@article{krueger_griffin_beales_lloyd_brown_elison_kay_neilson_tessem_2023, title={Bioavailable Microbial Metabolites of Flavanols Demonstrate Highly Individualized Bioactivity on In Vitro & beta;-Cell Functions Critical for Metabolic Health}, volume={13}, ISSN={["2218-1989"]}, DOI={10.3390/metabo13070801}, abstractNote={Dietary flavanols are known for disease preventative properties but are often poorly absorbed. Gut microbiome flavanol metabolites are more bioavailable and may exert protective activities. Using metabolite mixtures extracted from the urine of rats supplemented with flavanols and treated with or without antibiotics, we investigated their effects on INS-1 832/13 β-cell glucose stimulated insulin secretion (GSIS) capacity. We measured insulin secretion under non-stimulatory (low) and stimulatory (high) glucose levels, insulin secretion fold induction, and total insulin content. We conducted treatment-level comparisons, individual-level dose responses, and a responder vs. non-responder predictive analysis of metabolite composition. While the first two analyses did not elucidate treatment effects, metabolites from 9 of the 28 animals demonstrated significant dose responses, regardless of treatment. Differentiation of responders vs. non-responder revealed that levels of native flavanols and valerolactones approached significance for predicting enhanced GSIS, regardless of treatment. Although treatment-level patterns were not discernable, we conclude that the high inter-individual variability shows that metabolite bioactivity on GSIS capacity is less related to flavanol supplementation or antibiotic treatment and may be more associated with the unique microbiome or metabolome of each animal. These findings suggest flavanol metabolite activities are individualized and point to the need for personalized nutrition practices.}, number={7}, journal={METABOLITES}, author={Krueger, Emily S. S. and Griffin, Laura E. E. and Beales, Joseph L. L. and Lloyd, Trevor S. S. and Brown, Nathan J. J. and Elison, Weston S. S. and Kay, Colin D. D. and Neilson, Andrew P. P. and Tessem, Jeffery S. S.}, year={2023}, month={Jul} }
 @article{satheesh babu_petersen_iglesias-carres_paz_wankhade_neilson_anandh babu_2023, title={Blueberry intervention mitigates detrimental microbial metabolite trimethylamine N-oxide by modulating gut microbes}, ISSN={["1872-8081"]}, DOI={10.1002/biof.2014}, abstractNote={Abstract}, journal={BIOFACTORS}, author={Satheesh Babu, Adhini Kuppuswamy and Petersen, Chrissa and Iglesias-Carres, Lisard and Paz, Henry A. and Wankhade, Umesh D. and Neilson, Andrew P. and Anandh Babu, Pon Velayutham}, year={2023}, month={Nov} }
 @article{iglesias-carres_chadwick-corbin_sweet_neilson_2023, title={Dietary phenolics and their microbial metabolites are poor inhibitors of trimethylamine oxidation to trimethylamine N-oxide by hepatic flavin monooxygenase 3}, volume={120}, ISSN={["1873-4847"]}, DOI={10.1016/j.jnutbio.2023.109428}, abstractNote={High circulating levels of trimethylamine N-oxide (TMAO) have been associated with cardiovascular disease risk. TMAO is formed through a microbiome-host pathway utilizing primarily dietary choline as a substrate. Specific gut microbiota transform choline into trimethylamine (TMA), and, when absorbed, host hepatic flavin-containing monooxygenase 3 (FMO3) oxidizes TMA into TMAO. Chlorogenic acid and its metabolites reduce microbial TMA production in vitro. However, little is known regarding the potential for chlorogenic acid and its bioavailable metabolites to inhibit the last step: hepatic conversion of TMA to TMAO. We developed a screening methodology to study FMO3-catalyzed production of TMAO from TMA. HepG2 cells were unable to oxidize TMA into TMAO due to their lack of FMO3 expression. Although Hepa-1 cells did express FMO3 when pretreated with TMA and NADPH, they lacked enzymatic activity to produce TMAO. Rat hepatic microsomes contained active FMO3. Optimal reaction conditions were: 50 µM TMA, 0.2 mM NADPH, and 33 µL microsomes/mL reaction. Methimazole (a known FMO3 competitive substrate) at 200 µM effectively reduced FMO3-catalyzed conversion of TMA to TMAO. However, bioavailable chlorogenic acid metabolites did not generally inhibit FMO3 at physiological (1 µM) nor supra-physiological (50 µM) doses. Thus, the effects of chlorogenic acid in regulating TMAO levels in vivo are unlikely to occur through direct FMO3 enzyme inhibition. Potential effects on FMO3 expression remain unknown. Intestinal inhibition of TMA production and/or absorption are thus likely their primary mechanisms of action.}, journal={JOURNAL OF NUTRITIONAL BIOCHEMISTRY}, author={Iglesias-Carres, Lisard and Chadwick-Corbin, Sydney A. and Sweet, Michael G. and Neilson, Andrew P.}, year={2023}, month={Oct} }
 @article{babu_petersen_paz_iglesias-carres_li_zhong_neilson_wankhade_babu_2023, title={Gut Microbiota Depletion Using Antibiotics to Investigate Diet-Derived Microbial Metabolites: An Efficient Strategy}, ISSN={["1613-4133"]}, DOI={10.1002/mnfr.202300386}, abstractNote={ScopeGut microbiota depletion using antibiotics in drinking water is a valuable tool to investigate the role of gut microbes and microbial metabolites in health and disease. However, there are challenges associated with this model. Animals avoid drinking water because of the antibiotic bitterness, which affects their metabolic health. The present study develops an efficient strategy to deplete gut microbes without affecting metabolic parameters.}, journal={MOLECULAR NUTRITION & FOOD RESEARCH}, author={Babu, Adhini Kuppuswamy Satheesh and Petersen, Chrissa and Paz, Henry A. and Iglesias-Carres, Lisard and Li, Ying and Zhong, Ying and Neilson, Andrew P. and Wankhade, Umesh D. and Babu, Pon Velayutham Anandh}, year={2023}, month={Dec} }
 @article{iglesias-carres_bruno_'antuono_linsalata_cardinali_neilson_2023, title={In vitro evidences of the globe artichoke antioxidant, cardioprotective and neuroprotective effects}, volume={107}, ISSN={["2214-9414"]}, DOI={10.1016/j.jff.2023.105674}, abstractNote={The chemical composition and in vitro biological activities of two globe artichoke varieties, Romanesco Siciliano (RS) and Spinoso Sardo (SS), were studied for their antioxidant activity and potential effects against age-related diseases. The globe artichoke extracts were subjected to three antioxidant activity tests, DPPH, ABTS and FRAP, and to the acetylcholinesterase neuro-related assay. The potential artichoke cardioprotective capacity was investigated by evaluating the inhibition of choline-d9 conversion into proatherogenic trimethylamine-d9 (TMA-d9), in an ex vivo-in vitro fecal fermentation model. In both globe artichoke varieties, the polyphenols profile was similar with chlorogenic and di-caffeoylquinic acids as the main polyphenols identified, although the amount changed with the variety (RS: 108.5; SS: 64.8 mg polyphenols/g DW). The RS sample gave the highest values of antioxidant and anti-acetylcholinesterase activities and mostly inhibited choline-d9 utilization (+28.0 % choline-d9 Area Under the Curve (AUC) compared to control), and TMA-d9 production (-31.9 % TMA-d9 AUC compared to control). All the reported results demonstrated that globe artichoke may provide potential cardioprotective, neuroprotective and antioxidant effects.}, journal={JOURNAL OF FUNCTIONAL FOODS}, author={Iglesias-Carres, Lisard and Bruno, Angelica and 'Antuono, Isabella and Linsalata, Vito and Cardinali, Angela and Neilson, Andrew P.}, year={2023}, month={Aug} }
 @article{iglesias-carres_racine_chadwick_nunn_kalambur_neilson_ferruzzi_2023, title={Mechanism of off-color formation in potato chips fried in oil systems containing ascorbic acid as a stabilizer}, volume={179}, ISSN={["1096-1127"]}, DOI={10.1016/j.lwt.2023.114682}, abstractNote={The use of alternative, green antioxidant (AOX) systems is demanded by consumers. Natural AOX systems pose significant challenges. For example, in frying applications, these AOX can negatively alter potato chip color, one of the most important traits in consumer selection. We evaluated the role of natural AOX systems containing ascorbic acid, tocopherols, and other antioxidants in amino acid-related undesirable color formation in fried potato chips. Results indicated that both oil phase AOX and potato factors are critical to generation of off-color formation in fried potato chips through Maillard type reactions. Ascorbic acid solubilization in oil and migration to the chip surface play key roles in observed off-color formation. However, multiple complex reactions may be responsible for color development, which may involve food matrix components. Contributions of AOX other than ascorbic acid appear minimal. Nevertheless, some browning can occur regardless of the presence of ascorbic acid. Color formation through glutamine occurred in the absence of ascorbic acid, but its presence greatly exacerbates color generation, while color generation via asparagine is barely modulated by ascorbic acid. AOX and free amino acid concentrations, temperature, and moisture are critical factors for controlling undesirable color formation during frying with natural oil AOX systems.}, journal={LWT-FOOD SCIENCE AND TECHNOLOGY}, author={Iglesias-Carres, Lisard and Racine, Kathryn C. and Chadwick, Sydney and Nunn, Candace and Kalambur, Sathya B. and Neilson, Andrew P. and Ferruzzi, Mario G.}, year={2023}, month={Apr} }
 @article{hayes_mohamedshah_chadwick-corbin_hoskin_iorizzo_lila_neilson_ferruzzi_2022, title={Bioaccessibility and intestinal cell uptake of carotenoids and chlorophylls differ in powdered spinach by the ingredient form as measured using in vitro gastrointestinal digestion and anaerobic fecal fermentation models}, volume={13}, ISSN={["2042-650X"]}, url={https://doi.org/10.1039/D2FO00051B}, DOI={10.1039/d2fo00051b}, abstractNote={Insights into food matrix factors impacting bioavailability of bioactive carotenoids and chlorophylls from fruits and vegetable ingredients are essential to understanding their ability to promote health.}, number={7}, journal={FOOD & FUNCTION}, publisher={Royal Society of Chemistry (RSC)}, author={Hayes, Micaela and Mohamedshah, Zulfiqar and Chadwick-Corbin, Sydney and Hoskin, Roberta and Iorizzo, Massimo and Lila, Mary Ann and Neilson, Andrew P. and Ferruzzi, Mario G.}, year={2022}, month={Mar} }
 @article{mohamedshah_hayes_chadwick-corbin_neilson_ferruzzi_2022, title={Bioaccessibility, gut microbial metabolism and intestinal transport of phenolics from 100% Concord grape juice and whole grapes are similar in a simulated digestion and fecal fermentation model}, volume={3}, ISSN={["2042-650X"]}, DOI={10.1039/d1fo04226b}, abstractNote={Phenolic rich 100% grape juice has been associated with many health benefits, but its place in dietary guidance is controversial relative to whole fruit.}, journal={FOOD & FUNCTION}, author={Mohamedshah, Zulfiqar and Hayes, Micaela and Chadwick-Corbin, Sydney and Neilson, Andrew P. and Ferruzzi, Mario G.}, year={2022}, month={Mar} }
 @article{racine_iglesias-carres_herring_ferruzzi_kay_tessem_neilson_2022, title={Cocoa extract exerts sex-specific anti-diabetic effects in an aggressive type-2 diabetes model: A pilot study}, volume={626}, ISSN={["1090-2104"]}, DOI={10.1016/j.bbrc.2022.08.018}, abstractNote={Type 2 diabetes (T2D) is characterized by hyperglycemia and insulin resistance. Cocoa may slow T2D development and progression. This study employed male and female BTBR.Cg-Lepob/ob/WiscJ (ob/ob) and wild type (WT) controls to assess the potential for cocoa to ameliorate progressive T2D and compare responses between sexes. Mice received diet without (WT, ob/ob) or with cocoa extract (ob/ob + c) for 10 weeks. Acute cocoa reduced fasting hyperglycemia in females, but not males, after 2 weeks. Chronic cocoa supplementation (6-10 weeks) ameliorated hyperinsulinemia in males and worsened hyperlipidemia and hyperinsulinemia in females, yet also preserved and enhanced beta cell survival in females. The underlying mechanisms of these differences warrant further study. If sex differences are apparent in subsequent preclinical studies, clinical studies will be warranted to establish whether these differences are relevant in humans. Sex differences may need to be considered when designing human dietary interventions for T2D.}, journal={BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS}, author={Racine, Kathryn C. and Iglesias-Carres, Lisard and Herring, Jacob A. and Ferruzzi, Mario G. and Kay, Colin D. and Tessem, Jeffery S. and Neilson, Andrew P.}, year={2022}, month={Oct}, pages={205–210} }
 @article{weikart_indukuri_racine_coleman_kovac_cockburn_hopfer_neilson_lambert_2022, title={Effect of processing on the anti-inflammatory efficacy of cocoa in a high fat diet-induced mouse model of obesity}, volume={109}, ISSN={["1873-4847"]}, DOI={10.1016/j.jnutbio.2022.109117}, abstractNote={Obesity causes inflammation which may lead to development of co-morbidities like cardiovascular diseases. Cocoa is a popular food ingredient that has been shown to mitigate obesity and inflammation in preclinical models. Cocoa typically undergoes fermentation and roasting prior to consumption, which can affect the polyphenol content in cocoa. The aim of this study was to compare the effect of fermentation and roasting protocols on the ability of cocoa to mitigate obesity, gut barrier dysfunction, and chronic inflammation in high fat (HF)-fed, obese C57BL/6J mice. We found that treatment of mice with 80 mg/g dietary cocoa powder for 8 weeks reduced rate of body weight gain in both male and female mice (46-57%), regardless of fermentation and roasting protocol. Colonic length was increased (11-24%) and gut permeability was reduced (48-79%) by cocoa supplementation. Analysis of the cecal microbiome showed that cocoa, regardless of fermentation and roasting protocol, reduced the ratio of Firmicutes to Bacteroidetes. Multivariate statistical analysis of markers of inflammation and body weight data showed sex differences in the effect of both the HF diet as well as cocoa supplementation. Based on this data there was strong protective efficacy from cocoa supplementation especially for the more processed cocoa samples. Overall, this study shows that anti-obesity and anti-inflammatory efficacy of cocoa is resilient to changes in polyphenol content and composition induced by fermentation or roasting. Further, this study shows that although cocoa has beneficial effects in both males and females, there are significant sex differences.}, journal={JOURNAL OF NUTRITIONAL BIOCHEMISTRY}, author={Weikart, Daphne K. and Indukuri, Vijaya V. and Racine, Kathryn C. and Coleman, Kiana M. and Kovac, Jasna and Cockburn, Darrell W. and Hopfer, Helene and Neilson, Andrew P. and Lambert, Joshua D.}, year={2022}, month={Nov} }
 @misc{cheatham_nieman_neilson_lila_2022, title={Enhancing the Cognitive Effects of Flavonoids With Physical Activity: Is There a Case for the Gut Microbiome?}, volume={16}, ISSN={["1662-453X"]}, DOI={10.3389/fnins.2022.833202}, abstractNote={Age-related cognitive changes can be the first indication of the progression to dementias, such as Alzheimer’s disease. These changes may be driven by a complex interaction of factors including diet, activity levels, genetics, and environment. Here we review the evidence supporting relationships between flavonoids, physical activity, and brain function. Recent in vivo experiments and human clinical trials have shown that flavonoid-rich foods can inhibit neuroinflammation and enhance cognitive performance. Improved cognition has also been correlated with a physically active lifestyle, and with the functionality and diversity of the gut microbiome. The great majority (+ 90%) of dietary flavonoids are biotransformed into phytoactive phenolic metabolites at the gut microbiome level prior to absorption, and these prebiotic flavonoids modulate microbiota profiles and diversity. Health-relevant outcomes from flavonoid ingestion may only be realized in the presence of a robust microbiome. Moderate-to-vigorous physical activity (MVPA) accelerates the catabolism and uptake of these gut-derived anti-inflammatory and immunomodulatory metabolites into circulation. The gut microbiome exerts a profound influence on cognitive function; moderate exercise and flavonoid intake influence cognitive benefits; and exercise and flavonoid intake influence the microbiome. We conclude that there is a potential for combined impacts of flavonoid intake and physical exertion on cognitive function, as modulated by the gut microbiome, and that the combination of a flavonoid-rich diet and routine aerobic exercise may potentiate cognitive benefits and reduce cognitive decline in an aging population, via mechanisms mediated by the gut microbiome. Mechanistic animal studies and human clinical interventions are needed to further explore this hypothesis.}, journal={FRONTIERS IN NEUROSCIENCE}, author={Cheatham, Carol L. and Nieman, David C. and Neilson, Andrew P. and Lila, Mary Ann}, year={2022}, month={Feb} }
 @article{griffin_kohrt_rathore_kay_grabowska_neilson_2022, title={Microbial Metabolites of Flavanols in Urine are Associated with Enhanced Anti-Proliferative Activity in Bladder Cancer Cells In Vitro}, volume={74}, ISSN={["1532-7914"]}, url={https://doi.org/10.1080/01635581.2020.1869277}, DOI={10.1080/01635581.2020.1869277}, abstractNote={Dietary flavanols and their metabolites are excreted primarily via the urine, suggesting uroepithelial cells as a site of activity due to lengthy exposure to high concentrations of these compounds. Flavanols are metabolized by the gut microbiota to numerous bioavailable metabolites. The observed effects of flavanols, including cancer chemoprevention, may be due in part to the activities of microbial metabolites. Most in vitro mechanistic work in this area relies on a limited pool of commercially available or synthesized flavanol microbial metabolites, and little work has been done in the area of bladder cancer. The impact of physiologically relevant mixtures of native flavanols and their metabolites generated in vivo remains unknown. Rats were fed various flavanols after which 48 h urine samples, approximating the total bioavailable metabolome, were collected. Urine samples were profiled by UPLC-MS/MS, and their anti-proliferative activities were assayed in vitro in four bladder cancer cell models. Significant interindividual variability was observed for chemical profiles and anti-proliferative activities. Concentrations of microbial metabolites (valerolactones, phenylalkyl acids and hippuric acids) were positively associated with reduced bladder cancer cell proliferation in vitro, while native flavanols were poorly correlated with activity. These results suggest that microbial metabolites may be the primary compounds responsible for chemoprevention in uroepithelial cell following flavanol consumption. Furthermore, this highlights the potential for exploiting knowledge about individual genetics, microbiome profiles, flavonoid metabolism profiles, tumor characteristics, etc. to design personalized dietary interventions for cancer prevention and/or adjuvant therapy to reduce bladder cancer incidence and improve outcomes.}, number={1}, journal={NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL}, author={Griffin, Laura E. and Kohrt, Sarah E. and Rathore, Atul and Kay, Colin D. and Grabowska, Magdalena M. and Neilson, Andrew P.}, year={2022}, month={Jan}, pages={194–210} }
 @article{iglesias-carres_racine_neilson_2022, title={Phenolic-rich beverages reduce bacterial TMA formation in an ex vivo-in vitro colonic fermentation model}, ISSN={["2042-650X"]}, DOI={10.1039/d2fo01159j}, abstractNote={Upper tract gastrointestinal digestion unlocks the ability of cocoa and coffee bioactives to inhibit bacterial TMA formation.}, journal={FOOD & FUNCTION}, author={Iglesias-Carres, Lisard and Racine, Kathryn C. and Neilson, Andrew P.}, year={2022}, month={Jul} }
 @article{iglesias-carres_krueger_herring_tessem_neilson_2022, title={Potential of Phenolic Compounds and Their Gut Microbiota-Derived Metabolites to Reduce TMA Formation: Application of an In Vitro Fermentation High-Throughput Screening Model}, volume={70}, ISSN={["1520-5118"]}, DOI={10.1021/acs.jafc.2c00247}, abstractNote={Trimethylamine N-oxide (TMAO) is a pro-atherosclerotic product of dietary choline metabolism generated by a microbiome-host axis. The first step in this pathway is the enzymatic metabolism of choline to trimethylamine (TMA) by the gut microbiota. This reaction could be targeted to reduce atherosclerosis risk. We aimed to evaluate potential inhibitory effects of select dietary phenolics and their relevant gut microbial metabolites on TMA production via a human ex vivo-in vitro fermentation model. Various phenolics inhibited choline use and TMA production. The most bioactive compounds tested (caffeic acid, catechin, and epicatechin) reduced TMA-d9 formation (compared to control) by 57.5 ± 1.3 to 72.5 ± 0.4% at 8 h and preserved remaining choline-d9 concentrations by 194.1 ± 6.4 to 256.1 ± 6.3% at 8 h. These inhibitory effects were achieved without altering cell respiration or cell growth. However, inhibitory effects decreased at late fermentation times, which suggested that these compounds delay choline metabolism rather than completely inhibiting TMA formation. Overall, caffeic acid, catechin, and epicatechin were the most effective noncytotoxic inhibitors of choline use and TMA production. Thus, these compounds are proposed as lead bioactives to test in vivo.}, number={10}, journal={JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY}, author={Iglesias-Carres, Lisard and Krueger, Emily S. and Herring, Jacob A. and Tessem, Jeffery S. and Neilson, Andrew P.}, year={2022}, month={Mar}, pages={3207–3218} }
 @article{virdee_saini_kay_neilson_kwan_helfrich_mooney_smith_2021, title={An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder}, volume={11}, ISSN={["2045-2322"]}, url={https://europepmc.org/articles/PMC7794323}, DOI={10.1038/s41598-020-80093-8}, abstractNote={Abstract}, number={1}, journal={SCIENTIFIC REPORTS}, author={Virdee, Manjot S. and Saini, Nipun and Kay, Colin D. and Neilson, Andrew P. and Kwan, Sze Ting Cecilia and Helfrich, Kaylee K. and Mooney, Sandra M. and Smith, Susan M.}, year={2021}, month={Jan} }
 @article{griffin_essenmacher_racine_iglesias-carres_tessem_smith_neilson_2021, title={Diet-induced obesity in genetically diverse collaborative cross mouse founder strains reveals diverse phenotype response and amelioration by quercetin treatment in 129S1/SvImJ, PWK/EiJ, CAST/PhJ, and WSB/EiJ mice}, volume={87}, ISSN={["1873-4847"]}, DOI={10.1016/j.jnutbio.2020.108521}, abstractNote={Significant evidence suggests protective effects of flavonoids against obesity in animal models, but these often do not translate to humans. One explanation for this disconnect is use of a few mouse strains (notably C57BL/6 J) in obesity studies. Obesity is a multifactorial disease. The underlying causes are not fully replicated by the high-fat C57BL/6 J model, despite phenotypic similarities. Furthermore, the impact of genetic factors on the activities of flavonoids is unknown. This study was designed to explore how diverse mouse strains respond to diet-induced obesity when fed a representative flavonoid. A subset of Collaborative Cross founder strains (males and females) were placed on dietary treatments (low-fat, high-fat, high-fat with quercetin, high-fat with quercetin and antibiotics) longitudinally. Diverse responses were observed across strains and sexes. Quercetin appeared to moderately blunt weight gain in male C57 and both sexes of 129S1/SvImJ mice, and slightly increased weight gain in female C57 mice. Surprisingly, quercetin dramatically blunted weight gain in male, but not female, PWK/PhJ mice. For female mice, quercetin blunted weight gain (relative to the high-fat phase) in CAST/PhJ, PWK/EiJ and WSB/EiJ mice compared to C57. Antibiotics did not generally result in loss of protective effects of quercetin. This highlights complex interactions between genetic factors, sex, obesity stimuli, and flavonoid intake, and the need to move away from single inbred mouse models to enhance translatability to diverse humans. These data justify use of genetically diverse Collaborative Cross and Diversity Outbred models which are emerging as invaluable tools in the field of personalized nutrition.}, journal={JOURNAL OF NUTRITIONAL BIOCHEMISTRY}, author={Griffin, Laura E. and Essenmacher, Lauren and Racine, Kathryn C. and Iglesias-Carres, Lisard and Tessem, Jeffery S. and Smith, Susan M. and Neilson, Andrew P.}, year={2021}, month={Jan} }
 @article{steele_baugh_griffin_neilson_davy_hulver_davy_2021, title={Fasting and postprandial trimethylamine N-oxide in sedentary and endurance-trained males following a short-term high-fat diet}, volume={9}, ISSN={["2051-817X"]}, DOI={10.14814/phy2.14970}, abstractNote={Gut bacteria release trimethylamine (TMA) from dietary substrates. TMA is absorbed and is subsequently oxidized in the liver to produce trimethylamine N‐oxide (TMAO). Plasma TMAO levels are positively correlated with risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). High‐fat diet (HFD) consumption has been reported to increase fasting and postprandial TMAO in sedentary individuals. However, whether the increase in TMAO with consumption of an HFD is observed in endurance‐trained males is unknown. Healthy, sedentary (n = 17), and endurance‐trained (n = 7) males consumed a 10‐day eucaloric diet comprised of 55% carbohydrate, 30% total fat, and <10% saturated fat prior to baseline testing. Blood samples were obtained in a fasted state and for a 4‐hour high‐fat challenge (HFC) meal at baseline and then again following 5‐day HFD (30% carbohydrate, 55% total fat, and 25% saturated fat). Plasma TMAO and TMA‐moiety (choline, betaine, L‐carnitine) concentrations were measured using isocratic ultraperformance liquid chromatography‐tandem mass spectrometry. Age (23 ±3 vs. 22 ± 2 years) and body mass index (23.0 ± 3.0 vs. 23.5 ± 2.1 kg/m2) were similar (both p > 0.05) in the sedentary and endurance‐trained group, respectively. VO2max was significantly higher in the endurance‐trained compared with sedentary males (56.7 ± 8.2 vs. 39.9 ± 6.0 ml/kg/min). Neither the HFC nor the HFD evoked a detectable change in plasma TMAO (p > 0.05) in either group. Future studies are needed to identify the effects of endurance training on TMAO production.}, number={16}, journal={PHYSIOLOGICAL REPORTS}, author={Steele, Cortney N. and Baugh, Mary Elizabeth and Griffin, Laura E. and Neilson, Andrew P. and Davy, Brenda M. and Hulver, Matthew W. and Davy, Kevin P.}, year={2021}, month={Aug} }
 @article{krueger_beales_russon_elison_davis_hansen_neilson_hansen_tessem_2021, title={Gut Metabolite Trimethylamine N-Oxide Protects INS-1 beta-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions}, volume={11}, ISSN={["2218-273X"]}, DOI={10.3390/biom11121892}, abstractNote={Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.}, number={12}, journal={BIOMOLECULES}, author={Krueger, Emily S. and Beales, Joseph L. and Russon, Kacie B. and Elison, Weston S. and Davis, Jordan R. and Hansen, Jackson M. and Neilson, Andrew P. and Hansen, Jason M. and Tessem, Jeffery S.}, year={2021}, month={Dec} }
 @article{brunt_casso_gioscia-ryan_sapinsley_ziemba_clayton_bazzoni_vandongen_richey_hutton_et al._2021, title={Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans}, volume={78}, ISSN={["1524-4563"]}, DOI={10.1161/HYPERTENSIONAHA.120.16895}, abstractNote={
            Aging is associated with stiffening of the large elastic arteries and consequent increases in systolic blood pressure (SBP), which together increase cardiovascular disease risk; however, the upstream mechanisms are incompletely understood. Using complementary translational approaches in mice and humans, we investigated the role of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) in age-related aortic stiffening and increased SBP. Aortic stiffness was measured using carotid-femoral or aortic pulse wave velocity (PWV) in humans and mice, respectively. Study 1: Plasma TMAO concentrations were elevated (
            P
            <0.001) in healthy middle-aged to older (6.3±5.8 µmol/L) versus young (1.8±1.4 µmol/L) humans and positively related to carotid-femoral PWV (
            r
            
              2
            
            =0.15,
            P
            <0.0001) and SBP (
            r
            
              2
            
            =0.09,
            P
            <0.001), independent of traditional cardiovascular risk factors. Study 2: Dietary supplementation with TMAO increased aPWV in young mice and exacerbated the already elevated aPWV of old mice, accompanied by increases in SBP of ≈10 mm Hg in both groups. TMAO-supplemented versus control-fed mice also had higher intrinsic mechanical stiffness of the aorta (stress-strain testing) associated with higher aortic abundance of advanced glycation end-products, which form crosslinks between structural proteins to promote aortic stiffening. Study 3: Ex vivo incubation of aortic rings with TMAO increased intrinsic stiffness, which was attenuated by the advanced glycation end-products crosslink breaker alagebrium and prevented by inhibition of superoxide signaling. TMAO induces aortic stiffening and increases SBP via formation of advanced glycation end-products and superoxide-stimulated oxidative stress, which together increase intrinsic wall stiffness. Increases in circulating TMAO with aging represent a novel therapeutic target for reducing risk of aortic stiffening-related clinical disorders.
          }, number={2}, journal={HYPERTENSION}, author={Brunt, Vienna E. and Casso, Abigail G. and Gioscia-Ryan, Rachel A. and Sapinsley, Zachary J. and Ziemba, Brian P. and Clayton, Zachary S. and Bazzoni, Amy E. and VanDongen, Nicholas S. and Richey, James J. and Hutton, David A. and et al.}, year={2021}, month={Aug}, pages={499–511} }
 @article{bruno_neilson_lambert_moustaid-moussa_2021, title={Journal of Nutritional Biochemistry Special Issue: Polyphenols, obesity, and cardiometabolic health}, volume={89}, ISSN={["1873-4847"]}, DOI={10.1016/j.jnutbio.2020.108565}, journal={JOURNAL OF NUTRITIONAL BIOCHEMISTRY}, author={Bruno, Richard S. and Neilson, Andrew P. and Lambert, Joshua D. and Moustaid-Moussa, Naima}, year={2021}, month={Mar} }
 @article{mitchell_davy_ponder_mcmillan_hughes_hulver_neilson_davy_2021, title={Prebiotic Inulin Supplementation and Peripheral Insulin Sensitivity in adults at Elevated Risk for Type 2 Diabetes: A Pilot Randomized Controlled Trial}, volume={13}, ISSN={["2072-6643"]}, DOI={10.3390/nu13093235}, abstractNote={Prediabetes affects 84.1 million adults, and many will progress to type 2 diabetes (T2D). The objective of this proof-of-concept trial was to determine the efficacy of inulin supplementation to improve glucose metabolism and reduce T2D risk. Adults (n = 24; BMI: 31.3 ± 2.9 kg/m2; age: 54.4 ± 8.3 years) at risk for T2D were enrolled in this controlled feeding trial and consumed either inulin (10 g/day) or placebo (maltodextrin, 10 g/day) for six weeks. Assessments included peripheral insulin sensitivity, fasting glucose, and insulin, HOMA-IR, in vivo skeletal muscle substrate preference, Bifidobacteria copy number, intestinal permeability, and endotoxin concentrations. Participant retention was 92%. There were no baseline group differences except for fasting insulin (p = 0.003). The magnitude of reduction in fasting insulin concentrations with inulin (p = 0.003, inulin = Δ-2.9, placebo = Δ2.3) was attenuated after adjustment for baseline concentrations (p = 0.04). After adjusting for baseline values, reduction in HOMA-IR with inulin (inulin = Δ-0.40, placebo=Δ0.27; p = 0.004) remained significant. Bifidobacteria 16s increased (p = 0.04; inulin = Δ3.1e9, placebo = Δ-8.9e8) with inulin supplementation. Despite increases in gut Bifidobacteria, inulin supplementation did not improve peripheral insulin sensitivity. These findings question the need for larger investigations of inulin and insulin sensitivity in this population.}, number={9}, journal={NUTRIENTS}, author={Mitchell, Cassie M. and Davy, Brenda M. and Ponder, Monica A. and McMillan, Ryan P. and Hughes, Michael D. and Hulver, Matthew W. and Neilson, Andrew P. and Davy, Kevin P.}, year={2021}, month={Sep} }
 @article{jin_sean f. o'keefe_stewart_neilson_kim_huang_2021, title={Techno-economic analysis of a grape pomace biorefinery: Production of seed oil, polyphenols, and biochar}, volume={127}, ISSN={["1744-3571"]}, DOI={10.1016/j.fbp.2021.02.002}, abstractNote={Processing grape pomace (GP), a major waste from the wine industry, into multiple value-added products based on the biorefinery concept has a potential to reduce waste disposal and promote a sustainable bioeconomy. However, its economic feasibility at a commercial scale remains unknown. The present study aims to evaluate the economics of a biorefinery process of GP, by performing comparative techno-economic analysis of three processing scenarios: (1) a whole biorefinery process that fully utilizes GP biomass and produces grape seed oil, polyphenols, and biochar (GSO + GSKP + GB), (2) a process that produces grape seed oil and polyphenols (GSO + GSKP), and (3) a process that produces only grape seed oil (GSO). A plant capacity of about 33,000 metric tons/year was considered in the analysis. Among the three scenarios, the whole biorefinery process (GSO + GSKP + GB) showed the highest economic performance with the net present value (NPV), internal rate of return (IRR), and payback period of 111.7 million US-$, 34.3%, and 2.5 years, respectively, due to the diverse revenues and minimized waste disposal cost. The GSO plant showed the lowest economic performance with a negative NPV. Sensitivity analysis revealed that plant capacity, polyphenol price, polyphenol concentration (percentage) in grape pomace, and biochar price had dominating influences on the economic performance of the biorefinery process.}, journal={FOOD AND BIOPRODUCTS PROCESSING}, author={Jin, Qing and Sean F. O'Keefe and Stewart, Amanda C. and Neilson, Andrew P. and Kim, Young-Teck and Huang, Haibo}, year={2021}, month={May}, pages={139–151} }
 @article{brunt_larocca_bazzoni_sapinsley_miyamoto-ditmon_gioscia-ryan_neilson_link_seals_2021, title={The gut microbiome-derived metabolite trimethylamineN-oxide modulates neuroinflammation and cognitive function with aging}, volume={43}, ISSN={["2509-2723"]}, DOI={10.1007/s11357-020-00257-2}, abstractNote={Aging is associated with declines in cognitive performance, which are mediated in part by neuroinflammation, characterized by astrocyte activation and higher levels of pro-inflammatory cytokines; however, the upstream drivers are unknown. We investigated the potential role of the gut microbiome–derived metabolite trimethylamine N-oxide (TMAO) in modulating neuroinflammation and cognitive function with aging. Study 1: In middle-aged and older humans (65 ± 7 years), plasma TMAO levels were inversely related to performance on NIH Toolbox Cognition Battery tests of memory and fluid cognition (both r2 = 0.07, p < 0.05). Study 2: In mice, TMAO concentrations in plasma and the brain increased in parallel with aging (r2 = 0.60), suggesting TMAO crosses the blood-brain barrier. The greater TMAO concentrations in old mice (27 months) were associated with higher brain pro-inflammatory cytokines and markers of astrocyte activation vs. young adult mice (6 months). Study 3: To determine if TMAO independently induces an “aging-like” decline in cognitive function, young mice (6 months) were supplemented with TMAO in chow for 6 months. Compared with controls, TMAO-supplemented mice performed worse on the novel object recognition test, indicating impaired memory and learning, and had increased neuroinflammation and markers of astrocyte activation. Study 4: Human astrocytes cultured with TMAO vs. control media exhibited changes in cellular morphology and protein markers consistent with astrocyte activation, indicating TMAO directly acts on these cells. Our results provide translational insight into a novel pathway that modulates neuroinflammation and cognitive function with aging, and suggest that TMAO might be a promising target for prevention of neuroinflammation and cognitive decline with aging.}, number={1}, journal={GEROSCIENCE}, author={Brunt, Vienna E. and LaRocca, Thomas J. and Bazzoni, Amy E. and Sapinsley, Zachary J. and Miyamoto-Ditmon, Jill and Gioscia-Ryan, Rachel A. and Neilson, Andrew P. and Link, Christopher D. and Seals, Douglas R.}, year={2021}, month={Feb}, pages={377–394} }
 @article{iglesias-carres_hughes_steele_ponder_davy_neilson_2021, title={Use of dietary phytochemicals for inhibition of trimethylamine N-oxide formation}, volume={91}, ISSN={["1873-4847"]}, DOI={10.1016/j.jnutbio.2021.108600}, abstractNote={Trimethylamine-N-oxide (TMAO) has been reported as a risk factor for atherosclerosis development, as well as for other cardiovascular disease (CVD) pathologies. The objective of this review is to provide a useful summary on the use of phytochemicals as TMAO-reducing agents. This review discusses the main mechanisms by which TMAO promotes CVD, including the modulation of lipid and bile acid metabolism, and the promotion of endothelial dysfunction and oxidative stress. Current knowledge on the available strategies to reduce TMAO formation are discussed, highlighting the effect and potential of phytochemicals. Overall, phytochemicals (i.e., phenolic compounds or glucosinolates) reduce TMAO formation by modulating gut microbiota composition and/or function, inhibiting host's capacity to metabolize TMA to TMAO, or a combination of both. Perspectives for design of future studies involving phytochemicals as TMAO-reducing agents are discussed. Overall, the information provided by this review outlines the current state of the art of the role of phytochemicals as TMAO reducing agents, providing valuable insight to further advance in this field of study.}, journal={JOURNAL OF NUTRITIONAL BIOCHEMISTRY}, author={Iglesias-Carres, Lisard and Hughes, Michael D. and Steele, Cortney N. and Ponder, Monica A. and Davy, Kevin P. and Neilson, Andrew P.}, year={2021}, month={May} }
 @article{iglesias-carres_neilson_2021, title={Utilizing preclinical models of genetic diversity to improve translation of phytochemical activities from rodents to humans and inform personalized nutrition}, ISSN={["2042-650X"]}, DOI={10.1039/d1fo02782d}, abstractNote={Mouse models of genetic variation may facilitate translation of phytochemical activities from rodents to humans and inform personalized nutrition.}, journal={FOOD & FUNCTION}, author={Iglesias-Carres, Lisard and Neilson, Andrew P.}, year={2021}, month={Oct} }
 @article{wang_wang_alkhalidy_luo_moomaw_neilson_liu_2020, title={Flavone Hispidulin Stimulates Glucagon-Like Peptide-1 Secretion and Ameliorates Hyperglycemia in Streptozotocin-Induced Diabetic Mice}, volume={64}, ISSN={["1613-4133"]}, DOI={10.1002/mnfr.201900978}, abstractNote={ScopeLoss of functional β‐cell mass is central for the deterioration of glycemic control in diabetes. The incretin hormone glucagon‐like peptide‐1 (GLP‐1) plays a critical role in maintaining glycemic homeostasis via potentiating glucose‐stimulated insulin secretion and promoting β‐cell mass. Agents that can directly promote GLP‐1 secretion, thereby increasing insulin secretion and preserving β‐cell mass, hold great potential for the treatment of T2D.}, number={6}, journal={MOLECULAR NUTRITION & FOOD RESEARCH}, author={Wang, Yao and Wang, Aiping and Alkhalidy, Hana and Luo, Jing and Moomaw, Elizabeth and Neilson, Andrew P. and Liu, Dongmin}, year={2020}, month={Mar} }
 @article{jin_wang_feng_kim_stewart_sean f. o'keefe_neilson_he_huang_2020, title={Grape pomace and its secondary waste management: Biochar production for a broad range of lead (Pb) removal from water}, volume={186}, ISSN={["1096-0953"]}, DOI={10.1016/j.envres.2020.109442}, abstractNote={Grape pomace (GP) management has been a challenge worldwide. We have previously demonstrated a biorefinery process to recover oil and polyphenols, and produce biofuels from GP sequentially, although over 50% of GP solid waste remains post-processing. To approach zero solid waste during GP processing, herein a pyrolysis process was designed for converting GP and its secondary processing wastes to biochars, which were then evaluated for lead (Pb) adsorption from water. GP lignin pyrolyzed at 700 °C (GPL2700 biochar) with specific surface area of 485 m2/g showed the highest Pb adsorption capacity, and achieved 66.5% of Pb removal from an initially high concentration of 300 mg/L within 30 min. At low initial Pb concentrations (50–3000 μg/L), GPL2700 biochar could reduce Pb concentrations to 0.208–77.2 μg/L. In addition, experimental and modeling results revealed that both physisorption and chemisorption mechanisms were involved in the adsorption process of GPL2700 biochar.}, journal={ENVIRONMENTAL RESEARCH}, author={Jin, Qing and Wang, Zixuan and Feng, Yiming and Kim, Young-Teck and Stewart, Amanda C. and Sean F. O'Keefe and Neilson, Andrew P. and He, Zhen and Huang, Haibo}, year={2020}, month={Jul} }
 @article{li_griffin_corbin_neilson_ferruzzi_2020, title={Modulating Phenolic Bioaccessibility and Glycemic Response of Starch-Based Foods in Wistar Rats by Physical Complexation between Starch and Phenolic Acid}, volume={68}, ISSN={["1520-5118"]}, DOI={10.1021/acs.jafc.0c01387}, abstractNote={This study assessed the impact of caffeic and ferulic acid complexation with maize amylopectin or potato starch on glycemic parameters. Compared with starch-phenolic mixtures, starch-phenolic complexes resulted in significant modification of phenolic bioaccessibility and cellular uptake (p < 0.05). In addition, glucose release from in vitro digestion of starch was modestly reduced in the complexes compared to native starch alone (21.2-26.8mM vs. 29.8-30.5mM). Furthermore, intestinal glucose transport, assessed in Caco-2 cell monolayers was not affected by presence of complexes (82.4-124% vs. 100% at 90 min). However, a reduced glycemic response was evident in a Wistar rat model with significant reduction in 240 min blood glucose AUC following oral administration of potato starch-ferulic acid complex compared to native potato starch (26170±556 vs. 28951±486 mg*min/dL, p < 0.001). These alterations were attributed to complexation-induced resistant starch formation and phenolic entrapment providing an alternative mechanism approach to modulate glycemic properties of starch-based foods.}, number={46}, journal={JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY}, author={Li, Min and Griffin, Laura E. and Corbin, Sydney and Neilson, Andrew P. and Ferruzzi, Mario G.}, year={2020}, month={Nov}, pages={13257–13266} }
 @article{baugh_bowser_mcmillan_davy_essenmacher_neilson_hulver_davy_2020, title={Postprandial skeletal muscle metabolism following a high-fat diet in sedentary and endurance-trained males}, volume={128}, ISSN={["1522-1601"]}, DOI={10.1152/japplphysiol.00576.2019}, abstractNote={Our objective was to determine the influence of a high-fat diet (HFD) on fasting and postprandial skeletal muscle substrate metabolism in endurance-trained (ET) compared with sedentary (SED) humans. SED ( n = 17) and ET ( n = 7) males were control-fed a 10-day moderate-fat diet followed by a 5-day isocaloric HFD (55% fat, 30% carbohydrate). Skeletal muscle biopsies were taken in the fasted condition and 4 h after a high-fat meal (820 kcals; 63% fat and 25% carbohydrate). Palmitate-induced suppression of pyruvate oxidation, an indication of substrate preference, and oxidation of fat and glucose were measured in homogenized skeletal muscle in fasted and fed states. Postprandial responses were calculated as percent changes from fasting to fed states. Postprandial suppression of pyruvate oxidation was maintained after the HFD in ET, but not SED skeletal muscle, suggesting greater adaptability to dietary intake changes in the former. Fasting total fat oxidation increased due to the HFD in ET skeletal muscle ( P = 0.006), which was driven by incomplete fat oxidation ( P = 0.008). Fasting fat oxidation remained unchanged in skeletal muscle of SED individuals. Yet, postprandial fat oxidation was similar between groups. Fasting glucose oxidation was elevated after the HFD in ET ( P = 0.036), but not SED, skeletal muscle. Postprandial glucose oxidation was reduced due to the HFD in SED ( P = 0.002), but not ET, skeletal muscle. These findings provide insight into differing substrate metabolism responses between SED and ET individuals and highlight the role that the prevailing diet may play in modulating fasting and postprandial metabolic responses in skeletal muscle.}, number={4}, journal={JOURNAL OF APPLIED PHYSIOLOGY}, author={Baugh, Mary Elizabeth and Bowser, Suzanne M. and McMillan, Ryan P. and Davy, Brenda M. and Essenmacher, Lauren A. and Neilson, Andrew P. and Hulver, Matthew W. and Davy, Kevin P.}, year={2020}, month={Apr}, pages={872–883} }
 @article{griffin_diako_miller_neilson_ross_stewart_2020, title={Preference for and sensitivity to flavanol mean degree of polymerization in model wines is correlated with body composition}, volume={144}, ISSN={["1095-8304"]}, DOI={10.1016/j.appet.2019.104442}, abstractNote={Bitterness and astringency (dryness) are characteristic sensory attributes of flavanol-rich foods. The degree of polymerization (DP) of flavanols influences their bitter and astringent sensations. Smaller DP compounds can enter the papillae on the tongue, eliciting a bitter response. Larger DP compounds are sterically inhibited from entering papillae and instead interact with oral proteins, cause precipitation, and elicit astringent sensations. Previous research has indicated that bitterness preference is related to health status, density of fungiform papillae on the tongue, and sensitivity to bitter compounds such as 6-n-propyl-thiouracil (PROP). The purpose of this study was to examine trends in liking, bitterness intensity, and astringency intensity of wine-like products with flavanols of different DP using a consumer sensory panel. Participants (n = 102) were segmented by phenotypes: body fat percentage (BF%), body mass index (BMI), PROP sensitivity, and stated bitter food preference. Differences in wine liking, perceived bitterness intensity, and astringency intensity were observed between three model wine samples of varying flavanol mean degrees of polymerization (mDP, i.e. the average size (polymer length) of flavanol compounds in a mixture). Specifically, with increased mDP, overall liking and bitterness liking decreased, with concurrent increased perception of bitterness and astringency intensity. Greater differences between phenotypes were observed when participants were segmented by BF% and BMI classification, than when segmented by PROP sensitivity classification. Reduced ability to detect differences in bitterness and astringency were noted in participants of higher weight status. Overall, these data suggest that weight status in adults is a greater predictor of liking of flavanol-rich foods than bitterness sensitivity (as determined by PROP classification), and that reduced perception of bitterness and astringency associated with weight gain may impact selection and preference for these foods.}, journal={APPETITE}, author={Griffin, Laura E. and Diako, Charles and Miller, Lindsey E. and Neilson, Andrew P. and Ross, Carolyn F. and Stewart, Amanda C.}, year={2020}, month={Jan} }
 @article{bowser_mcmillan_boutagy_tarpey_smithson_osterberg_neilson_davy_davy_hulver_2020, title={Serum endotoxin, gut permeability and skeletal muscle metabolic adaptations following a short term high fat diet in humans}, volume={103}, ISSN={["1532-8600"]}, DOI={10.1016/j.metabol.2019.154041}, abstractNote={Our previous work demonstrated that a short-term high fat diet (HFD) increased fasting serum endotoxin, altered postprandial excursions of serum endotoxin, and led to metabolic and transcriptional responses in skeletal muscle in young, healthy male humans.The purpose of the present study was to determine if a short-term high fat diet: 1) increases intestinal permeability and, in turn, fasting endotoxin concentrations and 2) decreases postprandial skeletal muscle fat oxidation.Thirteen normal weight young adult males (BMI 23.1 ± 0.8 kg/m2, age 22.2 ± 0.4 years) were fed a control diet (55% carbohydrate, 30% fat, 9% of which was saturated, 15% protein) for two weeks, followed by 5 days of an isocaloric HFD (30% carbohydrate, 55% fat, 25% of which was saturated, 15% protein, isocaloric to the control diet). Intestinal permeability (via four sugar probe test) was assessed in the fasting state. Both before and after the HFD, a high fat meal challenge (HFM, 820 kcal, 25% carbohydrate, 63% fat, 26% of which was saturated, and 12% protein) was administered. After an overnight fast, blood samples were collected before and every hour for 4 h after the HFM to assess endotoxin, and other serum blood measures. Muscle biopsies were obtained from the vastus lateralis before and 4 h after the HFM in order to assess substrate oxidation (glucose, fatty acid and pyruvate) using radiolabeled techniques. Insulin sensitivity was assessed via intravenous glucose tolerance test. Intestinal permeability, blood samples and muscle biopsies were assessed in the same manner before and following the HFD.Intestinal permeability was not affected by HFD (p > 0.05), but fasting endotoxin increased two fold following the HFD (p = 0.04). Glucose oxidation and fatty acid oxidation in skeletal muscle homogenates significantly increased after the HFM before the HFD (+97%, and +106% respectively) but declined after the HFM following 5 days of the HFD (-24% and +16% respectively). Fatty acid suppressibility of pyruvate oxidation increased significantly after the HFM (+32%) but this physiological effect was abolished following 5 days of the HFD (+7%). Insulin sensitivity did not change following the HFD.These findings demonstrate that in healthy young men, consuming an isocaloric HFD for 5 days increases fasting endotoxin, independent of changes in gut permeability. These changes in endotoxin are accompanied by a broad effect on skeletal muscle substrate metabolism including increases in postprandial fat oxidation. Importantly, the latter occurs independent of changes in body weight and whole-body insulin sensitivity.}, journal={METABOLISM-CLINICAL AND EXPERIMENTAL}, author={Bowser, Suzanne M. and McMillan, Ryan P. and Boutagy, Nabil E. and Tarpey, Michael D. and Smithson, Andrew T. and Osterberg, Kristin L. and Neilson, Andrew P. and Davy, Brenda M. and Davy, Kevin P. and Hulver, Matthew W.}, year={2020}, month={Feb} }
 @article{lloyd_griffin_krueger_beales_barlow_sheets_ekpo_ross_chandra_rathore_et al._2020, title={Supplemental treatment options for diabetes: how flavanol metabolites improve beta-cell function}, volume={34}, ISSN={["1530-6860"]}, DOI={10.1096/fasebj.2020.34.s1.05762}, abstractNote={Diabetes is one of the fastest growing non‐infectious diseases in the world. Current treatments are composed of pharmaceutical agents that enhance insulin sensitivity and eventual insulin monotherapy. Type 2 diabetes is characterized by insulin insensitivity of peripheral tissue, glucose intolerance, and β‐cell dysfunction. Dietary interventions may benefit patients with diabetes, and various plant derived flavonoids have been shown to exert anti‐diabetic effects. While these flavonoids are large, difficult to absorb, and rarely found in circulation, gut bacteria metabolize these into smaller metabolites which can be observed in circulation. We hypothesize that these gut bacteria derived flavanoid metabolites are absorbed and have direct effects on β‐cell function. Male outbred wistar rats were fed one of three diets in the presence or absence of antibiotic treatment: standard diet, standard diet supplemented with catechin hydrate and epicatechin, or standard diet supplemented with grape seed extract. Total urine was collected from the animals (representing the total amount of absorbed metabolites), then metabolites were extracted and reconstituted in water. Here we present data regarding the in vitro effects of these absorbed gut bacteria derived flavanoids on INS‐1 832/13 β‐cell insulin secretion and proliferation. This study sheds further light on the potential ability of flavanoids and their gut bacteria derived metabolites to enhance functional β‐cell mass.}, journal={FASEB JOURNAL}, author={Lloyd, Trevor and Griffin, Laura and Krueger, Emily and Beales, Joseph and Barlow, Andrew and Sheets, Jared and Ekpo, Idongesit and Ross, Mimi and Chandra, Preeti and Rathore, Atul and et al.}, year={2020}, month={Apr} }
 @article{brunt_gioscia-ryan_casso_vandongen_ziemba_sapinsley_richey_zigler_neilson_davy_et al._2020, title={Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans}, volume={76}, ISSN={["1524-4563"]}, DOI={10.1161/HYPERTENSIONAHA.120.14759}, abstractNote={
            Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation (
            r
            
              2
            
            =0.29,
            P
            <0.00001). In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%,
            P
            <0.01). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress, and reversed by the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation, as assessed with the nitric oxide synthase inhibitor L-NAME (N
            G
            -nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events. Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation. Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide. Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases.
          }, number={1}, journal={HYPERTENSION}, author={Brunt, Vienna E. and Gioscia-Ryan, Rachel A. and Casso, Abigail G. and VanDongen, Nicholas S. and Ziemba, Brian P. and Sapinsley, Zachary J. and Richey, James J. and Zigler, Melanie C. and Neilson, Andrew P. and Davy, Kevin P. and et al.}, year={2020}, month={Jul}, pages={101–112} }
 @article{griffin_djuric_angiletta_mitchell_baugh_davy_neilson_2019, title={A Mediterranean diet does not alter plasma trimethylamine N-oxide concentrations in healthy adults at risk for colon cancer}, volume={10}, ISSN={["2042-650X"]}, DOI={10.1039/c9fo00333a}, abstractNote={A Mediterranean diet does not reduce circulating TMAO, a metabolite that is associated with chronic disease risks.}, number={4}, journal={FOOD & FUNCTION}, author={Griffin, Laura E. and Djuric, Zora and Angiletta, Chris J. and Mitchell, Cassie M. and Baugh, Mary E. and Davy, Kevin P. and Neilson, Andrew P.}, year={2019}, month={Apr}, pages={2138–2147} }
 @article{ma_kim_neilson_griffin_peck_sean f. o'keefe_stewart_2019, title={Comparison of Common Analytical Methods for the Quantification of Total Polyphenols and Flavanols in Fruit Juices and Ciders}, volume={84}, ISSN={["1750-3841"]}, DOI={10.1111/1750-3841.14713}, abstractNote={AbstractMultiple analytical methods are used for quantification of total polyphenols and total flavanols in fruit juices and beverages. Four methods were evaluated in this study: Folin‐Ciocalteu (F‐C), Lowenthal permanganate (L‐P), 4‐dimethylaminocinnamaldehyde (DMAC), and the bovine serum albumin (BSA) precipitation method. Method validation parameters, including working range, limit of detection, limit of quantitation, precision (repeatability), accuracy, and specificity, were assessed and compared. The F‐C method was not specific to polyphenols, and the L‐P method had the widest working range but lacked accuracy. The DMAC method was the most specific to flavanols, and the BSA method was not suitable for quantification of smaller flavanols, such as catechin and epicatechin. Quantitative performance was evaluated using commercial fruit juice samples (n = 14), apple juice samples of different cultivars (n = 22), and commercial ciders (n = 17). In general, the L‐P titration method and DMAC method resulted in higher quantitative values than the F‐C method and BSA precipitation method, respectively. However, ratios of results obtained by the L‐P and F‐C method ranged from 1 to 28, and ratios of results obtained by the DMAC and BSA precipitation method ranged from <1 to 280. This tremendous variation is likely due to variation in polyphenol composition and sample matrix. This information provides perspective for comparison of results obtained through these different methods, and a basis for choosing the most appropriate analytical method for quantification of polyphenols to address a specific research question when working with commercial fruit juice, apple juice from different apple cultivars, and commercial ciders.}, number={8}, journal={JOURNAL OF FOOD SCIENCE}, author={Ma, Sihui and Kim, Cathlean and Neilson, Andrew P. and Griffin, Laura E. and Peck, Gregory M. and Sean F. O'Keefe and Stewart, Amanda C.}, year={2019}, month={Aug}, pages={2147–2158} }
 @article{jin_o'hair_stewart_sean f. o'keefe_neilson_kim_mcguire_lee_wilder_huang_2019, title={Compositional Characterization of Different Industrial White and Red Grape Pomaces in Virginia and the Potential Valorization of the Major Components}, volume={8}, ISSN={["2304-8158"]}, DOI={10.3390/foods8120667}, abstractNote={To better evaluate potential uses for grape pomace (GP) waste, a comprehensive chemical composition analysis of GP in Virginia was conducted. Eight commercial white and red pomace samples (cv. Viognier, Vidal Blanc, Niagara, Petit Manseng, Petit Verdot, Merlot, Cabernet Franc, and Chambourcin) obtained from different wineries in Virginia, USA were used. For extractives, GPs contained 2.89%–4.66% titratable acids, 4.32%–6.60% ash, 4.62%–12.5% lipids with linoleic acid being the predominant (59.0%–70.9%) fatty acid, 10.4–64.8 g total phenolic content (gallic acid equivalents)/kg GP, 2.09–53.3 g glucose/kg GP, 3.79–52.9 g fructose/kg GP, and trace sucrose. As for non-extractives, GPs contained 25.2%–44.5% lignin, 8.04%–12.7% glucan, 4.42%–7.05% xylan, and trace amounts of galactan, arabinan, and mannan (less than 3% in total). Potential usages of these components were further examined to provide information on better valorization of GP. Considering the valuable extractives (e.g., polyphenols and oil) and non-extractives (e.g., lignin), designing a biorefinery process aiming at fully recover and/or utilize these components is of future significance.}, number={12}, journal={FOODS}, author={Jin, Qing and O'Hair, Joshua and Stewart, Amanda C. and Sean F. O'Keefe and Neilson, Andrew P. and Kim, Young-Teck and McGuire, Megan and Lee, Andrew and Wilder, Geoffrey and Huang, Haibo}, year={2019}, month={Dec} }
 @article{racine_lee_stewart_blakeslee_neilson_2019, title={Development of a rapid ultra performance hydrophilic interaction liquid chromatography tandem mass spectrometry method for procyanidins with enhanced ionization efficiency}, volume={1594}, ISSN={["1873-3778"]}, DOI={10.1016/j.chroma.2019.02.007}, abstractNote={Cocoa flavanols (catechins and procyanidins) can exist in various polymerization states and are commonly classified by their degree of polymerization (DP). There is increasing evidence that flavanols of distinct DP possess different biological activities, but separation and quantification of the higher DP procyanidins is challenging and has thus created the need for new methodologies that utilize advancements in columns and LC–MS/MS systems. An aqueous normal phase (hydrophilic interaction liquid chromatography, HILIC), UPLC method with post-column ESI adjuvant infusion was developed to reduce the total analysis time, increase peak separation, and increase detection specificity (compared to traditional fluorescence methods) by coupling with mass spectrometry detection. The total elution time was reduced from 70 to 90 min (typically used for normal phase and HILIC HPLC separation of procyanidins) down to 9 min by employing UPLC. Results indicate that by using a post-column 0.04 M ammonium formate infusion (5 μL/min), ionization of procyanidins was significantly enhanced. Lower limits of detection ranged from 3.19 × 10−2 to 4.56 pmol-on-column, and lower limits of quantification ranged from 2.79 × 10−2 to 1.17 × 102 pmol-on-column across compounds DP 1–9. This method builds upon the foundation set by existing analytical methods and employs new technologies to dramatically increase sample throughput and enhance detection limits and specificity, facilitating improved analysis for procyanidins.}, journal={JOURNAL OF CHROMATOGRAPHY A}, author={Racine, Kathryn C. and Lee, Andrew H. and Stewart, Amanda C. and Blakeslee, Kenneth W. and Neilson, Andrew P.}, year={2019}, month={Jun}, pages={54–64} }
 @article{racine_wiersema_griffin_essenmacher_lee_hopfer_lambert_stewart_neilson_2019, title={Flavanol Polymerization Is a Superior Predictor of alpha-Glucosidase Inhibitory Activity Compared to Flavanol or Total Polyphenol Concentrations in Cocoas Prepared by Variations in Controlled Fermentation and Roasting of the Same Raw Cocoa Beans}, volume={8}, ISSN={["2076-3921"]}, DOI={10.3390/antiox8120635}, abstractNote={Raw cocoa beans were processed to produce cocoa powders with different combinations of fermentation (unfermented, cool, or hot) and roasting (not roasted, cool, or hot). Cocoa powder extracts were characterized and assessed for α-glucosidase inhibitory activity in vitro. Cocoa processing (fermentation/roasting) contributed to significant losses of native flavanols. All of the treatments dose-dependently inhibited α-glucosidase activity, with cool fermented/cool roasted powder exhibiting the greatest potency (IC50: 68.09 µg/mL), when compared to acarbose (IC50: 133.22 µg/mL). A strong negative correlation was observed between flavanol mDP and IC50, suggesting flavanol polymerization as a marker of enhanced α-glucosidase inhibition in cocoa. Our data demonstrate that cocoa powders are potent inhibitors of α-glucosidase. Significant reductions in the total polyphenol and flavanol concentrations induced by processing do not necessarily dictate a reduced capacity for α-glucosidase inhibition, but rather these steps can enhance cocoa bioactivity. Non-traditional compositional markers may be better predictors of enzyme inhibitory activity than cocoa native flavanols.}, number={12}, journal={ANTIOXIDANTS}, author={Racine, Kathryn C. and Wiersema, Brian D. and Griffin, Laura E. and Essenmacher, Lauren A. and Lee, Andrew H. and Hopfer, Helene and Lambert, Joshua D. and Stewart, Amanda C. and Neilson, Andrew P.}, year={2019}, month={Dec} }
 @article{griffin_fausnacht_tuzo_addington_racine_zhang_hughes_england_bruno_sean f. o'keefe_et al._2019, title={Flavanol supplementation protects against obesity-associated increases in systemic interleukin-6 levels without inhibiting body mass gain in mice fed a high-fat diet}, volume={66}, ISSN={["0271-5317"]}, DOI={10.1016/j.nutres.2019.03.011}, abstractNote={Weight gain and obesity are associated with increased levels of proinflammatory cytokines. Studies have demonstrated the ability of dietary flavanols to reduce the severity of metabolic derangements due to high-fat (HF) feeding. The degree of polymerization of the flavanols appears to play a role in determining the extent of these protective effects. This study evaluated the preventative effects of grape seed and pine bark flavanol supplementation, with significantly different flavanol degree of polymerization, in the context of an HF diet. For 13 weeks, mice were given 35 mg/kg body weight per day grape seed or pine bark as part of an HF diet and compared to mice fed a low-fat diet and control HF diet. All flavanol-supplemented groups and the HF control incurred significantly higher weight gain compared to the lean control, and the grape seed group gained significantly more weight than the HF control. Increased weight gain of treatment groups was likely caused by hyperphagia. Despite lack of improvements to weight gain and glycemic control, it was observed that all flavanol treatment groups were able to significantly reduce interleukin-6 compared to HF control. The grape seed group, which gained the most weight overall, also exhibited the lowest levels of interleukin-6 compared to other groups. Overall, low-dose flavanol extract supplementation, regardless of mean degrees of polymerization, blunted cytokine production despite increased weight gain. This obesity-independent effect suggests flavanols may be used as complementary interventions to ameliorate increased inflammatory tone in the contexts of obesity and diabetes. Furthermore, flavanol-induced hyperphagia may have use for attenuation of cachexia.}, journal={NUTRITION RESEARCH}, author={Griffin, Laura E. and Fausnacht, Dane W. and Tuzo, Jessica L. and Addington, Adele K. and Racine, Kathryn C. and Zhang, Haiyan and Hughes, Michael D. and England, Kathryn M. and Bruno, Richard S. and Sean F. O'Keefe and et al.}, year={2019}, month={Jun}, pages={32–47} }