Micronutrient deficiencies in children with coeliac disease; a double-edged sword of both untreated disease and treatment with gluten-free diet.

INTRODUCTION: In coeliac disease (CD) micronutrient deficiencies may occur due to malabsorption in active disease and diminished intake during treatment with a gluten-free diet (GFD). This study assessed the micronutrient status in children with CD at diagnosis and follow-up. METHODS: Fifteen micronutrients were analysed in 106 blood samples from newly diagnosed CD and from patients on a GFD for <6 months, 6-12 months and with longstanding disease (>12 months). Predictors of micronutrient status included: demographics, disease duration, anthropometry, gastrointestinal symptoms, raised tissue transglutaminase antibodies (TGA), multivitamin use and faecal gluten immunogenic peptide (GIP). Micronutrient levels were compared against laboratory reference values. RESULTS: At CD diagnosis (n = 25), low levels in ≥10% of patients were observed for: vitamins E (88%), B1 (71%), D (24%), K (21%), A (20%) and B6 (12%), ferritin (79%), and zinc (33%). One year post-diagnosis, repletion of vitamins E, K, B6 and B1 was observed (<10% patients). In contrast, deficiencies for vitamins D, A and zinc did not change significantly post-diagnosis. Copper, selenium and magnesium did not differ significantly between diagnosis and follow-up. All samples for B2, folate, vitamin C (except for one sample) and B12 were normal. A raised TGA at follow-up was associated with low vitamins A and B1 (raised vs normal TGA; vitamin A: 40% vs 17%, p = 0.044, vitamin B1: 37% vs 13%, p = 0.028). Low vitamin A (p = 0.009) and vitamin D (p = 0.001) were more common in samples collected during winter. There were no associations between micronutrient status with GIP, body mass index, height, socioeconomic status, or gastrointestinal symptom. Multivitamin use was less common in patients with low vitamin D. CONCLUSIONS: Several micronutrient deficiencies in CD respond to a GFD but others need to be monitored long-term and supplemented where indicated.

Effect of ß-Glucan and Black Tea in a Functional Bread on Short Chain Fatty Acid Production by the Gut Microbiota in a Gut Digestion/Fermentation Model.

ß-Glucan and black tea are fermented by the colonic microbiota producing short chain fatty acids (SCFA) and phenolic acids (PA). We hypothesized that the addition of ß-glucan, a dietary fiber, and tea polyphenols to a food matrix like bread will also affect starch digestion in the upper gut and thus further influence colonic fermentation and SCFA production. This study investigated SCFA and PA production from locally developed breads: white bread (WB), black tea bread (BT), ß-glucan bread (ßG), ß-glucan plus black tea bread (ßGBT). Each bread was incubated in an in vitro system mimicking human digestion and colonic fermentation. Digestion with α-amylase significantly (p = 0.0001) increased total polyphenol and polyphenolic metabolites from BT bread compared with WB, ßG, and ßGBT. Total polyphenols in ßGBT remained higher (p = 0.016; 1.3-fold) after digestion with pepsin and pancreatin compared with WB. Fermentations containing ßG and ßGBT produced similar propionate concentrations ranging from 17.5 to 18.6 mmol/L and total SCFA from 46.0 to 48.9 mmol/L compared with control WB (14.0 and 37.4 mmol/L, respectively). This study suggests that combination of black tea with ß-glucan in this functional bread did not impact on SCFA production. A higher dose of black tea and ß-glucan or in combination with other fibers may be needed to increase SCFA production.

Treatment of Active Crohn's Disease With an Ordinary Food-based Diet That Replicates Exclusive Enteral Nutrition.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) is the only established dietary treatment for Crohn's disease (CD), but its acceptability is limited. There is a need for novel dietary treatments for CD. METHODS: We evaluated the effects of an individualized food-based diet (CD-TREAT), with similar composition to EEN, on the gut microbiome, inflammation, and clinical response in a rat model, healthy adults, and children with relapsing CD. Twenty-five healthy adults randomly received EEN or CD-TREAT for 7 days, followed by a 14-day washout period, followed by the alternate diet. Fecal microbiome and metabolome were assessed before and after each diet. HLA-B7 and HLA-B27 transgenic rats with gut inflammation received EEN, CD-TREAT, or standard chow for 4 weeks. Fecal, luminal, and tissue microbiome, fecal metabolites, and gut inflammation were assessed. Five children with active CD activity received CD-TREAT and their clinical activity and calprotectin were evaluated after 8 weeks of treatment. RESULTS: For healthy adults, CD-TREAT was easier to comply with and more acceptable than EEN. CD-TREAT induced similar effects to EEN (EEN vs CD-TREAT) on fecal microbiome composition, metabolome, mean total sulfide (increase 133.0 ± 80.5 vs 54.3 ± 47.0 nmol/g), pH (increase 1.3 ± 0.5 vs 0.9 ± 0.6), and the short-chain fatty acids (µmol/g) acetate (decrease 27.4 ± 22.6 vs 21.6 ± 20.4), propionate (decrease 5.7 ± 7.8 vs 5.2 ± 7.9), and butyrate (decrease 7.0 ± 7.4 vs 10.2 ± 8.5). In the rat model, CD-TREAT and EEN produced similar changes in bacterial load (decrease 0.3 ± 0.3 log10 16S rRNA gene copies per gram), short-chain fatty acids, microbiome, and ileitis severity (mean histopathology score decreases of 1.25 for EEN [P = .015] and 1.0 for CD-TREAT [P = .044] vs chow). In children receiving CD-TREAT, 4 (80%) had a clinical response and 3 (60%) entered remission, with significant concurrent decreases in fecal calprotectin (mean decrease 918 ± 555 mg/kg; P = .002). CONCLUSION: CD-TREAT replicates EEN changes in the microbiome, decreases gut inflammation, is well tolerated, and is potentially effective in patients with active CD. ClinicalTrials.gov, numbers NCT02426567 and NCT03171246.

Neurostimulation Devices for the Treatment of Neurologic Disorders.

Rapid advancements in neurostimulation technologies are providing relief to an unprecedented number of patients affected by debilitating neurologic and psychiatric disorders. Neurostimulation therapies include invasive and noninvasive approaches that involve the application of electrical stimulation to drive neural function within a circuit. This review focuses on established invasive electrical stimulation systems used clinically to induce therapeutic neuromodulation of dysfunctional neural circuitry. These implantable neurostimulation systems target specific deep subcortical, cortical, spinal, cranial, and peripheral nerve structures to modulate neuronal activity, providing therapeutic effects for a myriad of neuropsychiatric disorders. Recent advances in neurotechnologies and neuroimaging, along with an increased understanding of neurocircuitry, are factors contributing to the rapid rise in the use of neurostimulation therapies to treat an increasingly wide range of neurologic and psychiatric disorders. Electrical stimulation technologies are evolving after remaining fairly stagnant for the past 30 years, moving toward potential closed-loop therapeutic control systems with the ability to deliver stimulation with higher spatial resolution to provide continuous customized neuromodulation for optimal clinical outcomes. Even so, there is still much to be learned about disease pathogenesis of these neurodegenerative and psychiatric disorders and the latent mechanisms of neurostimulation that provide therapeutic relief. This review provides an overview of the increasingly common stimulation systems, their clinical indications, and enabling technologies.

Effects of a beverage rich in (poly)phenols on established and novel risk markers for vascular disease in medically uncomplicated overweight or obese subjects: A four week randomized placebo-controlled trial.

OBJECTIVE: To determine if (poly)phenols alter cardiovascular risk factors, we assessed the potential of a high (poly)phenol beverage drink, rich in hydroxycinnamates and flavonoids, to modify vascular function in middle aged, overweight or obese subjects without medical co-morbidity in a randomized placebo controlled pilot study. METHODS: Randomly assigned active 250 ml beverages containing 361 mg of (poly)phenols and 120 mg of vitamin C or placebo (no polyphenol/vitamin C) were taken twice daily for 4 weeks. Both beverages contained 40 kcals/250 ml. The primary end-points were pulse wave velocity (PWV) and cutaneous microvascular responses to sodium nitroprusside (SNP) and acetyl choline (ACh) laser doppler iontophoresis. A range of established and novel plasma markers were also measured. RESULTS: Twenty subjects received active beverage and 19 placebo; all completed the study. There was no difference in cutaneous vascular response to either SNP or ACh with mean group differences (logΔ area under perfusion curve) of 0.30 (-0.65, 1.26) and 0.35 (-0.11, 0.81) respectively. Nor was there evidence of a change in log PWV with a mean group difference of 0.029 m/s (-0.042, 0.10). No significant differences were seen in plasma leptin, apolipoproteins, cystatin C, insulin, adiponectin, CRP, ICAM-1, E-Selectin or t-PA, but IL-6 increased in active versus placebo recipients (0.32 vs - 0.18 pg/ml; p=0.010). CONCLUSION: There was no evidence for a short-term beneficial effect of (poly)phenol intervention on microcutaneous vascular response or pulse wave velocity, and no evidence for a benefit on established or novel risk factors in overweight or obese subjects. Our results do not support a short-term benefit of (poly)phenol supplementation on cardiometabolic risk. REGISTRATION: Clinical Trials.gov (NCT00795834).

Towards microbial fermentation metabolites as markers for health benefits of prebiotics.

Available evidence on the bioactive, nutritional and putative detrimental properties of gut microbial metabolites has been evaluated to support a more integrated view of how prebiotics might affect host health throughout life. The present literature inventory targeted evidence for the physiological and nutritional effects of metabolites, for example, SCFA, the potential toxicity of other metabolites and attempted to determine normal concentration ranges. Furthermore, the biological relevance of more holistic approaches like faecal water toxicity assays and metabolomics and the limitations of faecal measurements were addressed. Existing literature indicates that protein fermentation metabolites (phenol, p-cresol, indole, ammonia), typically considered as potentially harmful, occur at concentration ranges in the colon such that no toxic effects are expected either locally or following systemic absorption. The endproducts of saccharolytic fermentation, SCFA, may have effects on colonic health, host physiology, immunity, lipid and protein metabolism and appetite control. However, measuring SCFA concentrations in faeces is insufficient to assess the dynamic processes of their nutrikinetics. Existing literature on the usefulness of faecal water toxicity measures as indicators of cancer risk seems limited. In conclusion, at present there is insufficient evidence to use changes in faecal bacterial metabolite concentrations as markers of prebiotic effectiveness. Integration of results from metabolomics and metagenomics holds promise for understanding the health implications of prebiotic microbiome modulation but adequate tools for data integration and interpretation are currently lacking. Similarly, studies measuring metabolite fluxes in different body compartments to provide a more accurate picture of their nutrikinetics are needed.

Combined effects of added beta glucan and black tea in breads on starch functionality.

Bread and tea are usually consumed separately, but there may be different food-matrix interactions and changes in starch characteristics when they are combined in bread. This study developed breads (white bread, WF; black tea, BT; beta glucan, ßG; beta glucan plus black tea, ßGBT) and determined their starch functionalities. Breads were developed using a standard baking recipe and determined their starch characteristics. There was no significant difference in starch hydrolysis between BT and WF but ßGBT reduced early (10 min) starch hydrolysis compared with ßG. The starch granules in ßG and ßGBT were elliptical and closely packed together. These results suggest that the addition of beta glucan and black tea to bread preserved the elliptical starch granules and lowered short-term starch hydrolysis.

Green tea flavan-3-ols: colonic degradation and urinary excretion of catabolites by humans.

Following the ingestion of green tea, substantial quantities of flavan-3-ols pass from the small to the large intestine (Stalmach et al. Mol. Nutr. Food Res. 2009, 53, S44-S53; Mol. Nutr. Food Res. 2009, doi: 10.1002/mnfr.200900194). To investigate the fate of the flavan-3-ols entering the large intestine, where they are subjected to the action of the colonic microflora, (-)-epicatechin, (-)-epigallocatechin, and (-)-epigallocatechin-3-O-gallate were incubated in vitro with fecal slurries and the production of phenolic acid catabolites was determined by GC-MS. In addition, urinary excretion of phenolic catabolites was investigated over a 24 h period after ingestion of either green tea or water by healthy volunteers with a functioning colon. The green tea was also fed to ileostomists, and 0-24 h urinary excretion of phenolic acid catabolites was monitored. Pathways are proposed for the degradation of green tea flavan-3-ols in the colon and further catabolism of phenolic compounds passing into the circulatory system from the large intestine, prior to urinary excretion in quantities corresponding to ca. 40% of intake compared with ca. 8% absorption of flavan-3-ol methyl, glucuronide, and sulfate metabolites in the small intestine. The data obtained point to the importance of the colonic microflora in the overall bioavailability and potential bioactivity of dietary flavonoids.

Milk decreases urinary excretion but not plasma pharmacokinetics of cocoa flavan-3-ol metabolites in humans.

BACKGROUND: Cocoa drinks containing flavan-3-ols are associated with many health benefits, and conflicting evidence exists as to whether milk adversely affects the bioavailability of flavan-3-ols. OBJECTIVE: The objective was to determine the effect of milk on the bioavailability of cocoa flavan-3-ol metabolites. DESIGN: Nine human volunteers followed a low-flavonoid diet for 2 d before drinking 250 mL of a cocoa beverage, made with water or milk, that contained 45 micromol (-)-epicatechin and (-)-catechin. Plasma and urine samples were collected for 24 h, and flavan-3-ol metabolites were analyzed by HPLC with photodiode array and mass spectrometric detection. RESULTS: Milk affected neither gastric emptying nor the transit time through the small intestine. Two flavan-3-ol metabolites were detected in plasma and 4 in urine. Milk had only minor effects on the plasma pharmacokinetics of an (epi)catechin-O-sulfate and had no effect on an O-methyl-(epi)catechin-O-sulfate. However, milk significantly lowered the excretion of 4 urinary flavan-3-ol metabolites from 18.3% to 10.5% of the ingested dose (P = 0.016). Studies that showed protective effects of cocoa and those that showed no effect of milk on bioavailability used products that have a much higher flavan-3-ol content than does the commercial cocoa used in the present study. CONCLUSIONS: Most studies of the protective effects of cocoa have used drinks with a very high flavan-3-ol content. Whether similar protective effects are associated with the consumption of many commercial chocolate and cocoa products containing substantially lower amounts of flavan-3-ols, especially when absorption at lower doses is obstructed by milk, remains to be determined.

Do flavan-3-ols from green tea reach the human brain?

Following acute ingestion of green tea by six human subjects, HPLC-MS2 analysis revealed that flavan-3-ol methyl, glucuronide and sulfate metabolites appeared in the bloodstream but did not pass through the blood-cerebrospinal fluid barrier. These observations emphasize the discrepancies between in vitro and in vivo evidence on the neuroprotective role of these compounds. If, as has been proposed, green tea exerts neuroprotective effects, this finding indicates that the active components are not flavan-3-ols or their metabolites. Alternatively, a systemic action may be hypothesised whereby dietary flavan-3-ols up-regulate antioxidant defences and/or reduce inflammation, the benefit of which may be effective throughout the body.

Absorption, excretion and metabolite profiling of methyl-, glucuronyl-, glucosyl- and sulpho-conjugates of quercetin in human plasma and urine after ingestion of onions.

It is essential to have a thorough knowledge of the bioavailability and metabolism of dietary flavonols to understand their role in disease prevention. Lightly fried onions containing 275 micromol flavonols, principally quercetin-4'-glucoside and quercetin-3,4'-diglucoside, were fed to healthy human volunteers and plasma and urine were collected over a 24 h period. Samples were analysed by HPLC with diode array and tandem mass spectrometric detection. Five flavonol metabolites, quercetin-3'-sulphate, quercetin-3-glucuronide, isorhamnetin-3-glucuronide, a quercetin diglucuronide and a quercetin glucuronide sulphate, were detected in plasma in quantifiable amounts with trace quantities of six additional quercetin metabolites. Sub-micromolar peak plasma concentrations (Cmax) of quercetin-3'-sulphate, quercetin-3-glucuronide, isorhamnetin-3-glucuronide and quercetin diglucuronide were observed 0.6-0.8 h after ingestion. In contrast, the Cmax of quercetin glucuronide sulphate was 2.5 h. The elimination half-lives (t1/2) of quercetin-3'-sulphate, quercetin-3-glucuronide and quercetin diglucuronide were 1.71, 2.33 and 1.76 h respectively, while the t1/2 of isorhamnetin-3-glucuronide was 5.34 h and that of quercetin glucuronide sulphate was 4.54 h. The profile of metabolites excreted in urine was markedly different to that of plasma with many of the major urinary components, including quercetin-3'-glucuronide, two quercetin glucoside sulphates and a methylquercetin diglucuronide, absent or present in only trace amounts in the bloodstream indicative of substantial phase II metabolism. Total urinary excretion of quercetin metabolites was 12.9 micromol, corresponding to 4.7 % of intake. If these samples had been subjected to hydrolysis, as in many previous studies, only quercetin and isorhamnetin would have been detected and quantified. The bioactivity of these metabolites should be considered.