A green tea extract confection decreases circulating endotoxin and fasting glucose by improving gut barrier function but without affecting systemic inflammation: A double-blind, placebo-controlled randomized trial in healthy adults and adults with metabolic syndrome.

Anti-inflammatory activities of catechin-rich green tea extract (GTE) in obese rodents protect against metabolic endotoxemia by decreasing intestinal permeability and absorption of gut-derived endotoxin. However, translation to human health has not been established. We hypothesized that GTE would reduce endotoxemia by decreasing gut permeability and intestinal and systemic inflammation in persons with metabolic syndrome (MetS) compared with healthy persons. A randomized, double-blind, placebo-controlled, crossover trial in healthy adults (n = 19, 34 ± 2 years) and adults with MetS (n = 21, 40 ± 3 years) examined 4-week administration of a decaffeinated GTE confection (890 mg/d total catechins) on serum endotoxin, intestinal permeability, gut and systemic inflammation, and cardiometabolic parameters. Compared with the placebo, the GTE confection decreased serum endotoxin (P = .023) in both healthy persons and those with MetS, while increasing concentrations of circulating catechins (P < .0001) and γ-valerolactones (P = .0001). Fecal calprotectin (P = .029) and myeloperoxidase (P = .048) concentrations were decreased by GTE regardless of health status. Following the ingestion of gut permeability probes, urinary lactose/mannitol (P = .043) but not sucralose/erythritol (P > .05) was decreased by GTE regardless of health status. No between-treatment differences (P > .05) were observed for plasma aminotransferases, blood pressure, plasma lipids, or body mass nor were plasma tumor necrosis factor-α, interleukin-6, or the ratio of lipopolysaccharide-binding protein/soluble cluster of differentiation-14 affected. However, fasting glucose in both study groups was decreased (P = .029) by the GTE confection compared with within-treatment arm baseline concentrations. These findings demonstrate that catechin-rich GTE is effective to decrease circulating endotoxin and improve glycemic control in healthy adults and those with MetS, likely by reducing gut inflammation and small intestinal permeability but without affecting systemic inflammation.

Gallation and B-Ring Dihydroxylation Increase Green Tea Catechin Residence Time in Plasma by Differentially Affecting Tissue-Specific Trafficking: Compartmental Model of Catechin Kinetics in Healthy Adults.

Catechins in green tea extract (GTE) (epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin (EC), epicatechin gallate (ECG)) vary in bioactivity. We developed a physiologically relevant mathematical model of catechin metabolism to test the hypothesis that fractional catabolic rates of catechins would be differentially affected by their structural attributes. Pharmacokinetic data of plasma and urine catechin concentrations were used from healthy adults (n = 19) who ingested confections containing 0.5 g GTE (290 mg EGCG, 87 mg EGC, 39 mg EC, 28 mg ECG). A 7-compartmental model of catechin metabolism comprised of the gastrointestinal tract (stomach, small and large intestine), liver, plasma, extravascular tissues, and kidneys was developed using a mean fraction dose of EGCG, ECG, EGC, and EC. Fitting was by iterative least squares regression analysis, and goodness of fit was ascertained by the estimated variability of parameters (FSD < 0.5). The interaction of gallation and B-ring dihydroxylation most greatly extended plasma residence time such that EGC > EC = EGCG > EGC. The interaction between gallation and B-ring dihydroxylation accelerated the transfer from the upper gastrointestinal tract to the small intestine but delayed subsequent transfers from the small intestine through the liver to plasma and from kidneys to urine. Gallation and B-ring dihydroxylation independently delayed the transfer from plasma to extravascular tissues, except the uptake to kidneys, which was slowed by gallation only. This multi-compartment model, to be validated in a future study, suggests that gallation and B-ring dihydroxylation affect catechin catabolism in a tissue-specific manner and thus their potential bioactivity.

Milk-Fat-Globule-Membrane-Enriched Dairy Milk Compared with a Soy-Lecithin-Enriched Beverage Did Not Adversely Affect Endotoxemia or Biomarkers of Gut Barrier Function and Cardiometabolic Risk in Adults with Metabolic Syndrome: A Randomized Controlled Crossover Trial.

Full-fat dairy milk may protect against cardiometabolic disorders, due to the milk fat globule membrane (MFGM), through anti-inflammatory and gut-health-promoting activities. We hypothesized that a MFGM-enriched milk beverage (MEB) would alleviate metabolic endotoxemia in metabolic syndrome (MetS) persons by improving gut barrier function and glucose tolerance. In a randomized crossover trial, MetS persons consumed for two-week period a controlled diet with MEB (2.3 g/d milk phospholipids) or a comparator beverage (COMP) formulated with soy phospholipid and palm/coconut oil. They then provided fasting blood and completed a high-fat/high-carbohydrate test meal challenge for evaluating postprandial metabolism and intestinal permeability. Participants had no adverse effects and achieved high compliance, and there were no between-trial differences in dietary intakes. Compared with COMP, fasting endotoxin, glucose, incretins, and triglyceride were unaffected by MEB. The meal challenge increased postprandial endotoxin, triglyceride, and incretins, but were unaffected by MEB. Insulin sensitivity; fecal calprotectin, myeloperoxidase, and short-chain fatty acids; and small intestinal and colonic permeability were also unaffected by MEB. This short-term study demonstrates that controlled administration of MEB in MetS persons does not affect gut barrier function, glucose tolerance, and other cardiometabolic health biomarkers, which contradicts observational evidence that full-fat milk heightens cardiometabolic risk. Registered at ClinicalTrials.gov (NCT03860584).

Moderate consumption of freeze-dried blueberry powder increased net bone calcium retention compared with no treatment in healthy postmenopausal women: a randomized crossover trial.

BACKGROUND: Preclinical studies suggest that blueberry consumption is associated with improved bone health. OBJECTIVES: We conducted a blueberry dose-response study in ovariectomized (OVX)-rats that informed a study in postmenopausal women using the urinary appearance of calcium (Ca) tracers from prelabeled bone to reflect changes in bone balance. We hypothesized that blueberry consumption would reduce bone loss in a dose-dependent manner compared with no treatment. METHODS: OVX rats were fed 4 doses of blueberry powder (2.5%, 5%, 10%, and 15%) in randomized order to determine bone 45Ca retention. Fourteen healthy, nonosteoporotic women ≥4 y past menopause were dosed with 50 nCi of 41Ca, a long-lived radioisotope, and equilibrated for 5 mo to allow 41Ca deposition in bone. Following a 6-wk baseline period, participants were assigned to a random sequence of 3 6-wk interventions, a low (17.5 g/d), medium (35 g/d), or high (70 g/d) dose of freeze-dried blueberry powder equivalent to 0.75, 1.5, or 3 cups of fresh blueberries incorporated into food and beverage products. Urinary 41Ca:Ca ratio was measured by accelerator mass spectrometry. Serum bone resorption biomarkers and urinary polyphenols were measured at the end of each control and intervention period. Data were analyzed using a linear mixed model and repeated measures analysis of variance. RESULTS: In both OVX rats and postmenopausal women, blueberry interventions benefited net bone calcium balance at lower but not at higher doses. In women, net bone calcium retention increased by 6% with the low (95% CI: 2.50, 8.60; P < 0.01) and 4% with the medium (95% CI: 0.96, 7.90; P < 0.05) dose compared with no treatment. Urinary excretion of hippuric acid increased dose-dependently with blueberry consumption. No significant relationships were found between bone resorption biomarkers, 25-hydroxyvitamin D, and interventions. CONCLUSIONS: Moderate consumption (<1 cup/d) of blueberries may be an effective strategy to attenuate bone loss in healthy postmenopausal women. This trial was registered at clinicaltrials.gov as NCT02630797.

Daily Inclusion of Resistant Starch-Containing Potatoes in a Dietary Guidelines for Americans Dietary Pattern Does Not Adversely Affect Cardiometabolic Risk or Intestinal Permeability in Adults with Metabolic Syndrome: A Randomized Controlled Trial.

Poor diet quality influences cardiometabolic risk. Although potatoes are suggested to adversely affect cardiometabolic health, controlled trials that can establish causality are limited. Consistent with potatoes being rich in micronutrients and resistant starch, we hypothesized that their inclusion in a Dietary Guidelines for Americans (DGA)-based dietary pattern would improve cardiometabolic and gut health in metabolic syndrome (MetS) persons. In a randomized cross-over trial, MetS persons (n = 27; 32.5 ± 1.3 year) consumed a DGA-based diet for 2 weeks containing potatoes (DGA + POTATO; 17.5 g/day resistant starch) or bagels (DGA + BAGEL; 0 g/day resistant starch) prior to completing oral glucose and gut permeability tests. Blood pressure, fasting glucose and insulin, and insulin resistance decreased (p < 0.05) from baseline regardless of treatment without any change in body mass. Oral glucose-induced changes in brachial artery flow-mediated dilation, nitric oxide homeostasis, and lipid peroxidation did not differ between treatment arms. Serum endotoxin AUC0−120 min and urinary lactulose/mannitol, but not urinary sucralose/erythritol, were lower in DGA + POTATO. Fecal microbiome showed limited between-treatment differences, but the proportion of acetate was higher in DGA + POTATO. Thus, short-term consumption of a DGA-based diet decreases cardiometabolic risk, and the incorporation of resistant starch-containing potatoes into a healthy diet reduces small intestinal permeability and postprandial endotoxemia.

Anti-inflammatory activities of green tea catechins along the gut-liver axis in nonalcoholic fatty liver disease: lessons learned from preclinical and human studies.

Nonalcoholic fatty liver disease (NAFLD), which is the most prevalent hepatic disorder worldwide, affecting 25% of the general population, describes a spectrum of progressive liver conditions ranging from relatively benign liver steatosis and advancing to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Hallmark features of NASH are fatty hepatocytes and inflammatory cell infiltrates in association with increased activation of hepatic nuclear factor kappa-B (NFκB) that exacerbates liver injury. Because no pharmacological treatments exist for NAFLD, emphasis has been placed on dietary approaches to manage NASH risk. Anti-inflammatory bioactivities of catechin-rich green tea extract (GTE) have been well-studied, especially in preclinical models that have detailed its effects on inflammatory responses downstream of NFκB activation. This review will therefore discuss the experimental evidence that has advanced an understanding of the mechanisms by which GTE, either directly through its catechins or potentially indirectly through microbiota-derived metabolites, limits NFκB activation and NASH-associated liver injury. Specifically, it will describe the hepatic-level benefits of GTE that attenuate intracellular redox distress and pro-inflammatory signaling from extracellular receptors that otherwise activate NFκB. In addition, it will discuss the anti-inflammatory activities of GTE on gut barrier function as well as prebiotic and antimicrobial effects on gut microbial ecology that help to limit the translocation of gut-derived endotoxins (e.g. lipopolysaccharides) to the liver where they otherwise upregulate NFκB activation by Toll-like receptor-4 signaling. This summary is therefore expected to advance research translation of the hepatic- and intestinal-level benefits of GTE and its catechins to help manage NAFLD-associated morbidity.

Intestinal-level anti-inflammatory bioactivities of catechin-rich green tea: Rationale, design, and methods of a double-blind, randomized, placebo-controlled crossover trial in metabolic syndrome and healthy adults.

Metabolic endotoxemia initiates low-grade chronic inflammation in metabolic syndrome (MetS) and provokes the progression towards more advanced cardiometabolic disorders. Our recent works in obese rodent models demonstrate that catechin-rich green tea extract (GTE) improves gut barrier integrity to alleviate the translocation of gut-derived endotoxin and its consequent pro-inflammatory responses mediated through Toll-like receptor-4/nuclear factor κB (TLR4/NFκB) signaling. The objective of this clinical trial is to establish the efficacy of GTE to alleviate metabolic endotoxemia-associated inflammation in persons with MetS by improving gut barrier function. We plan a double-blind, placebo-controlled cross-over trial in persons with MetS and age- and gender-matched healthy persons (18-65 y; n = 20/group) who will receive a low-energy GTE-rich (1 g/day; 890 mg total catechins) confection snack food while following a low-polyphenol diet for 28 days. Assessments will include measures of circulating endotoxin (primary outcome) and secondary outcomes including biomarkers of endotoxin exposure, region-specific measures of intestinal permeability, gut microbiota composition, diversity, and functions, intestinal and systemic inflammatory responses, and catechins and microbiota-derived catechin metabolites. Study outcomes will provide the first report of the GTE-mediated benefits that alleviate gut barrier dysfunction in relation to endotoxemia-associated inflammation in MetS persons. This is expected to help establish an effective dietary strategy to mitigate the growing burden of MetS that currently affects ~35% of Americans.

Lactose Intolerance and Bone Health: The Challenge of Ensuring Adequate Calcium Intake.

Calcium is an important nutrient with impact upon many biological systems, most notably bone. Ensuring adequate calcium intake throughout the lifespan is essential to building and maintaining bone. Lactose intolerance may predispose individuals to low calcium intake as the number of lactose-free, calcium-rich food sources is limited. In this review, we summarize data from human and animal studies on the influence of lactose and lactase deficiency on calcium absorption and bone health. Based on the available evidence, neither dietary lactose nor lactase deficiency have a significant impact on calcium absorption in adult humans. However, lactose intolerance may lead to reduced bone density and fragility fractures when accompanied by decreased intake or avoidance of dairy. Recently published human trials and meta-analyses suggest a weak but significant association between dairy consumption and bone health, particularly in children. Given the availability of simple dietary approaches to building lactose tolerance and the nutritional deficiencies associated with dairy avoidance, multiple public health organizations recommend that all individuals-including those that are lactose intolerant-consume three servings of dairy per day to ensure adequate nutrient intakes and optimal bone health.

What Is the Evidence Base for a Potassium Requirement?

Increased intake of potassium should be promoted to reduce the risk of cardiovascular disease and stroke and to protect against bone loss, but confidence in recommended intakes depends on the strength of the evidence. All public health recommendations are considerably higher than current average intakes. Evidence on which current potassium intake recommendations for the United States, Europe, and globally have limitations. More recent evidence reviewed by the Agency for Healthcare Research and Quality affirms that more evidence is needed to define specific values for optimal potassium intakes. Potassium requirements undoubtedly vary with a number of factors including energy needs, race, and intake of sodium.

Serum calcium concentration is maintained when bone resorption is suppressed by osteoprotegerin in young growing male rats.

Serum calcium (Ca) is maintained in a narrow range through regulation of Ca metabolism in the intestine, kidney, and bone. Calcium is incorporated and resorbed from bone during bone remodeling via cellular processes as well as by exchange. Both routes contribute to calcium homeostasis. To assess the magnitude of bone turnover contribution to calcium homeostasis we labeled bone with a Ca tracer and measured Ca release following stimulation or suppression of bone resorption. Young growing male rats (n = 162) were dosed with 45Ca to label skeletal Ca. After a one-month period to allow the label to incorporate into the skeleton, rats were treated with a bone resorption antagonist (OPG), a bone resorption agonist (RANKL), or vehicle control (PBS). Serum and urine 45Ca and total Ca, and serum TRACP5b (a bone resorption biomarker), were monitored for 45 days following treatment. Tracer data were analyzed by a compartmental model using WinSAAM to quantify dynamic changes in Ca metabolism and identify sites of change following treatment. In RANKL treated rats, both serum 45Ca and serum TRACP5b were increased by >70% due to a 25-fold increase in bone resorption. In OPG treated rats, both serum 45Ca and serum TRACP5b were suppressed by >70% due to a 75% decrease in bone resorption, a 3-fold increase in bone formation, and a 50% increase in absorption. Because TRACP5b and 45Ca responded similarly, we conclude that Ca release from bone into serum occurs mostly via osteoclast-mediated bone resorption. However, because serum Ca concentration did not change with altered resorption in response to either RANKL or OPG treatment, we also conclude that serum Ca concentration under normal dietary conditions in young growing male rats is maintained by processes in addition to cellular bone resorption.

Vitamin A supplementation redirects the flow of retinyl esters from peripheral to central organs of neonatal rats raised under vitamin A-marginal conditions.

Background: Vitamin A (VA; retinol) supplementation is used to reduce child mortality in countries with high rates of malnutrition. Existing research suggests that neonates (<1 mo old) may have a limited capacity to store VA in organs other than the liver; however, knowledge about VA distribution and kinetics in individual, nonhepatic organs is limited.Objective: We examined retinol uptake and turnover in nonhepatic organs, including skin, brain, and adipose tissue, in neonatal rats without and after VA supplementation.Design: Sprague-Dawley neonatal rats (n = 104) were nursed by mothers fed a VA-marginal diet (0.35 mg retinol/kg diet) and treated on postnatal day 4 with an oral dose of either VA (6 µg retinyl palmitate/g body weight) or canola oil (control), both containing 1.8 µCi of [3H]retinol. Subsequently, pups (n = 4 · group-1 · time-1) were killed at 13 different times from 30 min to 24 d after dosing. The fractional and absolute transfer of chylomicron retinyl esters (CM-REs), retinol bound to retinol-binding protein (RBP-ROH), and total retinol were estimated in WinSAAM software.Results: VA supplementation redirected the flow of CM-REs from peripheral to central organs and accumulated mainly in the liver. The RBP-ROH released from the liver was acquired mainly by the peripheral tissues but not retained efficiently, causing repeated recycling of retinol between plasma and tissues (541 compared with 5 times in the supplemented group and control group, respectively) and its rapid turnover in all organs, except the brain and white adipose tissue. Retinol stores in the liver lasted for ∼2 wk before being gradually transferred to other organs.Conclusions: VA supplementation administered in a single high dose during the first month after birth is readily acquired but not retained efficiently in peripheral tissues of neonatal rats, suggesting that a more frequent, lower-dose supplementation may be necessary to maintain steady VA concentrations in rapidly developing neonatal tissues.

Vitamin A and retinoic acid combined have a more potent effect compared to vitamin A alone on the uptake of retinol into extrahepatic tissues of neonatal rats raised under vitamin A-marginal conditions.

BACKGROUND: Vitamin A (VA, retinol) supplementation is widely used to reduce child mortality in low-income countries. However, existing research suggests that supplementation with VA alone may not be optimal for infants. OBJECTIVE: We compared the effect of VA vs. VA combined with retinoic acid (VARA) on retinol uptake and turnover in organs of neonatal rats raised under VA-marginal conditions. METHODS: Secondary analysis was conducted on data obtained from two prior kinetic studies of Sprague-Dawley neonatal rats nursed by mothers fed a VA-marginal diet (0.35 mg retinol equivalents/kg diet). On postnatal d 4, pups had been treated with a single dose of VA (6 µg/g; n = 52; VA study), VA + 10% retinoic acid (6 µg/g; n = 42; VARA study) or placebo (canola oil; n = 94; both studies), all containing ~2 µCi of [3H]retinol as the tracer for VA. Total retinol concentrations and tracer levels had been measured in plasma and tissues from 1 h to 14 d after dosing. Control group data from both studies were merged prior to analysis. Kinetic parameters were re-estimated and compared statistically. RESULTS: VARA supplementation administered to neonatal rats within a few days after birth resulted in a lower turnover of retinol in the lungs, kidneys, and carcass and less frequent recycling of retinol between plasma and organs (100 vs. 288 times in VARA- vs. VA-treated group). Although the VA supplementation resulted in a higher concentration of retinol in the liver, VARA supplementation led to a higher uptake of postprandial retinyl esters into the lungs, intestines, and carcass. CONCLUSIONS: Given the relatively higher retinol uptake into several extrahepatic organs of neonates dosed orally with VARA, this form of supplementation may serve as a targeted treatment of low VA levels in the extrahepatic organs that continue to develop postnatally.

Vitamin A Supplementation Increases the Uptake of Chylomicron Retinyl Esters into the Brain of Neonatal Rats Raised under Vitamin A-Marginal Conditions.

BACKGROUND: The most rapid phase of brain development occurs during the neonatal period. Vitamin A (VA; retinol) is critical for many aspects of this process, including neurogenesis, synaptic plasticity, learning, and memory formation. However, the metabolism of retinol in the neonatal brain has not been extensively explored. OBJECTIVE: We examined the uptake of VA into the brain in neonatal rats raised under VA-marginal conditions (control group) and assessed the effect of VA supplementation on the uptake of VA into the brain. METHODS: Sprague-Dawley neonatal rats (n = 104) nursed by mothers fed a VA-marginal diet were randomly assigned and treated on postnatal day 4 with an oral dose of either VA (6 µg retinyl palmitate/g body weight) or canola oil as the control, both of which contained 1.8 µCi [(3)H]retinol. Pups (n = 4/group at a time) were killed at 13 sampling times from 30 min to 24 d after dosing. The uptake of total retinol, chylomicron-associated retinyl esters (REs), and retinol bound to retinol-binding protein (RBP) was estimated with the use of WinSAAM version 3.0.8. RESULTS: Total retinol mass in the brain was closely dependent on its mass in plasma over time (r = 0.91; P < 0.001). The uptake of retinol into the brain involved both postprandial chylomicrons and RBP, with RBP delivering most of the retinol in the control group [0.27 nmol/d (RBP) compared with 0.01 nmol/d (chylomicrons)]. VA supplementation increased the fractional uptake of chylomicron REs from 0.3% to 1.2% of plasma pool/d, decreased that of RBP retinol from 0.5% to 0.2% of plasma pool/d, and increased the transfer rate of chylomicron REs from nearly zero to 0.7 nmol/d, causing a day-long elevation in the brain mass of total retinol. CONCLUSION: Postprandial chylomicrons may be a primary mechanism for delivering a recently ingested large dose of VA to the brain of neonatal rats raised under VA-marginal conditions.

Vitamin A Supplementation Transiently Increases Retinol Concentrations in Extrahepatic Organs of Neonatal Rats Raised under Vitamin A-Marginal Conditions.

BACKGROUND: Vitamin A (VA; retinol) supplementation is recommended for children aged >6 mo in countries with high rates of malnutrition, but the distribution and retention of VA in body tissues have not been extensively explored. OBJECTIVE: We sought to determine the distribution and retention of VA in tissues of neonatal rats raised under VA-marginal conditions. METHODS: Sprague-Dawley neonatal rats (n = 104; 63 males) nursed by mothers fed a VA-marginal diet (0.35 mg retinol equivalents/kg diet) were randomized and treated on postnatal day 4 with an oral dose of either VA (6 µg retinyl palmitate/g body weight) or canola oil as control. Pups (n = 4/group) were killed at 13 time points from 30 min to 24 d after dose administration. The total retinol concentration and mass were determined in all collected organs. RESULTS: In the control group, plasma VA was marginal (0.8 µmol/L), whereas liver VA was deficient (<70 nmol/g). Nonetheless, the liver contained most (∼76%) of the total VA mass in the body, whereas extrahepatic nondigestive organs together contained ∼13%. White adipose tissue (WAT), which was nearly absent before postnatal day 12, contained only ∼1%. In VA-supplemented neonates, the mean total retinol concentrations in all organs were significantly greater than in control pups. However, this increase lasted for only ∼1 d in most extrahepatic tissues, with the exception of WAT, in which it lasted 18 d. CONCLUSIONS: Extrahepatic organs in neonatal rats raised under VA-marginal conditions store relatively little VA, and the scarcity of adipose tissue may predispose neonates to a low-VA status. The effect of VA supplementation on VA content in most extrahepatic organs is transient. A more frequent supplementation along with other nutritional interventions may be necessary for maintaining a steady supply of retinol to the rapidly developing extrahepatic organs.