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Effect of dietary polyphenols on chronobiology in mammalian cells in vitro
- N. Sulaimani, M.J. Houghton, M.P. Bonham, G. Williamson
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- Journal:
- Proceedings of the Nutrition Society / Volume 83 / Issue OCE1 / April 2024
- Published online by Cambridge University Press:
- 07 May 2024, E134
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Circadian clocks play a key role in metabolic homeostasis, and disruption of circadian rhythms is inextricably intertwined with metabolic disorders [1]. Emerging evidence in the literature suggests that polyphenols possess the potential to modulate metabolic processes associated with circadian rhythms. This review aims to evaluate the effects of polyphenols on metabolic homeostasis via circadian rhythms and their potential mechanism(s) of action on circadian rhythmicity of clock components and linked metabolic processes, by critically assessing the literature on mammalian cells in vitro. To ensure that all relevant studies in this area were included, a systematic search protocol was developed by defining the inclusion and exclusion criteria based on the population, intervention, comparator and outcome framework, along with limiting the source of evidence to original research written in English. Three databases (Ovid Medline, Web of Science, and Scopus) were searched with no time constraints. The search identified 5842 studies and, after duplicate removal and initial screening, 48 studies were reviewed in full. Of those, 38 were eligible for inclusion. The included studies were published between 2008-2023, with a notable surge in publications after 2016, which is indicative of the growing attention towards polyphenols and circadian biology. 33 polyphenols were examined for their effects on circadian cellular processes (n = 16 papers), expression of clock genes and/or proteins (n = 26), or circadian rhythm features of clock genes (n = 10). A handful of studies examined the role of polyphenols in regulating disrupted glucose and lipid metabolism through clock components. The findings suggested that the underlying mechanisms were BMAL1-dependent. It must be noted that the effects of the reported polyphenols were elucidated at concentrations exceeding the normal range found in human plasma and target tissues (˃ 10 μM). However, a single study revealed that (−)-epigallocatechin-3-gallate (EGCG) at a physiologically-relevant concentration (10 μM), improved hepatic glucose metabolism [2]. Further, the polyphenols reported in this review exhibited the potential to influence numerous clock components, mainly BMAL1, PER2 and RORα/γ, at mRNA and/or protein levels when administered at physiologically-relevant concentrations. These polyphenols include nobiletin, tangeretin, curcumin, bavachalcone, cinnamic acid, (−)-epigallocatechin-3-gallate, resveratrol and Urolithin A. Polyphenols have the potential to regulate circadian oscillators and associated metabolic processes in various types of cells. However, there is significant methodological heterogeneity among the studies, which makes it difficult to compare outcomes. Thus, this review will help future research in the field of circadian impacts of polyphenols to integrate standardised approaches, in aspects such as utilisation of a synchronisation method and physiologically-relevant concentrations of polyphenols (≤ 10 μM) in cultured cells. This is critical for understanding how polyphenols might modulate circadian-metabolic health in humans.
Dietary phytochemicals as regulators of gut inflammation in the context of type 2 diabetes
- R. Visvanathan, G. Williamson, M.J. Houghton
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- Journal:
- Proceedings of the Nutrition Society / Volume 83 / Issue OCE1 / April 2024
- Published online by Cambridge University Press:
- 07 May 2024, E190
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Numerous disorders, including type 2 diabetes and even COVID-19, are linked to poor gut health and inflammation(1,2). In addition to impacting food digestion and absorption, gut inflammation worsens diabetes outcomes by causing gut microbial dysbiosis, disrupting tight junctions (allowing microbial metabolites to freely enter into circulation), and altering glucose absorption(3). ACE2 is a crucial regulator of gut health and has received much attention during the COVID-19 pandemic due to its role as a major viral entry protease. Studies have shown that the ACE2/Ang-(1-7)/Mas axis is important in managing inflammation and maintaining normal glucose metabolism(3). Dietary phytochemicals are plant bioactive compounds, with promising anti-inflammatory and anti-diabetic properties, and may affect these processes. In this work, we aimed to look at the link between inflammation, ACE2 and the glucose transporters, SGLT1 and GLUT2, and how phytochemicals could be used to normalise the changes brought about by inflammation in Caco-2/TC7 human intestinal epithelium cells. We first examined how gut inflammation, ACE2 and glucose transporters are related and proceeded to look at the effect of some chosen phytochemicals on regulating glucose transport via modulation of the ACE2/Ang(1-7)/Mas axis. This included genistein (an isoflavone from soyabeans), sulforaphane (an isothiocyanate found in Brassica, especially broccoli), apigenin (a flavone found in vegetables and herbs), and artemisinin (a sesquiterpene lactone used as a drug). The impact of phytochemicals on the SARS-CoV-2 viral entry receptors, ACE2 and TMPRSS2, was also examined as a secondary outcome. To induce inflammation, the Caco2/TC7 cells were co-stimulated with IL-1β (25 ng/mL) and TNF-α (50 ng/mL) for varying durations (24 h, 48 h, 72 h, 168 h) and changes in target gene expression (ACE2, SGLT1, GLUT2, TMPRSS2) were assessed by droplet digital PCR. IL-6 and IL-8 were assessed as markers of inflammation in the cell culture media by multiplex ELISA. Inflammation increased ACE2, TMPRSS2 and SGLT1 mRNA. ACE2 increased with cytokine exposure duration, coupled with an obvious decrease in IL-8, SGLT1 and TMPRSS2. Pearson correlation analysis revealed that the increase in ACE2 was strongly associated with decreases in SGLT1 (r = −0.99, p<0.01) and IL-8 (r = −0.959, p<0.05), implying ACE2 to play a crucial role in gut inflammation and postprandial glycaemia. After establishing the gut cell inflammation model, we compared the effect of the phytochemicals on our target genes in cells cultured in normal and pro-inflammatory environments. None of the tested phytochemicals were effective in reducing IL-8 secretion, while phytochemicals showed varying effects on the target genes. Genistein normalised the effects of inflammation on the target genes with less effect from the other tested phytochemicals. However, further research is required to assess the importance of genistein in vivo in the context of gut inflammation and type 2 diabetes.
Investigating the effect of polyphenols from nuts on human carbohydrate digestion in vitro
- M. Farazi, M.J. Houghton, M. Murray, B.R. Cardoso, G. Williamson
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- Journal:
- Proceedings of the Nutrition Society / Volume 83 / Issue OCE1 / April 2024
- Published online by Cambridge University Press:
- 07 May 2024, E55
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Recent studies have documented the importance of postprandial hyperglycaemia in the incidence of chronic diseases, including type 2 diabetes. Inhibition of digestive enzymes, including membrane-bound brush-border α-glucosidases, leads to slowed carbohydrate digestion and absorption, and reduced postprandial glycemia. Nuts are widely eaten around the world and have the potential to inhibit α-glucosidases through their content of polyphenols and other bioactive compounds. According to our recent systematic review(1), no study has investigated the inhibitory effects of nut extracts on human α-glucosidase activities. Almost all studies in this area have been conducted on yeast α-glucosidase, with only a few using rat α-glucosidase. While there is no sequence homology between yeast and human α-glucosidase, there is 74% to 78% sequence homology between rat and human α-glucosidases(1). The lack of studies on the effect of bioactive compounds from nuts on human α-glucosidases, along with the growing attention to nuts as an important component of a healthy diet with the potential to reduce the risk of chronic diseases(2), highlights the need for research to evaluate the inhibitory effect of nut extracts on human α-glucosidases. The aim of the current study is to explore the inhibitory effect of extracts from nuts on human carbohydrate digestive enzymes. Walnuts and almonds were ground and defatted with hexane, extracted in 80% (v/v) acetone, and further purified using solid-phase extraction to obtain phenolic-rich extracts. The Folin–Ciocalteu assay was used to approximate the polyphenol content of the samples. Following our recently published detailed protocol(3), cell-free extracts from human intestinal Caco-2/TC7 cells were used as a source of α-glucosidase in enzyme inhibition assays, with sucrose, maltose and isomaltose as substrates and appropriate controls. The assay products were quantified using high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Glucose production in the presence of various concentrations of phenol-rich nut extracts was compared using a one-way ANOVA and half-maximal inhibitory concentration (IC50) values were calculated. The Folin–Ciocalteu data demonstrate that walnut extracts comprise a relatively high polyphenol content, with 18.1 ± 0.23 mg (epigallocatechin gallate [EGCG] equivalent) per gram of fresh weight, while almond extracts contain 0.87 ± 0.03 mg EGCG equivalent/g of fresh weight. The walnut phenolic-rich extract dose-dependently inhibited human intestinal sucrase and maltase activities (both p<0.01), with IC50 values of 1.67 mg/mL and 2.84 mg/mL, respectively. We demonstrate that phenolic-rich walnut extracts can inhibit human α-glucosidases in vitro and therefore walnuts may contribute to slowing carbohydrate digestion in humans. As such, we plan to assess the effects of walnuts on postprandial glycaemia in vivo.
A novel approach to the dual sugar test for the assessment of intestinal epithelium permeability in response to exertional heat stress and nutritional intervention
- M.J. Houghton, R.M.J. Snipe, G. Williamson, R.J.S. Costa
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- Journal:
- Proceedings of the Nutrition Society / Volume 83 / Issue OCE1 / April 2024
- Published online by Cambridge University Press:
- 07 May 2024, E67
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An acute increase in intestinal epithelium permeability is induced by prolonged exertion in the heat, resulting in the translocation of pathogenic bacteria and endotoxins from the lumen into the circulation, causing a systemic inflammatory response and debilitating symptoms(1). Acute exercise-induced gastrointestinal syndrome mimics chronic health conditions with which an impaired intestinal barrier function is associated, including coeliac disease, inflammatory bowel disease, diabetes, Alzheimer’s and liver diseases(2). Intestinal epithelium permeability is typically assessed using a dual sugar absorption test, by administering a drink containing non-metabolisable sugars (e.g. lactulose [L] and L-rhamnose [R]) that can enter the circulation by paracellular translocation when the epithelium is compromised, and are subsequently excreted and measured cumulatively in the urine(3). We aimed to demonstrate that our recently developed ion chromatography protocol(4) can be used to accurately quantify L/R ratio in the plasma of participants exercising in hot ambient conditions and to determine the impact of nutritional intervention on intestinal epithelium permeability. Further, we hypothesised that measuring L/R in plasma collected at intervals during the post-exercise recovery period would reveal more information about intestinal permeability compared to previously published cumulative urine L/R data(3). Endurance-trained participants completed a set of randomised crossover studies, consisting of 2 h running at 60% V˙O2max in temperate, warm and hot ambient conditions (n = 8) and/or in the heat while consuming water, carbohydrate or protein (n = 9). The dual sugar solution was ingested at 90 min of exercise and blood was sampled at 0, 1, 2 and 4 h post-exercise. Plasma sugars were quantified by high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and L/R ratios were compared by two-way repeated measures ANOVA with Tukey’s multiple comparisons. Plasma L/R increased immediately post-exercise in the heat (0.15 ± 0.11) compared with temperate (0.06 ± 0.04, p<0.001) and warm (0.09 ± 0.08, p<0.01) conditions, while consuming glucose before and during exercise alleviated this (0.02 ± 0.02, p<0.001), and this novel information was otherwise missed when measuring urine L/R. Consuming glucose or whey protein hydrolysate during exercise attenuated intestinal permeability from exertional heat stress throughout recovery, with the mean plasma L/R over 4 h reduced from 0.11 ± 0.05 to 0.04 ± 0.03 (p<0.001) and 0.06 ± 0.04 (p<0.01) with glucose and protein, respectively. We recommend using the dual sugar test with quantification of plasma sugars at intervals by HPAEC-PAD to maximise intestinal permeability data collection in exercise gastroenterology research and beyond, as this gives additional acute response information compared to urinary measurements. Our approach can be employed to investigate and develop personalised nutrition strategies that prevent intestinal hyperpermeability during exertional heat stress. This has implications for athlete performance and safety, and can also build upon occupational health and safety practices and inform chronic disease management.