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Purpose: To determine whether altering the dietary content of ω-6 (n-6) and ω-3 (n-3) polyunsaturated fatty acids affects the growth of androgen-sensitive prostate cancer xenografts, tumor membrane fatty acid composition, and tumor cyclooxygenase-2 and prostaglandin E2 (PGE2) levels.Experimental Design: Individually caged male severe combined immunodeficiency mice were fed isocaloric 20% kcal fat diets with the fat derived either primarily from n-6 fatty acids (n-6 group) or with the fat consisting of n-6 and n-3 fatty acids in a ratio of 1:1 (n-3 group), and injected s.c. with Los Angeles Prostate Cancer 4 (LAPC-4) cells. Tumor volumes and mouse weights were measured weekly, caloric intake was measured 3 days per week, and tumors and serum were harvested at 8 weeks postinjection.Results: Tumor growth rates, final tumor volumes, and serum prostate-specific antigen levels were reduced in the n-3 group relative to the n-6 group. The n-3 group tumors had decreased proliferation (Ki67 staining) and increased apoptosis (terminal nucleotidyl transferase–mediated nick end labeling staining). In vitro proliferation of LAPC-4 cells in medium containing n-3 group serum was reduced by 22% relative to LAPC-4 cells cultured in medium containing serum from the n-6 group. The n-6/n-3 fatty acid ratios in serum and tumor membranes were lower in the n-3 group relative to the n-6 group. In addition, n-3 group tumors had decreased cyclooxygenase-2 protein and mRNA levels, an 83% reduction in PGE2 levels, and decreased vascular endothelial growth factor expression.Conclusion: These results provide a sound basis for clinical trials evaluating the effect of dietary n-3 fatty acids from fish oil on tumor PGE2 and membrane fatty acid composition, and serum and tumor biomarkers of progression in men with prostate cancer.

Supplementary Table S1 from Effect of Altering Dietary ω-6/ω-3 Fatty Acid Ratios on Prostate Cancer Membrane Composition, Cyclooxygenase-2, and Prostaglandin E2

BACKGROUND: The antiprostate cancer effects of dietary ω-3 fatty acids (FAs) were previously found to be dependent on host G-protein coupled receptor 120 (GPR120). Using an orthotopic tumor model and an ex-vivo model of bone marrow derived M2-like macrophages, we sought to determine if ω-3 FAs inhibit angiogenesis and activate T-cells, and if these effects are dependent on GPR120. METHODS: Gausia luciferase labeled MycCaP prostate cancer cells (MycCaP-Gluc) were injected into the anterior prostate lobe of FVB mice. After established tumors were confirmed by blood luminescence, mice were fed an ω-3 or ω-6 diet. Five weeks after tumor injection, tumor weight, immune cell infiltration and markers of angiogenesis were determined. An ex-vivo co-culture model of bone marrow derived M2-like macrophages from wild-type or GPR120 knockout mice with MycCap prostate cancer cells was used to determine if docosahexanoic acid (DHA, ω-3 FA) inhibition of angiogenesis and T-cell activation is dependent on macrophage GPR120. RESULTS: Feeding an ω-3 diet significantly reduced orthotopic MycCaP-Gluc tumor growth relative to an ω-6 diet. Tumors from the ω-3 group had decreased M2-like macrophage infiltration and decreased expression of angiogenesis factors. DHA significantly inhibited M2 macrophage-induced endothelial tube formation and reversed M2 macrophage-induced T-cell suppression, and these DHA effects were mediated, in part, by M2 macrophage GPR120. CONCLUSION: Omega-3 FAs delayed orthotopic tumor growth, inhibited M2-like macrophage tumor infiltration, and inhibited M2-like macrophage-induced angiogenesis and T-cell suppression. Given the central role of M2-like macrophages in prostate cancer progression, GPR120-dependent ω-3 FA inhibition of M2-like macrophages may play an important role in prostate cancer therapeutics.

We recently demonstrated that the consumption of mixed tree nuts (MTNs) during caloric restriction decreased cardiovascular risk factors and increased satiety. Tryptophan (Trp) metabolism has been indicated as a factor in cardiovascular disease. Here, we investigated the effect of MTNs on Trp metabolism and the link to cardiovascular risk markers. Plasma and stool were collected from 95 overweight individuals who consumed either MTNs (or pretzels) daily as part of a hypocaloric weight loss diet for 12 weeks followed by an isocaloric weight maintenance program for an additional 12 weeks. Plasma and fecal samples were evaluated for Trp metabolites by LC–MS and for gut microbiota by 16S rRNA sequencing. Trp–kynurenine metabolism was reduced only in the MTNs group during weight loss (baseline vs. week 12). Changes in Trp–serotonin (week 24) and Trp–indole (week 12) metabolism from baseline were increased in the MTNs group compared to the pretzel group. Intergroup analysis between MTN and pretzel groups does not identify significant microbial changes as indicated by alpha diversity and beta diversity. Changes in the relative abundance of genus Paludicola during intervention are statistically different between the MTNs and pretzel group with p < 0.001 (q = 0.07). Our findings suggest that consumption of MTNs affects Trp host and microbial metabolism in overweight and obese subjects.

OBJECTIVES: Almonds are a rich source of phenolic and polyphenolic compounds, which have antioxidant activity. In vitro and in vivo studies have demonstrated that topical application of almond oil and almond skin extract reduces UVB-induced photoaging. Ultraviolet-B (UVB) protection by oral almond consumption has not been previously studied in humans. It was the objective to investigate whether oral almond consumption can increase resistance to UVB radiation and reduce skin aging in healthy Asian women. METHODS: Thirty-nine female participants (18–45 years) with Fitzpatrick skin type II-IV were randomly assigned to consume either 1.5 oz of almonds or 1.8 oz of pretzels daily for 12 weeks. Minimal erythema dose (MED) was determined using a standardized protocol, which determined the minimal radiation inducing erythema on the inner arm 24 hours following UVB exposure. Facial skin texture was evaluated by two dermatologists using the Clinician's Erythema Assessment scale and Allergan Roughness scale. Facial melanin index, hydration, sebum, and erythema were determined using a cutometer. RESULTS: Women who consumed almonds, experienced a significant increase in MED from 415 ± 64 to 487 ± 59 (18.7 ± 19.2%, P = 0.006) from baseline to week 12 compared to women in the pretzel group from 415 ± 67 to 421 ± 67 (1.8 ± 11.1%). The exposure time to reach minimal erythema was also increased significantly in the almond group from 160 ± 23 to 187 ± 25 (17.5 ± 22.2%) compared to the pretzel group from 165 ± 27 to 166 ± 25 (1.7 ± 14%) (p=0.026). There were no differences noted between the groups consuming almonds versus pretzels in Allergan roughness, melanin, hydration, or sebum on facial skin. CONCLUSIONS: Our findings suggest that daily oral almond consumption may lead to enhanced protection from UVB photodamage by increasing the MED. Protection from other UV radiation was not tested and therefore almond consumption will not replace other methods of sun protection such as application of sunscreen or wearing protective closing. FUNDING SOURCES: Almond Board of California.

It was our hypothesis that foods high in polyphenols and fiber have prebiotic activity. This human intervention study aimed to determine if daily consumption of freeze-dried California strawberry powder (SBP) leads to changes in the intestinal microbiota, fecal cholesterol and bile acid (BA) microbial metabolites. Fifteen healthy adults consumed a beige diet+26 g of SBP for 4 weeks, followed by 2 weeks of beige diet only. Stool samples were collected at 0, 4, and 6 weeks. Fecal microbiota was analyzed by 16S rRNA sequencing; fecal cholesterol, BA, and microbial metabolites by gas chromatography. Confirming compliance, urine concentration of pelargonidin, urolithin A glucuronide and dimethylellagic acid glucuronide were present after 4 weeks of SBP consumption. Daily SBP altered the abundance of 24 operational taxonomic units (OTUs). Comparing week 4 to baseline the most significant increases were observed for one OTU from Firmicutes\Clostridia\ Christensenellaceae\NA, one OTU from Firmicutes\ Clostridia\Mogibacteriacea\NA, one OTU from Verrucomicrobia\ Verrucomicrobiaceae\Akkermansia\Muciniphila, one OTU from Actinobacteria\ Bifidobacteriaceae\Bifidobacterium\NA, and one OTU from Bacteroidetes\Bacteroidia\ Bacteroidaceae\Bacteroides and decrease of one OTU from Proteobacteria\ Betaproteobacteria\Alcaligenaceae\Sutterella. Comparing week 4 to 6, we observed a reversal of the same OTUs from C Christensenellaceae, V muciniphilia and C Mogibacteriaceae. Fecal short chain fatty acids and most of the fecal markers including cholesterol, coprostanol, primary and secondary BAs were not changed significantly except for lithocholic acid, which was increased significantly at week 6 compared to baseline. In summary, SBP consumption increased the abundance of gut microorganisms related to lean body weight, health and longevity, and increased fecal lithocholic acid at week 6 in healthy study participants.

Pomegranate juice (PomJ) contains ellagitannins (ETs) that are metabolized to ellagic acid (EA). Intestinal bacteria convert EA further to urolithins that are absorbed into the circulation and may provide health benefits. PomJ consumption by pregnant women was reported to be neuroprotective for their infants. In order to determine whether EA and metabolites are transferred from breast milk of mothers consuming PomJ to nursing infants, we performed an interventional pilot study and enrolled ten healthy women with full-term, exclusively breast-fed infants, consuming 8 oz. of PomJ daily for two weeks. Breast milk, plasma, urine and stool samples were collected from the mothers and the urine and stool samples from the infants before and after two weeks of PomJ consumption. Samples were analyzed using liquid chromatography-mass spectrometry to identify EA metabolites and 16S rRNA sequencing to determine changes in the microbiota. EA metabolite conjugates (dimethyl EA-glucuronide DMEAG and urolithin A-glucuronide UAG) were found in breast milk, plasma and urine from mothers and in urine of infants after 14 days of PomJ consumption. In addition, urolithin B-glucuronide (UBG) was found in breast milk, plasma and urine from two participants and urine from their infants. PomJ consumption was associated with a significant decrease in breast milk of

Kombucha is an increasingly popular functional beverage that has gained attention for its unique combination of phytochemicals, metabolites, and microbes. Previous chemical and microbial composition analyses of kombucha have mainly focused on understanding their changes during fermentation. Very limited information is available regarding nutrient profiles of final kombucha products in the market. In this study, we compared the major chemicals (tea polyphenols, caffeine), antioxidant properties, microbial and metabolomic profiles of nine commercial kombucha products using shotgun metagenomics, internal transcribed spacer sequencing, untargeted metabolomics, and targeted chemical assays. All of the nine kombucha products showed similar acidity but great differences in chemicals, metabolites, microbes, and antioxidant activities. Most kombucha products are dominated by the probiotic Bacillus coagulans or bacteria capable of fermentation including Lactobacillus nagelii, Gluconacetobacter, Gluconobacter, and Komagataeibacter species. We found that all nine kombuchas also contained varying levels of enteric bacteria including Bacteroides thetaiotamicron, Escherischia coli, Enterococcus faecalis, Bacteroides fragilis, Enterobacter cloacae complex, and Akkermansia muciniphila. The fungal composition of kombucha products was characterized by predominance of fermenting yeast including Brettanomyces species and Cyberlindnera jadinii. Kombucha varied widely in chemical content assessed by global untargeted metabolomics, with metabolomic variation being significantly associated with metagenomic profiles. Variation in tea bases, bacteria/yeast starter cultures, and duration of fermentation may all contribute to the observed large differences in the microbial and chemical profiles of final kombucha products.

BackgroundAvocados are a rich dietary source of monounsaturated fatty acids, carotenoids, and phenolic compounds. Clinical studies have demonstrated that oral consumption of carotenoids improved skin aging. However, no studies have investigated whether oral intake of avocado will reduce skin aging.ObjectivesWe therefore performed this pilot study to assess whether oral consumption of one avocado daily for 8weeks can reduce skin aging in healthy overweight women assessing skin physical characteristics and resistance to UVB radiation.MethodsThirty-nine female participants (age 27-73years) with Fitzpatrick skin type II-IV were randomly assigned to consume either one avocado daily or continue habitual diet for 8weeks. Facial skin elasticity, firmness, pigmentation, sebum, and hydration were determined using a cutometer on the forehead and under eye. Minimal erythema dose (MED) was determined by standardized protocol at inner arm.ResultsElasticity and firmness were increased at forehead comparing 8weeks to baseline in the avocado group. Comparing avocado to control, change in firmness marker from baseline to week 8 indicated a significant increase in forehead skin firmness in the avocado group. We did not observe any change in hydration, pigmentation, sebum, and UVB resistance between the avocado and control group, although changes in melanin and erythema were observed in both groups over time.ConclusionsOur findings suggest that daily oral avocado consumption may lead to enhanced elasticity and firmness of the facial skin in healthy women. Further studies of other skin locations are required to establish the connection between avocado consumption and skin aging.

Grapes provide a rich source of polyphenols and fibers. This study aimed to evaluate the effect of the daily consumption of 46 g of whole grape powder, providing the equivalent of two servings of California table grapes, on the gut microbiome and cholesterol/bile acid metabolism in healthy adults. This study included a 4-week standardization to a low-polyphenol diet, followed by 4 weeks of 46 g of grape powder consumption while continuing the low-polyphenol diet. Compared to the baseline, 4 weeks of grape powder consumption significantly increased the alpha diversity index of the gut microbiome. There was a trend of increasing Verrucomicrobia (p = 0.052) at the phylum level, and a significant increase in Akkermansia was noted. In addition, there was an increase in Flavonifractor and Lachnospiraceae_UCG-010, but a decrease in Bifidobacterium and Dialister at the genus level. Grape powder consumption significantly decreased the total cholesterol by 6.1% and HDL cholesterol by 7.6%. There was also a trend of decreasing LDL cholesterol by 5.9%, and decreasing total bile acid by 40.9%. Blood triglyceride levels and body composition were not changed by grape powder consumption. In conclusion, grape powder consumption significantly modified the gut microbiome and cholesterol/bile acid metabolism.

We evaluated if chronic consumption of quercetin (Q) with green tea extract (GTE) enhances the bioavailability of GT polyphenols (GTPs) and reduces methylation activity as previously observed in mouse xenograft tumors. In this prospective, randomized, parallel design, placebo controlled study, thirty-one men with prostate cancer consumed daily 1 gram of GTE (830 mg of GTP) with 800 mg of Q (GT + Q) or placebo (GT + PL) for four weeks before prostatectomy. First morning voided urine was collected at baseline, 3 weeks and the day of surgery, and prostate tissue on the day of surgery. In week 3, plasma concentration of GTPs and Q was measured in blood collected before and 2 hours after the morning dose. Prostate tissue epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) were detected in 67 and 93% of participants in the GT + Q group and 75 and 94% of participants in the GT + PL group. Q was increased 14-fold, 12-fold and 4.5-fold in plasma, urine, and prostate tissue, respectively, in the GT + Q compared to the GT + PL-group. There was a trend for decreased EGC levels in urine collected prior to prostatectomy in the GT + Q compared to GT + PL-group (p = 0.053). Plasma epigallocatechin (EGC) showed a trend to increase (p = 0.066) two hours after capsule intake in the GT + Q vs. the GT + PL-group. There was no significant difference between the groups in GTP content or methylation activity in prostate tissue or RBCs. No liver toxicity was observed. Although our findings are suggestive, further studies are warranted evaluating if Q alters GTP metabolism.

BackgroundRecent studies have shown that circulating branched-chain amino acids (BCAAs) are elevated in obese, insulin-resistant individuals. However, it is not known if supplementation of additional BCAAs will further impair glucose metabolism.ObjectivesThe aim of this pilot study was to determine the effects of BCAA supplementation on glucose metabolism in obese, prediabetic individuals.MethodsThis is a randomized crossover study involving 12 obese individuals with prediabetes. Participants were randomly assigned to receive a daily supplement containing either 20 g BCAA or protein low in BCAAs for 4 wk with a 2-wk washout in between. At each visit, an oral-glucose-tolerance test (OGTT) was performed. Collected blood samples were used to measure glucose, insulin, and insulin resistance-associated biomarkers.ResultsBCAA supplementation tended to decrease the plasma glucose area under the curve (AUC) measured by the OGTT (AUC percentage change from supplementation baseline, BCAA: -3.3%±3%; low-BCAA: 10.0%±6%; P=0.08). However, BCAA supplementation did not affect plasma insulin during OGTT challenge (BCAA: -3.9%±8%; low-BCAA: 14.8%±10%; P=0.28). The plasma concentrations of nerve growth factor (BCAA: 4.0±1 pg/mL; low-BCAA: 5.7±1 pg/mL; P=0.01) and monocyte chemoattractant protein-1 (BCAA: -0.4%±9%; low-BCAA: 29.0%±18%; P=0.02) were significantly lowered by BCAA supplementation compared to low-BCAA control. Plasma interleukin 1β was significantly elevated by BCAA supplementation (BCAA: 231.4%±187%; low-BCAA: 20.6%±33%; P=0.05). BCAA supplementation did not affect the circulating concentrations of the BCAAs leucine (BCAA: 9.0%±12%; low-BCAA: 9.2%±11%), valine (BCAA: 9.1%±11%; low-BCAA: 12.0%±13%), or isoleucine (BCAA: 2.5%±11%; low-BCAA: 7.3%±11%).ConclusionsOur data suggest that BCAA supplementation did not impair glucose metabolism in obese, prediabetic subjects. Further studies are needed to confirm the results seen in the present study. This study was registered at clinicaltrials.gov as NCT03715010.

OBJECTIVES: Homeostasis of amino acids (AA) such as branched chain AAs (BCAAs), and aromatic AAs are associated with glucose regulation. Fermentable carbohydrates (FC), such as xylooligosaccharide (XOS), have been shown to improve glucose and lipid metabolism. Therefore, we aim to study the potential of dietary FC to modulate systemic and tissue specific amino acid (AA) homeostasis in normal physiological condition. Two FCs of different molecular size were included in this study, XOS (0.3–1 kDa) and a new sulfated fucose containing polysaccharide (SPS) isolated from seaweed (82 kDa). METHODS: Male C57BL6 mice at age 7 week were randomized into three groups and fed AIN93M, AIN93M supplemented with 2% XOS or SPS (w/w) for 8 weeks (n = 6–8/group). SPS was prepared from Laminaria japonica. At the end of the intervention, fasting serum samples were collected and processed for glucose, insulin, AA analysis. Liver and skeletal muscle samples were frozen and processed for AA analysis. RESULTS: Blood glucose was significantly lower in XOS-fed mice but not SPS-fed mice compared to mice fed the control AIN93M diet. No significant differences in blood insulin, lipids, AA as well as body weight and fat depots were observed among the three experimental groups (XOS, SPS and control). In skeletal muscle, the concentration of total free AA, as well as 9 AAs (Asp, Glu, Arg, Tyr, Met, Phe and BCAAs) was significantly lower and 1 AA (Thr) was higher in SPS mice compared to control mice, while free AA levels in skeletal muscle were not significantly different between XOS and control mice. In liver, levels of total free AA, Arg, Thr and leucine metabolite ketoleucine were significantly lower in XOS mice compared to control mice. No significant change in free AA levels in liver was observed between SPS and control mice. CONCLUSIONS: Our data show the differential modulation of systemic and tissue-specific AA and glucose homeostasis by dietary XOS and SPS intake, indicating the key role that AA signaling may play in metabolic homeostasis. FUNDING SOURCES: This project was supported by the National Institutes of Health and UCLA Center for Human Nutrition.

OBJECTIVES: Tree nuts are an excellent dietary source of protein and healthy fat leading to increased satiety. Tree nuts also provide polyphenols, vitamins and minerals supporting the immune response. However, there is a concern that tree nuts are not suitable to be included in a weight loss diet due to their fat content. Therefore, it was the objective of the study to test whether including mixed tree nuts in a weight loss and maintenance program will lead to weight loss by increasing satiety and decreasing inflammation. METHODS: We performed a randomized, controlled, two-arm study in 95 overweight individuals consuming 1.5 oz of mixed tree nuts daily (n = 56) or equal amount of calories in the form of a pretzel snack (n = 39) as part of a hypocaloric weight loss diet (−500 calories of resting metabolic rate) for 12 wks followed by an isocaloric weight maintenance program for an additional 12 wks. RESULTS: The dropout rate was significantly lower in the tree nut (16.4%) compared to the pretzel (35.9%) group. Participants experienced significant weight loss (12 wks: −1.6 and −1.9 and 24 wks: −1.5 kg and −1.4 kg) in the tree nut and pretzel group, respectively, without difference between groups at any time point. In addition, both groups showed a significant decrease in diastolic blood pressure at 12 wks and a significant increase in satiety at 24 wks, but only participants in the mixed tree nut group showed significant decrease in heart rate at 4, 12 and 24 wks. Plasma oleic acid concentration was significantly increased at 12 and 24 wks in the tree nut group, while in the pretzel group plasma oleic acid was significantly increased and stearic acid decreased at 12 wks and linolenic acid was increased at 24 wks. No change in fasting plasma triglyceride, total cholesterol and HDL-cholesterol was observed in both groups. No change in inflammatory markers except plasma MCP-1 was decreased significantly in the tree nut group at 4 wks. CONCLUSIONS: In summary, including mixed tree nuts in a weight loss and maintenance diet can maintain compliance and promote weight loss similar to standard weight loss and maintenance diets. Although both, the mixed tree nut diet and pretzel diet resulted in decreased diastolic blood pressure, only consumption of the mixed tree nut diet led to significantly decreased heart rate and increased study retention. FUNDING SOURCES: International Tree Nut Council.

OBJECTIVES: Avocados are an excellent source of bioactive compounds such as monounsaturated fatty acids, sterols, polyhydroxylated fatty alcohols and carotenoids. A common cause of photoaging is exposure to UV light, as the radiation generates oxidative stress, which leads to inflammation and erythema of the skin. Studies have demonstrated that topical application of bioactive compounds from avocado reduce UVB-induced photoaging. Ultraviolet-B (UVB) protection by oral avocado consumption has not been clinically investigated in humans. Therefore, it is the objective of this pilot study to determine if the consumption of one avocado daily for 16 weeks can increase resistance to UVB radiation and reduce skin aging in healthy women. METHODS: This study is a randomized, two arm, parallel group comparison of daily avocado consumption vs. habitual diet. Eligible participants are females, at least 25 years of age, Fitzpatrick Skin type II-IV, in good health with an increased waist circumference of 35 cm. Participants will be excluded if they are habitually eating 2 avocados per month, allergic to avocado and any unstable medical conditions. At screening, informed consent and HIPAA authorization will be reviewed and signed. In addition, Fitzpatrick Skin type and response to UVB will be assessed. Subjects will consume 1 avocado a day (Hass Avocado) or maintain habitual diet (up to 2 avocados/month) daily for 16 weeks. Skin will be assessed at weeks 0, 8 and 16. Minimal erythema dose (MED) will be determined by exposing the inner arm covered by a sleeve with 6 cut out windows with an increasing dose of UVB using the Dermalight 90. Facial melanin index, hydration and sebum will be determined using the mexameter MA18, corneometer CM825 and sebumeter SM815 probes attached to the Cutometer dual MPA 580 (Courage&Khazaka electronic GmbH, Koeln, Germany). 22 participants will be enrolled in each group considering a 10%dropout rate. RESULTS: Primary outcome will be the effect of daily avocado consumption on MED assessed by UVB exposure compared to habitual diet. Secondary outcomes will be the effect of daily avocado consumption on facial skin elasticity, sebum, melanin and hydration status as assessed by cutometer compared to habitual diet. CONCLUSIONS: This study is currently recruiting participants. FUNDING SOURCES: Hass Avocado Board.

Patients exposed to pollutants are more likely to suffer from allergic rhinitis and may benefit from antioxidant treatment. Our study determined if patients diagnosed with grass-induced allergic rhinitis could benefit from broccoli sprout extract (BSE) supplementation. In total, 47 patients were confirmed with grass-induced allergic rhinitis and randomized to one of four groups: group 1 (nasal steroid spray + BSE), group 2 (nasal steroid spray + placebo tablet), group 3 (saline nasal spray + BSE) and group 4 (saline nasal spray + placebo tablet). Peak Nasal Inspiratory Flow (PNIF), Total Nasal Symptoms Scores (TNSS) and nasal mucus cytokine levels were analyzed in samples collected before and after the 3-week intervention. Comparing before and after the intervention, PNIF improved significantly when comparing Groups 1 and 2, vs. placebo, at various time points (p ≤ 0.05 at 5, 15, 60 and 240 min) following nasal challenge, while TNSS was only statistically significant at 5 (p = 0.03), 15 (p = 0.057) and 30 (p = 0.05) minutes. There were no statistically significant differences in various cytokine markers before and after the intervention. Combining nasal corticosteroid with BSE led to the most significant improvement in objective measures.

Mixed tree nuts (MTNs) are an excellent source of protein and healthy fat contributing to satiety. However, their relatively high caloric content might not be beneficial in a weight loss diet. The present study was designed to test whether including MTNs in a weight loss and maintenance program interferes with weight management compared to a refined carbohydrate pretzel snack (PS). We performed a randomized, controlled, two-arm study in 95 overweight individuals consuming 1.5 oz of MTNs or PS daily as part of a hypocaloric weight loss diet (−500 kcal) over 12 weeks followed by an isocaloric weight maintenance program for 12 weeks. Participants in both groups experienced significant weight loss (12 weeks: −1.6 and −1.9 and 24 weeks: −1.5 and −1.4 kg) compared to baseline in the MTN and PS groups, respectively. However, there was no difference in weight loss and other outcome parameters between the MTN and PS groups. The MTN group showed a significant increase in satiety at 24 weeks. Both groups had a decrease in diastolic blood pressure at 12 weeks. Participants in the MTN group showed significant decreases in heart rate at 4, 12, and 24 weeks. Plasma oleic acid was significantly increased at 12 and 24 weeks in the MTN group but only at 12 weeks in the PS group. Plasma MCP-1 was decreased significantly in the MTN group at 4 weeks. In summary, participants in both groups lost weight, but only the MTN intervention increased satiety at 24 weeks, enhanced retention, decreased heart rate, and increased serum oleic acid at 24 weeks.

OBJECTIVES: Systemic amino acid (AA) levels are tightly regulated. Homeostasis of certain AAs, such as branched chain AAs (BCAAs), and aromatic AAs are not only associated with impaired glucose control but also important determinants of mood. The health benefits of dietary xylooligosaccharides (XOS) in glucose control have been published. In addition, XOS consumption was reported to increase participant-reported vitality and happiness. Therefore, we hypothesized that dietary XOS supplementation induce changes of AA homeostasis, which contributes to its metabolic and mood benefit. METHODS: Male db/db BSK mice and their respective lean control db/m BSK mice were used in this study. Mice at age 7 wk were randomized into three groups and fed AIN93M, AIN93M + 2%−, or 7%-XOS (w/w) for 8 weeks (n = 8–10/group). At the end of the intervention, fasting serum samples were collected and processed for glucose, insulin, AA analysis. RESULTS: db/db mice developed obesity, hyperglycemia and hyperinsulinemia compared to db/m mice. We did not detect difference in serum BCAAs and aromatic AAs, including phenylalanine (phe), tryptophan (Trp) and tyrosine (Tyr) between db/db and db/m mice. Serum arginine (Arg), proline (Pro) and methionine (Met) were significantly lower in db/db compared db/m. Dietary XOS supplementation (2 and 7%) did not change body weight and fat depots in db/m and db/db mice. Fasting blood glucose, Met and Pro levels were significantly reduced by 7% XOS in db/m not db/db mice. XOS did not change any other AAs in either db/db or db/m mice. Serum Trp microbial metabolites indole acetate (IAA) was significantly higher while indole propionate (IPA) was lower in db/db mice compared to db/m mice. XOS (both 2 and 7%) decreased IAA in both db/m and db/db mice, while 2% XOS increased IPA only in db/db mice. Tyr was decreased by 7% XOS in db/m mice but not db/db mice, while Tyr metabolite, p-cresol sulfate, was reduced by 2% XOS in db/db mice only. CONCLUSIONS: Our data indicate interactions between dietary XOS and Leptin R genotype/or host metabolic status on glucose control and systemic AA homeostasis. The mechanism of how dietary XOS intake modulate AA homeostasis needs further investigation. FUNDING SOURCES: This project was supported by NIH-R01 and Center for Human Nutrition.

Xylooligosaccharide (XOS), an oligosaccharide with great prebiotic potential, has been shown to modulate the gut microbiota. Our aim was to determine the effects of dietary XOS supplementation on body composition, lipid metabolism and intestinal microbiota using a mouse model. Our data showed that XOS dietary supplementation at 2.1 and 7.0% significantly changed the gut microbial composition. A decrease in visceral fat depots, concentration of inflammatory cytokine MCP-1, and abundance of the two most important obesity associated gut microbial phyla Firmicutes and Bacteroidetes were observed with 7% XOS supplementation. No change in blood or liver lipids was observed with both XOS doses. The production of SCFAs in the cecum was increased and relative abundance of Actinobacteria was decreased with supplementation of both doses of XOS. To conclude, XOS supplementation reduced adiposity through decreasing gene expression of markers of adipogenesis and fat synthesis and induced changes in intestinal microbial composition.

Background GPR120, a G protein-coupled receptor for long-chain polyunsaturated fatty acids (FAs), mediates the anti-inflammatory effects of omega-3 (ω-3) FAs. We investigated whether host or tumor GPR120 plays a role in the anti-prostate cancer effects of ω-3 FAs. Methods MycCap prostate cancer allografts were grown in immunocompetent wild-type (WT) and GPR120 knockout (KO) mice fed ω-3 (fish oil) or ω-6 (corn oil) diets. Immune cell infiltration was quantified by flow cytometry, and gene expression of immune cell markers in isolated tumor-associated macrophages (TAMs) was quantified by quantitative real-time polymerase chain reaction. Archived tissue from a fish oil intervention trial was used to correlate gene expression of GPR120 with cell cycle progression (CCP) genes and Ki67 index (n = 11-15 per group). All statistical tests were two-sided. Results In WT mice (n = 7 per group), dietary ω-3 FAs decreased MycCap allograft tumor growth (mean [SD] final tumor volume ω-6 = 491 [437] mm3 vs ω-3 = 127 [77] mm3, P = .04), whereas in global GPR120KO mice (n = 7 per group) ω-3 FAs had no anticancer effects. Dietary ω-3 FAs inhibited GPR120KO-MycCaP allografts grown in WT mice (n = 8 per group; mean [SD] final tumor volume ω-6 = 776 [767] mm3 vs ω-3 = 36 [34] mm3, P = .02). Omega-3 FA treatment decreased the number of M2-like TAMs in tumor tissue and gene expression of M2 markers in isolated TAMs compared with ω-6 controls in WT (n = 7 per group) but not in GPR120KO mice (n = 7 per group). In human tissue, higher expression of stromal GPR120 correlated with greater reduction in expression of CCP genes in men with prostate cancer on a high-ω-3 diet (r = -.57, P = .04). Conclusions Host GPR120 plays a central role in the anti-prostate cancer effects of dietary ω-3 FAs. Future studies are required to determine if the anticancer effects of ω-3 FAs are mediated through inhibition of M2-like macrophages and if host GPR120 status predicts anticancer effects of dietary ω-3 FAs in men with prostate cancer.

The study tests the hypothesis that dietary pomegranate extract (PomX) supplementation attenuates colitis in a Western diet feed IL-10 deficient (IL-10-/-) murine model.Four-week-old male IL-10-/- mice are randomly assigned to a high fat high sucrose (HFHS) diet or a HFHS diet supplement with 0.25% PomX for 8 weeks. PomX supplementation lead to significantly lower histological score for colitis (2.6 ± 0.5 vs 3.9 ± 1.0), lower spleen weight (0.11 ± 0.01 vs 0.15 ± 0.02), and lower circulating Interleukin 6(IL-6) levels (15.8±2.2 vs 29.5±5.5) compared with HFHS fed controls. RNAseq analysis of colonic tissues showed 483 downregulated and 263 upregulated genes with PomX supplementation, which are mainly associated with inflammatory responses, defenses, and neutrophil degranulation. In addition, PomX treatment affects the cecal microbiome with increased alpha diversity, altered microbial composition, and increased levels of the tryptophan-related microbial metabolite indole propionate.The data demonstrate that dietary PomX supplementation ameliorated colitis and lowered inflammatory markers in HFHS fed IL-10-/- mice. These data support the anti-inflammatory effects of dietary PomX supplementation for IBD and a potential mediating role of gut microbiome, suggesting the need for future clinical studies to explore the use of PomX dietary supplementation in IBD patients.

Background It has been demonstrated in animal studies that both polyphenol-rich pomegranate extract (PomX) and the polysaccharide inulin, ameliorate metabolic changes induced by a high-fat diet, but little is known about the specific mechanisms. Objective This study evaluated the effect of PomX (0.25%) and inulin (9%) alone or in combination on cholesterol and lipid metabolism in mice. Methods Male C57BL/6 J mice were fed high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose)] diets supplemented with PomX (0.25%) and inulin (9%) alone or in combination for 4 weeks. At the end of intervention, serum and hepatic cholesterol, triglyceride levels, hepatic gene expression of key regulators of cholesterol and lipid metabolism as well as fecal cholesterol and bile acid excretion were determined. Results Dietary supplementation of the HF/HS diet with PomX and inulin decreased hepatic and serum total cholesterol. Supplementation with PomX and inulin together resulted in lower hepatic and serum total cholesterol compared to individual treatments. Compared to HF/HS control, PomX increased gene expression of Cyp7a1 and Cyp7b1, key regulators of bile acid synthesis pathways. Inulin decreased gene expression of key regulators of cholesterol de novo synthesis Srebf2 and Hmgcr and significantly increased fecal elimination of total bile acids and neutral sterols. Only PomX in combination with inulin reduced liver and lipid weight significantly compared to the HF/HS control group. PomX showed a trend to decrease liver triglyceride (TG) levels, while inulin or PomX-inulin combination had no effect on either serum or liver TG levels. Conclusion Dietary PomX and inulin supplementation decreased hepatic and serum total cholesterol by different mechanisms and the combination leading to a significant enhancement of the cholesterol-lowering effect.

Obesity is associated with poorly differentiated and advanced prostate cancer and increased mortality. In preclinical models, caloric restriction delays prostate cancer progression and prolongs survival. We sought to determine if weight loss (WL) in men with prostate cancer prior to radical prostatectomy affects tumor apoptosis and proliferation, and if WL effects other metabolic biomarkers. In this Phase II prospective trial, overweight and obese men scheduled for radical prostatectomy were randomized to a 5–8 week WL program consisting of standard structured energy-restricted meal plans (1200–1500 Kcal/day) and physical activity or to a control group. The primary endpoint was apoptotic index in the radical prostatectomy malignant epithelium. Secondary endpoints were proliferation (Ki67) in the radical prostatectomy tissue, body weight, body mass index (BMI), waist to hip ratio, body composition, and serum PSA, insulin, triglyceride, cholesterol, testosterone, estradiol, leptin, adiponectin, interleukin 6, interleukin 8, insulin-like growth factor 1, and IGF binding protein 1. In total 23 patients were randomized to the WL intervention and 21 patients to the control group. Subjects in the intervention group had significantly more weight loss (WL:−3.7 ± 0.5 kg; Control:−1.6 ± 0.5 kg; p = 0.007) than the control group and total fat mass was significantly reduced (WL:−2.1 ± 0.4; Control: 0.1 ± 0.3; p = 0.015). There was no significant difference in apoptotic or proliferation index between the groups. Among the other biomarkers, triglyceride, and insulin levels were significantly decreased in the WL compared with the control group. In summary, this short-term WL program prior to radical prostatectomy resulted in significantly more WL in the intervention vs. the control group and was accompanied by significant reductions in body fat mass, circulating triglycerides, and insulin. However, no significant changes were observed in malignant epithelium apoptosis or proliferation. Future studies should consider a longer term or more intensive weight loss intervention.

Growing evidence suggests that dysbiosis of gut microbiota is associated with pathogenesis of a variety of human diseases. Using dietary intervention to shape the composition and metabolism of the gut microbiota is increasingly recognized. In the present study, we investigated the effects of polysaccharide inulin and polyphenol-rich pomegranate extract (PomX) alone or in combination on the cecal microbiota composition and function in a diet induced obesity mouse model. Male C57BL/6 mice were randomly divided into four experimental groups and consumed either high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose, 17% energy from protein)] diet, HF/HS diet supplemented with PomX (0.25%), or inulin (9%) or PomX and inulin in combination for 4 weeks. In mice fed the PomX-diet the proportion of Turicibacteraceae and Ruminococcaceae was significantly increased compared to the control HF/HS diet. Supplementation with inulin alone and inulin + PomX combination significantly increased the proportion of Verrucomicrobiaceae (A. muciniphila) and decreased Clostridiaceae. Only mice fed the inulin diet experienced an increase in serum lipopolysaccharide (LPS) and monocyte chemoattractant protein 1 (MCP-1), which was reversed when feeding the inulin + PomX diet. Feeding the inulin + PomX diet was associated with a significant increase in Bifidobacteriaceae and Rikenellaceae, which may have contributed to the reduction of endotoxemia markers. Inulin supplementation showed lower species richness of gut microbiota compared to mice fed with HF/HS or HF/HS/PomX, and the reduction was reversed by the addition of PomX. Inulin alone and in combination with PomX had distinct microbial clusters determined by both weighted and unweighted UniFrac Beta-Diversity principle coordinate analysis. A total of 19 KEGG biological pathways were significantly regulated in the gut microbiota with PomX and inulin alone or combined treatment. Inulin significantly enhanced KEGG infectious disease-related pathway associated with increase of serum LPS and MCP-1. No changes in gene expression of ileal proinflammatory cytokine and tight junction genes were observed in mice treated with PomX and inulin. Our results demonstrated that the gut microbiota and their biological pathways were differentially effected by dietary PomX and inulin fed combined or alone. It is therefore very important to consider the interaction among bioactive components of food when evaluating potential prebiotic effects.

The objective of this study was to investigate prebiotic potential, chemical composition, and antioxidant capacity of spice extracts. Seven culinary spices including black pepper, cayenne pepper, cinnamon, ginger, Mediterranean oregano, rosemary, and turmeric were extracted with boiling water. Major chemical constituents were characterized by RP-HPLC-DAD method and antioxidant capacity was determined by measuring colorimetrically the extent to scavenge ABTS radical cations. Effects of spice extracts on the viability of 88 anaerobic and facultative isolates from intestinal microbiota were determined by using Brucella agar plates containing serial dilutions of extracts. A total of 14 phenolic compounds, a piperine, cinnamic acid, and cinnamaldehyde were identified and quantitated. Spice extracts exhibited high antioxidant capacity that correlated with the total amount of major chemicals. All spice extracts, with the exception of turmeric, enhanced the growth of Bifidobacterium spp. and Lactobacillus spp. All spices exhibited inhibitory activity against selected Ruminococcus species. Cinnamon, oregano, and rosemary were active against selected Fusobacterium strains and cinnamon, rosemary, and turmeric were active against selected Clostridium spp. Some spices displayed prebiotic-like activity by promoting the growth of beneficial bacteria and suppressing the growth of pathogenic bacteria, suggesting their potential role in the regulation of intestinal microbiota and the enhancement of gastrointestinal health. The identification and quantification of spice-specific phytochemicals provided insight into the potential influence of these chemicals on the gut microbial communities and activities. Future research on the connections between spice-induced changes in gut microbiota and host metabolism and disease preventive effect in animal models and humans is needed.

The gut microbiota is an important contributor to human health. Vegetable/fruit juices provide polyphenols, oligosaccharides, fiber and nitrate (beet juice), which may induce a prebiotic-like effect. Juice-based diets are becoming popular. However, there is a lack of scientific evidence of their health benefits. It was our hypothesis that changes in the intestinal microbiota induced by a juice-based diet play an important role in their health benefits. Twenty healthy adults consumed only vegetable/fruit juices for 3 days followed by 14 days of customary diet. On day 4 we observed a significant decrease in weight and body mass index (p = 2.0E−05), which was maintained until day 17 (p = 3.0E−04). On day 4 the proportion of the phylum Firmicutes and Proteobacteria in stool was significantly decreased and Bacteroidetes and Cyanobacteria was increased compared to baseline and was partially reversed on day 17. On day 4 plasma and urine nitric oxide was increased by 244 ± 89% and 450 ± 360%, respectively, and urinary lipid peroxidation marker malondialdehyde was decreased by 32 ± 21% compared to baseline. General well-being score was increased at the end of the study. In summary a 3-day juice-based diet altered the intestinal microbiota associated with weight loss, increase in the vasodilator NO, and decrease in lipid oxidation.

Resistance to high-fat diet-induced obesity (DIR) has been observed in mice fed a high-fat diet and may provide a potential approach for anti-obesity drug discovery. However, the metabolic status, gut microbiota composition, and its associations with DIR are still unclear. Here, ultraperformance liquid chromatography-tandem mass spectrometry-based urinary metabolomic and 16S rRNA gene sequencing-based fecal microbiome analyses were conducted to investigate the relationship between metabolic profile, gut microbiota composition, and body weight of C57BL/6J mice on chow or a high-fat diet for 8 weeks. PICRUSt analysis of 16S rRNA gene sequences predicted the functional metagenomes of gut bacteria. The results demonstrated that feeding a high-fat diet increased body weight and fasting blood glucose of high-fat diet-induced obesity (DIO) mice and altered the host-microbial co-metabolism and gut microbiota composition. In DIR mice, high-fat diet did not increase body weight while fasting blood glucose was increased significantly compared to chow fed mice. In DIR mice, the urinary metabolic pattern was shifted to a distinct direction compared to DIO mice, which was mainly contributed by xanthine. Moreover, high-fat diet caused gut microbiota dysbiosis in both DIO and DIR mice, but in DIR mice, the abundance of Bifidobacteriaceae, Roseburia, and Escherichia was not affected compared to mice fed a chow diet, which played an important role in the pathway coverage of FormylTHF biosynthesis I. Meanwhile, xanthine and pathway coverage of FormylTHF biosynthesis I showed significant positive correlations with mouse body weight. These findings suggest that gut microbiota-mediated xanthine metabolism correlates with resistance to high-fat DIO.

The potential anti-cancer properties of selenium (Se) and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) have been documented. However, few studies have been conducted examining anti-tumor effects of nutritional supplements (NS) containing Se and EPA/DHA in combination with anti-cancer agents, such as taxol (Tax), adriamycin (Adr), and avastin (Ava). Compared with triple-negative breast cancer (TNBC)-bearing positive control (TB) mice, a low dose of Tax, Adr, and Ava decreased tumor size and the incidence of metastasis in TB-Tax, TB-Adr, and TB-Ava groups. Combination treatment with anti-cancer agent and NS (2.7 μg Se and 5.1 mg EPA/3.7 mg DHA/g) induced additional decreases in TB-Tax-NS, TB-Adr-NS, and TB-Ava-NS groups. Th1-associated cytokines were increased, and Th2-type cytokines were decreased significantly in TB mice with combination treatment than that of anti-cancer agent treatment alone. Combination treatment with anti-cancer agents and NS has also been shown to further increased tumor malondialdehyde (MDA) levels, lowered hypoxia-inducible factor (HIF)-1α, angiogenic markers (vascular endothelial growth factor [VEGF] and CD31) and metastatic potential, as well as reduced heat shock proteins, receptor tyrosine kinase AXL, and surface markers of cancer stem cells, and increased apoptotic proteins. For immune checkpoint molecules, combination treatment was associated with a greater decrease in programmed cell death ligand-1 (PD-L1) in both tumors and mammary glands, but PD-1 level in primary tumors was increased. Our results suggest that combination treatment with low-dose anti-cancer agents (Tax, Adr, and Ava) and oral supplementation of Se/ EPA/DHA significantly decreased tumor growth and metastatic progression in TNBC mice through multiple anti-tumor mechanisms.

SCOPE: We aimed at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in mice with diet-induced IR. METHODS AND RESULTS: DBA2J mice were fed a high fat/high sucrose diet (HF/HS) for 8 weeks to induce IR and then 0.1% EA, UA, or EA and UA combined (EA+UA) were added to the HF/HS-diet for another 8 weeks. UA significantly decreased fasting glucose and increased serum adiponectin compared with HF/HS-controls. During intraperitoneal insulin tolerance test, EA+UA significantly improved insulin-mediated glucose lowering effects at 15 and 120 min and reduced blood triglycerides compared with HF/HS-controls. Serum free fatty acids were significantly decreased by EA, UA and EA+UA. We observed differential expression of genes related to mitochondrial function by EA, UA and EA+UA in liver and skeletal muscle. Primary hepatocytes from IR-mice had higher proton leak, basal and ATP-linked oxygen consumption rates compared with healthy controls. EA and EA+UA but not UA reduced the proton leak in hepatocytes from IR-mice. CONCLUSION: EA and UA induced different metabolic benefits in HF/HS diet induced IR mice. The effects of EA and UA on mitochondrial function suggest a potentially novel mechanism modulating metabolism. This article is protected by copyright. All rights reserved.

This study investigated the inhibitory effect of arctigenin, a novel anti-inflammatory lignan, on prostate cancer in obese conditions both in vitro and in vivo. In vitro obese models were established by co-culture of mouse adipocytes 3T3-L1 with androgen-sensitive LNCaP human prostate cancer cells, or by culturing LNCaP cells in adipocytes-conditioned medium. Arctigenin significantly inhibited LNCaP proliferation, along with decreased androgen receptor (AR) and increased Nkx3.1 cellular expression. Male severe combined immunodeficiency mice were subcutaneously implanted with human prostate cancer LAPC-4 xenograft tumors for in vivo study. Mice were fed high-fat (HF) diet and orally given arctigenin at 50 mg/kg body weight daily or vehicle control for 6 weeks. Tumor bearing HF control mice showed a significant increase in serum free fatty acids (FFAs) and decrease in subcutaneous/peritoneal fat depots compared to non-tumor bearing control mice. Arctigenin intervention significantly reduced tumor growth by 45%, associated with decreased circulating FFAs and adipokines/cytokines including IGF-1, VEGF, and MCP-1, along with decreased AR, Ki67, and microvessel density and increased Nkx3.1 expression in tumors. These results indicate the strong ability of arctigenin to co-target obesity and tumor itself in inhibition of prostate tumor growth at a lower concentration compared to most phytochemicals.

In vitro and animal studies have demonstrated that topical application and oral consumption of pomegranate reduces UVB-induced skin damage. We therefore investigated if oral pomegranate consumption will reduce photodamage from UVB irradiation and alter the composition of the skin microbiota in a randomized controlled, parallel, three-arm, open label study. Seventy-four female participants (30–45 years) with Fitzpatrick skin type II-IV were randomly assigned (1:1:1) to 1000 mg of pomegranate extract (PomX), 8 oz of pomegranate juice (PomJ) or placebo for 12 weeks. Minimal erythema dose (MED) and melanin index were determined using a cutometer (mexameter probe). Skin microbiota was determined using 16S rRNA sequencing. The MED was significantly increased in the PomX and PomJ group compared to placebo. There was no significant difference on phylum, but on family and genus level bacterial composition of skin samples collected at baseline and after 12 week intervention showed significant differences between PomJ, PomX and placebo. Members of the Methylobacteriaceae family contain pigments absorbing UV irradiation and might contribute to UVB skin protection. However, we were not able to establish a direct correlation between increased MED and bacterial abundance. In summary daily oral pomegranate consumption may lead to enhanced protection from UV photodamage.

OBJECTIVES: The objective of this study is to investigate the effect of one time intake of cinnamon spice on the postprandial glucose tolerance and insulin secretion following consumption of a high glycemic index meal in normal weight and glucose tolerance individuals. METHODS: Sixteen healthy controls (BMI = 18.5–24.9 kg/m(2) and fasting blood glucose (BG)

OBJECTIVES: The gut microbiota produces numerous metabolites from dietary nutrients that can circulate systemically and influence the host physiology. Bacterial enzymes convert dietary L-tryptophan (Trp) to indole, from which several metabolites can be formed by mammalian and bacterial enzymes. The bacterial metabolite indole propionic acid (IPA) is anti-inflammatory, neuroprotective and has been linked to a lower risk of type 2 diabetes. Little is known about which bacteria are responsible for IPA formation. Pomegranates (Pom) are excellent sources of ellagitannins (ET) and ellagic acid (EA) with prebiotic function. Therefore, it was our hypothesis that long-term Pom consumption will change bacterial Trp metabolite formation. METHODS: We performed a 12-month, randomized, double-blind, placebo-controlled trial of pomegranate juice in middle-aged and older, healthy adults. Nineteen subjects (ages 50–60) were randomized to consume 8 oz of pomegranate juice (the Wonderful Company, LLC) (N = 11) or placebo drink (N = 8) every day. The placebo drink contained high fructose corn syrup, Pom essence and flavor and FD&C Red#40, Blue#1. Stool samples were collected at baseline and after 1 year of Pom J consumption. Bacterial composition was determined using 16S rRNA microbiome sequencing. Plasma IPA concentrations were determined by HPLC. Correlation between fecal bacterial content and plasma IPA was evaluated in all samples using Spearman's analysis. RESULTS: The IPA was significantly reduced in the placebo group (P = 0.017), while there was no change in the Pom J group (P = 0.458). The change in plasma IPA during one year of Pom J compared to placebo drink consumption was significantly different (P = 0.028). At 12 months, plasma IPA concentration was significantly positively correlated with the relative proportion of Roseburia (0.57), Lachnospira (0.53) in the phylum Firmicutes; Sutterella (0.63) in the phylum Proteobacterium and Collinsella (0.46) in the phylum Actinobacteria. A significant negative correlation was observed with the relative proportion of Campylobacteraceae (−0.46). CONCLUSIONS: Formation of IPA associated with a microbial profile supported by Pom J consumption might contribute to the cardiovascular health benefits of Pom. FUNDING SOURCES: Supported by Center for Human Nutrition, UCLA.

OBJECTIVES: In the GI tract, Pomegranates (Pom) ellagitannins undergo hydrolysis to ellagic acid (EA) and are further metabolized into urolithins by the gut microbiota. Both EA and UA have significant health benefits. EA is also available as dietary supplement. We aimed to compare the bioavailability of EA and its biotransformation to UA between pure EA and Pom juice (PomJ). METHODS: 17 healthy male participants were randomly assigned to take a single dose of 8 oz of PomJ or 500 mg of EA, followed by 2-week washout, and crossover to the other intervention. We collected blood prior and 1 and 2 h after consumption of EA or PomJ and urine for 24hours. Plasma concentration of EA was measured using HPLC. Urinary EA metabolites (DMEAG and UAG) were determined by LC/MS and normalized to urine creatinine levels. Circulating MCP1, insulin and leptin were analyzed using the multiplex human cytokine panel (Millipore). RESULTS: There was no difference in plasma EA concentration after administration of PomJ versus 500 mg EA. Urinary DMEAG, normalized to creatinine, was significantly higher after PomJ compared to EA intake (PomJ: 0.11 + 0.02; EA: 0.05 + 0.01 µg/mg; P

Spices were used as food preservatives prior to the advent of refrigeration, suggesting the possibility of effects on microbiota. Previous studies have shown prebiotic activities in animals and in vitro, but there has not been a demonstration of prebiotic or postbiotic effects at culinary doses in humans. In this randomized placebo-controlled study, we determined in twenty-nine healthy adults the effects on the gut microbiota of the consumption daily of capsules containing 5 g of mixed spices at culinary doses by comparison to a matched control group consuming a maltodextrin placebo capsule. The 16S ribosomal RNA sequencing data were used for microbial characterization. Spice consumption resulted in a significant reduction in Firmicutes abundance (p &lt, 0.033) and a trend of enrichment in Bacteroidetes (p &lt, 0.097) compared to placebo group. Twenty-six operational taxonomic units (OTUs) were different between the spice and placebo groups after intervention. Furthermore, there was a significant negative correlation between fecal short-chain fatty acid propionate concentration and Firmicutes abundance in spice intervention group (p &lt, 0.04). The production of individual fecal short-chain fatty acid was not significantly changed by spice consumption in this study. Mixed spices consumption significantly modified gut microbiota, suggesting a prebiotic effect of spice consumption at culinary doses.

Background Antioxidant nutrients such as the polyphenols in pomegranate juice may prevent neuronal damage from the free radicals produced during normal metabolism. Previous research in animals and a short-term clinical trial in middle-aged and older adults support the potential memory benefits of pomegranate juice; however, the long-term effects of pomegranate juice consumption on cognition have not been studied. Objective In this study, we investigated the long-term effect of pomegranate juice on memory in nondemented middle-aged and older adults. Methods We performed a 12-month, randomized, double-blind, placebo-controlled trial of pomegranate juice in middle-aged and older adults. Two hundred and sixty-one subjects (aged 50-75 y) were randomly assigned to consume pomegranate juice [8 oz (236.5 mL) per day] or a placebo drink (8 oz, matched constituents of pomegranate juice except for pomegranate polyphenols). Memory measures [Brief Visuospatial Memory Test-Revised (BVMT-R) and Buschke Selective Reminding Test (SRT)] were assessed at 6 and 12 mo and analyzed using a mixed-effects general linear model. Results Twenty-eight subjects in the pomegranate juice group and 33 subjects in the placebo group dropped out before completing the study. Baseline variables in the 98 pomegranate juice and 102 placebo group subjects who completed the study did not differ significantly. Group by time interaction was statistically significant for BVMT-R Learning (F[2, 257]= 5.90, P = 0.003; between-group effect size [ES] = 0.45): the change within the pomegranate group was not significant (ES = 0.15), whereas the placebo group showed a significant decline (ES = -0.35). Changes in the other BVMT-R scores as well as the SRT measures were not significantly different between groups. Conclusions Daily consumption of pomegranate juice may stabilize the ability to learn visual information over a 12-mo period. This trial was registered at clinicaltrials.gov as NCT02093130.

OBJECTIVES: Inflammatory bowel disease (IBD) results from a complex interaction among host, microbial and environmental factors. Among these, diet has emerged as an important and actionable modifier of IBD activity. Pomegranate major bioactive metabolites, ellagic acid and urolithins, have been shown to improve symptoms of IBD in chemically induced mouse models of colitis. Here, we aim to test the hypothesis that dietary pomegranate extract (PomX) supplementation will reduce the development of colitis in IL-10 knock out (IL-10(−/−)) mice, which spontaneously develop chronic colitis after birth. METHODS: 4 week old male IL-10(−/−) mice were randomly assigned to a high fat high sucrose (HFHS) diet, or to a HFHS diet supplemented with 0.25% PomX for 8 weeks. At the end of the experiment, the mice were euthanized and intestinal tissues were isolated and frozen for RNA extraction, or fixed for histologic analysis. Plasma samples were collected and processed for lipocalin 2 assay. RESULTS: Histomorphological analysis of colonic tissues revealed lower histological scores in HFHS-PomX fed mice, 3.9 ± 1.0 vs. 2.6 ± 0.5 in HFHS fed mice (n = 8, P = 0.02). In addition, signs of rectal prolapse were observed in 62.5% of IL-10(−/−) mice in the HFHS group vs. 12.5% in the HFHS/PomX group (P = 0.04). RNAseq and bioinformatic analysis, obtained from the colonic tissues (n = 4 mice/each group), showed in PomX treated mice a downregulation of 483 genes and an upregulation of 263 genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome analyses showed that PomX downregulated genes which are mainly associated with immune inflammatory responses, defenses, and neutrophil degranulation, including IL1α, IL6 and TNFα pro-inflammatory cytokines. Spleen weights were lower in HFHS-PomX treated mice as compared to HFHS fed control mice (P = 0.04). In addition, PomX treated mice showed a trend of higher body weights (∼13%) and lower lipocalin 2 plasma levels (∼46%) as compared to HFHS fed mice. CONCLUSIONS: Our data demonstrated that PomX supplementation decreased colitis symptoms and lowered the inflammatory parameters of colitis in HFHS fed IL10(−/−) mice. These data support the anti-inflammatory effects of dietary PomX supplementation that were previously observed in the DSS colitis murine model. FUNDING SOURCES: This project was supported by UCLA Center for Human Nutrition.

Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of oncomirs and their downstream targets. We found that GSE significantly down-regulated oncomirs miR-19a and −19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and −19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and −19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, −19b and the miR-17–92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60–90 minutes after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC(50)) (1.3 μg/ml) in vitro was much higher than the IC(50) (0.032–0.13μg/ml) observed in vivo. Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer.

BACKGROUND Preclinical and clinical studies suggest that a fish oil-based diet may play a role in delaying the progression of prostate cancer through a number of different mechanisms involving inflammatory pathways. Given the importance of tumor-associated macrophages (TAMs) in carcinogenesis, we hypothesized that a fish oil-based diet will inhibit TAM infiltration and delay the growth of prostate cancer. METHODS Androgen sensitive mouse prostate cancer (MycCaP) allograft tumors were grown in fully immunocompetent FVB mice fed a high- fat fish oil (omega-3) or corn oil (omega-6) diet. Gene expression of markers for immune cell populations, cytokines, chemokines, and signaling pathways were determined by real-time PCR and western blot in tumor tissue. Cell proliferation and apoptosis in vitro were measured by MTS assay and flow cytometry. RESULTS Tumor volumes were significantly smaller in mice in ω-3 versus the ω-6 group (P = 0.048). Gene expression of markers for M1 and M2 macrophages (F4/80, iNOS, ARG1), associated cytokines (IL-6, TNF alpha, IL-10), and the chemokine CCL-2 were also lower in the omega-3 group. Correlative in vitro studies were performed in M1 and M2 polarized macrophages and mirrored the in vivo findings. Dietary fish oil and in vitro omega-3 fatty acid administration reduced protein expression of transcription factors in the nuclear factor kappa B pathway leading to a significant decrease in gene expression of downstream targets (Bcl-2, BCL-XL, XIAP, survivin) in MycCap cells. CONCLUSIONS These findings underscore the potential of fish oil in modulating the clinical course of human prostate cancer through the immune system. Further preclinical and clinical studies are warranted evaluating fish oil-based therapies for inhibiting the recruitment and function of M1 and M2 tumor infiltrating macrophages. Prostate 9999: 1–10, 2016. © 2016 Wiley Periodicals, Inc.

Background Accurate assessment of diet in study populations is still a challenge. Some statistical strategies that use biomarkers of dietary intake attempt to compensate for the biasing effects of reporting errors. Objective The objective was to correlate biomarkers of dietary intake with 2 direct measures of dietary intake. Methods Subjects provided repeated 24-h dietary recalls and 2 food-frequency questionnaires (FFQs) separated by ∼3 y. Correlations between biomarkers and reported dietary intakes as measured by the recalls and FFQs were de-attenuated for within-person variability. The Adventist Health Study-2 (AHS-2) has a large database of biomarkers of dietary intake (blood, urine, adipose tissue) from a calibration study (909 analytic subjects) representing the cohort. Participants were black and non-black Adventists in the United States and Canada. Results Dietary items with higher-valued de-attenuated correlations (≥0.50) between biomarkers and recalls included some fatty acids (FAs), the non-fish meats, fruit (non-black subjects), some carotenoids, vitamin B-12 (non-black subjects), and vitamin E. Moderately valued correlations (0.30-0.49) were found for very long chain ω-3 (n-3) FAs, some carotenoids, folate, isoflavones, cruciferous vegetables, fruit (black subjects), and calcium. The highest correlation values in non-black and black subjects were 0.69 (urinary 1-methyl-histidine and meat consumption) and 0.72 (adipose and dietary 18:2 ω-6), respectively. Correlations comparing biomarkers with recalls were generally similar for black and non-black subjects, but correlations between biomarkers and the FFQ were slightly lower than corresponding recall correlations. Correlations between biomarkers and a single FFQ estimate (the usual cohort situation) were generally much lower. Conclusions Many biomarkers that have relatively high-valued correlations with dietary intake were identified and were usually of similar value in black and non-black subjects. These may be used to correct effects of dietary measurement errors in the AHS-2 cohort, and in some cases they also provide evidence supporting the validity of the dietary data.

Background We showed that pomegranate juice (PomJ) can help to maintain memory in adults aged >50 y. The mechanism for this effect is unknown, but might involve Trp and its metabolites, which are important in brain function. Objectives We aimed to test the hypothesis that PomJ and its metabolites ellagic acid (EA) and urolithin A (UA) affect Trp metabolism. Methods Stool and plasma from a cohort [11 PomJ, 9 placebo drink (PL)] of subjects enrolled in our double-blind, placebo-controlled trial (NCT02093130) were collected at baseline and after 1 y of PomJ or PL consumption. In a mouse study, cecum and serum were collected from DBA/2J mice receiving 8 wk of dietary 0.1% EA or UA supplementation. Trp metabolites and intestinal microbiota were analyzed by LC-MS and 16S rRNA gene sequencing, respectively. Results In the human study, the change in the plasma Trp metabolite indole propionate (IPA) over 1 y was significantly different between PomJ and PL groups (P = 0.03). In serum of experimental mice, we observed a 230% increase of IPA by EA but not UA, a 54% increase of indole sulfate by UA but not EA, and 43% and 34% decreases of kynurenine (KYN) by EA and UA, respectively. In cecum, there was a 32% decrease of Trp by UA but not EA, and an 86% decrease of KYN by EA but not UA (P

OBJECTIVES: We recently showed that a single dose of pomegranate juice (PomJ) intake reduced fasting glucose and increased insulin in young healthy subjects. Our study aims to determine the responses of blood glucose as well as principle hormones involved in glucose homeostasis (insulin, C-peptide, glucagon and gastric inhibitory polypeptide (GIP)) after consuming a single dose of 8 oz PomJ, glucose/fructose dissolved in water compared to water in healthy subjects. METHODS: 21 Healthy, normal weight individuals (BMI of >18 to 26.9 kg/m(2), fasting serum glucose 995 pg/mL (HFSI, n = 9). In all subjects, water intake did not change the levels of glucose and hormonal markers. In LFSI subjects, significant lower glucose at 15 min and GIP at both 15 min and 30 min were observed after PomJ compared to sugar water intake. The area under the curve of serum GIP from LFSI volunteers consuming PomJ was lower compared to sugar water. The levels of insulin, C-peptides and glucagon in response to PomJ and sugar water intake were similar. In HFSI subjects, levels of glucose, C-peptide and glucagon in response to PomJ and sugar water intake were similar. Significant higher insulin at 15 and 30 min, and lower GIP at both 15, 30 and 60 min were observed after PomJ compared to sugar water intake. CONCLUSIONS: Compared to identical amount of sugar in water, lower glucose response was observed after Pom J in LFSI subjects while higher insulin level and decreased GIP level in HFSI subjects without any difference in glucose. Our data suggest that components in PomJ likely regulate individuals’ glucose metabolism. FUNDING SOURCES: Center for Human Nutrition.

OBJECTIVES: Based on the polyphenol and fiber content of strawberries (SB), it was our hypothesis that daily consumption of California strawberries will lead to changes in the composition of the intestinal microbiota, and concentration of fecal cholesterol and bile acid (BA) microbial metabolites. METHODS: We performed a randomized, double blind, parallel design intervention study. 28 healthy adults were randomized to either daily consumption of 26 g of SB powder (2 servings of fresh SB) or placebo (PL) powder for 4 wks. Stool samples were collected at baseline (BL), 4 and 6 wks (2 wks no SB/PL). Fecal microbiota was analyzed by 16S rDNA sequencing of the V4 region; fecal cholesterol, coprostanol, cholestanol, cholic acid (primary BA), chenodeoxycholic acid (primary BA), deoxycholic acid (2(nd)BA), lithocholic acid (2(nd)BA) by gas chromatography, serum cholesterol, triglyceride by colorimetric assay and serum pelargonidin glucuronide (PG) by high performance liquid chromatography. RESULTS: Serum PG, a SB anthocyanin, was found in all participants in the SB group. Two participants in the PL group showed serum PG and were excluded from the analyses. Daily SB increased the abundance of Christensenellaceae, Bifidobacteriaceae, Verrucomicrobiaceae and multiple members of the Lachnospiraceae, Ruminococcaceae family, and decreased significantly Alcaligenaceae/Sutterella comparing BL to wk4. Comparing the change from BL to wk4 between the SB and PL group, we found increased abundance of Alcaligenaceae/Sutterella and several members of the Clostridia class including Lachnopsiraceae and Ruminococcaceae and a decrease in Clostridiaceae. Comparing wk 4 to wk 6, we observed a reversal of Clostridiales/Christensenellaceae, Verrucomicrobiaceae, and Alcaligenaceae/Sutterella. No effects on alpha and beta diversity were observed. No significant difference in serum and fecal cholesterol, BA and bacterial metabolites was observed between SB and PL groups. Five participants did not form coprostanol. Comparing coprostanol producers to non-producers at baseline showed that most differences were observed in the Lachnospiraceae, Ruminococcaceae and Bacteroidaceae families. CONCLUSIONS: SB consumption altered the gut microbiota, which was partially reversed after 2 wks of customary diet without SB. FUNDING SOURCES: California Strawberry Commission.

Background Avocados contain fiber, lutein, and vitamin E, and they are a rich source of MUFAs. The effect of including an avocado daily as part of a hypocaloric weight-loss diet on weight loss is not known. Objective The aim of this study was to determine the effect of daily avocado consumption as part of a hypocaloric diet on weight loss, body composition, satiety, biomarkers of inflammation, and intestinal microbiota composition. Methods In this randomized, parallel-controlled, open-label, 2-arm intervention study, 51 healthy overweight/obese women and men were assigned to a hypocaloric diet with 1 Hass avocado daily (AVO; n = 24) or a hypocaloric diet (CTRL; n = 27) without daily avocado for 12 wk. Serum markers and intestinal microbiota were analyzed at baseline and week 12. Results Both groups experienced significant weight loss, decrease in BMI (in kg/m2), total body fat, and visceral adipose tissue, respectively (AVO: -2.3 ± 2 kg, -0.8 ± 0.8, -1.1% ± 2%, and -81.2 ± 118 g; CTRL: -2.6 ± 3.6 kg, -0.9 ± 1, -1.5% ± 2%, and -87.4 ± 216 g). We observed a significant decrease in serum glucose over time in the control group compared with the AVO group. There was no change between the groups in serum triglyceride, but a significant decrease from baseline to 12 wk was observed in the AVO group. Serum hepatic growth factor (HGF) and relative proportion of bacterial phyla (Firmicutes and Bacteroidetes), family (Bacteroidaceae and Erysipelotrichaceae), and genus (Bacteroides, Clostridium, Methanosphaera, and Candidatus Soleaferrea) were significantly altered in the AVO group compared with the CTRL group. A trend to decrease in serum inflammatory factors IL-1β (P = 0.07) and C-reactive protein (P = 0.074) was observed in the AVO group compared with CTRL. Conclusions Daily Hass avocado consumption as part of a hypocaloric diet supported weight loss, a decrease in serum HGF, and an increase in the abundance of bacteria involved in plant polysaccharide fermentation. This trial was registered at clinicaltrials.gov as NCT02953158.