A key objective of this study was to explore the potential of dietary grape consumption to modulate adverse effects caused by a high-fat (western-pattern) diet. Female C57BL/6J mice were purchased at six-weeks-of-age and placed on a standard (semi-synthetic) diet (STD). At 11 weeks-of-age, the mice were continued on the STD or placed on the STD supplemented with 5% standardized grape powder (STD5GP), a high-fat diet (HFD), or an HFD supplemented with 5% standardized grape powder (HFD5GP). After being provided with the respective diets for 13 additional weeks, the mice were euthanized, and liver was collected for biomarker analysis, determination of genetic expression (RNA-Seq), and histopathological examination. All four dietary groups demonstrated unique genetic expression patterns. Using pathway analysis tools (GO, KEGG and Reactome), relative to the STD group, differentially expressed genes of the STD5GP group were significantly enriched in RNA, mitochondria, and protein translation related pathways, as well as drug metabolism, glutathione, detoxification, and oxidative stress associated pathways. The expression of Gstp1 was confirmed to be upregulated by about five-fold (RT-qPCR), and, based on RNA-Seq data, the expression of additional genes associated with the reduction of oxidative stress and detoxification (Gpx4 and 8, Gss, Gpx7, Sod1) were enhanced by dietary grape supplementation. Cluster analysis of genetic expression patterns revealed the greatest divergence between the HFD5GP and HFD groups. In the HFD5GP group, relative to the HFD group, 14 genes responsible for the metabolism, transportation, hydrolysis, and sequestration of fatty acids were upregulated. Conversely, genes responsible for lipid content and cholesterol synthesis (Plin4, Acaa1b, Slc27a1) were downregulated. The two top classifications emerging as enriched in the HFD5GP group vs. the HFD group (KEGG pathway analysis) were Alzheimer’s disease and nonalcoholic fatty liver disease (NAFLD), both of which have been reported in the literature to bear a causal relationship. In the current study, nonalcoholic steatohepatitis was indicated by histological observations that revealed archetype markers of fatty liver induced by the HFD. The adverse response was diminished by grape intervention. In addition to these studies, life-long survival was assessed with C57BL/6J mice. C57BL/6J mice were received at four-weeks-of-age and placed on the STD. At 14-weeks-of-age, the mice were divided into two groups (100 per group) and provided with the HFD or the HFD5GP. Relative to the HFD group, the survival time of the HFD5GP group was enhanced (log-rank test, p = 0.036). The respective hazard ratios were 0.715 (HFD5GP) and 1.397 (HFD). Greater body weight positively correlated with longevity; the highest body weight of the HFD5GP group was attained later in life than the HFD group (p = 0.141). These results suggest the potential of dietary grapes to modulate hepatic gene expression, prevent oxidative damage, induce fatty acid metabolism, ameliorate NAFLD, and increase longevity when co-administered with a high-fat diet.

(1) Background: Adverse effects of a chronic high-fat diet (HFD) on murine behavior, cognition, and memory are well established. Polyphenols such as resveratrol, anthocyanins, and flavonoids, that are known for antioxidative and anti-inflammatory properties, are present in grapes. The objective of this work was to determine if the dietary intake of grapes has the potential of alleviating HFD-induced deficiencies. (2) Methods: The effect of dietary grape intake was studied using behavioral assays and high throughput genome-wide RNA transcriptome analyses with female C57BL6/J mice. (3) Results: Mice that were fed a HFD from 3-weeks of age showed anxiety-like behaviors compared with the standard diet (STD). This HFD-induced effect was attenuated by supplementing the HFD with 1% grape powder (HF1G) (open field test). Similar results were observed with the novel object recognition test; there was a significant difference in time spent exploring a novel object between the HFD and the HF1G groups. There was no significant difference between the HFD1G and the STD groups. Based on the RNA-Seq analysis, genetic expression in the brain varied as a result of diet, with 210, 360, and 221 uniquely expressed genes in the STD, HFD, and HF1G groups, respectively. Cluster analysis revealed that the HFIG group mapped more closely with the STD group than the HFD group. Focusing on some specific areas, based on genetic expression, Dopamine receptor 2 (Drd2) was increased in the HFD group and normalized in the HF1G group, relative to the STD group. In addition, as judged by cluster hierarchy, the expression of genes that are associated with the dopamine receptor 2 pathway were increased in the HFD group, whereas the pattern that was derived from mouse brain from the HF1G group showed greater similarity to the STD group. KEGG pathway analyses were consistent with these results. For example, neuroactive ligand-receptor interaction (KEGG ID: mmu04080) was altered due to HFD compared with STD, but normalized by grape supplementation or the HFD; there was no significant difference between the STD and HF1G groups. In addition, the expression of genes related to feeding behavior, such as Adora2a, Th, and Trh, were also increased in the HFD group compared with the STD group, and attenuated by grape supplementation. (4) Conclusions: Dietary grape consumption has positive effects on behavior and cognition that are impaired by a HFD. Attenuation of these effects correlates with global transcriptional changes in mouse brain.

Over three million Americans are affected by skin cancer each year, largely as a result of exposure to sunlight. The purpose of this study was to determine the potential of grape consumption to modulate UV-induced skin erythema. With 29 human volunteers, we report that nine demonstrated greater resistance to UV irradiation of the skin after consuming the equivalent of three servings of grapes per day for two weeks. We further explored any potential relationship to the gut–skin axis. Alpha- and beta-diversity of the gut microbiome were not altered, but grape consumption modulated microbiota abundance, enzyme levels, and KEGG pathways. Striking differences in the microbiome and metabolome were discerned when comparing the nine individuals showing greater UV resistance with the 20 non-responders. Notably, three urinary metabolites, 2′-deoxyribonic acid, 3-hydroxyphenyl acetic and scyllo-inositol, were depressed in the UV-resistant group. A ROC curve revealed a 71.8% probability that measurement of urinary 2′-deoxyribonic acid identifies a UV skin non-responder. 2′-Deoxyribonic acid is cleaved from the DNA backbone by reactive oxygen species. Three of the nine subjects acquiring UV resistance following grape consumption showed a durable response, and these three demonstrated unique microbiomic and metabolomic profiles. Variable UV skin sensitivity was likely due to glutathione S-transferase polymorphisms. We conclude that a segment of the population is capable of demonstrating greater resistance to a dermal response elicited by UV irradiation as a result of grape consumption. It is uncertain if modulation of the gut-skin axis leads to enhanced UV resistance, but there is correlation. More broadly, it is reasonable to expect that these mechanisms relate to other health outcomes anticipated to result from grape consumption.

As a whole food, the potential health benefits of table grapes have been widely studied. Some individual constituents have garnered great attention, particularly resveratrol, but normal quantities in the diet are meniscal. On the other hand, the grape contains hundreds of compounds, many of which have antioxidant potential. Nonetheless, the achievement of serum or tissue concentrations of grape antioxidants sufficient to mediate a direct quenching effect is not likely, which supports the idea of biological responses being mediated by an indirect catalytic-type response. We demonstrate herein with Hsd:ICR (CD-1^® Outbred, 18–24 g, 3–4 weeks old, female) mice that supplementation of a semi-synthetic diet with a grape surrogate, equivalent to the human consumption of 2.5 servings per day for 12 months, modulates gene expression in the liver, kidney, colon, and ovary. As might be expected when sampling changes in a pool of over 35,000 genes, there are numerous functional implications. Analysis of some specific differentially expressed genes suggests the potential of grape consumption to bolster metabolic detoxification and regulation of reactive oxygen species in the liver, cellular metabolism, and anti-inflammatory activity in the ovary and kidney. In the colon, the data suggest anti-inflammatory activity, suppression of mitochondrial dysfunction, and maintaining homeostasis. Pathway analysis reveals a combination of up- and down-regulation in the target tissues, primarily up-regulated in the kidney and down-regulated in the ovary. More broadly, based on these data, it seems logical to conclude that grape consumption leads to modulation of gene expression throughout the body, the consequence of which may help to explain the broad array of activities demonstrated in diverse tissues such as the brain, heart, eye, bladder, and colon. In addition, this work further supports the profound impact of nutrigenomics on mammalian phenotypic expression.