in a forthright and clear manner. This may mean reexamining the health implications of adding large amounts of antioxidants to foods.
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 the gut microbiome, gut short-chain fatty acids (SCFAs) concentration, and gut inflammation 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.
•Mouse prebiotic studies may overstate beneficial effect by providing super-physiological doses.•When scaled via nutrient density, prebiotics and probiotics had small, but significant effects on the microbiome.•Semi-purified diets are associated with higher levels of fecal calprotectin, an inflammatory marker.
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.
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
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.
Ferritins, an ancient family of protein nanocages, concentrate iron in iron-oxy minerals for iron-protein biosynthesis and protection against oxy radical damage. Of the two genetic mechanisms that ...regulate rates of ferritin-L synthesis, DNA transcription and mRNA translation, more is known about mRNA regulation where iron targets complexes of an mRNA structure, the iron-responsive element (IRE) sequence, and ferritin IRE repressors (iron regulatory proteins 1 and 2). Neither the integration of mRNA and DNA regulation nor the ferritin-L DNA promoter are well studied. We now report the combined effects of DNA transcription and mRNA translation regulation of ferritin-L synthesis. First, the promoter of human ferritin-L, encoding the animal-specific subunit associated with human diseases, was identified, and contained an overlapping Maf recognition element (MARE) and antioxidant responsive element (ARE) that was positively regulated by tert-butylhydroquinone, sulforaphane, and hemin with responses comparable to thioredoxin reductase (ARE regulator) or quinone reductase (MARE/ARE regulator). Iron, a poor regulator of the ferritin-L promoter, was 800 times less effective than sulforaphane. Combining the ferritin-L MARE/ARE and IRE produced a response to hemin that was 3-fold greater than the sum of responses of the MARE/ARE or IRE alone. Regulation of ferritin-L by a MARE/ARE DNA sequence emphasizes the importance of ferritin-L in oxidative stress that complements the mRNA regulation in iron stress. Combining DNA and mRNA mechanisms of regulation, as for ferritin-L, illustrates the advantages of using two types of genetic targets to achieve sensitive responses to multiple signals.
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 B6, B12, 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.
•60% of the SCFA receptor mRNA in the hippocampus colocalize with activated microglia.•80% of SCFA receptor mRNA in the dorsal raphe colocalize with serotonergic neurons.•In the dorsal raphe, SCFA ...receptor expression is driven by dietary fiber solubility.•In the hippocampus, SCFA receptor expression is driven by dietary fiber amount.•High dietary fiber decreases tyrosine hydroxylase gene expression.
Short-chain fatty acids (SCFAs) are bioactive lipids that are released into the colon as a metabolite of bacterial fermentation of dietary fibers. Beyond their function in the gastrointestinal tract, SCFAs can also have effects inthe brain, as a part of the gut-brain axis. Recent investigations into potential therapeutic interventions via the manipulation of the gut microbiome—and thus their SCFA metabolites—has been emerging as a new branch of personalized medicine,especially for mental health conditions. The current study sought to measure and localize SCFA receptors in the mouse brain. Two cell types have been implicated in the gut-brain axis: microglia and serotonergic neurons. We used fluorescentin situhybridization in brain sections from mice fed diets with different compositions of fat and fiber to quantify the mRNA levels of known gene markers of these two cell types and colocalize each with mRNA for free fatty acid receptors that bind SCFAs. We focused onmicroglia in the hippocampus and the serotonergic neurons of the dorsal raphe. We found high colocalization of SCFA receptors in both microglia and serotonergic neurons and discovered that SCFA receptor expression in the dorsal raphe is driven by fiber solubility, while SCFA receptor expression in the hippocampus is driven by fiber amount. Higher dietary fiber was associated with decreased tyrosine hydroxylase expression. Thus, our results indicate that the amount and solubility of dietary fiber can change gene expression in the brain’s microglia and serotonin neurons, potentially via sensitivity to circulating levels of SCFAs produced in the gut.
Excess vitamin intake during pregnancy leads to obesogenic phenotypes, and folic acid accounts for many of these effects in male, but not in female, offspring. These outcomes may be modulated by ...another methyl nutrient choline and attributed to the gut microbiota. Pregnant Wistar rats were fed an AIN-93G diet with recommended vitamin (RV), high 10-fold multivitamin (HV), high 10-fold folic acid with recommended choline (HFol) or high 10-fold folic acid without choline (HFol-C) content. Male and female offspring were weaned to a high-fat RV diet for 12 weeks post-weaning. Removing choline from the HFol gestational diet resulted in obesogenic phenotypes that resembled more closely to HV in male and female offspring with higher body weight, food intake, glucose response to a glucose load and body fat percentage with altered activity, concentrations of short-chain fatty acids and gut microbiota composition. Gestational diet and sex of the offspring predicted the gut microbiota differences. Differentially abundant microbes may be important contributors to obesogenic outcomes across diet and sex. In conclusion, a gestational diet high in vitamins or imbalanced folic acid and choline content contributes to the gut microbiota alterations consistent with the obesogenic phenotypes of in male and female offspring.
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 preclinical 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.
Black raspberries (BRB) are rich in anthocyanins with purported anti-inflammatory properties. However, it is not known whether dietary supplementation would ameliorate Western-diet enhanced gut ...inflammation and colon tumorigenesis. We employed a mouse model of colitis-associated colorectal cancer (CAC) to determine the effects of dietary supplementation with 5 to 10% (
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) whole, freeze-dried BRB in male C57BL/6J mice fed either a standard healthy diet (AIN93G) or the total Western diet (TWD). In a pilot study, BRB suppressed colitis and colon tumorigenesis while also shifting the composition of the fecal microbiome in favor of taxa with purported health benefits, including
. In a follow-up experiment using a 2 × 2 factorial design with AIN and TWD basal diets with and without 10% (
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) BRB, supplementation with BRB reduced tumor multiplicity and increased colon length, irrespective of the basal diet, but it did not apparently affect colitis symptoms, colon inflammation or mucosal injury based on histopathological findings. However, BRB intake increased alpha diversity, altered beta diversity and changed the relative abundance of Erysipelotrichaceae, Bifidobacteriaceae, Streptococcaceae, Rikenellaceae, Ruminococcaceae and Akkermansiaceae, among others, of the fecal microbiome. Notably, changes in microbiome profiles were inconsistent with respect to the basal diet consumed. Overall, these studies provide equivocal evidence for in vivo anti-inflammatory effects of BRB on colitis and colon tumorigenesis; yet, BRB supplementation led to dynamic changes in the fecal microbiome composition over the course of disease development.
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