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Green tea extract prevents obesity in male mice by alleviating gut dysbiosis in association with improved intestinal barrier function that limits endotoxin translocation and adipose inflammation

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Abstract

Gut-derived endotoxin translocation provokes obesity by inducing TLR4/NFκB inflammation. We hypothesized that catechin-rich green tea extract (GTE) would protect against obesity-associated TLR4/NFκB inflammation by alleviating gut dysbiosis and limiting endotoxin translocation. Male C57BL/6J mice were fed a low-fat (LF) or high-fat (HF) diet containing 0% or 2% GTE for 8-wk. At wk 7, fluorescein isothiocyanate (FITC)-dextran was administered by oral gavage before assessing its serum concentrations as a gut permeability marker. HF-feeding increased (P<0.05) adipose mass and adipose expression of genes involved in TLR4/NFκB-dependent inflammation and macrophage activation. GTE attenuated HF-induced obesity and pro-inflammatory gene expression. GTE in HF mice decreased serum FITC-dextran, and attenuated portal vein and circulating endotoxin concentrations. GTE in HF mice also prevented HF-induced decreases in the expression of intestinal tight junction proteins (TJPs) and hypoxia inducible factor-1α while preventing increases in TLR4/NFκB-dependent inflammatory genes. Gut microbial diversity was increased, and the Firmicutes:Bacteroidetes ratio was decreased, in HF mice fed GTE compared with HF controls. GTE in LF mice did not attenuate adiposity but decreased endotoxin and favorably altered several gut bacterial populations. Serum FITC-dextran was correlated with portal vein endotoxin (P<0.001; rP = 0.66) and inversely correlated with colonic mRNA levels of TJPs (P<0.05; rP = -0.38 to -0.48). Colonic TJPs mRNA were inversely correlated with portal endotoxin (P<0.05; rP = -0.33 to -0.39). These data suggest that GTE protects against diet-induced obesity consistent with a mechanism involving the gut-adipose axis that limits endotoxin translocation and consequent adipose TLR4/NFκB inflammation by improving gut barrier function.

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... Subjects with chronic metabolic diseases are often associated with lower butyrate-producing microbes, lower abundance of Akkermansia muciniphila, and increased abundance of bacteria with inflammatory potentials (e.g., E. coli) [36]. Mice fed an obesogenic diet with liver disease and insulin resistance demonstrate a significant increase in microbial metabolic functions related to amino sugar and nucleotide metabolism, energy metabolism, and lipopolysaccharide (LPS) biosynthesis [85]. Similarly patients with type 2 diabetes show enrichment of microbial pathways related to cellular sugar uptake, xenobiotic degradation, branched-chain amino acid export related to increased insulin resistance, and sulfate reduction associated with reduction of insulin sensitivity [86]. ...
... These SCFA can exert diverse beneficial effects on the host (Fig. 5). SCFA, especially butyrate has been attributed to limiting weight gain, whereas health-beneficial effects of phytochemicals could be attributed to improving butyrogenic microbes at the intestine or improving their SCFA metabolism capacity [85]. SCFA can signal through GPCR to affect a wide spectrum of processes such as secretion of insulin and ghrelin, GLP-1, peptide tyrosine tyrosine (PYY), neutrophil migration, formation of inflammasomes and induce pro-inflammatory milieu [190]. ...
... Gut-derived endotoxin translocation to the liver through portal vein due to loss of gut barrier integrity triggers TLR4/NFκB-dependent inflammatory insult at the liver and promotes NASH [29,81]. The endotoxin load in both lean and obese mice in the portal vein is significantly higher than that of normal systemic circulation [85]. Translocation of bacterial products to the systemic circulation occurs even in healthy individuals [41] that facilitates priming of gut immune system to microbial products as a preparative measure for extensive invasion of pathobionts, and also helps to develop immune tolerance towards commensal symbionts [210]. ...
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The role of the intestine in human health and disease has historically been neglected and was mostly attributed to digestive and absorptive functions. In the past two decades, however, discoveries related to human nutrition and intestinal host-microbe reciprocal interaction have established the essential role of intestinal health in the pathogenesis of chronic diseases and the overall wellbeing. That transfer of gut microbiota could be a means of disease phenotype transfer has revolutionized our understanding of chronic disease pathogenesis. This narrative review highlights the major concepts related to intestinal microbiota, metabolism, and metabolome (3M) that have facilitated our fundamental understanding of the association between the intestine and human health and disease. In line with increased interest of microbiota-dependent modulation of human health by dietary phytochemicals, we have also discussed the emerging concepts beyond the phytochemical bioactivities which emphasizes the integral role of microbial metabolites of parent phytochemicals at extraintestinal tissues. Finally, this review concludes with challenges and future prospects in defining the 3 M interactions and has emphasized the fact that, it takes ‘guts’ to stay healthy.
... Thirty-two studies reported changes in energy/food intake, among which three studies that used pure phenolic compounds (PPC) [35,40,42,43] and two [68,78] studies that investigated phenolic extracts (PE) reported a significant drop in energy/food intake compared to HFD. Significantly higher food consumption was recorded in three studies 50], 1-PE [73], while 24 studies reported non-significant difference in energy/food intake [45][46][47]51,52,57,59,60,62,63,66,74,75,80] (Figure S4). As for bodyweight, thirty studies (67%) recorded a significant drop post-treatment, of which 16 with PPC [35][36][37][38][39][40][41][42][43][44][45]50,[52][53][54]56,57], and 15 with PE [60,61,63,65,66,68,[71][72][73][74][75][76][77][78][79]81]. ...
... Significantly higher food consumption was recorded in three studies 50], 1-PE [73], while 24 studies reported non-significant difference in energy/food intake [45][46][47]51,52,57,59,60,62,63,66,74,75,80] (Figure S4). As for bodyweight, thirty studies (67%) recorded a significant drop post-treatment, of which 16 with PPC [35][36][37][38][39][40][41][42][43][44][45]50,[52][53][54]56,57], and 15 with PE [60,61,63,65,66,68,[71][72][73][74][75][76][77][78][79]81]. Non-significant observations were made in 19 studies 38,44,[46][47][48][49]51,55,58], 60,62,64,65,67,69,70,80]] ( Figure S4). ...
... The adiposity in animal models was presented as the weight of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) or total body fat (TBF). The VAT was significantly reduced in 24 studies [PPC-14 [37][38][39][41][42][43][44]46,48,[50][51][52][53][54]57], PE- [61,63,65,68,[71][72][73]77,78,81]], and 11 studies reported non-significance [40,44,45,49,65,67,69,70,76,80,81]. As for the SAT, seven studies showed a significant reduction 37,40,42,43],3-PE [61,62,73]], while 10 studies showed non-significant findings [36,38,39,[44][45][46]48,49,51,[53][54][55][56][57][58][59]63,65,66,71,74,75,77,[79][80][81]. ...
Article
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Obesity is a disease growing at an alarming rate and numerous preclinical studies have proven the role of polyphenols in managing this disease. This systematic review explores the prebiotic effect of polyphenols in the management of obesity among animals fed on a high-fat diet. A literature search was carried out in PubMed, Scopus, CINAHL, Web of Science, and Embase databases following the PRISMA guidelines. Forty-four studies reported a significant reduction in obesity-related parameters. Most notably, 83% of the studies showed a decrease in either body weight/visceral adiposity/plasma triacylglyceride. Furthermore, 42 studies reported a significant improvement in gut microbiota (GM), significantly affecting the genera Akkermansia, Bacteroides, Blautia, Roseburia, Bifidobacteria, Lactobacillus, Alistipes, and Desulfovibrio. Polyphenols’ anti-obesity, anti-hyperglycaemic, and anti-inflammatory properties were associated with their ability to modulate GM. This review supports the notion of polyphenols as effective prebiotics in ameliorating HFD-induced metabolic derangements in animal models.
... The main food sources investigated were green tea, black tea, oolong tea, and Pu-erh tea. The intervention doses were very different among studies, and intervention periods ranged from 28 to 196 days (Dey et al., 2019;Henning et al., 2018;Liu et al., 2019;Lu et al., 2019;Ma et al., 2019;Wang et al., 2018;Xia et al., 2019). An increase in the abundance of Akkermansia and Bifidobacterium was observed in mice fed a high-fat diet after the consumption of green tea polyphenols (Dey et al., 2019;Ma et al., 2019;Wang et al., 2018). ...
... The intervention doses were very different among studies, and intervention periods ranged from 28 to 196 days (Dey et al., 2019;Henning et al., 2018;Liu et al., 2019;Lu et al., 2019;Ma et al., 2019;Wang et al., 2018;Xia et al., 2019). An increase in the abundance of Akkermansia and Bifidobacterium was observed in mice fed a high-fat diet after the consumption of green tea polyphenols (Dey et al., 2019;Ma et al., 2019;Wang et al., 2018). Supplementation of the oolong tea extract and decaffeinated black tea extract increased the butyrate production Henning et al., 2018), while the Pu-erh tea extract consumption stimulated the Akkermansia and Roseburia growth (Lu et ...
... and/or Bifidobacterium spp. (Cheng, Chen, Liu, et al., 2019;Cho et al., 2016;Dey et al., 2019;Li, Wu, et al., 2019;Ma et al., 2019;Qiao et al., 2014;Vendrame et al., 2011;Xie et al., 2019); 10 showed an increased abundance of Akkermansia spp. (Anhê et al., 2015(Anhê et al., , 2017Dey et al., 2019;Etxeberria et al., 2017;Liu et al., 2018;Lu et al., 2019;Ma et al., 2019;Masumoto et al., 2016;Xia et al., 2019;Xie et al., 2019); 3 showed an increased abundance of Faecalibacterium spp. ...
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Prebiotics are substrates selectively metabolized by hindgut microorganisms conferring health benefits. Recent studies suggest polyphenols as candidate to prebiotics. Thus, this systematic review aimed to investigate the prebiotic effect of dietary polyphenols in preclinical and clinical studies. Animal studies demonstrated that the consumption of polyphenols, especially catechins, anthocyanins and proanthocyanidins, increases the abundance of Lactobacillus, Bifidobacterium, Akkermansia, Roseburia, and Faecalibacterium spp. Moreover, polyphenols supplementation increased the production of short-chain fatty acids (SCFA), including butyrate. The included clinical trials showed an increased abundance of Lactobacillus acidophilus, Bifidobacterium and Faecalibacterium spp., and a reduction in plasma lipopolysaccharide-binding protein after the consumption of anthocyanins and ellagic acid. In conclusion, there is strong evidence in preclinical studies that dietary polyphenols can stimulate both the growth of microorganisms identified as prebiotic targets and an increase in the production of SCFA. Therefore, clinical trials are warranted to investigate the prebiotic effect of dietary polyphenols on humans.
... Gut dysbiosis and gut barrier dysfunction increase the translocation of gut-derived endotoxins (e.g., LPS), which can initiate the activation of NFκB-mediated inflammatory responses, including the release of ROS and TNFα that further provoke NFκB-dependent inflammation. Evidence suggests that GTE initially suppresses TLR4-NFκB signaling to inhibit the downstream potentiating effects of the TNFα-TNFR1 pathway on NFκB-driven inflammation [112,135]. Although GTE protects against NASH independent of the cytoprotective activities of Nrf2 [47], GTE can also scavenge ROS directly [10,54] and/or limit ROS production indirectly by attenuating the NFκB-mediated inflammatory response [12,80,112]. ...
... However, studies in vitro demonstrate that EGCG and EC prevent the loss of epithelial barrier function induced by inflammatory cytokines (TNFα and interferon-γ), as evidenced by restored transepithelial resistance and reduced permeability to fluorescein isothiocyanate (FITC)-dextran [132][133][134]. Similarly, GTE supplementation in a rodent model of HF diet-induced NASH increased the expression of the TJPs occludin and claudin [13,135]. These observations were accompanied by increased protein levels of intestinal hypoxia inducible factor-1α (HIF-1α) [135], which transcriptionally upregulates TJPs and limits the activation of leukocytes and other pro-inflammatory mediators in the intestines [136]. ...
... Similarly, GTE supplementation in a rodent model of HF diet-induced NASH increased the expression of the TJPs occludin and claudin [13,135]. These observations were accompanied by increased protein levels of intestinal hypoxia inducible factor-1α (HIF-1α) [135], which transcriptionally upregulates TJPs and limits the activation of leukocytes and other pro-inflammatory mediators in the intestines [136]. Therefore, GTE catechins may act directly on the intestinal epithelial barrier to regulate the function of TJPs in a HIF-1αdependent manner to prevent "leaky gut" that otherwise contributes to NASH. ...
Article
Nonalcoholic fatty liver disease (NAFLD), which is the most prevalent hepatic disorder worldwide affecting 25% of the general population, describes a spectrum of progressive liver conditions ranging from relatively benign liver steatosis and advancing to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Hallmark features of NASH are fatty hepatocytes and inflammatory cell infiltrates in association with increased activation of hepatic nuclear factor kappa-B (NFκB) that exacerbates liver injury. Because no pharmacological treatments exist for NAFLD, emphasis has been placed on dietary approaches to manage NASH risk. Anti-inflammatory bioactivities of catechin-rich green tea extract (GTE) have been well-studied, especially in preclinical models that have detailed its effects on inflammatory responses downstream of NFκB activation. This review will therefore discuss the experimental evidence that has advanced an understanding of the mechanisms by which GTE, either directly through its catechins or potentially indirectly through microbiota-derived metabolites, limits NFκB activation and NASH-associated liver injury. Specifically, it will describe the hepatic-level benefits of GTE that attenuate intracellular redox distress and pro-inflammatory signaling from extracellular receptors that otherwise activate NFκB. In addition, it will discuss the anti-inflammatory activities of GTE on gut barrier function as well as prebiotic and antimicrobial effects on gut microbial ecology that help to limit the translocation of gut-derived endotoxins (e.g. lipopolysaccharides) to the liver where they otherwise upregulate NFκB activation by Toll-like receptor-4 signaling. This summary is therefore expected to advance research translation of the hepatic- and intestinal-level benefits of GTE and its catechins to help manage NAFLD-associated morbidity.
... Gut dysbiosis i.e. alterations in intestinal microbial abundance, diversity and metabolic functions potentiates host-specific metabolic dysfunction along the gut-liver/adipose axis. Several phytochemical-rich plant extracts and dietary supplements attenuate metabolic dysfunction by means of normalization of dysbiosis coupled with microbiota-associated mechanisms such as barrier protection, short chain fatty acid production and attenuation of mucosal inflammation [115][116][117]. Several pre-clinical data have reported attenuation of chronic metabolic conditions by oleander extracts, while clinical reports indicated oleander-mediated acute toxicity. ...
... β-sitosterol [24,89] supplementation lowers systemic inflammation in association with increasing the population of Prevotella, Rikenellaceae and lowers the abundance of Lachnospiraceae [140]. Finally, catechin and catechinassociated polyphenols found in oleander [19,20] exert metabolic benefits by improving the population of gut commensal bacteria, increasing diversity and modulating microbial metabolic functions [115,141,142]. Therefore, ethnopharmacological usage of dose-regulated oleander extract, but not isolated compounds, likely exert additive and synergistic activities that likely provide metabolic benefits by modulating gut microbiome. ...
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Nerium oleander L., commonly known as oleander, is a toxic shrub and also a medicinal plant. All parts of oleander are rich in cardiac glycosides that inhibits Na⁺/K⁺-ATPase and induce inotropic effect on the cardiomyocytes. Several pre-clinical and clinical reports indicate acute toxicity due to intentional, accidental and suicidal oleander consumption. Contrarily, oleander is used for the treatment of diverse ailments in traditional medicinal practices around the globe and several evidence-based pre-clinical studies indicated metabolic and immunological health benefits of polyphenol-rich oleander extracts. Thus, the current review aims to address this pharmaco-toxicological conundrum of oleander by addressing the possible role of gut microflora in the differential oleander toxicity. Additionally, a comprehensive account of ethnopharmacological usage, metabolic and immunological health benefits has been documented that supplement the conflicting arguments of pharmaco-toxicological properties of oleander. Finally, by addressing the gap of knowledge of ethnomedicinal, pharmacological and toxicological reports of oleander, the current review is expected to pave the way to address the differential pharmaco-toxicological effects of oleander.
... Flavonoids are a more functional classification of phenolic compounds, and their basic unit structure is 2-phenyl-1,4-benzopyrone. The classic flavonoids include estrogen, anthocyanin, and catechins [30]. The function of flavonoids is similar to that of phenols. ...
... The function of flavonoids is similar to that of phenols. Among them, catechin, the classic flavonoid in green tea, can increase the antioxidant capacities, and also promote fat metabolism in animals, thereby reducing low-grade inflammation caused by excessive accumulation of fat [30,31]. Catechins can be found not only in tea but also in Pennisetum [3]. ...
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With the increase in world food demand, the output of agricultural by-products has also increased. Agricultural by-products not only contain more than 50% dietary fiber but are also rich in functional metabolites such as polyphenol (including flavonoids), that can promote animal health. The utilization of dietary fibers is closely related to their types and characteristics. Contrary to the traditional cognition that dietary fiber reduces animal growth, it can promote animal growth and maintain intestinal health, and even improve meat quality when added in moderate amounts. In addition, pre-fermenting fiber with probiotics or enzymes in a controlled environment can increase dietary fiber availability. Although the use of fiber has a positive effect on animal health, it is still necessary to pay attention to mycotoxin contamination. In summary, this report collates the fiber characteristics of agricultural by-products and their effects on animal health and evaluates the utilization value of agricultural by-products.
... TLR4 plays an essential role in the mucosal inflammation associated with gut microbiota, and is a lucrative target for mitigating intestine-derived pathological insults associated with metabolic disease [185][186][187]. Mice lacking TLR-4 are substantially less likely to develop colitis-related cancer [188]. ...
... The consumption of polyphenol-rich food has been implicated in reducing cancer risks by mechanisms associated with improvements in gut microbiota. We have demonstrated that catechin-rich green tea can limit the clinical progression from nonalcoholic steatohepatitis to HCC by mitigating hepatic inflammation and pro-carcinogenic responses [232], in association with mitigating GI and hepatic inflammation, gut barrier dysfunction, and favorable modulation of gut microbial population, diversity, and metabolic functions [185][186][187]. The mechanism through which a polyphenolic-rich diet can be preventive of carcinogenesis through the favorable modulation of microbiota can include the modulation of hormonal regulation, limiting oxidative and inflammatory injury, and maintaining cellular proliferative/apoptotic homeostasis [233]. ...
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Helicobacter pylori infection is the only well-established bacterial cause of cancer. However, due to the integral role of tissue-resident commensals in maintaining tissue-specific immunometabolic homeostasis, accumulated evidence suggests that an imbalance of tissue-resident microbiota that are otherwise considered as commensals, can also promote various types of cancers. Therefore, the present review discusses compelling evidence linking tissue-resident microbiota (especially gut bacteria) with cancer initiation and progression. Experimental evidence supporting the cancer-causing role of gut commensal through the modulation of host-specific processes (e.g., bile acid metabolism, hormonal effects) or by direct DNA damage and toxicity has been discussed. The opportunistic role of commensal through pathoadaptive mutation and overcoming colonization resistance is discussed, and how chronic inflammation triggered by microbiota could be an intermediate in cancer-causing infections has been discussed. Finally, we discuss microbiota-centric strategies, including fecal microbiota transplantation, proven to be beneficial in preventing and treating cancers. Collectively, this review provides a comprehensive understanding of the role of tissue-resident microbiota, their cancer-promoting potentials, and how beneficial bacteria can be used against cancers.
... Microbiota composition will be assessed from fecal samples collected on day 13 of each study period as we described (53). In brief, total DNA is extracted and subjected to MiSeq sequencing on an Illumina platform using the 2 × 300 paired-end protocol (54). ...
... Thus, this intervention is expected to provide novel evidence supporting MFGM to help reduce MetS risk consistent with a mechanism that improves intestinal barrier functions to reduce endotoxin-TLR4-NFκB inflammation. These outcomes are expected therefore to support research translation of earlier preclinical investigations indicating that MFGM or its bioactive constituents protect against metabolic derangements resulting from obesity and insulin resistance (20,53,63). ...
Article
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Background: Milk fat globule membrane (MFGM) is a phospholipid-rich component of dairy fat that might explain the benefits of full-fat dairy products on cardiometabolic risk. Preclinical studies support that MFGM decreases gut permeability, which could attenuate gut-derived endotoxin translocation and consequent inflammatory responses that impair cardiometabolic health. Objectives: To describe the rationale, study design, and planned outcomes that will evaluate the efficacy of MFGM-enriched milk compared with a comparator beverage on health-promoting gut barrier functions in persons with metabolic syndrome (MetS). Methods: We plan a double-blind, randomized, crossover trial in which people with MetS will receive a rigorously controlled eucaloric diet for 2 wk that contains 3 daily servings of an MFGM-enriched bovine milk beverage or a comparator beverage that is formulated with nonfat dairy powder, coconut and palm oils, and soy phospholipids. Compliance will be monitored by assessing urinary para-aminobenzoic acid that is added to all test beverages. After the intervention, participants will ingest a high-fat/high-carbohydrate meal challenge to assess metabolic excursions at 30-min intervals for 3 h. Nondigestible sugar probes also will be ingested prior to collecting 24-h urine to assess region-specific gut permeability. Intervention efficacy will be determined based on circulating endotoxin (primary outcome) and glycemia (secondary outcome). Tertiary outcomes include: gut and systemic inflammatory responses, microbiota composition and SCFAs, gut permeability, and circulating insulin and incretins. Expected results: MFGM is expected to decrease circulating endotoxin and glycemia without altering body mass. These improvements are anticipated to be accompanied by decreased gut permeability, decreased intestinal and circulating biomarkers of inflammation, increased circulating incretins, and beneficial antimicrobial and prebiotic effects in the gut microbiome. Conclusions: Demonstration of improvements in gut barrier functions that limit endotoxemia and glycemia could help to establish direct evidence that full-fat dairy lowers cardiometabolic risk, especially in people with MetS.The clinical trial associated with this article has been registered at clinicaltrials.gov (NCT03860584).
... With regard to Akkermansia, a mucin-degrading bacterium, its adequate proportion is directly associated with the health of the intestinal mucosal barrier [107]. Another in vivo study demonstrated that a dietary supplementation with 2% (m/m) green tea extract for 8 weeks protected high-fat diet feeding mice from inflammation and endotoxin translocation [108]. The intestinal barrier protection of green tea extract may contribute, at least in part, to its ability to remodel gut microbial homeostasis, mainly manifested in enriching the overall bacterial diversity and decreasing F/B ratio [108]. ...
... Another in vivo study demonstrated that a dietary supplementation with 2% (m/m) green tea extract for 8 weeks protected high-fat diet feeding mice from inflammation and endotoxin translocation [108]. The intestinal barrier protection of green tea extract may contribute, at least in part, to its ability to remodel gut microbial homeostasis, mainly manifested in enriching the overall bacterial diversity and decreasing F/B ratio [108]. ...
Article
Tea represents an abundant source of naturally occurring polyphenols. Tea polyphenols (TPs) have received growing attentions for its wide consumption in the world, and more importantly its pleiotropic bioeffects for human health. After ingestion, TPs may undergo absorption and phase II reaction in the small intestine, and most undigested proportion would be submitted to the colon to interact with gut microbiota. Interactions between gut microbiota and TPs are bidirectional, including not only bacteria-mediated TPs metabolism, e.g., removal of gallic acid moiety and ring fission to release phenolic acid catabolites, but also TPs-based modification of bacterial profiles. Crosstalk between TPs and gut microbes may benefit for gut barrier function, for example, improvement of the intestinal permeability to alleviate inflammation. Moreover, by reshaping microbial composition and associated metabolites, TPs may exert a systemic protection on host metabolism, which contributes to improve certain chronic metabolic disorders. Given that, further understanding of the metabolic fate of TPs and interplay with gut microbiota as well as potential health-promoting effects are of great significance to development and application of tea and their polyphenolic components in the future as dietary supplements and/or functional ingredients in medical foods.
... In addition to improving intestinal dysbiosis, GTE decreases the effects of HFD, decreasing the metabolic disorders associated with obesity. 31 This article confirmed the results obtained by Wang and co-workers 32 where the effects of HFD and tea polyphenols on gut microbiota and lipid metabolism had been investigated. Overall, the results showed that HFD significantly impacted gut microbiota, increasing F/B ratio, but this ratio could be reduced by tea polyphenols administration, together with a reduction in BW gain and levels of serum lipids. ...
... Proteobacteria phylum is involved in hepatic fibrosis and the presence of Bilophila wadsworthia can amplify the inflammatory response in the HFD-induced hepatic pathology. 46 As already mentioned above, EGCG can modulate the gut microbiota in HFD-fed mouse 31 ; a similar protective effect can be observed in NAFLD where EGCG reduced liver injury, and thus protected against liver steatosis. Indeed, Ning and co-workers 47 observed that EGCG improved gut microbiota dysbiosis in male C57BL/6J mice with meth-ionineÀcholine deficient (MCD) diet-derived NASH. ...
Article
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The human intestine contains an intricate ecological community of bacteria, referred as the gut microbiota, which plays a pivotal role in the host homeostasis. Multiple factors could interfere with this delicate balance, thus causing a disruption of the microbiota equilibrium, the so called dysbiosis. Gut microbiota dysbiosis is involved in gastrointestinal and extra‐intestinal metabolic diseases, as obesity and diabetes. Polyphenols, present in a broad range of plant foods, are known to have numerous health benefits; however, their beneficial effect on pre‐existing dysbiosis is less clear. Indeed, in most of the conducted animal studies the administration of polyphenols or foods rich in polyphenols occurred simultaneously with the induction of the pathology to be examined, then analyzing the preventive action of the polyphenols on the onset of dysbiosis, while very low studies analyzed the modulatory activity of polyphenols on the pre‐existing dysbiosis. For this reason, the present review aims to update the current information about the modulation of the pre‐established gut microbiota dysbiosis by dietary phenolic compounds in a broad range of disorders in both animal studies and human trials, distinguishing the preventive or treatment approaches in animal studies. The described studies highlight that dietary polyphenols, exerting prebiotic‐like effects, can modulate the pre‐existing dysbiosis stimulating the growth of beneficial bacteria and inhibiting pathogenic bacteria in both animal models and humans. Anyway, most of the conducted studies are related to obesity and metabolic syndrome, and so further studies are needed to understand this polyphenols' ability in relation to other pathologies.
... Growing evidence suggests that tea and its metabolites could maintain gut health and attenuate obesity through exerting prebiotic-like effects and modulating the gut community structure (Guo et al. 2017). In obese mice, green tea extract, fermented green tea extract, green tea polyphenols, oolong tea polyphenols, Fuzhuan brick tea, ripened Pu-erh tea extract, decaffeinated green tea combined with black tea were observed to change the gut microbiota composition and ameliorate the dysbiosis mostly by decreasing the ratio of Firmicutes to Bacteroidetes (Seo et al. 2015;Cheng et al. 2018;Henning et al. 2018;Zhang et al. 2018;Dey et al. 2019;Lu et al. 2019). Other microorganisms and related intestinal function are also affected by tea. ...
... The green tea extract not only increased the gut microbial diversity but also improved the gut barrier function which inhibited the endotoxin translocation and reduced adipose Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) inflammation (Dey et al. 2019). In addition, the ripened Pu-erh tea extract reduced the weight gain and fat accumulation and increased the intestinal barrier integrity in obese mice. ...
Article
Obesity has become a global health concern. It increases the risk of several diseases, such as type 2 diabetes mellitus, nonalcoholic fatty liver disease, and certain cancers, which threatens human health and increases social economic burden. As one of the most consumed beverages, tea contains various phytochemicals with potent bioactive properties and health-promoting effects, such as antioxidant, immune-regulation, cardiovascular protection and anticancer. Tea and its components are also considered as potential candidates for anti-obesity. Epidemiological studies indicate that regular consumption of tea is beneficial for reducing body fat. In addition, the experimental studies demonstrate that the potential anti-obesity mechanisms of tea are mainly involved in increasing energy expenditure and lipid catabolism, decreasing nutrient digestion and absorption as well as lipid synthesis, and regulating adipocytes, neuroendocrine system and gut microbiota. Moreover, most of clinical studies illustrate that the intake of green tea could reduce body weight and alleviate the obesity. In this review, we focus on the effect of tea and its components on obesity from epidemiological, experimental, and clinical studies, and discuss their potential mechanisms.
... Altogether, GTE is a beneficial food constituent for preventing and treating obesity. A potential mechanism for the anti-obesity of GTE was attributed to the alteration of gut microbiota, based on observations of increased Bacteroides abundance in response to GTE treatment (82)(83)(84). Two mechanisms may be responsible for the beneficial effects of GTE on obesity via improving gut microbiota. One hypothesized mechanism may be the increased production of short chain fatty acids (SCFAs) and the inhibition of endotoxin formation and translocation, thus attenuating obesity-associated adipose inflammation and decreasing body weight (84,85). ...
... Two mechanisms may be responsible for the beneficial effects of GTE on obesity via improving gut microbiota. One hypothesized mechanism may be the increased production of short chain fatty acids (SCFAs) and the inhibition of endotoxin formation and translocation, thus attenuating obesity-associated adipose inflammation and decreasing body weight (84,85). Another hypothesized mechanism may be via gut microbiota-improved intestinal redox state (86). ...
Article
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Obesity has become one of the most serious chronic diseases threatening human health. Its occurrence and development are closely associated with gut microbiota since the disorders of gut microbiota can promote endotoxin production and induce inflammatory response. Recently, numerous plant extracts have been proven to mitigate lipid dysmetabolism and obesity syndrome by regulating the abundance and composition of gut microbiota. In this review, we summarize the potential roles of different plant extracts including mulberry leaf extract, policosanol, cortex moutan, green tea, honokiol, and capsaicin in regulating obesity via gut microbiota. Based on the current findings, plant extracts may be promising agents for the prevention and treatment of obesity and its related metabolic diseases, and the mechanisms might be associated with gut microbiota.
... Similarly, the impact of GM could also affect inflammation in peripheral tissues. Accordingly, the supplementation with a catechin-rich green tea extract attenuated the gut dysbiosis in diet-induced obese mice, and totally prevented gut-derived endotoxin translocation, and consequent hepatic and adipose TLR4/NF-κB inflammation [110]. In addition, GSPE treatment in HFD-fed mice decreased systemic and metabolic tissue inflammation and totally avoided macrophage infiltration in epidydimal fat and liver tissues by modulating the gut microbial composition [111]. ...
Article
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Flavanols are natural occurring polyphenols abundant in fruits and vegetables to which have been attributed to beneficial effects on health, and also against metabolic diseases, such as diabetes, obesity and metabolic syndrome. These positive properties have been associated to the modulation of different molecular pathways, and importantly, to the regulation of immunological reactions (pro-inflammatory cytokines, chemokines, adhesion molecules, nuclear factor-κB [NF-κB], inducible enzymes), and the activity of cells of the immune system. In addition, flavanols can modulate the composition and function of gut microbiome in a prebiotic-like manner, resulting in the positive regulation of metabolic pathways and immune responses, and reduction of low-grade chronic inflammation. Moreover, the biotransformation of flavanols by gut bacteria increases their bioavailability generating a number of metabolites with potential to affect human metabolism, including during metabolic diseases. However, the exact mechanisms by which flavanols act on the microbiota and immune system to influence health and disease remain unclear, especially in humans where these connections have been scarcely explored. This review seeks to summarize recent advances on the complex interaction of flavanols with gut microbiota, immunity and inflammation focus on metabolic diseases.
... Among the many biological effects attributed to green tea, catechins were found to be associated with potential anticancer activity [6][7][8], to interact with gut microbiota [9,10], and to protect against nonalcoholic steatohepatitis [11,12]. More interestingly, for the purpose of the present work, green tea catechins improved cardiovascular and metabolic health [13][14][15][16], one aspect of which was the provision of protection against diet-induced obesity [17]. Mechanisms involving reactive oxygen species (ROS) scavenging and reduction of tissue inflammation [18,19], mitochondrial function improvement, and transcriptional control of genes involved in the adaptive response to oxidative stress [20] have been reported. ...
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We recently showed that the long-term in vivo administration of green tea catechin extract (GTE) resulted in hyperdynamic cardiomyocyte contractility. The present study investigates the mechanisms underlying GTE action in comparison to its major component, epigallocatechin-3-gallate (EGCG), given at the equivalent amount that would be in the entirety of GTE. Twenty-six male Wistar rats were given 40 mL/day of a tap water solution with either standardized GTE or pure EGCG for 4 weeks. Cardiomyocytes were then isolated for the study. Cellular bioenergetics was found to be significantly improved in both GTE- and EGCG-fed rats compared to that in controls as shown by measuring the maximal mitochondrial respiration rate and the cellular ATP level. Notably, the improvement of mitochondrial function was associated with increased levels of oxidative phosphorylation complexes, whereas the cellular mitochondrial mass was unchanged. However, only the GTE supplement improved cardiomyocyte mechanics and intracellular calcium dynamics, by lowering the expression of total phospholamban (PLB), which led to an increase of both the phosphorylated-PLB/PLB and the sarco-endoplasmic reticulum calcium ATPase/PLB ratios. Our findings suggest that GTE might be a valuable adjuvant tool for counteracting the occurrence and/or the progression of cardiomyopathies in which mitochondrial dysfunction and alteration of intracellular calcium dynamics constitute early pathogenic factors.
... Intestinal permeability as a measurable characteristic for the mucosal barrier, can be increased by the alterations of intestinal mucosa barrier components (Bischoff et al., 2014;Jiang et al., 2020;Wang et al., 2021). Importantly, intestinal mucosal barrier dysfunction is an important factor for symptoms or diseases, such as diarrhea, growth impairment, inflammatory bowel disease, and obesity-associated metabolic diseases (Basil et al., 2021;Bischoff et al., 2014;Dey et al., 2019;Morais and Silva, 2019;Wang et al., 2020b). ...
Article
Lead (Pb) entering the body through different channels can damage the function of intestinal mucosal barrier and cause the body stressful inflammatory response to enhance. This study conducted a cross-sectional study to investigate the effects of Pb exposure on intestinal permeability in children by measuring the level of bacterial endotoxin and index of inflammatory cell types in peripheral blood. From November to December 2018, we recruited 187 participants aged 3–6 years by stratified randomization, from an electronic-waste-exposed group (n = 82) and a referent group (n = 105). General demographic information, past history of the digestive system in child, and family situation were informed by children's guardians with questionnaires. Children in the exposed group showed lower weight, height, and body mass index while more diarrhea in a month. Blood Pb and plasma endotoxin were elevated in exposed children than referent children and the positive relationship between them was shown in all children [B (95% CI): 0.072 (0.008, 0.137), P = 0.033]. Peripheral monocyte counts and leukotriene B4 (LTB4) levels were significantly increased in the exposed group. Endotoxin levels were positively correlated with neutrophils, monocytes, and LTB4 [B (95% CI): 0.054 (0.015, 0.093), 0.018 (0.005, 0.031), and 0.049 (0.011, 0.087), respectively, P < 0.05]. To sum up, the exposed children showed lower physical growth levels, poorer gut health, and increased intestinal permeability, which was related to high blood Pb and peripheral inflammatory indices. These results suggest the possible adverse impact of environmental Pb exposure on the intestinal health of children.
... Intestinal permeability was measured by a FITC-labeled dextran method before the mice were sacrificed (Dey et al., 2019). Briefly, after being fasted for 4 h, all mice were gavaged with the permeability tracer FITC-labeled dextran (4 kDa) (40 mg/100 g, Sigma-Aldrich, Missouri, United States). ...
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Aims The present study aimed to investigate alterations in neuroinflammation after heart failure (HF) and explore the potential mechanisms. Methods Male wild-type (WT) and Toll-like receptor 4 (TLR4)-knockout (KO) mice were subjected to sham operation or ligation of the left anterior descending coronary artery to induce HF. 8 weeks later, cardiac functions were analyzed by echocardiography, and intestinal barrier functions were examined by measuring tight junction protein expression, intestinal permeability and plasma metabolite levels. Alterations in neuroinflammation in the brain were examined by measuring microglial activation, inflammatory cytokine levels and the proinflammatory signaling pathway. The intestinal barrier protector intestinal alkaline phosphatase (IAP) and intestinal homeostasis inhibitor L-phenylalanine (L-Phe) were used to examine the relationship between intestinal barrier dysfunction and neuroinflammation in mice with HF. Results Eight weeks later, WT mice with HF displayed obvious increases in intestinal permeability and plasma lipopolysaccharide (LPS) levels, which were accompanied by elevated expression of TLR4 in the brain and enhanced neuroinflammation. Treatment with the intestinal barrier protector IAP significantly attenuated neuroinflammation after HF while effectively increasing plasma LPS levels. TLR4-KO mice showed significant improvements in HF-induced neuroinflammation, which was not markedly affected by intestinal barrier inhibitors or protectors. Conclusion HF could induce intestinal barrier dysfunction and increase gut-to-blood translocation of LPS, which could further promote neuroinflammation through the TLR4 pathway.
... Lipopolysaccharide (LPS) is a toxic component of gram-negative bacteria. In clinical and experimental studies, gut microbial dysbiosis associated with increased intestinal permeability is commonly observed in obesity (Dey et al., 2019), diarrhoea , constipation (Chassard et al., 2012) and ageing (Brunt et al., 2019;Maynard and Weinkove, 2018) and leads to gut-derived LPS translocation (Grosicki et al., 2018), which causes an increase in circulating LPS concentrations (Ghosh et al., 2015). LPS from a number of bacterial species effectively inhibits gastric acid secretion in vivo (Doherty et al., 2003;Baume et al., 1967;Uehara et al., 1990). ...
Article
Na⁺-K⁺-2Cl⁻ cotransporter (NKCC) is expressed at exceptionally high levels in gastric parietal cells. Bumetanide, a potent loop diuretic that blocks NKCC, usually causes a decrease in gastric acid secretion. Endotoxaemia causes hypochlorhydria in vivo, in which lipopolysaccharide (LPS) plays an important role. This study aimed to investigate the effect of NKCC2 on gastric acid secretion and its alteration in LPS-treated mice. The scanning ion-selective electrode technique and real-time pH titration combined with RNA interference were used to determine the effects of bumetanide on gastric acid secretion. Immunochemistry and Western blotting were performed to investigate the changes in NKCC2 expression in LPS-treated mice. Immunoreactivity of NKCC1 and NKCC2 was mainly observed near the basolateral and apical membranes of parietal cells, respectively. Pretreatment with bumetanide reduced the histamine-stimulated H⁺ flux in the mouse gastric mucosa. The apical, but not the basolateral, addition of bumetanide inhibited forskolin- or histamine/3-isobutyl-1-methylxanthine(IBMX)-induced gastric acid secretion. In vivo treatment with NKCC2 siRNA inhibited forskolin-induced acid secretion. Upon histamine stimulation, the majority of NKCC2 was targeted to the apical membrane in the gastric mucosa and in primary cultured parietal cells. The expression of NKCC2 and vesicle-associated membrane protein-2 (VAMP2), but not that of H⁺/K⁺-ATPase, was decreased in the gastric mucosa of LPS-treated mice. Blocking apical NKCC2, but not basolateral NKCC1, by bumetanide inhibited secretagogue-induced gastric acid secretion, during which the membrane trafficking of NKCC2 may be necessary. The downregulation of NKCC2 and VAMP2 may be related to the reduced gastric acid secretion induced by LPS.
... As reported in previous studies, green tea has potential antiobesity properties (Dey et al., 2019;Dinh et al., 2019;Westerterp-Plantenga, 2010). These properties are attributed to several bioactive compounds, such as EC, EGC, ECG, and EGCG (Hayat et al., 2015;Li et al., 2020). ...
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Adipose browning leads to increased energy expenditure and reduced adiposity and has, therefore, become an attractive therapeutic strategy for obesity. In this study, we elucidated the effect of green tea aqueous extract (GTAE) on the browning of inguinal white adipose tissue (Ing‐WAT) and brown adipose tissue (BAT) in high‐fat diet (HFD)‐fed mice. The main phytochemical components identified in GTAE through high‐performance liquid chromatography (HPLC) included (−)‐gallocatechin, (−)‐epigallocatechin, (−)‐catechin, (−)‐epigallocatechin‐3‐gallate, caffeine, (−)‐epicatechin, (−)‐gallocatechin gallate, and (−)‐epicatechin‐3‐gallate. Daily supplementation with 1% GTAE for 12 weeks markedly reduced bodyweight gain, systemic inflammation, oxidative stress, and improved insulin resistance. Additionally, histological analysis revealed that dietary supplementation with 1% GTAE reversed HFD‐induced adipocyte size and hepatic steatosis. These effects were associated with activation of browning in the Ing‐WAT and BAT, which mediate systemic metabolic dysfunction in HFD‐fed mice. Taken together, our data support the use of GTAE, a natural product, for the attenuation of obesity through the activation of fat browning. The present study found that mice fed a high‐fat diet showed significantly lower weight gain upon GTAE administration than their control counterparts. In addition, GTAE ameliorated the high‐fat diet‐induced hepatic steatosis, insulin resistance, and low‐systematic inflammatory. These effects were associated with browning activation in the Ing‐WAT and BAT.
... In this same study, the authors concluded that an anthocyanins-rich formula improves hyperglycemia and insulin resistance in obese mice fed with a high-fat diet by modulating glucose metabolism in the liver and skeletal muscle [10]. Resveratrol and green tea have shown efficacy in decreasing weight gain induced by OLZ in rodents [20]. This evidence is important since OLZ-induced diabetes is a severe, lifethreatening condition with very limited prophylactic interventions. ...
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Type 2 diabetes and obesity are major problems worldwide and dietary polyphenols have shown efficacy to ameliorate signs of these diseases. Anthocyanins from berries display potent antioxidants and protect against weight gain and insulin resistance in different models of diet- induced metabolic syndrome. Olanzapine is known to induce an accelerated form of metabolic syndrome. Due to the aforementioned, we evaluated whether delphinidin-3,5-O-diglucoside (DG) and delphinidin-3-O-sambubioside-5-O-glucoside (DS), two potent antidiabetic anthocyanins isolated from Aristotelia chilensis fruit, could prevent olanzapine-induced steatosis and insulin resistance in liver and skeletal muscle cells, respectively. HepG2 liver cells and L6 skeletal muscle cells were co- incubated with DG 50 μg/mL or DS 50 μg/mL plus olanzapine 50 μg/mL. Lipid accumulation was determined in HepG2 cells while the expression of p-Akt as a key regulator of the insulin-activated signaling pathways, mitochondrial function, and glucose uptake was assessed in L6 cells. DS and DG prevented olanzapine-induced lipid accumulation in liver cells. However, insulin signaling impairment induced by olanzapine in L6 cells was not rescued by DS and DG. Thus, anthocyanins modulate lipid metabolism, which is a relevant factor in hepatic tissue, but do not significantly influence skeletal muscle, where a potent antioxidant effect of olanzapine was found.
... We have previously identified a combination of tea polyphenol EGCG and probiotic bacteria Lactobacillus fermentum that can differentially and beneficially modulate the functions of the aging immune system in mice as opposed to individual treatments of EGCG or probiotic bacteria [177]. Similarly, several studies have shown that consumption of green or black tea polyphenols can modulate the gut microbiota which positively impacts the host health [178][179][180][181][182][183]. In addition, there appears to be evidence that the health beneficial effects of polyphenol-rich sources, such as in tea, may actually be mediated by the reciprocal interactions between polyphenols and the gut microbiome. ...
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A cellular senescence-centric understanding of biological aging and age-related chronic diseases is rapidly emerging. As a result, strategies aimed at mitigating the deleterious aspects of cellular senescence are increasingly becoming desirable. Tea is a globally admired and nutrient-rich beverage that not only refreshes the senses but is also implicated in several health beneficial effects including the extension of organismal healthspan and lifespan. The present review discusses the emerging anti-cellular senescence attributes of tea consumption and provides a perspective that the anti-aging aspects of tea should be studied in the purview of cellular senescence. Current understanding of the integrative effects of the immune system and gut microbiome on cellular senescence have also been discussed with the rationale of mitigatory effects of tea. Future research directions and recommendations have been provided which may ultimately help augment tea-oriented successful and healthy aging approaches.
... Bacterial DNA was extracted using a QIAamp Fast DNA Stool Mini Kit (Qiagen, Hilden, Germany) as described [38]. Then, the V4-V5 hypervariable region of the 16S rRNA gene was amplified by PCR to prepare amplicon libraries followed by MiSeq sequencing (Illumina, San Diego, CA, USA) [39]. Paired-end reads (2 × 300 paired-end protocol) were analyzed using QIIME2 (version 2020.2) [40]. ...
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Poor diet quality influences cardiometabolic risk. Although potatoes are suggested to adversely affect cardiometabolic health, controlled trials that can establish causality are limited. Consistent with potatoes being rich in micronutrients and resistant starch, we hypothesized that their inclusion in a Dietary Guidelines for Americans (DGA)-based dietary pattern would improve cardiometabolic and gut health in metabolic syndrome (MetS) persons. In a randomized cross-over trial, MetS persons (n = 27; 32.5 ± 1.3 year) consumed a DGA-based diet for 2 weeks containing potatoes (DGA + POTATO; 17.5 g/day resistant starch) or bagels (DGA + BAGEL; 0 g/day resistant starch) prior to completing oral glucose and gut permeability tests. Blood pressure, fasting glucose and insulin, and insulin resistance decreased (p < 0.05) from baseline regardless of treatment without any change in body mass. Oral glucose-induced changes in brachial artery flow-mediated dilation, nitric oxide homeostasis, and lipid peroxidation did not differ between treatment arms. Serum endotoxin AUC0–120 min and urinary lactulose/mannitol, but not urinary sucralose/erythritol, were lower in DGA + POTATO. Fecal microbiome showed limited between-treatment differences, but the proportion of acetate was higher in DGA + POTATO. Thus, short-term consumption of a DGA-based diet decreases cardiometabolic risk, and the incorporation of resistant starch-containing potatoes into a healthy diet reduces small intestinal permeability and postprandial endotoxemia.
... Other studies have proposed LPS-binding proteins (LBP) as possible markers of obesity, as higher levels of LBP have been observed in diet-induced obese mice [86]. A recent study found that anti-obesity effects of green-tea extracts were due to its beneficial effects on gut microbiota; the extract reversed gut dysbiosis and prevented the loss of intestinal barrier integrity by up-regulating the expression of tight junction proteins [87]. ...
Article
Intestinal hyperpermeability is a complex metabolic process mediated by different pathways in close relation to the gut microbiota. Previous studies suggested that the gut microbiota is involved in different metabolic regulations, and its imbalance is associated with several metabolic diseases, including obesity. It is well known that intestinal hyperpermeability is associated with dysbiosis, and the combination of these two conditions can lead to an increase in the level of low-grade inflammation in obese patients due to an increase in pro-inflammatory cytokine levels. Inflammatory bowel syndrome often accompanies this condition causing an alteration of the intestinal mucosa and thus reinforcing the dysbiosis and gut hyperpermeability. The onset of metabolic disorders depends on violations of the integrity of the intestinal barrier as a result of increased intestinal permeability. Chronic inflammation due to endotoxemia is responsible for the development of obesity. Metabolic disorders are associated with dysregulation of the microbiota-gut-brain axis and with an altered composition of gut flora. In this review, we will discuss the mechanisms that illustrate the relationship between hyperpermeability, the composition of the gut microbiota, and obesity.
... Such a way of processing allows maintaining high amounts of antimicrobial and antioxidant phenolic compounds, which are absent in refined forms. In another study, the phenolic compounds obtained from green tea were shown to prevent the mouse intestine from alterations in TJ proteins and dysbiosis caused by HFD [61]. ...
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Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation.
... All rights reserved the liver receives a larger influx of endotoxin in comparison to other tissues due to the portal vein. For instance, LPS concentration in the portal system has been reported to be 10 times greater versus concentrations in peripheral blood [100]. Though LPS is also absorbed with lipids, it effectively binds to lipoproteins in chylomicrons due to the action of LBP [101]. ...
Article
Systemic inflammation is associated with chronic disease and is purported to be a main pathogenic mechanism underlying metabolic conditions. Microbes harbored in the host gastrointestinal tract release signaling byproducts from their cell wall, such as lipopolysaccharides (LPS), which can act locally and, after crossing the gut barrier and entering circulation, also systemically. Defined as metabolic endotoxemia, elevated concentrations of LPS in circulation are associated with metabolic conditions and chronic disease. As such, measurement of LPS is highly prevalent in animal and human research investigating these states. Indeed, LPS can be a potent stimulant of host immunity but this response depends on the microbial species’ origin, a parameter often overlooked in both preclinical and clinical investigations. Indeed, the lipid A portion of LPS is mutable and comprises the main virulence and endotoxic component, thus contributing to the structural and functional diversity among LPSs from microbial species. In this review, we discuss how such structural differences in LPS can induce differential immunological responses in the host. Spurring metabolic endotoxemia, lipopolysaccharides from microbes in the gut act locally and systemically by crossing the gut barrier and entering host circulation. Lipopolysaccharides are associated with major chronic diseases and are a prevalent biomarker in animal and human research. However, just as microbes vary, so do their products. Structural differences in LPS can induce differential health responses in the host.
... 5 The beneficial effects of phenolic acids on intestinal leakage are currently attracting increasing attention. 6,7 Phenolic acids are classified into hydroxybenzoic acid derivatives [e.g. protocatechuic acid (PCA), vanillic acid (VA) and hippuric acid (HA)] and hydroxycinnamic acid derivatives [e.g. ...
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Phenolic acids play an active role in protecting the intestinal barrier, the structural integrity and function of which are crucial for host health. In the present study, we aimed to identify phenolic compounds that protect the intestine and explore the underlying mechanisms. We performed an imaging-based, quantitative, high-content screening (using Caco-2 and LS174T incubated with lipopolysaccharide/palmitic acid, respectively) to identify phenolic acids that could improve the mucosal barrier. We found that chlorogenic acid (CGA), 5-caffeoylquinic acid, protocatechuic acid, and caffeic acid alleviated intestinal barrier disruption. Furthermore, CGA increased transepithelial electrical resistance (TEER) and decreased paracellular permeability. Mechanistically, CGA inhibited the activation of myosin light chain kinase (MLCK) and Rho-associated kinase 1 (ROCK1) signals, thereby downregulating the expression of the downstream molecules phosphorylated myosin phosphatase target subunit 1 (p-MYPT1), MLCK, and phosphorylated myosin light chain (p-MLC), and upregulating the expression of tight junction proteins. In addition, CGA alleviated endoplasmic reticulum (ER) stress by inhibiting the expression levels of ER markers [glucose-regulated protein78 (GRP78) and C/EBP homologous protein (CHOP)] and the nuclear translocation of activating transcription factor 6 (ATF6), thereby promoting the expression of mucin [mucin 2 (Muc2), mucin 5AC (MUC5AC)] and secretory factor trefoil factor family 3 (TFF3) proteins. In summary, we identified four substances that can stabilise intestinal homeostasis. Of these, CGA protects the intestinal barrier by inhibiting ROCK/MLCK signalling pathways and relieving ER stress. These findings highlight the importance of rapidly screening potential active ingredients that benefit the intestinal barrier and provide a theoretical basis for enteral nutrition.
... In recent years, the role of the intestine in the development of obesity and T2D is increasingly recognized. Studies conducted in various animal models provide convincing evidence that inflammation originates in the intestine due to the modulation of gut barrier function leading to metabolic endotoxemia (14)(15)(16)(17)(18). Metabolic endotoxemia refers to a diet-induced 2-3 fold increase in gut-derived plasma lipopolysaccharide (LPS) level (14), which may result in low-grade systemic and tissue inflammation, contributing to a metabolic disease phenotype (14,15,(19)(20)(21)(22). Metabolic endotoxemia is indicative of decreased intestinal epithelial barrier function, also referred to as "leaky gut" syndrome ( Figure 1), which allows undesirable luminal immunogens, such as LPS, but also bacterial DNA and RNA and to some degree viable bacteria, to cross into the blood and lymphatic system (14,29). ...
Article
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Noncommunicable diseases, such as type 2 diabetes (T2D), place a burden on healthcare systems worldwide. The rising prevalence of obesity, a major risk factor for T2D, is mainly attributed to the adoption of Westernized diets and lifestyle, which cause metabolic dysfunction and insulin resistance. Moreover, diet may also induce changes in the microbiota composition, thereby affecting intestinal immunity. The critical role of intestinal immunity and intestinal barrier function in the development of T2D is increasingly acknowledged, however, limited studies have investigated the link between intestinal function and metabolic disease. In this review, studies reporting specific roles of the intestinal immune system and intestinal epithelial cells (IECs) in metabolic disease are highlighted. Innate chemokine signaling, eosinophils, immunoglobulin A (IgA), T helper (Th) 17 cells and their cytokines were associated with obesity and/or dysregulated glucose homeostasis. Intestinal epithelial cells (IECs) emerged as critical modulators of obesity and glucose homeostasis through their effect on lipopolysaccharide (LPS) signaling and decontamination. Furthermore, IECs create a link between microbial metabolites and whole-body metabolic function. Future in depth studies of the intestinal immune system and IECs may provide new opportunities and targets to develop treatments and prevention strategies for obesity and T2D.
... QIIME (v.1.80) and LEFSe online, and PICRUSt software was applied to predict gut microbial functions aligned to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database [37]. After growth to logarithmic phase, the bacterial suspension was prepared at a concentration of 5 × 109 colony-forming unit (CFU) per milliliter in sterile saline and immediately placed on ice prior to oral gavage to mice. ...
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Background Obesity and its comorbidities are associated with abnormal lipid metabolism and gut microbiota dysbiosis. Bupleuri Radix is a medicinal plant used in traditional Chinese medicine with the prevention and treatment of obesity-related diseases. In this study, we aim to validate the regulation of Bupleuri Radix Extract (BupE) on lipid metabolism in obese mice, and try to find out the potential active components and reveal the underlying mechanisms. Methods Ingredients in BupE, their circulating metabolites in mice and fecal biotransformation products were analyzed by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). Western blotting, RT-PCR and ELISA were used for tests of objective genes and proteins. 16 s rRNA sequencing was performed to examine intestinal bacteria composition and microbes’ functional changes were predicted with PICRUSt software. An absolute quantification method was set up via the construction of recombinant plasmid for the assays of intestinal flora. Specific microbial strains were cultured in anaerobic conditions and oral administrated to mice for intestinal mono-colonization. Results BupE attenuated obesity, liver steatosis, and dyslipidemia in HFD-fed mice by up-regulating the expression of FGF21 in liver and white adipose tissue (WAT) as well as the downstream proteins of FGF21 signal pathway including β-klotho, GLUT1 and PGC-1α, etc. UPLC/Q-TOF-MS fingerprints showed no compounds from BupE or their metabolites or biotransformation products were detected in rodent serum samples. High-throughput pyrosequencing data indicated that BupE reversed obesity-induced constructional and functional alterations of intestinal flora. Two bacterial strains, Bacteroides acidifaciens (B. acidifaciens) and Ruminococcus gnavus (R. gnavus), were separated and identified from the feces of obese mice and by intestinal mono-colonization they were verified to intervene in the anti-obesity effects of BupE on mice. Conclusion These data suggest that BupE protects against diet-induced obesity and counteracts metabolic syndrome features consistent with a mechanism involving the gut-liver axis that boosts hepatic FGF21 secretion and consequent down-stream proteins expression relating to lipid metabolism. And in this gut-liver axis, intestinal microbes such as B.acidifaciens and R.gnavus play an indispensable role.
Article
The caseinate and glycated caseinate generated from the transglutaminase-catalyzed reaction of caseinate and oligochitosan were digested using pepsin and trypsin, and the activity of the resultant digests was measured in rat intestinal epithelial cell line (IEC-6) using several biological responses as indicators. Compared with the caseinate digest, the glycated caseinate digest had similar contents in 17 amino acids but less reactable –NH2 contents, and 6.57 g glucosamine per kg protein; moreover, it showed higher activity in the cells (P < 0.05) to promote cell growth, accumulate the cell-cycle progression at the S-phase, and prevent the camptothecin-induced cell apoptosis. The glycated caseinate digest also showed higher differentiation activity in the cells than the caseinate digest, resulting in enhanced activities of the three brush-border membrane enzymes (P < 0.05) and increased microvilli on the cell surfaces. The real-time reverse transcription-polymerase chain reaction, Western-blot assay, and Dickkopf-1 (a receptor inhibitor of the Wnt/β-catenin signaling pathway) were used to determine both gene and protein expression changes in the cells. A Wnt/β-catenin signaling pathway responsible for these enhanced effects was proposed because the five genes (glycogen synthase kinase 3β, Wnt3a, β-catenin, c-Myc, and cyclin D1) and three proteins (nuclear and cytosolic β-catenin, cyclin D1, and c-Myc) as part of this signaling pathway were regulated in the treated cells. The oligochitosan glycation of caseinate induced by transglutaminase is thus suggested endowing the peptic-tryptic caseinate digest with higher activity in the cells through its effects on the Wnt/β-catenin signaling pathway.
Article
The role of the gut microbiome in bone health has received significant attention in the past decade. We investigated the effects of green tea polyphenols (GTP) and annatto-extracted tocotrienols (AT) on bone properties and gut microbiome in obese mice. Male mice were assigned to a two (no AT vs. 400 mg/kg diet AT)×two (no GTP vs. 0.5% w/v GTP) factorial design, namely control, G, T, and G+T group respectively, for 14 weeks. The 4th lumbar vertebra (LV-4) and femur were harvested for bone microstructural analysis using μ-CT. Microbiome analysis using 16S rRNA gene sequencing of cecal feces was performed. AT increased bone volume at distal femur. GTP increased serum procollagen type 1 N-terminal propeptide concentration, bone volume at the distal femur and the LV-4, and trabecular number at distal femur; whereas GTP decreased trabecular separation at distal femur. Interactions between GTP and AT were observed in serum C-terminal telopeptide of type I collagen level (control>G=T=G+T) as well as the cortical bone area (control<G=T=G+T) and thickness (T≥G+T≥G≥control) at femur mid-diaphysis. Redundancy analysis showed a significant difference in the gut microbiome profile among different groups and the relative abundance of Akkermansia muciniphila, Clostridum saccharogumia, and Subdoligranulum variabile was increased in the GTP- and AT-supplemented groups. Functional profiling of the gut microbiome showed the combination of GTP and AT induced biosynthetic pathways for vitamin K2. Our results suggest that GTP and AT supplementation benefits bone properties in obese mice through modifying gut microbiome composition and function.
Article
The intestinal epithelial layer serves as a physical and functional barrier between the microbe-rich lumen and immunologically active submucosa; it prevents systemic translocation of microbial pyrogenic products (e.g. endotoxin) that elicits immune activation upon translocation to the systemic circulation. Loss of barrier function has been associated with chronic ‘low-grade’ systemic inflammation which underlies pathogenesis of numerous no-communicable chronic inflammatory disease. Thus, targeting gut barrier dysfunction is an effective strategy for the prevention and/or treatment of chronic disease. This review intends to emphasize on the beneficial effects of herbal formulations, phytochemicals and traditional phytomedicines in attenuating intestinal barrier dysfunction. It also aims to provide a comprehensive understanding of intestinal-level events leading to a ‘leaky-gut’ and systemic complications mediated by endotoxemia. Additionally, a variety of detectable markers and diagnostic criteria utilized to evaluate barrier improving capacities of experimental therapeutics has been discussed. Collectively, this review provides rationale for targeting gut barrier dysfunction by phytotherapies for treating chronic diseases that are associated with endotoxemia-induced systemic inflammation.
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The pathology of osteoporosis is multifactorial, but a growing body of evidence supports an important role of the gut-bone axis, especially in bone loss associated with menopause, rheumatoid arthritis, and periodontal disease. Aberrant T cell responses favoring an increase in the ratio of T helper (Th)17 cells to T regulatory (Treg) cells play a critical role in the underlying etiology of this bone loss. Many of the dietary phytochemicals known to have osteoprotective activity such as flavonoids, organosulfur compounds, phenolic acids, as well as the oligosaccharides also improve gut barrier function and affect T cell differentiation and activation within gut-associated lymphoid tissues and at distal sites. Here, we examine the potential of these phytochemicals to act as prebiotics and immunomodulating agents, in part targeting the gut to mediate their effects on bone.
Article
Catechin-rich green tea extract (GTE) protects against nonalcoholic steatohepatitis (NASH) by alleviating gut-derived endotoxin translocation and hepatic TLR4-NFκB-inflammation. We hypothesized that intact GTE would attenuate NASH-associated responses along the gut-liver axis to a greater extent than purified (-)-epigallocatechin gallate (EGCG) or (+)-catechin (CAT). Male C57BL/6J mice were fed a low-fat diet, a high-fat (HF) diet, or the HF diet with 2% GTE, 0.3% EGCG, or 0.3% CAT for 8-wk prior to assessing NASH relative to endotoxemia, hepatic and intestinal inflammation, intestinal tight junction proteins (TJPs) and gut microbial ecology. GTE prevented HF-induced obesity to a greater extent than EGCG and CAT, whereas GTE and EGCG more favorably attenuated insulin resistance. GTE, EGCG and CAT similarly attenuated serum alanine aminotransferase and serum endotoxin, but only GTE and EGCG fully alleviated HF-induced NASH. However, hepatic TLR4/NFκB inflammatory responses that were otherwise increased in HF mice were similarly attenuated by GTE, EGCG and CAT. Each treatment also similarly prevented the HF-induced loss in expression of intestinal TJPs and HIF-1α and the otherwise increased levels of ileal and colonic TNFα mRNA and fecal calprotectin protein concentrations. Gut microbial diversity that was otherwise lowered in HF mice was maintained by GTE and CAT only. Further, microbial metabolic functions were more similar between GTE and CAT. Collectively, GTE catechins similarly protect against endotoxin-TLR4-NFκB inflammation in NASH, but EGCG and CAT exert differential prebiotic and antimicrobial activities suggesting that catechin-mediated shifts in microbiota composition are not entirely responsible for their benefits along the gut-liver axis.
Article
Flavonols are bioactive substances in plant foods. In this study, two flavonols galangin and kaempferol were heated at 100°C for 30 min prior to assessing their effects on barrier function of rat intestinal epithelial (IEC-6) cells. Both heated and unheated flavonols (2.5−20 µmol/L dosages) were nontoxic to the cells up to 48 h post-treatment, and could promote cell viability values to 102.2−141.2% of control. By treatment with 5 µmol/L flavonols for 24 and 48 h, the treated cells time-dependently showed better improved physical and biological barrier functions than the control cells without any flavonol treatment, including higher transepithelial electrical resistance and antibacterial effect but reduced paracellular permeability and bacterial translocation. The results from real-time PCR and western-blot assays indicated that the cells treated with heated and unheated flavonols of 5 µmol/L dosage had up-regulated mRNA (1.13−1.81 folds) and protein (1.15−5.11 folds) expression for zonula occluden-1, occludin, and claudin-1 that are vital to the tight junctions of the cells. Moreover, protein expression of RhoA and ROCK were down-regulated into 0.41−0.98 and 0.40−0.92 folds, respectively, demonstrating a Rho inactivation that led to enhanced cell barrier integrity via the RhoA/ROCK pathway. Overall, galangin was more active than kaempferol to perform three biofunctions like improving cell barrier function, up-regulating tight junctions protein expression, and down-regulating RhoA/ROCK expression. Moreover, the heated flavonols were less effective than the unheated counterparts to perform these biofunctions. It is concluded that this heat treatment of galangin and kaempferol could inhibit their benefits to improve barrier function of IEC-6 cells.
Article
The role of gut microbiome in human health and disease is well established. While evidence-based pharmacological studies utilize a variety of chemical-induced metabolic and toxicological disease models that in part recapitulate the natural mode of disease pathogenesis, the mode of actions of these disease models are likely underexplored. Conventionally, the mechanistic principles of these disease models are established as direct tissue toxicity through redox imbalance and pro-inflammatory injury. However, emerging evidences suggest that the mode of action of these chemicals could be largely associated with changes in gut microbial populations, diversity and metabolic functions, affecting pathological changes along the gut-liver and gut-pancreas axis. Especially in these disease models, reversal of disease severity or less sensitivity to induced disease pathogenesis has been observed when germ-free or antibiotic-supplemented microbiota-depleted rodents were treated with disease causing chemicals. Thus, by summarizing evidences from in vivo pharmacological interventions, this review revisits the mode of action of carbon tetrachloride-induced cirrhosis, diethylnitrosamine-induced hepatocellular carcinoma, acetaminophen-induced hepatotoxicity and alloxan- and streptozotocin-induced diabetes through the light of gut microbiota. How changes in gut microbiome affects tissue-level toxicity likely through intestinal-level mechanisms like gastrointestinal inflammation and gut barrier dysfunction has also been discussed. Additionally, this review discusses potential pitfalls of inconsistent experimental models that precludes defining the gut microbial effects in evidence-based pharmacology. Collectively, this review emphasizes the underexplored role of microbial intervention in experimental pharmacology and aims to provide direction towards redefining and establishing microbiome-centric alternative mode of action of chemical-induced metabolic and toxicological disease models in pharmacological research.
Article
Type 1 diabetes mellitus (T1DM) is a disease marked by oxidative stress, chronic inflammation, and the presence of autoantibodies. The gut microbiota has been shown to be involved in the alleviation of oxidative stress and inflammation as well as strengthening immunity, thus its’ possible involvement in the pathogenesis of T1DM has been highlighted. The goal of the present study is to analyze information on the relationship between the structure of the intestinal microbiome and the occurrence of T1DM. The modification of the intestinal microbiota can increase the proportion of SCFA-producing bacteria, which could in turn be effective in the prevention and/or treatment of T1DM. The increased daily intake of soluble and non-soluble fibers, as well as the inclusion of pro-biotics, prebiotics, herbs, spices, and teas that are sources of phytobiotics, in the diet, could be important in improving the composition and activity of the microbiota and thus in the prevention of metabolic disorders. Understanding how the microbiota interacts with immune cells to create immune tolerance could enable the development of new therapeutic strategies for T1DM and improve the quality of life of people with T1DM.
Article
Scope Catechin‐rich green tea extract (GTE) limits inflammation in nonalcoholic steatohepatitis (NASH) consistent with a Toll‐like receptor 4 (TLR4)‐dependent mechanism. It is hypothesized that GTE supplementation during NASH will shift the hepatic metabolome similar to that attributed to the loss‐of‐TLR4 signaling. Methods and results Wild‐type (WT) and loss‐of‐function TLR4‐mutant (TLR4mut) mice are fed a high‐fat diet containing 0% or 2% GTE for 8 weeks prior to performing untargeted mass spectrometry‐based metabolomics on liver tissue. The loss‐of‐TLR4 signaling and GTE shift the hepatic metabolome away from that of WT mice. However, relatively few metabolites are altered by GTE in WT mice to the same extent as the loss‐of‐TLR4 signaling in TLR4mut mice. GTE increases acetyl‐coenzyme A precursors and spermidine to a greater extent than the loss‐of‐TLR4 signaling. Select metabolites associated with thiol metabolism are similarly affected by GTE and the loss‐of‐TLR4 signaling. Glycerophospholipid catabolites are decreased by GTE, but are unaffected in TLR4mut mice. Conversely, the loss‐of‐TLR4 signaling but not GTE increases several bile acid metabolites. Conclusion GTE limitedly alters the hepatic metabolome consistent with a TLR4‐dependent mechanism. This suggests that the anti‐inflammatory activities of GTE and loss‐of‐TLR4 signaling that regulate hepatic metabolism to abrogate NASH are likely due to distinct mechanisms.
Article
Obesity-induced colonic inflammation-stimulated colitis is one of the main causes of colorectal cancer. Dietary phytochemicals are considered to be an effective strategy for relieving obesity-induced inflammatory diseases such as diabetes and colitis. Ginsenoside Rk3 (Rk3) is the main bioactive component of ginseng. Our previous study has demonstrated that Rk3 can effectively alleviate obesity-induced type 2 diabetes, but whether it plays a beneficial role in obesity-induced colitis remains poorly understood. Here, we found that Rk3 intervention repaired the intestinal barrier dysfunction by increasing the expression of the tight junction proteins (zonula occludens-1, claudin, and occludin), and reduced colonic inflammatory cytokine levels, oxidative stress, and macrophage infiltration in high-fat diet-induced mice. Importantly, Rk3 effectively ameliorated the metabolic dysbiosis of intestinal flora with significantly decreased Firmicute/Bacteroidete ratios and suppressed the inflammatory cascade by inhibiting the TLR4/NF-κB signaling pathway. Taken together, our findings indicate that Rk3 can be used as a potential natural anti-inflammatory agent to reduce chronic obesity-induced colitis.
Article
Skin aging is characterized by the gradual loss of elasticity, the formation of wrinkles and various color spots, the degradation of extracellular matrix proteins, and the structural changes of the dermis. With the increasingly prominent problems of environmental pollution, social pressure, ozone layer thinning and food safety, skin problems have become more and more complex. The skin can reflect the overall health of the body. Skincare products for external use alone cannot fundamentally solve skin problems; it needs to improve the overall health of the body. Based on the literature review in recent 20 years, this paper systematically reviewed the potential delaying effect of tea and its active ingredients on skin aging by oral and external use. Tea is the second-largest health drink after water. It is rich in tea polyphenols, l-theanine, tea pigments, caffeine, tea saponins, tea polysaccharides and other secondary metabolites. Tea and its active substances have whitening, nourishing, anti-wrinkle, removing spots and other skincare effects. Its mechanism of action is ultraviolet absorption, antioxidant, anti-inflammatory, inhibition of extracellular matrix aging, inhibiting the accumulation of melanin and toxic oxidation products, balancing intestinal and skin microorganisms, and improving mood and sleep, among other effects. At present, tea elements skincare products are deeply loved by consumers. This paper provides a scientific theoretical basis for tea-assisted beauty and the high-end application of tea in skincare products.
Article
Obesity is regarded to be associated with fat accumulation, chronic inflammation, and gut microbiota dysbiosis. Raw and ripened pu-erh tea extract (PETe) have the effect of reducing body weight gain and fat accumulation, which are associated with gut microbiota. However, little is known about the difference of raw and ripened PETe on the regulation of gut microbiota. Here, our results suggested that supplementation of raw and ripened PETe displayed similar anti-obesogenic effect in high fat diet (HFD)-induced obesity mice, by attenuating the body weight gain, fat accumulation, oxidative injury, and low-grade inflammation, improving the glucose tolerance, alleviating the metabolic endotoxemia, and regulating the mRNA and protein expression levels of the lipid metabolism-related genes. 16S rRNA sequencing of fecal samples indicated that raw and ripened PETe intervention displayed different regulatory effect on the HFD-induced gut microbiota dysbiosis at different taxonomic levels. The microbial diversity, the relative abundance of Firmicutes and Bacteroidetes as well as F/B ratio were reversed more closer to normal by ripened PETe. Phylotypes of Bacteroidaceae, Ruminococcaceae, Lachnospiraceae, Muribaculaceae, and Rikenellaceae which are negatively correlated with obesity were enhanced notably by the intervention of ripened PETe, while Erysipelotrichaceae and Lactobacillaceae which have positive correlation with obesity were decreased dramatically. In addition, the treatment of ripened PETe had better effect on the increase of benefical Bacteroides, Alistipes, and Akkemansia and decrease of obesity associated Faecalibaculum and Erysipelatoclostridium (p < 0.05). These findings suggested that pu-erh tea especially ripened pu-erh tea could serve as a great candidate for alleviation of obesity in association with the modulation of gut microbiota.
Article
Flavanols are important polyphenols of the human diet with extensive demonstrations of their beneficial effects on cardiometabolic health. They contribute to preserve health acting on a large range of cellular processes. The underlying mechanisms of action of flavanols are not fully understood but involve a nutrigenomic regulation. To further capture how the intake of dietary flavanols results in the modulation of gene expression, nutrigenomics data in response to dietary flavanols obtained from animal models of cardiometabolic diseases have been collected and submitted to a bioinformatics analysis. This systematic analysis shows that dietary flavanols modulate a large range of genes mainly involved in endocrine function, fatty acid metabolism, and inflammation. Several regulators of the gene expression have been predicted and include transcription factors, miRNAs and epigenetic factors. This review highlights the complex and multilevel action of dietary flavanols contributing to their strong potential to preserve cardiometabolic health. This article is protected by copyright. All rights reserved
Article
Metabolomics is an important branch of systems biology, which can detect changes in the body's metabolism before and after the intervention of functional foods, identify effective metabolites, and predict the interventional effects and the mechanism. This review summarizes the latest research outcomes regarding interventional effects of functional foods on metabolic diseases via metabolomics analysis. Since metabolomics approaches are powerful strategies for revealing the changes in bioactive compounds of functional foods during processing and storage, we also discussed the effects of these parameters on functional food metabolites using metabolomics approaches. To date, a number of endogenous metabolites related to the metabolic diseases after functional foods intervention have been discovered. Unfortunately, the mechanisms of metabolic disease-related molecules are still unclear and require further studies. The combination of metabolomics with other omics technologies could further promote its ability to fully understand the precise biological processes of functional food intervention on metabolic diseases.
Article
Context Obesity-associated chronic metabolic disease is a leading contributor to mortality globally. Plants belonging to the genera Acacia are routinely used for the treatment of diverse metabolic diseases under different ethnomedicinal practices around the globe. Objective The current review centres around the pharmacological evidence of intestinal-level mechanisms for metabolic health benefits by Acacia spp. Results Acacia spp. increase the proportions of gut commensals (Bifidobacterium and Lactobacillus) and reduces the population of opportunistic pathobionts (Escherichia coli and Clostridium). Acacia gum that is rich in fibre, can also be a source of prebiotics to improve gut health. The intestinal-level anti-inflammatory activities of Acacia are likely to contribute to improvements in gut barrier function that would prevent gut-to-systemic endotoxin translocation and limit “low-grade” inflammation associated with metabolic diseases. Conclusion This comprehensive review for the first time has emphasised the intestinal-level benefits of Acacia spp. which could be instrumental in limiting the burden of metabolic disease.
Article
The metabolic syndrome (MS) has become one of the main problems in public health. Tea polyphenols (TPs), the main bioactive components of tea, has been claimed to have the potential to regulate metabolism and effectively prevent or mitigate the MS. However, many studies into the effects of TPs on MS have provided conflicting findings and the underlying mechanism has been elusive. The predominant TPs in unfermentedand and fermented tea are catechins and oxidized polyphenols (theaflavins and thearubigins), both of which have low bioavailability and reach the colon where most gut microbes inhabit. Gut microbiota has been demonstrated to be tightly associated with host metabolism. The interactions between TPs and gut microbiota will lead to the alterations of gut microbiota composition and the production of metabolites including short chain fatty acids, bile acids, amino acids and TPs derived metabolites, accordingly exerting their biological effects both locally and systemically. This review highlighted the contribution of metabolites and specific gut bacteria in the process of TPs intervention on the MS and further discuss how TPs impact the MS via gut microbiota from the viewpoint of gut organ/tissue axis.
Article
Scope Obesity prevalence continues to increase and contribute to metabolic diseases, potentially by driving systemic inflammation. Curcumin is an anti-inflammatory spice with claimed health benefits. However, mechanisms by which curcumin may reduce obesity-associated inflammation are poorly understood; thus, we hypothesized that benefits of curcumin consumption may occur through reduced white adipose tissue (WAT) inflammation and/or beneficial changes in gut bacteria. Methods and results Male B6 mice were fed high fat diets (HFD, 45% kcal fat) or HFD supplemented with 0.4% (w/w) curcumin (HFC) for 14 weeks. Curcumin supplementation significantly reduced adiposity and total macrophage infiltration in WAT, compared to HFD group, consistent with reduced mRNA levels of M1 (Cd80, Cd38, Cd11c) and M2 (Arginase-1) macrophage markers. Moreover, curcumin supplementation reduced expression of other key pro-inflammatory genes, such as NF-κB p65 subunit (p65), Stat1, Tlr4, and Il6, in WAT (p<0.05). Using microbial 16S RNA sequencing, we demonstrated that the relative abundance of the Lactococcus, Parasutterella, and Turicibacter genera were increased in the HFC group versus HFD. Conclusions Curcumin exerts protective metabolic effects in dietary obesity, in part through downregulation of adipose tissue inflammation, which may be mediated by alterations in composition of gut microbiota, and metabolism of curcumin into curcumin-o- glucuronide. This article is protected by copyright. All rights reserved
Article
Background: Green tea, obtained from the plant Camellis sinensis, is one of the oldest drinks in the world and contains numerous bioactive compounds. Studies have demonstrated the efficacy of green tea in preventing obesity and cardiovascular diseases that may be related to the reduction of lipid levels. Aim: This study aimed to evidence, through a systematic review, the therapeutic potential of green tea on the lipid profile in preclinical studies in obese animals and clinical studies in obese individuals. Methods: This systematic review follows the recommendations of the preferred report items for systematic reviews and meta-analyses. The electronic databases, PubMed (Medline), Science Direct, Scopus, and Web of Science were consulted. Articles from January 2009 to December 2019 were selected. Results: This search resulted in twenty-nine articles were included cirtically reviewed. In experimental studies, green tea administration has been shown to reduce total cholesterol, triglycerides and low-density lipoprotein cholesterol in animals exposed to obesity-inducing diet. In humans’ studies green tea was not shown to be effective for obese lipid control. Because supplementation with green tea extract reduced total cholesterol, triglycerides, low-density lipoprotein for three months at a specific dose. Conclusion: Therefore, green tea appears to act as a protective agent for dyslipidemia in obesity-induced animals. In human studies, green tea has not been shown to be effective in controlling obese lipids.
Article
Scope: Vine tea (Ampelopsis grossedentata), a traditional Chinese tea, has displayed various biological activities. We aimed to investigate the effect of Vine Tea (Ampelopsis grossedentata) extract (VTE) on CCl4 -induced acute liver injury (ALI) in mice and to explore the underlying role of gut microbiota during the treatment. Methods and results: C57BL/6J mice injected with CCl4 were treated with VTE for 6 weeks. By using H&E staining, immunofluorescence staining, RT-PCR, and western blot, it was shown that VTE treatment significantly ameliorated hepatocyte necrosis, alleviated the mRNA levels of Tlr4, Il-6, iNOS, Acc1, and increased the mRNA levels of Ppar-γ and Hmg-coar compared to the CCl4 group. Also, VTE abrogated the decreased mRNA expressions of Zo-1, Occludin, and Mucin1 in colon tissues. Using microbial 16S rDNA sequencing, VTE treatment significantly downregulated the abundances of some harmful intestinal bacteria like Helicobacter and Oscillibacter. In contrast, VTE upregulated the contents of several beneficial bacteria, such as Ruminococcaceae_UCG-014 and Eubacterium_fissicatena_group. Further, VTE failed to improve ALI in the mice with gut microbiota depletion using antibiotic treatment. Conclusions: Our studies suggest that VTE exhibited a protective effect against CCl4 -induced ALI in mice by alleviating hepatic inflammation, suppressing intestinal epithelial barrier injury, and restoring gut microbiota dysbiosis. This article is protected by copyright. All rights reserved.
Article
Catechins are a phytochemical present in plants such as tea leaves, beans, black grapes, cherries, and cacao, and have various physiological activities. It is reported that catechins have a health improvement effect and ameliorating effect against various diseases. In addition, antioxidant activity, liver damage prevention, cholesterol lowering effect, and anti-obesity activity were confirmed through in vivo animal and clinical studies. Although most diseases are reported as ones mediating various inflammations, the mechanism for improving inflammation remains unclear. Therefore, the current review article evaluates the physiological activity and various pharmacological actions of catechins and conclude by confirming an improvement effect on the inflammatory response.
Article
Scope: Hawk tea, a non-Camellia tea, is an ancient tea drink from southwest China and has been proven to exhibit significant hypoglycaemic and lipid-lowering effects. The aim of this study was to evaluate whether Hawk tea extract (HTE) can improve obesity induced by a high-fat diet (HFD) in a mouse model and to determine whether its anti-obesity effects are related to improvements in lipid metabolism and the gut microbiota. Methods and results: We tested the ability of HTE to prevent obesity and regulate gut microbiota in C57BL/6J mice fed with a HFD. We found that HTE significantly reduced body weight, fat deposition, serum triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, and significantly increased serum levels of high-density lipoprotein cholesterol (HDL-C) induced by HFD. HTE also increased the levels of AMPK and ACC phosphorylation, up-regulated the expression of CPT-1, and downregulated the expression of SREBP1c and FAS. In addition, the administration of HTE significantly altered the composition of the gut microbiota, reduced the ratio of Firmicutes to Bacteroidetes, increased the relative abundance of Akkermansia muciniphila, Bacteroides-vulgatus, and Faecalibaculum_rodentium, and decreased the relative abundance of Desulfovibrionaceae and Lachnospiraceae. Conclusions: Collectively, our data demonstrate that HTE can prevent HFD-induced obesity by regulating the AMPK/ACC/SREBP1c signaling pathways and the gut microbiota.
Article
Gut microbiota (GM) play important roles in multiple organ function, homeostasis and several diseases. More recently, increasing evidences have suggested that the compositional and functional alterations of GM play a crucial role in the accumulation of foam cells and the formation of atherosclerotic plaque in atherosclerosis. In particular, the effects of bacterial components and metabolites on innate and adaptive immune cells have been explored as the underlying mechanisms. Understanding the effects of GM and metabolites on immunoregulation are important for clinical therapy for atherosclerosis. Herein, we summarize the potential role of the GM (such as bacterial components lipopolysaccharide and peptidoglycan) and GM‐derived metabolites (such as short‐chain fatty acids, trimethylamine N‐oxide and bile acids) in the immunopathology of atherosclerosis. Based on that, we further discuss the anti‐atherosclerotic effects of GM‐directed dietary bioactive factors such as dietary fibers, dietary polyphenols and probiotics. Because of drug‐induced adverse events in anti‐inflammatory therapies, personalized dietary interventions would be potential therapies for atherosclerosis, and the interactions between GM‐derived products and immune cells should be studied further.
Article
Uncontrolled inflammatory responses or cytokine storm associated with viral infections results in deleterious consequences such as vascular leakage, severe hemorrhage, shock, immune paralysis, multi‐organ failure, and even death. With the emerging new viral infections and lack of effective prophylactic vaccines, evidence‐based complementary strategies that limit viral infection‐mediated hyperinflammatory responses could be a promising approach to limit host tissue injury. The present review emphasizes the potentials of antiinflammatory phytochemicals in limiting hyperinflammatory injury caused by viral infections. The predominant phytochemicals along with their mechanism in limiting hyperimmune and pro‐inflammatory responses under viral infection have been reviewed comprehensively. How certain phytochemicals can be effective in limiting hyper‐inflammatory response indirectly by favorably modulating gut microbiota and maintaining a functional intestinal barrier has also been presented. Finally, we have discussed improved systemic bioavailability of phytochemicals, efficient delivery strategies, and safety measures for effective antiinflammatory phytotherapies, in addition to emphasizing the requirement of tightly controlled clinical studies to establish the antiinflammatory efficacy of the phytochemicals. Collectively, the review provides a scooping overview on the potentials of bioactive phytochemicals to mitigate pro‐inflammatory injury associated with viral infections.
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Metabolic disorders associated with obesity and cardiometabolic disorders are worldwide epidemic. Among the different environmental factors, the gut microbiota is now considered as a key player interfering with energy metabolism and host susceptibility to several non-communicable diseases. Among the next-generation beneficial microbes that have been identified, Akkermansia muciniphila is a promising candidate. Indeed, A. muciniphila is inversely associated with obesity, diabetes, cardiometabolic diseases and low-grade inflammation. Besides the numerous correlations observed, a large body of evidence has demonstrated the causal beneficial impact of this bacterium in a variety of preclinical models. Translating these exciting observations to human would be the next logic step and it now appears that several obstacles that would prevent the use of A. muciniphila administration in humans have been overcome. Moreover, several lines of evidence indicate that pasteurization of A. muciniphila not only increases its stability but more importantly increases its efficacy. This strongly positions A. muciniphila in the forefront of next-generation candidates for developing novel food or pharma supplements with beneficial effects. Finally, a specific protein present on the outer membrane of A. muciniphila, termed Amuc_1100, could be strong candidate for future drug development. In conclusion, as plants and its related knowledge, known as pharmacognosy, have been the source for designing drugs over the last century, we propose that microbes and microbiomegnosy, or knowledge of our gut microbiome, can become a novel source of future therapies.
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Human health is dependent upon the ability of the body to extract nutrients, fluids and oxygen from the external environment while at the same time, maintaining a state of internal sterility. Therefore, the cell layers that cover the surface areas of the body such as the lung, skin and gastrointestinal mucosa provide vital semi-permeable barriers which allow the transport of essential nutrients, fluid and waste products while at the same time keeping the internal compartments free of microbial organisms. These epithelial surfaces are highly specialized and differ in their anatomical structure depending on their location to provide appropriate and effective site-specific barrier function. Given this important role, it is not surprising that significant disease is often associated with alterations in epithelial barrier function. Examples of such diseases include inflammatory bowel disease (IBD)¹, chronic obstructive pulmonary disease (COPD)² and atopic dermatitis (AD)³. These chronic inflammatory disorders are often characterized by diminished tissue oxygen levels (hypoxia). Hypoxia triggers an adaptive transcriptional response governed by hypoxia inducible factors (HIFs), which are repressed by a family of oxygen-sensing HIF-hydroxylases. Here, we review recent evidence suggesting that pharmacologic hydroxylase inhibition may be of therapeutic benefit in IBD through the promotion of intestinal epithelial barrier function through both HIF-dependent and HIF-independent mechanisms.
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The trillions of microbes that exist in the gastrointestinal tract have emerged as pivotal regulators of mammalian development and physiology. Disruption of this gut microbiome, a process known as dysbiosis, causes or exacerbates various diseases, but whether gut dysbiosis affects recovery of neurological function or lesion pathology after traumatic spinal cord injury (SCI) is unknown. Data in this study show that SCI increases intestinal permeability and bacterial translocation from the gut. These changes are associated with immune cell activation in gut-associated lymphoid tissues (GALTs) and significant changes in the composition of both major and minor gut bacterial taxa. Postinjury changes in gut microbiota persist for at least one month and predict the magnitude of locomotor impairment. Experimental induction of gut dysbiosis in naive mice before SCI (e.g., via oral delivery of broad-spectrum antibiotics) exacerbates neurological impairment and spinal cord pathology after SCI. Conversely, feeding SCI mice commercial probiotics (VSL#3) enriched with lactic acid-producing bacteria triggers a protective immune response in GALTs and confers neuroprotection with improved locomotor recovery. Our data reveal a previously unknown role for the gut microbiota in influencing recovery of neurological function and neuropathology after SCI.
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Scope: Green tea has been known to confer numerous health benefits such as the prevention of cardiovascular disease, cancers, and obesity. Epigallocatechin-3-gallate (EGCG) is the major polyphenol present in green tea. Since EGCG is a food-derived component, intestinal epithelial cells (IECs) lining the gastrointestinal tract are constantly and directly exposed to EGCG. It is anticipated that EGCG can exert beneficial effects in the intestine. The aim of this study was to explore the protective effects of EGCG on intestinal barrier functions against bacterial translocation by using a porcine jejunal epithelial cell line, IPEC-J2. Methods and results: EGCG reduced bacterial translocation across IPEC-J2 cell monolayers through the enhancement of the intestinal epithelial immunological barrier function by inducing secretion of antimicrobial peptides, porcine β-defensins 1 and 2 (pBD-1 and 2), which possessed higher antimicrobial activity against Escherichia coli. Further mechanistic studies demonstrated that EGCG up-regulated pBD-2 but not pBD-1 via the p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Such effects were not an "artifact" of hydrogen peroxide (H2 O2 ), catechin dimers or other auto-oxidation products generated from EGCG in cell culture media. Conclusion: Our results imply that EGCG may be useful for prevention of intestinal disorders or bacterial infection in animals/humans. This article is protected by copyright. All rights reserved.
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Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestine. IBD is a multifactorial disorder, and IBD-associated genes are critical in innate immune response, inflammatory response, autophagy, and epithelial barrier integrity. Moreover, epithelial oxygen tension plays a critical role in intestinal inflammation and resolution in IBD. The intestines have a dynamic and rapid fluctuation in cellular oxygen tension, which is dysregulated in IBD. Intestinal epithelial cells have a steep oxygen gradient where the tips of the villi are hypoxic and the oxygenation increases at the base of the villi. IBD results in heightened hypoxia throughout the mucosa. Hypoxia signals through a well-conserved family of transcription factors, where hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. In inflamed mucosa, HIF-1α increases barrier protective genes, elicits protective innate immune responses, and activates an antimicrobial response through the increase in β-defensins. HIF-2α is essential in maintaining an epithelial-elicited inflammatory response and the regenerative and proliferative capacity of the intestine following an acute injury. HIF-1α activation in colitis leads to a protective response, whereas chronic activation of HIF-2α increases the pro-inflammatory response, intestinal injury, and cancer. In this mini-review, we detail the role of HIF-1α and HIF-2α in intestinal inflammation and injury and therapeutic implications of targeting HIF signaling in IBD.
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Immune cell infiltration in (white) adipose tissue (AT) during obesity is associated with the development of insulin resistance. In AT, the main population of leukocytes are macrophages. Macrophages can be classified into two major populations: M1, classically activated macrophages, and M2, alternatively activated macrophages, although recent studies have identified a broad range of macrophage subsets. During obesity, AT M1 macrophage numbers increase and correlate with AT inflammation and insulin resistance. Upon activation, pro-inflammatory M1 macrophages induce aerobic glycolysis. By contrast, in lean humans and mice, the number of M2 macrophages predominates. M2 macrophages secrete anti-inflammatory cytokines and utilize oxidative metabolism to maintain AT homeostasis. Here, we review the immunologic and metabolic functions of AT macrophages and their different facets in obesity and the metabolic syndrome.
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Animals assemble and maintain a diverse but host-specific gut microbial community. In addition to characteristic microbial compositions along the longitudinal axis of the intestines, discrete bacterial communities form in microhabitats, such as the gut lumen, colonic mucus layers and colonic crypts. In this Review, we examine how the spatial distribution of symbiotic bacteria among physical niches in the gut affects the development and maintenance of a resilient microbial ecosystem. We consider novel hypotheses for how nutrient selection, immune activation and other mechanisms control the biogeography of bacteria in the gut, and we discuss the relevance of this spatial heterogeneity to health and disease.
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Available evidence on the bioactive, nutritional and putative detrimental properties of gut microbial metabolites has been evaluated to support a more integrated view of how prebiotics might affect host health throughout life. The present literature inventory targeted evidence for the physiological and nutritional effects of metabolites, for example, SCFA, the potential toxicity of other metabolites and attempted to determine normal concentration ranges. Furthermore, the biological relevance of more holistic approaches like faecal water toxicity assays and metabolomics and the limitations of faecal measurements were addressed. Existing literature indicates that protein fermentation metabolites (phenol, p -cresol, indole, ammonia), typically considered as potentially harmful, occur at concentration ranges in the colon such that no toxic effects are expected either locally or following systemic absorption. The endproducts of saccharolytic fermentation, SCFA, may have effects on colonic health, host physiology, immunity, lipid and protein metabolism and appetite control. However, measuring SCFA concentrations in faeces is insufficient to assess the dynamic processes of their nutrikinetics. Existing literature on the usefulness of faecal water toxicity measures as indicators of cancer risk seems limited. In conclusion, at present there is insufficient evidence to use changes in faecal bacterial metabolite concentrations as markers of prebiotic effectiveness. Integration of results from metabolomics and metagenomics holds promise for understanding the health implications of prebiotic microbiome modulation but adequate tools for data integration and interpretation are currently lacking. Similarly, studies measuring metabolite fluxes in different body compartments to provide a more accurate picture of their nutrikinetics are needed.
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Toll-like receptors (TLRs) belong to the pattern recognition receptor (PRR) family, a key component of the innate immune system. TLRs detect invading pathogens and initiate an immediate immune response to them, followed by a long-lasting adaptive immune response. Activation of TLRs leads to the synthesis of pro-inflammatory cytokines and chemokines and the expression of co-stimulatory molecules. TLR4 specifically recognizes bacterial lipopolysaccharide, along with several other components of pathogens and endogenous molecules produced during abnormal situations, such as tissue damage. Evolution across species can lead to substantial diversity in the TLR4's affinity and specificity to its ligands, the TLR4 gene and cellular expression patterns and tissue distribution. Consequently, TLR4 functions vary across different species. In recent years, the use of synthetic TLR agonists as adjuvants has emerged as a realistic therapeutic goal, notably for the development of vaccines against poorly immunogenic targets. Given that an adjuvanted vaccine must be assessed in pre-clinical animal models before being tested in humans, the extent to which an animal model represents and predicts the human condition is of particular importance. This review focuses on the current knowledge on the critical points of divergence between human and the mammalian species commonly used in vaccine research and development (non-human primate, mouse, rat, rabbit, swine, and dog), in terms of molecular, cellular, and functional properties of TLR4.
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Background: In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013. Methods: We systematically identified surveys, reports, and published studies (n=1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n=19,244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs). Findings: Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m(2) or greater increased between 1980 and 2013 from 28·8% (95% UI 28·4-29·3) to 36·9% (36·3-37·4) in men, and from 29·8% (29·3-30·2) to 38·0% (37·5-38·5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23·8% (22·9-24·7) of boys and 22·6% (21·7-23·6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8·1% (7·7-8·6) to 12·9% (12·3-13·5) in 2013 for boys and from 8·4% (8·1-8·8) to 13·4% (13·0-13·9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down. Interpretation: Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene. Funding: Bill & Melinda Gates Foundation.
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