Metabolomics of head and neck cancer in biofluids: an integrative systematic review.

INTRODUCTION: Head and neck cancer (HNC) is the fifth most common cancer globally. Diagnosis at early stages are critical to reduce mortality and improve functional and esthetic outcomes associated with HNC. Metabolomics is a promising approach for discovery of biomarkers and metabolic pathways for risk assessment and early detection of HNC. OBJECTIVES: To summarize and consolidate the available evidence on metabolomics and HNC in plasma/serum, saliva, and urine. METHODS: A systematic search of experimental research was executed using PubMed and Web of Science. Available data on areas under the curve was extracted. Metabolic pathway enrichment analysis were performed to identify metabolic pathways altered in HNC. Fifty-four studies were eligible for data extraction (33 performed in plasma/serum, 15 in saliva and 6 in urine). RESULTS: Metabolites with high discriminatory performance for detection of HNC included single metabolites and combination panels of several lysoPCs, pyroglutamate, glutamic acid, glucose, tartronic acid, arachidonic acid, norvaline, linoleic acid, propionate, acetone, acetate, choline, glutamate and others. The glucose-alanine cycle and the urea cycle were the most altered pathways in HNC, among other pathways (i.e. gluconeogenesis, glycine and serine metabolism, alanine metabolism, etc.). Specific metabolites that can potentially serve as complementary less- or non-invasive biomarkers, as well as metabolic pathways integrating the data from the available studies, are presented. CONCLUSION: The present work highlights utility of metabolite-based biomarkers for risk assessment, early detection, and prognostication of HNC, as well as facilitates incorporation of available metabolomics studies into multi-omics data integration and big data analytics for personalized health.

Postprandial Dried Blood Spot-Based Nutritional Metabolomic Analysis Discriminates a High-Fat, High-Protein Meat-Based Diet from a High Carbohydrate Vegan Diet: A Randomized Controlled Crossover Trial.

BACKGROUND: Due to the challenges associated with accurate monitoring of dietary intake in humans, nutritional metabolomics (including food intake biomarkers) analysis as a complementary tool to traditional dietary assessment methods has been explored. Food intake biomarker assessment using postprandial dried blood spot (DBS) collection can be a convenient and accurate means of monitoring dietary intake vs 24-hour urine collection. OBJECTIVE: The objective of this study was to use nutritional metabolomics analysis to differentiate a high-fat, high-protein meat (HFPM) diet from a high-carbohydrate vegan (HCV) diet in postprandial DBS and 24-hour urine. DESIGN: This was a randomized controlled crossover feeding trial. PARTICIPANTS/SETTING: Participants were healthy young adult volunteers (n = 8) in California. The study was completed in August 2019. INTERVENTION: The standardized isocaloric diet interventions included an HFPM and an HCV diet. Participants attended 2 intervention days, separated by a 2-week washout. MAIN OUTCOME MEASURES: During each intervention day, a finger-prick blood sample was collected in the fasting state, 3 hours post breakfast, and 3 hours post lunch. Participants also collected their urine for 24 hours. DBS and urine samples were analyzed by ultra-performance liquid chromatography mass spectrometry to identify potential food intake biomarkers. STATISTICAL ANALYSES PERFORMED: Principal component analysis for discriminatory analysis and univariate analysis using paired t tests were performed. RESULTS: Principal component analysis found no discrimination of baseline DBS samples. In both the postprandial DBS and 24-hour urine, post-HFPM consumption had higher (P < 0.05) levels of acylcarnitines, creatine, and cis-trans hydroxyproline, and the HCV diet was associated with elevated sorbitol (P < 0.05). The HFPM diet had higher concentrations of triacylglycerols with fewer than 54 total carbons in DBS, and 24-hour urine had higher nucleoside mono- and di-phosphates (P < 0.05). CONCLUSIONS: Nutritional metabolomics profiles of postprandial DBS and 24-hour urine collections were capable of differentiating the HFPM and HCV diets. The potential use of postprandial DBS-based metabolomic analysis deserves further investigation for dietary intake monitoring.

Phytochemicals as modifiers of gut microbial communities.

A healthy gut microbiota (GM) is paramount for a healthy lifestyle. Alterations of the GM have been involved in the aetiology of several chronic diseases, including obesity and type 2 diabetes, as well as cardiovascular and neurodegenerative diseases. In pathological conditions, the diversity of the GM is commonly reduced or altered, often toward an increased Firmicutes/Bacteroidetes ratio. The colonic fermentation of dietary fiber has shown to stimulate the fraction of bacteria purported to have beneficial health effects, acting as prebiotics, and to increase the production of short chain fatty acids, e.g. propionate and butyrate, while also improving gut epithelium integrity such as tight junction functionality. However, a variety of phytochemicals, often associated with dietary fiber, have also been proposed to modulate the GM. Many phytochemicals possess antioxidant and anti-inflammatory properties that may positively affect the GM, including polyphenols, carotenoids, phytosterols/phytostanols, lignans, alkaloids, glucosinolates and terpenes. Some polyphenols may act as prebiotics, while carotenoids have been shown to alter immunoglobulin A expression, an important factor for bacteria colonization. Other phytochemicals may interact with the mucosa, another important factor for colonization, and prevent its degradation. Certain polyphenols have shown to influence bacterial communication, interacting with quorum sensing. Finally, phytochemicals can be metabolized in the gut into bioactive constituents, e.g. equol from daidzein and enterolactone from secoisolariciresinol, while bacteria can use glycosides for energy. In this review, we strive to highlight the potential interactions between prominent phytochemicals and health benefits related to the GM, emphasizing their potential as adjuvant strategies for GM-related diseases.

Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease.

The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease (NAFLD), cholestasis, and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC) and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 wk either a control (CON) or high-fructose high-fat (HFF) diet with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had a decreased number of neurons and an increase in reactive astrocytes in FC tissue. There was also a decrease in one-carbon metabolites choline and betaine and a marked accumulation of bile acids, cholesteryl esters, and polyol pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test and FC levels of amyloid-ß and phosphorylated Tau did not differ between diets, whereas probiotics increased amyloid-ß and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.

Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH.

To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a "Western-style diet" [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine-N-oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver.NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine-N-oxide in the liver.

Diet-induced obesity and weight loss alter bile acid concentrations and bile acid-sensitive gene expression in insulin target tissues of C57BL/6J mice.

Bile acids (BAs) influence the metabolism of glucose, lipids, and energy expenditure. We hypothesized that BA concentrations and related gene expression would be altered in lean (low-fat diet fed; LFD) vs diet-induced obese (high-fat diet fed; HFD) groups of mice and that some detected changes would remain after weight loss in an HFD group switched to the LFD (SW). Taurine conjugates dominated the bile acid composition of the liver, epididymal white adipose tissue (eWAT), and hypothalamus, with the latter having lower levels (~95%, ~95%, and ~80%, respectively; P<.05). Plasma conjugated bile acids were elevated in the HFD relative to the LFD and SW animals. Total hepatic BA concentrations decreased in obese mice fed HFD, and levels returned to preobese levels in the SW group. Subtle changes in unconjugated bile acids were detected in the eWAT, hypothalamus, and muscle. Liver expression of a variety of enzymes involved in BA synthesis (eg, Cyp27a1, Acox2), BA transport (eg, Slc22a8), and BA-sensitive receptors (Fxr, Tgr5) were unchanged by HFD feeding but decreased with SW. Other hepatic enzymes were induced in the SW group (eg, Amacr and Bal). In eWAT, Cyp27a1 and Acox2 also declined in the SW group, whereas the HFD group showed reduced expression of BA transporters (eg, Abcc3), and changes in Fxr and Tgr5 were unclear. Therefore, although most detectable changes in BA metabolism associated with diet-induced obesity are reversed by diet-induced weight loss, some effects on BA composition, concentrations, and gene expression can persist after weight loss.

Red palm oil-supplemented and biofortified cassava gari increase the carotenoid and retinyl palmitate concentrations of triacylglycerol-rich plasma in women.

Boiled biofortified cassava containing ß-carotene can increase retinyl palmitate in triacylglycerol-rich plasma. Thus, it might alleviate vitamin A deficiency. Cassava requires extensive preparation to decrease its level of cyanogenic glucosides, which can be fatal. Garification is a popular method of preparing cassava that removes cyanogen glucosides. Our objective was to compare the effectiveness of biofortified gari to gari prepared with red palm oil. The study was a randomized crossover trial in 8 American women. Three gari preparations separated by 2-week washout periods were consumed. Treatments (containing 200-225.9 g gari) were as follows: biofortified gari (containing 1 mg ß-carotene), red palm oil-fortified gari (1 mg ß-carotene), and unfortified gari with a 0.3-mg retinyl palmitate reference dose. Blood was collected 6 times from -0.5 to 9.5 hours after ingestion. Triacylglycerol-rich plasma was separated by ultracentrifugation and analyzed by high-performance liquid chromatography (HPLC) with diode array detection. Area under the curve for ß-carotene, α-carotene, and retinyl palmitate increased after the fortified meals were fed (P < .05), although the retinyl palmitate increase induced by the red palm oil treatment was greater than that induced by the biofortified treatment (P < .05). Vitamin A conversion was 2.4 ± 0.3 and 4.2 ± 1.5 µg pro-vitamin A carotenoid/1 µg retinol (means ± SEM) for red palm oil and biofortified gari, respectively. These results show that both treatments increased ß-carotene, α-carotene, and retinyl palmitate in triacylglycerol-rich plasma concentrations in healthy well-nourished adult women, supporting our hypothesis that both interventions could support efforts to alleviate vitamin A deficiency.

Bioavailability of iron, zinc, and provitamin A carotenoids in biofortified staple crops.

International research efforts, including those funded by HarvestPlus, a Challenge Program of the Consultative Group on International Agricultural Research (CGIAR), are focusing on conventional plant breeding to biofortify staple crops such as maize, rice, cassava, beans, wheat, sweet potatoes, and pearl millet to increase the concentrations of micronutrients that are commonly deficient in specific population groups of developing countries. The bioavailability of micronutrients in unfortified staple crops in developing regions is typically low, which raises questions about the efficacy of these crops to improve population micronutrient status. This review of recent studies of biofortified crops aims to assess the micronutrient bioavailability of biofortified staple crops in order to derive lessons that may help direct plant breeding and to infer the potential efficacy of food-based nutrition interventions. Although reducing the amounts of antinutrients and the conduction of food processing generally increases the bioavailability of micronutrients, antinutrients still possess important benefits, and food processing results in micronutrient loss. In general, biofortified foods with relatively higher micronutrient density have higher total absorption rates than nonbiofortified varieties. Thus, evidence supports the focus on efforts to breed plants with increased micronutrient concentrations in order to decrease the influence of inhibitors and to offset losses from processing.

Biofortified cassava increases ß-carotene and vitamin A concentrations in the TAG-rich plasma layer of American women.

Biofortification of cassava with the provitamin A carotenoid ß-carotene is a potential mechanism for alleviating vitamin A deficiency. Cassava is a staple food in the African diet, but data regarding the human bioavailability of ß-carotene from this food are scarce. The objective of the present study was to evaluate provitamin A-enhanced cassava as a source of ß-carotene and vitamin A for healthy adult women. The study was a randomised, cross-over trial of ten American women. The subjects consumed three different porridges separated by 2 week washout periods. Treatment meals (containing 100 g cassava) included: biofortified cassava (2 mg ß-carotene) porridge with added oil (15 ml peanut or rapeseed oil, 20 g total fat); biofortified cassava porridge without added oil (6 g total fat); unfortified white cassava porridge with a 0·3 mg retinyl palmitate reference dose and added oil (20 g total fat). Blood was collected six times from - 0·5 to 9·5 h post-feeding. TAG-rich lipoprotein (TRL) plasma was separated by ultracentrifugation and analysed using HPLC with coulometric array electrochemical detection. The AUC for retinyl palmitate increased after the biofortified cassava meals were fed (P< 0·05). Vitamin A conversion was 4·2 (sd 3·1) and 4·5 (sd 3·1) µg ß-carotene:1 µg retinol, with and without added oil, respectively. These results show that biofortified cassava increases ß-carotene and retinyl palmitate TRL plasma concentrations in healthy well-nourished adult women, suggesting that it is a viable intervention food for preventing vitamin A deficiency.