@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{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{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{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{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{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{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{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} }