Effect of cinnamon spice on continuously monitored glycemic response in adults with prediabetes: a 4-week randomized controlled crossover trial.

BACKGROUND: Previous clinical studies showing that cinnamon spice lowers blood glucose concentrations had inconsistent results. OBJECTIVES: To determine the effect of daily cinnamon spice supplementation in an amount commonly used for seasoning on glucose concentrations in adults with obesity and prediabetes. METHODS: Following a 2-wk run-in period of maintaining a low polyphenol/fiber diet, 18 participants with obesity and prediabetes underwent a 10-wk randomized, controlled, double-blind, crossover trial (mean age 51.1 y; mean fasting plasma glucose 102.9 mg/dL). The participants were randomly assigned to take cinnamon (4 g/d) or placebo for 4-wk, followed by a 2-wk washout period, and then crossed over to the other intervention for an additional 4-wk. Glucose changes were measured with continuous glucose monitoring. Oral glucose tolerance testing immediately following ingestion of cinnamon or placebo was performed at 4-time points to assess their acute effects both at the baseline and end of each intervention phase. Digestive symptom logs were obtained daily. RESULTS: There were 694 follow-up days with 66,624 glucose observations. When compared with placebo, 24-h glucose concentrations were significantly lower when cinnamon was administered [mixed-models; effect size (ES) = 0.96; 95 % confidence interval (CI): -2.9, -1.5; P < 0.001]. Similarly, the mean net-area-under-the-curve (netAUC) for glucose was significantly lower than for placebo when cinnamon was given (over 24 h; ES = -0.66; 95 % CI: 2501.7, 5412.1, P = 0.01). Cinnamon supplementation resulted in lower glucose peaks compared with placebo (Δpeak 9.56 ± 9.1 mg/dL compared with 11.73 ± 8.0 mg/dL; ES = -0.57; 95 % CI: 0.8, 3.7, P = 0.027). Glucose-dependent-insulinotropic-polypeptide concentrations increased during oral glucose tolerance testing + cinnamon testing (mixed-models; ES = 0.51; 95 % CI: 1.56, 100.1, P = 0.04), whereas triglyceride concentrations decreased (mixed-models; ES = 0.55; 95 % CI: -16.0, -1.6, P = 0.02). Treatment adherence was excellent in both groups (cinnamon: 97.6 ± 3.4 % compared with placebo: 97.9 ± 3.7 %; ES = -0.15; 95 % CI: -1.8, 0.2, P = 0.5). No differences were found in digestive symptoms (abdominal pain, borborygmi, bloating, excess flatus, and stools/day) between cinnamon and placebo groups. CONCLUSIONS: Cinnamon, a widely available and low-cost supplement, may contribute to better glucose control when added to the diet in people who have obesity-related prediabetes. This trial was registered at clinicaltrials.gov as NCT04342624.

Concentrated Grape Powder Consumption Modulates Cholesterol Metabolism and Homeostasis in Healthy Subjects.

SCOPE: Four weeks' of concentrated grape powder (GP) consumption reduces circulating cholesterol in healthy free-living subjects consuming a low-fiber/low-polyphenol diet. Here, the study aims to investigate the underlying mechanisms for cholesterol reduction by evaluating biomarkers of cholesterol de novo biosynthesis, intestinal absorption, miRNA involved in transcriptional regulation of cholesterol metabolism, as well as cholesterol oxidation. METHODS AND RESULTS: Fasting plasma samples collected from 19 healthy free-living subjects at baseline and week 4 of GP consumption are used in this study. Gas chromatography-mass (GC-MS) analysis of plasma samples shows that lathosterol, a precursor of cholesterol synthesis, is significantly decreased after GP consumption indicating reduced cholesterol de novo biosynthesis. Markers of intestinal absorption, campesterol, and ß-sitosterol are not changed. Realtime PCR shows that plasma exosomal miRNA-1 is increased after GP consumption. GC-MS also shows that GP consumption reduces the plasma cholesterol oxidation product 27-hydroxycholesterol (27-HC). CONCLUSIONS: This study enhances the understanding of the mechanisms of the cholesterol lowering effects of GP, and provides new insights into the potential health benefits of grape consumption.

Mixed Nuts as Healthy Snacks: Effect on Tryptophan Metabolism and Cardiovascular Risk Factors.

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.

Combinations of grape seed procyanidin extract and milk thistle silymarin extract against lung cancer - The role of MiR-663a and FHIT.

AIMS: Grape seed procyanidin extract (GSE), and milk thistle silymarin extract (MTE) contain structurally distinct polyphenols, and each agent has been shown to exert antineoplastic effects against lung cancer. We hypothesize that combinations of GSE and MTE will additively enhance their anticancer effects against lung cancer. MATERIALS AND METHODS: The anti-proliferative effects of GSE, MTE and combinations were evaluated in lung neoplastic cell lines. A dose range finding (DRF) study to determine safety, bioavailability and bioactivity, followed by human lung cancer xenograft efficacy studies were conducted in female nude mice with once daily gavage of leucoselect phytosome (LP), a standardized GSE, and/or siliphos, a standardized MTE. The roles of tumor suppressors miR-663a and its predicted target FHIT in mediating the additive, anti-proliferative effecs of GSE/MTE were also assessed. KEY FINDINGS: GSE with MTE additively inhibited lung preneoplastic and cancer cell proliferations. Mice tolerated all dosing regimens in the DRF study without signs of clinical toxicity nor histologic abnormalities in the lungs, livers and kidneys. Eight weeks of LP and siliphos additively inhibited lung tumor xenograft growth. Plasma GSE/metabolites and MTE/metabolites showed that the combinations did not decrease systemic bioavailabilities of each agent. GSE and MTE additively upregulated miR-663a and FHIT in lung cancer cell lines; transfection of antisense-miR-663a significantly abrogated the anti-proliferative effects of GSE/MTE, upregulation of FHIT mRNA and protein. LP and siliphos also additively increased miR-663a and FHIT protein in lung tumor xenografts. SIGNIFICANCE: Our findings support clinical translations of combinations of GSE and MTE against lung cancer.

Pomegranate juice alters the microbiota in breast milk and infant stool: a pilot study.

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 Lactococcus, Subdoligranulum, and Acinetobacter, while the abundance of Firmicutes/Faecalibacterium increased significantly. In breast milk Escherichia/Shigella was inversely correlated to breast milk UAG. In infant stools, the abundance of Lachnoclostridium and Staphylococcus was increased. Infant stool Blautia was positively correlated to breast milk and mother plasma UBG. This pilot study demonstrates that EA and its metabolites are absorbed by the nursing infant from breast milk, excreted in urine and impact the infant gut microbiome. The concentration of EA metabolites in breast milk increased over time. Phenolic compounds in breast milk could be a way to promote neuroprotective, antioxidant and anti-inflammatory health benefits in infants.

Pomegranate Extract Improves Colitis in IL-10 Knockout Mice Fed a High Fat High Sucrose Diet.

SCOPE: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Effect of Standardized Grape Powder Consumption on the Gut Microbiome of Healthy Subjects: A Pilot Study.

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.

The Effect of Broccoli Sprout Extract on Seasonal Grass Pollen-Induced Allergic Rhinitis.

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.

California strawberry consumption increased the abundance of gut microorganisms related to lean body weight, health and longevity in healthy subjects.

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 Metabolites Impact Tryptophan Metabolism in Humans and Mice.

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 < 0.05). The abundance of 2 genera, Shigella and Catenibacterium, was reduced by PomJ in humans as well as by UA in mice, and their abundance was negatively associated with blood IPA in humans and mice (P < 0.05). CONCLUSIONS: These results suggest a novel mechanism involving the regulation of host and microbial Trp metabolism that might contribute to the health benefits of ellagitannins and EA-enriched food, such as PomJ.

Prospective randomized trial evaluating blood and prostate tissue concentrations of green tea polyphenols and quercetin in men with prostate cancer.

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.

Pomegranate Juice and Extract Consumption Increases the Resistance to UVB-induced Erythema and Changes the Skin Microbiome in Healthy Women: a Randomized Controlled Trial.

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.

Bioavailability and bioactivity of free ellagic acid compared to pomegranate juice.

Pomegranates are an excellent source of ellagic acid (EA), ellagitannins (ETs), anthocyanins and other phytochemicals. The health benefits of pomegranate (Pom) have been mainly related to its EA and ET content. The objective of the present study was to determine EA bioavailability and bioactivity from different sources such as pure/free or natural form (PomJ). This was a cross-over study with healthy volunteers consuming one dose of EA dietary supplement (500 mg free EA) vs. one serving of PomJ (237 mL, ∼120 mg of EA) in a random order. Our data showed that there was no difference in plasma EA concentration between PomJ and EA intake; however, urinary dimethylellagic acid glucuronide (DMEAG), normalized to creatinine, was significantly higher after the consumption of PomJ compared to EA. Plasma insulin at 1 h increased after PomJ consumption compared to the baseline while decreased after EA consumption compared to the baseline. Plasma glucose decreased below the baseline 2 h after the consumption of PomJ but not EA. Plasma leptin was significantly decreased at 1 and 2 h after PomJ and EA consumption. Plasma MCP1 decreased only after PomJ but not after pure EA consumption. To conclude, one serving of PomJ provided the same level of EA in blood, while the increase in phase II metabolism of EA and an acute suppression of plasma MCP1 were only observed after PomJ consumption, suggesting that other constituents present in PomJ, in addition to EA, are bioactive and likely play a role in regulating EA phase II metabolism.

Hass Avocado Inclusion in a Weight-Loss Diet Supported Weight Loss and Altered Gut Microbiota: A 12-Week Randomized, Parallel-Controlled Trial.

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-1ß (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.

Mixed Spices at Culinary Doses Have Prebiotic Effects in Healthy Adults: A Pilot Study.

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 < 0.033) and a trend of enrichment in Bacteroidetes (p < 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 < 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.

Vertical Sleeve Gastrectomy Attenuates the Progression of Non-Alcoholic Steatohepatitis in Mice on a High-Fat High-Cholesterol Diet.

OBJECTIVE: To determine whether vertical sleeve gastrectomy (VSG) attenuates fibrosis in mice on a high-fat high-cholesterol (HFHC) diet. BACKGROUND: Bariatric surgery mitigates non-alcoholic steatohepatitis in 85-90% of obese patients. While animal models demonstrate similar results on a high-fat diet, none have observed the effects of bariatric surgery on a combined HFHC diet. METHODS: Mice on a HFHC diet were used to confirm the development of hepatic fibrosis at 8 (n = 15) and 24 (n = 15) weeks. A separate cohort of mice on a HFHC diet for 12 weeks was subjected to either VSG (n = 18) or sham (n = 12) operations and remained on a HFHC diet for an additional 20 weeks. Changes in weight, dyslipidemia, and the development of steatosis and fibrosis were documented. Serum was obtained for bile acid analysis by liquid chromatography and mass spectrometry, while hepatic gene expression by RT-PCR was performed to evaluate intrahepatic lipid metabolism. RESULTS: Hepatic steatosis and fibrosis developed after 8 weeks on the HFHC diet. After VSG, mice demonstrated a sustained decrease in weight with a significant decrease in fibrosis compared to sham mice. Serum total cholesterol, HDL, and LDL were significantly reduced following surgery, while serum bile acids were significantly elevated. Intra-hepatic cholesterol excretion was not upregulated based on hepatic gene expression of CYP7A1 and ABCG5/8. CONCLUSIONS: VSG attenuates the development of hepatic fibrosis in diet-induced obese mice, presumably through enhancement of cholesterol elimination at the intestinal level.

Effects of branched-chain amino acids on glucose metabolism in obese, prediabetic men and women: a randomized, crossover study.

BACKGROUND: Recent 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. OBJECTIVES: The aim of this pilot study was to determine the effects of BCAA supplementation on glucose metabolism in obese, prediabetic individuals. METHODS: This 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. RESULTS: BCAA 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 1ß 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%). CONCLUSIONS: Our 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.

Effects of Prebiotic Fiber Xylooligosaccharide in Adenine-Induced Nephropathy in Mice.

SCOPE: This study evaluates the effect of the prebiotic fiber xylooligosaccharide (XOS) on kidney function and gut microbiome in mice with adenine-induced chronic kidney disease (CKD). METHOD AND RESULTS: Mice are fed the control diet containing adenine for 3 weeks to induce CKD and are switched to XOS supplemented (2 or 7%) or control diets for another 3 weeks. Mice with CKD exhibit increased blood urea nitrogen (BUN), creatinine, and kidney histopathology. XOS significantly reverses kidney injuries in CKD mice. Analysis of cecum microbiota reveales that adenine-induced CKD does not change alpha diversity, and XOS induces a decrease of alpha diversity in control mice and mice with CKD. Beta diversity analysis shows significant clustering according to experimental groups. Six out of the nine bacterial genera enriched in CKD are significantly reduced with XOS intervention. Furthermore, XOS increases cecal short-chain fatty acid (SCFA) production in both control and CKD mice. Cecal SCFAs and blood propionate are negatively correlated with BUN. XOS also decreases blood p-cresol sulfate in CKD mice, likely resulting from altered microbial tyrosine metabolism. CONCLUSION: These results show that XOS intervention improves kidney function in mice with CKD, and is associated with profound changes in microbial composition and metabolism.

Decaffeinated green and black tea polyphenols decrease weight gain and alter microbiome populations and function in diet-induced obese mice.

PURPOSE: Decaffeinated green tea (GT) and black tea (BT) polyphenols inhibit weight gain in mice fed an obesogenic diet. Since the intestinal microflora is an important contributor to obesity, it was the objective of this study to determine whether the intestinal microflora plays a role in the anti-obesogenic effect of GT and BT. METHODS: C57BL/6J mice were fed a high-fat/high-sucrose diet (HF/HS, 32% energy from fat; 25% energy from sucrose) or the same diet supplemented with 0.25% GTP or BTP or a low-fat/high-sucrose (LF/HS, 10.6% energy from fat, 25% energy from sucrose) diet for 4 weeks. Bacterial composition was assessed by MiSeq sequencing of the 16S rRNA gene. RESULTS: GTP and BTP diets resulted in a decrease of cecum Firmicutes and increase in Bacteroidetes. The relative proportions of Blautia, Bryantella, Collinsella, Lactobacillus, Marvinbryantia, Turicibacter, Barnesiella, and Parabacteroides were significantly correlated with weight loss induced by tea extracts. BTP increased the relative proportion of Pseudobutyrivibrio and intestinal formation of short-chain fatty acids (SCFA) analyzed by gas chromatography. Cecum propionic acid content was significantly correlated with the relative proportion of Pseudobutyrivibrio. GTP and BTP induced a significant increase in hepatic 5'adenosylmonophosphate-activated protein kinase (AMPK) phosphorylation by 70 and 289%, respectively (P < 0.05) determined by Western blot. CONCLUSION: In summary, both BTP and GTP induced weight loss in association with alteration of the microbiota and increased hepatic AMPK phosphorylation. We hypothesize that BTP increased pAMPK through increased intestinal SCFA production, while GTPs increased hepatic AMPK through GTP present in the liver.

Cholesterol-lowering effects of dietary pomegranate extract and inulin in mice fed an obesogenic diet.

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.