No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
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
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.
... A common effect of flavanols, decaffeinated green and black tea polyphenols, aqueous extracts of tea, marc, cinnamon, inulin, vanillin, and lignans is the reduction in the Firmicutes/Bacteroidetes ratio [51][52][53][54][55][56]. This ratio is considered as a possible hallmark for obesity, as it is high in obese people and tends to decrease following weight loss. ...
... However, in the case of following a low-calorie diet for 12 months, Bacteroidetes increased, with the consequent normalization of the Firmicutes/Bacteroidetes ratio, along with weight loss [57]. Bacteroides can reduce serum triglyceride levels, improve glucose intolerance, and counteract body weight gain [51]. ...
... Flavanols and aqueous extract of tea were also able to promote the growth of A. muciniphila [51,53] and similarly did other potential prebiotic compounds, such as cranberry extract, apple procyanidins, aqueous tea extracts, resveratrol, pterostilbene, and catechins [6,[58][59][60][61]. ...
Prebiotic compounds were originally defined as “a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improves host health”; however, a significant modulation of the definition was carried out in the consensus panel of The International Scientific Association for Probiotics and Prebiotics (ISAPP), and the last definition states that “prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit”. Health effects of prebiotics compounds attracted the interest of researchers, food companies and Regulatory Agencies, as inferred by the number of articles on Scopus for the keywords “prebiotic” and “health effects”, that is ca. 2000, for the period January 2021–January 2024. Therefore, the aim of this paper is to contribute to the debate on these topics by offering an overview of existing knowledge and advances in this field. A literature search was performed for the period 2012–2023 and after the selection of the most relevant items, the attention was focused on seven conditions for which at least 8–10 different studies were found, namely colorectal cancer, neurological or psychiatric conditions, intestinal diseases, obesity, diabetes, metabolic syndrome, and immune system disorders. In addition, the analysis of the most recent articles through the software VosViewer version 1.6.20 pointed out the existence of five clusters or macro-categories, namely: (i) pathologies; (ii) metabolic condvitions; (iii) structure and use in food; (iv) immunomodulation; (v) effect on gut microbiota.
... In the absence of stressors, a 12-weeks oral supplementation of a green tea extract (2% w/w diet) did not significantly change colonic TJ expression (i.e., ZO-1, occludin, claudin-1), nor FITC-Dx permeability in mice, although serum and portal vein endotoxemia were decreased significantly. 81 Furthermore, daily supplementation of animals with green tea-derived products significantly prevented or ameliorated impairments of the gut barrier caused by a high-fat diet, in terms of permeability to endotoxin and TJ expression. [81][82][83][84] Broadly in line with these results are the outputs reported for fu brick tea, 85 pu-erh tea 86 and its ripened version, 87,88 raw bowl tea, 89 and other teaderived products. ...
... 81 Furthermore, daily supplementation of animals with green tea-derived products significantly prevented or ameliorated impairments of the gut barrier caused by a high-fat diet, in terms of permeability to endotoxin and TJ expression. [81][82][83][84] Broadly in line with these results are the outputs reported for fu brick tea, 85 pu-erh tea 86 and its ripened version, 87,88 raw bowl tea, 89 and other teaderived products. 86 As with lingonberries, 72 batch effects were evident in the efficacy of ripened pu-erh tea (year of production 2006 vs. 2010) with respect to attenuation of DSSinduced ZO-1 protein expression decrease, but not in the modulation of MPO activity. ...
Gut barrier integrity is of fundamental importance for human health. Effects of flavan-3-ols, their metabolites, and their dietary sources in maintaining its functionality was analysed in this review.
... 33,34 The catechin content was measured using HPLC-UV using an established method. 35,36 In brief, HPLC analysis was performed on a Shimadzu LC-20AD instrument equipped with a DAD detector. Samples were run at 1 mL min −1 in a C-18G column (250 × 4.6 mm, 5 mm) in an isocratic mode using a mobile phase of water/acetonitrile/formic acid (899/100/1, v/v, solvent A) and water/acetonitrile/formic acid (699/300/1, v/v, solvent B). ...
... These prebiotic effects were further supported by earlier data demonstrating that phytoextract rich in catechin enhances the growth of gut commensals, especially the populations of prebiotics like Bidobacterium, Lactobacillus, and Akkermansia. 36 Recent studies show that synbiotic formulations containing Lactobacillus spp. and EGCG could reduce inammation, confer cytoprotective antioxidative effects, and exert hypolipidemic effects. ...
Endophytes acquire flavonoid biosynthetic genes from the host medicinal plants. Despite tea (Camellia sinensis (L.) Kuntze) being the major source of bioactive catechins, catechin-producing endophytic fungi have never been reported from the tea plant. Here, we report the isolation and characterization of catechin-producing endophytic fungi isolated from tea leaves, their chemical characterization, and associated bioactivities. Among the nine isolated endophytes, two (CSPL6 and CSPL5b) produced catechin (381.48 and 166.40 μg per mg extract) and epigallocatechin-o-gallate (EGCG; 484.41 and 281.99 μg per mg extract) as quantified by high-performance liquid chromatography (HPLC). The isolates were identified as Pseudopestalotiopsis camelliae-sinensis and Didymella sinensis based on molecular and morphological characterization. Untargeted metabolomics using gas-chromatography mass spectroscopy (GCMS) revealed the presence of several bioactive phytochemicals mostly belonging to tyrosols, pyridoxines, fatty acids, aminopyrimidine, and benzenetriol classes. Metabolic pathways pertaining to the biosynthesis of unsaturated fatty acids (UFAs), butanoate metabolism, and linoleic acid metabolism were highly enriched in both catechin-producing isolates. The isolates were able to differentially scavenge intracellular O2 and N2 free-radicals, but CSPL5b demonstrated relatively superior bioactivities compared to CSPL6. Both isolates stimulated the growth of various probiotic strains, indicating prebiotic effects that are otherwise known to be associated with catechins. Collectively, the current study demonstrated that fungal endophytes CSPL6 and CSPL5b, isolated from tea leaves, could be used as alternative sources of catechins, and hold promising potential in evidence-based therapeutics.
... Kaempferol present in tea leaves improves the integrity of the intestinal barrier and inhibits inflammation in the intestines by reducing the activation of the TLR4/NF-κB pathway [248]. Studies on laboratory animals and in humans have shown that catechins inhibit the growth of pathogenic bacteria, Clostridium difficile and Staphylococcus spp., and stimulate the growth of beneficial Bifidobacterium bacteria [240,[249][250][251]. They also improve the integrity of the intestinal barrier and reduce pro-inflammatory reactions, which have been demonstrated in studies on laboratory animals and in humans [240,[249][250][251]. Studies on rats with colitis showed that the EGCG present in green tea stimulates an increase in Akkermansia abundance and the production of SCFA [252]. ...
... Studies on laboratory animals and in humans have shown that catechins inhibit the growth of pathogenic bacteria, Clostridium difficile and Staphylococcus spp., and stimulate the growth of beneficial Bifidobacterium bacteria [240,[249][250][251]. They also improve the integrity of the intestinal barrier and reduce pro-inflammatory reactions, which have been demonstrated in studies on laboratory animals and in humans [240,[249][250][251]. Studies on rats with colitis showed that the EGCG present in green tea stimulates an increase in Akkermansia abundance and the production of SCFA [252]. ...
Depressive disorders can affect up to 350 million people worldwide, and in developed countries, the percentage of patients with depressive disorders may be as high as 10%. During depression, activation of pro-inflammatory pathways, mitochondrial dysfunction, increased markers of oxidative stress, and a reduction in the antioxidant effectiveness of the body are observed. It is estimated that approximately 30% of depressed patients do not respond to traditional pharmacological treatments. However, more and more attention is being paid to the influence of active ingredients in food on the course and risk of neurological disorders, including depression. The possibility of using foods containing polyphenols as an element of diet therapy in depression was analyzed in the review. The possibility of whether the consumption of products such as polyphenols could alleviate the course of depression or prevent the progression of it was also considered. Results from preclinical studies demonstrate the potential of phenolic compounds have the potential to reduce depressive behaviors by regulating factors related to oxidative stress, neuroinflammation, and modulation of the intestinal microbiota.
... Traditional obesity management approaches, including diet, exercise, surgery, and pharmaceuticals, often show limitations due to side effects and high relapse rates (Kong et al., 2019). Consequently, natural compounds, including green tea extracts, soy isoflavones, and Platycodon grandiflorus extracts, have gained attention for their potential as anti-obesity agents, with promising preclinical and clinical findings indicating their potential as adjunctive or standalone therapies (Dey et al., 2019;Ke et al., 2023;Wu et al., 2023). Constipation is a prevalent gastrointestinal disorder characterized by infrequent or difficult bowel movements, abdominal bloating, and fecal blockage (Shah et al., 2015). ...
Brown seaweed oligosaccharides (BSO) have demonstrated potential as nutraceuticals with cholesterol‐lowering, anti‐obesity, and anti‐constipation properties. In this study, we initially examined how BSO impact body weight, blood lipid levels, and adipose tissue in a rat model of obesity induced by a high‐fat diet. Our findings revealed that BSO administration significantly attenuated body weight gain, ameliorated dyslipidemia, and reduced visceral adiposity. Additionally, we evaluated the prophylactic efficacy of BSO in a loperamide hydrochloride‐induced constipation mouse model by assessing defecation parameters and gastrointestinal motility. Our results indicated that BSO intervention significantly increased fecal pallet output and fecal water content, as well as improved intestinal transit. In conclusion, this study lays the foundation for a deeper understanding of how BSO may influence obesity and constipation, offering novel insights into its potential safe and efficacious clinical applications.
... In these studies, germ-free mice that receive fecal microbiota from obese donors develop an obese phenotype, whereas the transfer of microbiota from healthy donors to patients with metabolic syndrome results in improved biomarkers of metabolic health [1,3]. These divergent outcomes are largely attributed to the microbiome's effects on gut barrier function, endotoxin production, dietary fiber fermentation to produce short-chain fatty acids (SCFAs), bile acid homeostasis, and other microbial-derived metabolites that affect inflammation and energy metabolism [4][5][6]. Thus, modulating or controlling the composition of the gut microbiota could be a promising strategy to maintain gut health and mitigate metabolic diseases. ...
The gut microbiome plays a critical role in maintaining gut and metabolic health, and its composition is often altered by aging and obesity. This study aimed to investigate the protective effects of curcumin on gut dysbiosis, gut barrier integrity, and bile acid homeostasis in aged mice fed a high-fat, high-sugar diet (HFHSD). Eighteen- to twenty-one-month-old male C57BL/6 mice were divided into groups fed a normal chow diet or HFHSD, with or without curcumin supplementation (0.4% w/w) for 8 and 15 weeks. We assessed body weight, food intake, insulin sensitivity, gut microbiota composition, and gene expression in the gut and liver and performed histological analysis of gut tissues. Curcumin supplementation prevented HFHSD-induced weight gain and metabolic disturbances. In the gut, curcumin-treated mice showed a higher abundance of beneficial bacterial genera, such as Lachnospiraceae, Akkermansia, Mucispirillum, and Verrucomicrobiota, alongside a lower abundance of harmful bacterial genera like Desulfobacteria, Alistipes, and Muribaculaceae compared to control. This shift in gut microbiota was associated with improved gut integrity, as demonstrated by increased expression of the tight junction protein occludin and reduced levels of the pro-inflammatory marker interleukin-1β in the ileum. Additionally, curcumin modulated hepatic gene expression involved in bile acid homeostasis, suggesting a positive effect on liver health. Curcumin supplementation can alleviate the negative effects of aging and an HFHSD on the gut microbiome, improve gut barrier integrity, and maintain bile acid homeostasis. These findings highlight curcumin’s potential as a dietary intervention for managing obesity- and age-associated gut health issues.
... Green tea extract (GTE) abundant in catechins alleviated gut dysbiosis and restricted endotoxin translocation. For instance, epigallocatechin gallate, a primary constituent of GTE, has been identified as preventing nonalcoholic steatohepatitis through its impact on the gut microbiota 45 . Shepherd's purse, a wild vegetable, significantly alleviated gut dysbiosis induced by HF and increased the abundance of potentially beneficial bacteria. ...
Liver fibrosis (LF) is a common sequela to diverse chronic liver injuries, leading to rising rates of cirrhosis and hepatocellular carcinoma (HCC). As the medicinal and edible homologous material, traditional teas have exhibited promising applications in the clinical management of liver fibrosis. Here, we generated a liver fibrosis mouse model to explore the potent therapeutic ability of Ampelopsis grossedentata (AG) tea on this condition by multi-omics analysis. The biochemistry results pointed towards mitigated increases of ALT, AST, TBIL, and ALP triggered by BDL in the AG-treated group. Examination using H&E and Sirius Red staining revealed severe liver injuries, inflammation infiltration, amplified fibrosed regions, and the creation of bile ducts, all of which were fallout from BDL. Immunohistochemistry findings also implicated a noteworthy upregulation of the HSC activation marker α-smooth muscle actin (α-SMA) and the fibrosis marker collagen I in the BDL group. However, these symptoms demonstrated a significant improvement in the group treated with 100 mg/kg AG. Findings from the Western Blot test corroborated the prominent elevation of TNF-α, col1a1, α-SMA, and TGF-β, instigated by BDL, while AG treatment meaningfully modulated these proteins. Furthermore, our study underscored the potential involvement of several microbiota, such as Ruminococcaceae UCG-014, Eubacterium Ruminantium, Ruminococcus 1, Christensenellaceae R-7, Acetatifactor, Dubosiella, Parasutterella, Faecalibaculum, and Defluviitaleaceae UCG-011, in the progression of liver fibrosis and the therapeutic efficacy of AG. This investigation shows that during the process of AG ameliorating BDL-induced liver fibrosis, bile acid derivatives such as CDCA, TCDCA, 3-DHC, UCA, DCA, among others, play significant roles. In this study, we identified that several non-bile acid metabolites, such as Deltarasin, Thr-Ile-Arg, etc., are entailed in the process of AG improving liver fibrosis.
... Sequence data was analyzed using Quantitative Insights into Microbial Ecology (QIIME v2) for the removal of primers and spacers from the sequences as described before (42,43). Divisive Amplicon Denoising Algorithm 2 (DADA2) was utilized for trimming, denoising, merging paired-end forward and reverse reads, and removing the chimera sequences (44). ...
Introduction
The differential effects of probiotic, prebiotic, and synbiotic formulations on human health are dictated by the inter-individual gut microbial profile. The effects of probiotics such as Escherichia coli Nissle 1917 (ECN) on gut microbiota may vary according to the microbiome profiles of individuals and may be influenced by the presence of certain carbohydrates, which can impact microbial community structure and treatment results.
Method
Processed fecal samples from donors having contrasting lifestyles, dietary patterns, and disease histories were mixed with 5 × 10⁶ CFU/mL ECN with or without 1% (w/v) sugars (glucose, galactose, or rice starch) in a host-free system. Post-incubation, 16 s rRNA sequencing was performed. Microbial diversity and taxonomic abundance were computed in relation to the probiotic, prebiotic, and synbiotic treatment effects and interpersonal microbiome variance.
Result
Baseline gut microbial profiles showed significant inter-individual variations. ECN treatment alone had a limited impact on the inter-personal gut microbial diversity and abundance. Prebiotics caused a substantial enrichment in Actinobacteria, but there were differences in the responses at the order and genus levels, with enrichment shown in Bifidobacterium, Collinsella, and Megasphaera. Subject B exhibited enrichment in Proteobacteria and Cyanobacteria, but subject A showed more diversified taxonomic alterations as a consequence of the synbiotic treatments. Despite negligible difference in the α-diversity, probiotic, prebiotic, and synbiotic treatments independently resulted in distinct segregation in microbial communities at the β-diversity level. The core microbiota was altered only under prebiotic and synbiotic treatment. Significant correlations primarily for minor phyla were identified under prebiotic and synbiotic treatment.
Conclusion
The interindividual microbiome composition strongly influences the effectiveness of personalized diet and treatment plans. The responsiveness to dietary strategies varies according to individual microbiome profiles influenced by health, diet, and lifestyle. Therefore, tailored approaches that consider individual microbiome compositions are crucial for maximizing gut health and treatment results.
... Sequence data was analyzed using Quantitative Insights into Microbial Ecology (QIIME v2) for the removal of primers and spacers from the sequences as described before (42,43). Divisive Amplicon Denoising Algorithm 2 (DADA2) was utilized for trimming, denoising, merging paired-end forward and reverse reads, and removing the chimera sequences (44). ...
Introduction: The differential effects of probiotic, prebiotic, and synbiotic
formulations on human health are dictated by the inter-individual gut microbial
profile. The effects of probiotics such as Escherichia coli Nissle 1917 (ECN) on
gut microbiota may vary according to the microbiome profiles of individuals and
may be influenced by the presence of certain carbohydrates, which can impact
microbial community structure and treatment results.
Method: Processed fecal samples from donors having contrasting lifestyles,
dietary patterns, and disease histories were mixed with 5×106 CFU/mL ECN with or
without 1% (w/v) sugars (glucose, galactose, or rice starch) in a host-free system.
Post-incubation, 16s rRNA sequencing was performed. Microbial diversity and
taxonomic abundance were computed in relation to the probiotic, prebiotic, and
synbiotic treatment effects and interpersonal microbiome variance.
Result: Baseline gut microbial profiles showed significant inter-individual
variations. ECN treatment alone had a limited impact on the inter-personal gut
microbial diversity and abundance. Prebiotics caused a substantial enrichment in
Actinobacteria, but there were differences in the responses at the order and genus
levels, with enrichment shown in Bifidobacterium, Collinsella, and Megasphaera.
Subject B exhibited enrichment in Proteobacteria and Cyanobacteria, but subject
A showed more diversified taxonomic alterations as a consequence of the
synbiotic treatments. Despite negligible difference in the α-diversity, probiotic,
prebiotic, and synbiotic treatments independently resulted in distinct segregation
in microbial communities at the β-diversity level. The core microbiota was altered
only under prebiotic and synbiotic treatment. Significant correlations primarily for
minor phyla were identified under prebiotic and synbiotic treatment.
Conclusion: The interindividual microbiome composition strongly influences
the effectiveness of personalized diet and treatment plans. The responsiveness
to dietary strategies varies according to individual microbiome profiles
influenced by health, diet, and lifestyle. Therefore, tailored approaches that
consider individual microbiome compositions are crucial for maximizing gut
health and treatment results.
... The intestinal barrier serves as a crucial protective barrier against pathogens and toxins, and heightened intestinal permeability is associated with the occurrence of intestinal damage [24]. The mice in the ETEC group displayed compromised intestinal barrier function when compared to the CON group. ...
This study aimed to investigate the effects of dietary bacteriophage administration on diarrhea and intestinal impairment induced by enterotoxigenic Escherichia coli (ETEC) in a newly weaned mouse model. Forty-four newly weaned C57BL/6 mice were divided into four treatment groups, where they were provided either the control diet or the bacteriophage-supplemented diet, with or without ETEC infection. The results show that the bacteriophage administration resulted in increased body weight, decreased diarrhea score, and improved jejunal histopathology in ETEC-infected mice. The bacteriophage administration enhanced the intestinal barrier function of the ETEC-infected mice, as indicated by the reduced serum DAO level and the increased expression of Claudin-1, Occludin, and ZO-1 at both the mRNA and protein levels in the jejunum. Also, the bacteriophage administration resulted in a decrease in serum TNF-α and IL-1β levels, a down-regulation of TNF-α and IL-6 mRNA levels in the jejunum, and the inhibition of jejunal TLR-4/NF-κB pathway activation induced by ETEC infection. Moreover, the bacteriophage administration increased the levels of acetic acid, propionic acid, butyric acid, and total short-chain fatty acids in the caecum content. The bacteriophage administration increased the Shannon index, increased the abundance of Bacteroidota and Muribaculaceae, and decreased the abundance of Verrucomicrobiota and Akkermansiaceae in the colon contents of the ETEC-infected mice. Spearman’s correlation analysis indicates that the protective effects of bacteriophage on ETEC-induced intestinal impairment, inflammation, and intestinal barrier function are associated with regulating the abundance of Bacteroidota and Muribaculaceae in the colon contents of mice. Collectively, bacteriophage administration alleviates ETEC-induced diarrhea and intestinal impairment through regulating intestinal inflammation and gut microbiota in newly weaned mice.
... In addition, the intestinal epithelial tight junction structure composed of proteins such as Claudins, Occludin and ZO-1 forms a selectively permeable intercellular barrier by sealing the intercellular space between adjacent intestinal epithelial cells, preventing environmental toxins, intestinal cavity antigens, and microorganisms from entering the circulatory system (41). Studies have shown that green tea extract can improve the intestinal barrier function of high-fat mice, alleviate the decrease in tight junction protein ZO-1 and Claudins genes, and reduce the endotoxin content in the serum, thus providing some protection against intestinal damage (42). The administration of catechin, the main component of tea polyphenols, to mice can also reduce the activity of serum DAO and the concentration of D-LA, while also increasing the abundance of Occludin and ZO-1 in the duodenum, jejunum, and ileum, which further indicates that catechin supplementation can maintain the integrity of the intestinal barrier in mice (43). ...
Introduction
The purpose of this study was to explore the effects of tea polyphenols on growth performance, cytokine content, intestinal antioxidant status and intestinal barrier function of lambs, in order to provide reference for intestinal health of ruminants.
Methods
Thirty weaned lambs (average initial weight 9.32 ± 1.72 kg) were randomly divided into five groups with six lambs in each group. The control group did not add anything but the basic diet mainly composed of Pennisetum and Corn, and the other four groups added 2, 4, 6 g/kg tea polyphenols and 50 mg/kg chlortetracycline to the basic diet, respectively. The experiment lasted for 42 days.
Results
Dietary tea polyphenols improved the growth and stress response and reduced intestinal permeability of lambs (p > 0.05), while CTC did not affect the final lamb weight (p > 0.05). Both tea phenols and CTC significantly reduced inflammatory factors and enhanced the immune system (p > 0.05). Dietary tea polyphenols increased villus height, villus height/crypt depth, secretory immunoglobulin A (p > 0.05), and antioxidant enzymes, while decreasing MDA and apoptosis in the intestine (p > 0.05). However, compared with other groups, the content of T-AOC in jejunum did not change significantly (p > 0.05). Tea polyphenols also increased claudin-1 levels in the duodenum, jejunum, and ileum more than CTC (p > 0.05). CTC had a limited effect on the mRNA expression of Occludin and ZO-1, while tea polyphenols increased these in both the duodenum and ileum (p > 0.05).
Conclusion
This study demonstrated that tea polyphenols can effectively improve the intestinal barrier of weaned lambs, and that they have anti-inflammatory and antioxidant effects similar to those of antibiotics. Thus, tea polyphenols could be used to replace antibiotics in ensuring safety of livestock products and in achieving the sustainable development of modern animal husbandry.
... A sufficient amount of green tea polyphenols particularly epigallocatechin gallate, caffeine, and theanine promoted the gut microbiota by increasing the growth of Bifidobacteria and Lactobacillus spp., indicating potential prebiotic effects (Jung et al. 2019). Green tea polyphenols reduced the obesity in male mice by improving gut health, strengthening the intestinal barrier, limiting the translocation of endotoxins and eventually reducing the inflammation of adipose (Dey et al. 2019). Effective modulation of gut microbiota was observed due to green tea polyphenols in mice Wang et al. 2018a, b) and canines ) fed with high-fat diet, thereby suggesting the potential of green tea polyphenols as a dietary intervention for managing obesity and promoting gut health. ...
There is growing interest in polyphenolic compounds due to their possible health advantages as they are naturally occurring plant-derived bioactive compounds. The bioavailability of dietary polyphenols is fairly low due to their varied structural features that impact their biological properties. Significant portion of polyphenols remain unabsorbed in small intestine and these unabsorbed polyphenols tends to buildup in large intestine, where they are effectively metabolised by intestinal microbiota. The gut microbiota has been recognised as crucial player in regulating biological activity and bioavailability of phenolic metabolites. In addition to this, emerging studies suggest the importance of dietary polyphenols in modulating the population or activity of microbes in the colon and also in maintenance of gut microbial balance of beneficial and harmful bacteria. Moreover, these interactions have been linked to a number of beneficial health effects, including improved gut barrier integrity, reduced inflammation, and improved immunological functions. Recent researches have shown that dietary polyphenols offer broad range of health benefits through their mutually beneficial and symbiotic relationship with the microorganisms residing in the gastrointestinal tract.
... Recently, Chen et al. [11] and Rha et al. [13] showed that GT metabolites bio-transformed by intestinal microbes, such as C-ring cleaved derivative and flavonoid aglycone, have greater antioxidant activity compared to their precursor compounds. In addition, GT polyphenols and their bio-transformed derivatives are shown to modulate gut microbiota through promoting the growth of beneficial microbes [14][15][16]. An increasing number of studies are now exploring the effects of nutrient-derived and bio-transformed metabolites on the emergent community properties of gut microbiome. ...
In this study, we aim to investigate the precise alterations in the gut microbiota during the onset and advancement of diabetic nephropathy (DN) and examine the impact of Ruminococcus gnavus (R. gnavus) on DN. Eight-week-old male KK-Ay mice were administered antibiotic cocktails for a duration of two weeks, followed by oral administration of R. gnavus for an additional eight weeks. Our study revealed significant changes in the gut microbiota during both the initiation and progression of DN. Specifically, we observed a notable increase in the abundance of Clostridia at the class level, higher levels of Lachnospirales and Oscillospirales at the order level, and a marked decrease in Clostridia_UCG-014 in DN group. Additionally, there was a significant increase in the abundance of Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae at the family level. Moreover, oral administration of R. gnavus effectively aggravated kidney pathology in DN mice, accompanied by elevated levels of urea nitrogen (UN), creatinine (Cr), and urine protein. Furthermore, R. gnavus administration resulted in down-regulation of tight junction proteins such as Claudin-1, Occludin, and ZO-1, as well as increased levels of uremic toxins in urine and serum samples. Additionally, our study demonstrated that orally administered R. gnavus up-regulated the expression of inflammatory factors, including nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) and Interleukin (IL)-6. These changes indicated the involvement of the gut-kidney axis in DN, and R. gnavus may worsen diabetic nephropathy by affecting uremic toxin levels and promoting inflammation in DN.
... Recently, Chen et al. [11] and Rha et al. [13] showed that GT metabolites bio-transformed by intestinal microbes, such as C-ring cleaved derivative and flavonoid aglycone, have greater antioxidant activity compared to their precursor compounds. In addition, GT polyphenols and their bio-transformed derivatives are shown to modulate gut microbiota through promoting the growth of beneficial microbes [14][15][16]. An increasing number of studies are now exploring the effects of nutrient-derived and bio-transformed metabolites on the emergent community properties of gut microbiome. ...
ρ-Hydroxyacetophenone is an important and versatile compound that has been widely used in medicine, cosmetics, new materials, and other fields. At present, there are two ways to obtain ρ-hydroxyacetophenone. One is to extract it from plants, such as Artemisia capillaris Thunb and Cynanchum otophyllum Schneid, and the other is to synthesize it by using chemical methods. Of these two methods, the second is the main one, although it has problems, such as flammable and explosive reagents, difficult separation of by-products, and harsh reaction conditions. To solve these issues, we adopted genetic engineering in this study to construct engineered Escherichia coli containing Hped gene or EbA309 gene. Whole-cell biotransformation was conducted under the same conditions to select the engineered E. coli with the higher activity. Orthogonal tests were conducted to determine the optimal biotransformation condition of the engineered E. coli. The results showed that the optimal condition was as follows: substrate concentration of 40 mmol/l, IPTG concentration of 0.1 mmol/l, an induction temperature of 25°C, and a transformation temperature of 35°C. Under this condition, the effects of transformation time on the ρ-hydroxyacetophenone concentration and cell growth were further studied. We found that as the transformation time extended, the ρ-hydroxyacetophenone concentration showed a gradually increasing trend. However, when the ρ-hydroxyacetophenone concentration increased to 1583.19 ± 44.34 mg/l in 24 h, cell growth was inhibited and then entered a plateau. In this research, we realized the synthesis of ρ-hydroxyacetophenone by biotransformation, and our findings lay a preliminary foundation for further improving and developing this method.
... Microbe-Induced Inflammation. Downstream effects of endotoxin translocation may include the induction of Toll-like receptors (TLR4) in the liver, with downstream activation of transcription factors inducing an inflammatory response [57]. Saturated fatty acids (SFA) such as palmitate can induce the production of IL-1β and TNF-α by activation of proinflammatory signals through TLR4 that subsequently induce the production of ROS in hepatic infiltrating macrophages. ...
The increased global prevalence of viral and noninfectious liver illnesses has coincided with a surge in scientific interest in gut microbiota (GM), a multispecies community of bacteria, fungi, archaea, and protozoans. Dietary nutrients that make up the host’s microbiome are responsible for maintaining intestinal homeostasis, whereas a disconnect between gut flora and nutrition might have serious consequences for digestive health. The risk of liver dysfunction was continuously elevated by changes in the commensal bacteria of the gut microbiome, which were carried to the liver via the portal vein. Insights into the role of gut microbiota in alcoholic liver disease, nonalcoholic liver disease, primary sclerosing cholangitis, and other liver disorders, as well as their link to liver cancer, continue to emerge. Systemic host defence against infections by the gut microbiota depends on the interplay between the microbiome, liver immunology, and liver disorders. Translocation of microbiota to the liver following injury and/or inflammation may mediate dysbiosis and the formation of gut microbial metabolite. This review discusses the role of the gut microbiota in connection to dysbiosis and how this knowledge might help us better understand the pathophysiology of various liver illnesses.
... Obesity is associated with intestinal barrier dysfunction and dysbiosis, which contributes to the activation of local inflammation, contributing to systemic inflammation (17)(18)(19). Studies conducted with animal models provided evidence that inflammation may originate in the gut owing to modulation of gut barrier function leading to metabolic endotoxemia (20,21) with an increase in gut-derived plasma lipopolysaccharide (LPS) levels, which may result in lowgrade systemic inflammation (22). LPSs are an indicator of impaired intestinal epithelial barrier function, also known as "leaky gut" syndrome. ...
Aim
This prospective pilot study evaluated inflammatory and intestinal barrier biomarkers and the effects of a synbiotic in obese adolescents.
Methods
Eighteen obese and 20 eutrophic adolescents were evaluated for body composition using bioimpedance analysis (BIA), body mass index (BMI), IL-6 and lipopolysaccharide (LPS) serum levels, CD4 and FoxP3 Treg lymphocytes and monocytes. Synbiotic supplementation for 60 days was also evaluated for these parameters only in obese adolescents.
Results
We observed an increase in CD4 lymphocyte (18.0 ± 12.4 vs. 8.9 ± 7.5; p < 0.01), IL-6 (0.30 ± 0.06 vs. 0.20 ± 0.06; p = 0.02) and LPS (0.18 ± 0.15 vs. 0.08 ± 0.05; p < 0.01) levels in obese compared to eutrophic adolescents. After synbiotic supplementation, FoxP3 Treg lymphocytes increased (14.0 ± 6.7 vs. 9.9 ± 5.4; p = 0.02) in obese adolescents.
Conclusions
Obese adolescents presented a state of microinflammation and intestinal barrier breakdown, and synbiotic supplementation increased the expression of FoxP3 Treg lymphocytes, an anti-inflammatory regulator. Whether the increase in FoxP3 Treg lymphocytes may have an impact on inflammation and outcomes in obese adolescents deserves further evaluation.
... Obesity has become a serious global health problem, and its prevalence has increased rapidly [2,3]. It was reported that more than 50% of the world's population will be obese by 2030 [4]. In recent years, simple obesity caused by overnutrition has become the main type of obesity with the change of people's dietary habits and the improvement of living standards [5]. ...
Obesity is associated with gut dysbiosis and metabolic endotoxin. Junshanyinzhen tea extract (JSTE) reduced fat accumulation and body weight in obese mice. However, the effects and mechanism of JSTE in preventing obesity were unclear. Therefore, we used different doses of JSTE (75, 150 and 300 mg/(kg·day)) to evaluate the effect on high-fat diet (HFD) -induced rats under 8 weeks of intervention. Here, our results showed that JSTE could significantly reduce body weight gain, blood lipid levels and fat accumulation, improve fatty damage in liver tissue (P < 0.05). In addition, JSTE increased the expression of intestinal tight junction proteins (P < 0.05), relieved metabolic endotoxemia (P < 0.05) and chronic low- grade inflammation in HFD rats. Sequencing of fecal samples showed that JSTE could effectively reverse the microbial diversity and the ratio of Firmicutes to Bacteroidetes to normal levels in HFD- fed rats. Desulfovibrioceae and Erysipelotrichaceae, which are positively related to obesity, were decreased by JSTE intervention (P < 0.05). while Bifidobacteriaceae, Bacteroidaceae, Akkermansia, and Clostridium, which are negatively related to obesity, were increased. Together, these results suggested that JSTE might effectively prevent obesity by modulating gut microbiota dysbiosis, intestinal barrier dysfunction, metabolic endotoxemia and chronic low-grade inflammation in HFD-induced rats.
... Jumlah senyawa ini lebih banyak pada ekstrak segar dibanding hasil fermentasinya [33]. Sedangkan C. sinensis bekerja dengan menurunkan endotoksin yang diduga mampu mencegah obesitas terinduksi endotoksin [34]. Sebanyak 4 senyawa golongan biflavonoid pada G. biloba berefek menghambat enzim PL, sehingga menimbulkan efek antiobesitas [22]. ...
Obesitas adalah salah satu ancaman kesehatan yang sangat serius dan dihadapi semua negara. Masalah kesehatan ini sering berasosiasi dengan penyakit lain seperti diabetes dan gangguan kardiovaskuler. Penyebab obesitas pada seseorang bervariasi mulai dari genetik sampai gaya hidup. Didukung konsep back to nature dan pemanfaatan kekayaan nabati mendorong masyarakat untuk menggunakan obat-obatan yang berasal dari alam sebagai alternatif terapi. Pada review ini, disajikan daftar tanaman herbal serta mekanisme kerjanya mengatasi obesitas yang disusun dalam bentuk narasi dari hasil penelusuran literatur di beberapa search engine seperti PubMed, ScienceDirect, SpringerLink dan Google Scholar menggunakan kata kunci “herbal treatment, obesity, medicine plant dan mechanism of herbal medicine”. Dari hasil penelusuran diperoleh sebanyak 35 artikel penelitian yang membahas berbagai jenis tanaman serta uji dan mekanisme kerja yang didukung dengan hasil laboratorium. Kesimpulannya, terdapat banyak tanaman herbal yang dapat dimanfaatkan untuk membantu mengatasi obesitas melalui berbagai target farmakologi, terutama melalui modulasi faktor kaskade pensinyalan seluler AMPK, faktor transkripsi PPARℽ, PPARα dan C/EBP atau protein-protein lipogenik seperti SREBP-1c, ACC, FAS, PL dan LPL.
... A disrupted mucus barrier and gut inflammation is strongly evidenced in the development of metabolic disorders such as obesity and diabetes, and microbial dysbiosis is suggested to play a role in these effects (Cani et al., 2007(Cani et al., , 2008Wang et al., 2012;Boutagy et al., 2016;Dey et al., 2019;Schroeder et al., 2020). Associations between the virome and these diseases have been more recently established. ...
In the human gastrointestinal tract, the gut mucosa and the bacterial component of the microbiota interact and modulate each other to accomplish a variety of critical functions. These include digestion aid, maintenance of the mucosal barrier, immune regulation, and production of vitamins, hormones, and other metabolites that are important for our health. The mucus lining of the gut is primarily composed of mucins, large glycosylated proteins with glycosylation patterns that vary depending on factors including location in the digestive tract and the local microbial population. Many gut bacteria have evolved to reside within the mucus layer and thus encode mucus-adhering and -degrading proteins. By doing so, they can influence the integrity of the mucus barrier and therefore promote either health maintenance or the onset and progression of some diseases. The viral members of the gut – mostly composed of bacteriophages – have also been shown to have mucus-interacting capabilities, but their mechanisms and effects remain largely unexplored. In this review, we discuss the role of bacteriophages in influencing mucosal integrity, indirectly via interactions with other members of the gut microbiota, or directly with the gut mucus via phage-encoded carbohydrate-interacting proteins. We additionally discuss how these phage-mucus interactions may influence health and disease states.
Bacaba (Oenocarpus bacaba Mart.) is an underexplored Amazonian fruit rich in polyphenols that can serve as a substrate for probiotic survival and may positively impact on the composition and metabolism of the intestinal microbiota. This study aimed to evaluate the bacaba pulp fermented with probiotics Lactobacillus acidophilus 05 (LA-05) and Lacticaseibacillus casei 01 (LC1) regarding the chemical composition and probiotics survivability during fermentation (48 h), and the effect on the modulation of the intestinal microbiota of healthy adults through 16S rRNA sequencing. The probiotic-fermented bacaba pulps showed decreased pH and total soluble
solids values and sugar content (maltose, glucose, fructose, and rhamnose), and increased titratable acidity values, organic acid content (lactic and tartaric acids), and phenolic compounds concentration compared to the control pulp. Furthermore, it presented adequate probiotic viability after fermentation and simulated gastrointestinal conditions. The bacaba pulp fermented with LC1 showed a higher concentration of butyric acid and phenolic compounds concentration (trans-resveratrol, cis resveratrol, catechin, procyanidin B2, and pelargonidin 3-glucoside) and bioaccessibility compared to the control pulp. The bacaba pulp fermented with LA-5 showed a higher concentration of pelargonidin 3-glucoside and procyanidin B2 compared to the control pulp and the highest bioaccessibility of some phenolic compounds (trans-resveratrol, cis-resveratrol, catechin, epicatechin, procyanidin B1, procyanidin B2, myricetin, and isorhamnetin). In vitro fecal fermentation reduced the pH and
increased the abundance of Desulfovibrionales, Lactobacillales, and Peptostreptococcales-Tissierellales for all treatments. Bacaba pulp with LC1 resulted in the lowest pH values, and increased production of organic acids and concentration of phenolic compounds. Furthermore, both probiotic pulps increased the abundance of Lactobacillales and Acidaminococcales and decreased the abundance of Clostridiales. These findings provide new information about the potential of using bacaba in a functional pulp that may benefit human health through colonic microbiota changes.
Metabolic syndrome encompasses a cluster of predictive metabolic risk factors, including obesity, insulin resistance, dyslipidemia, hyperglycemia and hypertension. It is strongly associated with the development of type 2 diabetes and cardiovascular disease. Given the increasing morbidity and mortality associated with metabolic syndrome, along with the limited availability of drug treatments, it is high time to investigate the pathogenesis of this condition and explore potential pharmacotherapies. Macrophages, well‐known innate immune cells, play an essential role in maintaining tissue immune homeostasis and multiple physiological processes, including glucose and lipid metabolism, oxidative stress and inflammation. Emerging evidence indicates that the effects of macrophages in metabolic syndrome are linked to macrophage‐mediated metaflammation. Phytochemicals derived from natural plants have been shown to exert therapeutic effects on metabolic syndrome by modulating macrophage function. In this review, we sort out the role of macrophage‐mediated metaflammation in the pathogenesis of metabolic syndrome and summarise potential phytochemicals that target macrophages for the treatment of this condition.
Roselle extract (RE) is rich in anthocyanins and chlorogenic acids. This study investigated the health‐promoting effects of RE on lipid metabolism, oxidative stress, glycometabolism, and gut microbiota in obese mice fed a high‐fat diet (HFD). The obesity model was induced by feeding mice a HFD, with RE supplementation added to their drinking water at concentrations of 2 and 4 mg/mL for 12 weeks. RE significantly reduced body weight gain and fat accumulation compared to the control group, alleviated hepatic steatosis, and improved insulin sensitivity. Additionally, RE restored antioxidative enzyme activities such as SOD and GSH‐PX while reducing MDA levels. Transcriptomic analysis of the liver was performed to evaluate gene expression related to lipid metabolism, particularly in the PPAR signaling pathway. Gut microbiota analysis showed that RE increased beneficial bacteria and reduced the Firmicutes ‐to‐ Bacteroidetes ratio, suggesting an improvement in gut dysbiosis caused by the HFD. RE enhanced lipid metabolism, reduced oxidative stress, and improved insulin sensitivity in obese mice, potentially through modulation of the PPAR signaling pathway and gut microbiota, suggesting its potential as a therapeutic candidate for obesity‐related metabolic disorders.
Green tea kombucha (GTK) has emerged as a promising probiotic fermented beverage. Few studies have investigated its effect on human health, mainly focusing on intestinal health, microbiota composition, and metabolomics. The present study is a pioneer in investigating the effect of GTK consumption in individuals with excess body weight. This is a randomized controlled trial, lasting ten weeks, with two groups placed under an energy-restricted diet: control (CG, n = 29), kombucha (KG, n = 30; 200 mL/d). Biological samples and questionnaires were collected before and after the intervention. Microbiota analysis used an amplification of the V4 region of 16S rRNA. Serum untar-geted metabolomics used HPLC-TOF mass spectrometry. Intestinal permeability considered the urine excretion of lactulose and mannitol, plasma zonulin, and LPS-binding protein. After the intervention, no differences related to intestinal permeability and microbiota were found between groups, but only the CG had increased fecal pH, lactulose/mannitol ratio, and zonulin. In addition to this, the KG reported lower gastrointestinal symptoms related to motility compared to the CG, and discriminant metabolites (e.g., diethyl malonate) were found strictly in the KG. GTK did not significantly improve gut microbiota and intestinal permeability. However, GTK ameliorated gastrointestinal symptoms and positively influenced the serum metabolome, which may contribute to enhancing the metabolic health of individuals with excess body weight.
Insulin resistance (IR) is considered the pathogenic driver of diabetes, and can lead to obesity, hypertension, coronary artery disease, metabolic syndrome, and other metabolic disorders. Accumulating evidence indicates that the connection between gut microbiota and IR. This bibliometric analysis aimed to summarize the knowledge structure of gut microbiota in IR.
Articles and reviews related to gut microbiota in IR from 2013 to 2022 were retrieved from the Web of Science Core Collection (WoSCC), and the bibliometric analysis and visualization were performed by Microsoft Excel, Origin, R package (bibliometrix), Citespace, and VOSviewer.
A total of 4 749 publications from WoSCC were retrieved, including 3 050 articles and 1 699 reviews. The majority of publications were from China and USA. The University Copenhagen and Shanghai Jiao Tong University were the most active institutions. The journal of Nutrients published the most papers, while Nature was the top 1 co-cited journal, and the major area of these publications was molecular, biology, and immunology. Nieuwdorp M published the highest number of papers, and Cani PD had the highest co-citations. Keyword analysis showed that the most frequently occurring keywords were “gut microbiota”, “insulin-resistance”, “obesity”, and “inflammation”. Trend topics and thematic maps showed that serum metabolome and natural products, such as resveratrol, flavonoids were the research hotspots in this field.
This bibliometric analysis summarised the hotspots, frontiers, pathogenesis, and treatment strategies, providing a clear and comprehensive profile of gut microbiota in IR.
Scope
Gut microbiota (GM) is involved in nonalcoholic steatohepatitis (NASH) development. Phytochemicals soyasaponins can prevent NASH possibly by modulating GM. This study aims to investigate the preventive bioactivities of soyasaponin monomers (SS‐A 1 and SS‐Bb) against NASH and explores the mechanisms by targeting GM.
Methods and results
Male C57BL/6 mice are fed with methionine and choline deficient (MCD) diet containing SS‐A 1 , SS‐Bb, or not for 16 weeks. Antibiotics‐treated pseudo germ‐free (PGF) mice are fed with MCD diet containing SS‐A 1 , SS‐Bb, or not for 8 weeks. GM is determined by 16S rRNA amplicon sequencing. Bile acids (BAs) are measured by UPLC‐MS/MS. In NASH mice, SS‐A 1 and SS‐Bb alleviate steatohepatitis and fibrosis, reduce ALT, AST, and LPS in serum, decrease TNF‐α, IL‐6, α‐SMA, triglycerides, and cholesterol in liver. SS‐A 1 and SS‐Bb decrease Firmicutes , Erysipelotrichaceae , unidentified‐Clostridiales , Eggerthellaceae , Atopobiaceae , Aerococcus , Jeotgalicoccus , Gemella , Rikenella , increase Proteobacteria , Verrucomicrobia , Akkermansiaceae , Romboutsia , and Roseburia . SS‐A 1 and SS‐Bb alter BAs composition in liver, serum, and feces, activate farnesoid X receptor (FXR) in liver and ileum, increase occludin and ZO‐1 in intestine. However, GM clearance abrogates the preventive bioactivities of SS‐A 1 and SS‐Bb against NASH.
Conclusion
GM plays essential roles in soyasaponin's preventive bioactivities against steatohepatitis in MCD diet‐induced NASH mice.
Obesity has become a serious global public health problem, affecting over 988 million people worldwide. Nevertheless, current pharmacotherapies have proven inadequate. Natural compounds have garnered significant attention due to their potential antiobesity effects. Over the past three decades, ca. 50 natural compounds have been evaluated for the preventive and/or therapeutic effects on obesity in animals and humans. However, variations in the antiobesity efficacies among these natural compounds have been substantial, owing to differences in experimental designs, including variations in animal models, dosages, treatment durations, and administration methods. The feasibility of employing these natural compounds as pharmacotherapies for obesity remained uncertain. In this review, we systematically summarized the antiobesity efficacy and mechanisms of action of each natural compound in animal models. This comprehensive review furnishes valuable insights for the development of antiobesity medications based on natural compounds.
Green tea (GT) polyphenols undergo extensive metabolism within gastrointestinal tract (GIT), where their derivatives compounds potentially modulate the gut microbiome. This biotransformation process involves a cascade of exclusive gut microbial enzymes which chemically modify the GT polyphenols influencing both their bioactivity and bioavailability in host. Herein, we examined the in vitro interactions between 37 different human gut microbiota and the GT polyphenols. UHPLCLTQ-Orbitrap-MS/MS analysis of the culture broth extracts unravel that genera Adlercreutzia, Eggerthella and Lactiplantibacillus plantarum KACC11451 promoted C-ring opening reaction in GT catechins. In addition, L. plantarum also hydrolyzed catechin galloyl esters to produce gallic acid and pyrogallol, and also converted flavonoid glycosides to their aglycone derivatives. Biotransformation of GT polyphenols into derivative compounds enhanced their antioxidant bioactivities in culture broth extracts. Considering the effects of GT polyphenols on specific growth rates of gut bacteria, we noted that GT polyphenols and their derivate compounds inhibited most species in phylum Actinobacteria, Bacteroides, and Firmicutes except genus Lactobacillus. The present study delineates the likely mechanisms involved in the metabolism and bioavailability of GT polyphenols upon exposure to gut microbiota. Further, widening this workflow to understand the metabolism of various other dietary polyphenols can unravel their biotransformation mechanisms and associated functions in human GIT.
As it is well known, the gut is one of the primary sites in any host for xenobiotics, and the many microbial metabolites responsible for the interactions between the gut microbiome and the host. However, there is a growing concern about the negative impacts on human health induced by toxic xenobiotics. Metabolomics, broadly including lipidomics, is an emerging approach to studying thousands of metabolites in parallel. In this review, we summarized recent advancements in mass spectrometry (MS) technologies in metabolomics. In addition, we reviewed recent applications of MS-based metabolomics for the investigation of toxic effects of xenobiotics on microbial and host metabolism. It was demonstrated that metabolomics, gut microbiome profiling, and their combination have a high potential to identify metabolic and microbial markers of xenobiotic exposure and determine its mechanism. Further, there is increasing evidence supporting that reprogramming the gut microbiome could be a promising approach to the intervention of xenobiotic toxicity.
Non-communicable diseases, such as cardiovascular disease, cancer, diabetes, obesity, and hypertension, represent the cause of 60% of all deaths around the globe. With proper diet and natural dietary antioxidant supplements, these diseases can be prevented by up to 40% according to the British Nutrition Foundation.
This book provides a comprehensive overview of the literature on the health benefits of natural dietary antioxidant supplements. It presents state-of-the-art research and information as well as the global regulations, labelling, and health claims of natural dietary antioxidant supplements.
Written by expert authors, the wealth of research is arranged by disease type rather than by supplement type making it much more useful to the reader. Filling a gap in the literature, the book is aimed at researchers and professionals working in food chemistry, nutrition, and health benefits.
The influx of intestinal bacteria-derived lipopolysaccharide (LPS) into the blood has attracted attention as a cause of diseases. The aim of this study is investigating the associations between the influx of LPS, dietary factors, gut microbiota, and health status in the general adult population. Food/nutrient intake, gut microbiota, health status and plasma LPS-binding protein (LBP; LPS exposure indicator) were measured in 896 residents (58.1% female, mean age 54.7 years) of the rural Iwaki district of Japan, and each correlation was analyzed. As the results, plasma LBP concentration correlated with physical (right/left arms’ muscle mass [β = −0.02, −0.03]), renal (plasma renin activity [β = 0.27], urine albumin creatinine ratio [β = 0.50]), adrenal cortical (cortisol [β = 0.14]), and thyroid function (free thyroxine [β = 0.05]), iron metabolism (serum iron [β = −0.14]), and markers of lifestyle-related diseases (all Qs < 0.20). Plasma LBP concentration were mainly negatively correlated with vegetables/their nutrients intake (all βs ≤ −0.004, Qs < 0.20). Plasma LBP concentration was positively correlated with the proportion of Prevotella (β = 0.32), Megamonas (β = 0.56), and Streptococcus (β = 0.65); and negatively correlated with Roseburia (β = −0.57) (all Qs < 0.20). Dietary factors correlated with plasma LBP concentration correlated with positively (all βs ≥ 0.07) or negatively (all βs ≤ −0.07) the proportion of these bacteria (all Qs < 0.20). Our results suggested that plasma LBP concentration in the Japanese general adult population was associated with various health issues, and that dietary habit was associated with plasma LBP concentration in relation to the intestinal bacteria.
Nerium oleander L. is a medicinal plant, used for the treatment of cancers and hyperglycemia across the world, especially in Indian sub-continent, Turkey, Morocco, and China. Although clinical studies supporting its pharmacological effects remain critically underexplored, accidental and intentional consumption of any part of the plant causes fatal toxicity in animals and humans. While the polyphenolic fraction of oleander leaves has been attributed to its pre-clinical pharmacological activities, the presence of diverse cardiac glycosides (especially oleandrin) causes apoptosis to cancer cells in vitro and results in clinical signs of oleander poisoning. Thus, the dual pharmacological and toxicological role of oleander is a perplexing dichotomy in phytotherapy. The current investigative review, therefore, intended to analyze the intrinsic and extrinsic factors that likely contribute to this conundrum. Especially by focusing on gut microbial diversity, abundance, and metabolic functions, oleander-associated pharmacological and toxicological studies have been critically analyzed to define the dual effects of oleander. Electronic databases were extensively screened for relevant research articles (including pre-clinical and clinical) related to oleander bioactivities and toxicity. Taxonomic preference was given to the plant N. oleander L. and synonymous plants as per 'The World Flora Online' database (WCSP record #135196). Discussion on yellow oleander (Cascabela thevetia (L.) Lippold) has intentionally been avoided since it is a different plant. The review indicates that the gut microbiota likely plays a key role in differentially modulating the pharmacological and toxicological effects of oleander. Other factors identified influencing the oleander bioactivities include dose and mode of treatment, cardiac glycoside pharmacokinetics, host-endogenous glycosides, plant material processing and phytochemical extraction methods, plant genotypic variations, environmental effects on the phytochemical quality and quantity, gene expression variations, host dietary patterns and co-morbidity, etc. The arguments proposed are also relevant to other medicinal plants containing toxic cardiac glycosides.
Coffee and tea are the most consumed beverages among the globe after water regarding their desirable organoleptic characteristics and well-demonstrated health benefits. A great number of the minor compounds present in coffee and tea have shown considerable bioactive potential; they can reduce inflammation by influencing metabolic processes and prevent cardiovascular diseases (CVD). These compounds regarding the coffee beans are the phenolic compounds (mainly chlorogenic acid and its derivatives), methylxanthines (mainly caffeine but also theophylline and theobromine), diterpenes (cafestol and kahweol), and trigonelline (the precursor of nicotinic acid). The concentration of them can differ significantly depending on the type of the bean and the processing they undergo. Regarding the bioactive compounds that can be found in tea leaves, the polyphenols (catechins in green tea, oxidized polyphenols such as theaflavins in black tea), l-theanine, and caffeine are the most abundant. Although there is only one type of tea leaves from which all types of tea are produced (e.g., black tea, green tea, and oolong tea), the production process for each tea type differs to a great extent providing every tea type with unique bioactive composition and therefore unique health benefits. This book chapter will define the differences in the chemical composition of different coffee and tea types, and it will summarize the findings of literature regarding their bioactive potential. According to these findings, moderate consumption of coffee (up to three cups per day) and tea (three to six cups per day) can maximize their effect on the prevention of inflammatory conditions and CVD.
Microbial exopolysaccharides (EPS) are extracellular carbohydrate polymers forming capsules or slimy coating around the cells. EPS can be secreted by various bacterial genera that can help bacterial cells in attachment, environmental adaptation, stress tolerance and are an integral part of microbial biofilms. Several gut commensals (e.g., Lactobacillus, Bifidobacterium) produce EPS that possess diverse bioactivities. Bacterial EPS also has extensive commercial applications in the pharmaceutical and food industries. Owing to the structural and functional diversity, genetic and metabolic engineering strategies are currently employed to increase EPS production. Therefore, the current review provides a comprehensive overview of the fundamentals of bacterial exopolysaccharides, including their classification, source, biosynthetic pathways, and functions in the microbial community. The review also provides an overview of the diverse bioactivities of microbial EPS, including immunomodulatory, anti-diabetic, anti-obesity, and anti-cancer properties. Since several gut microbes are EPS producers and gut microbiota helps maintain a functional gut barrier, emphasis has been given to the intestinal-level bioactivities of the gut microbial EPS. Collectively, the review provides a comprehensive overview of microbial bioactive exopolysaccharides.
Several DNA extraction methods have been reported for use with digesta or fecal samples, but problems are often encountered in terms of relatively low DNA yields and/or recovering DNA free of inhibitory substances. Here we report a modified method to extract PCR-quality microbial community DNA from these types of samples, which employs bead beating in the presence of high concentrations of sodium dodecyl sulfate (SDS), salt, and EDTA, and with subsequent DNA purification by QIA ® columns [referred to as repeated bead beating plus column (RBB+C) method]. The RBB+C method resulted in a 1.5- to 6-fold increase in DNA yield when compared to three other widely used methods. The community DNA prepared with the RBB+C method was also free of inhibitory substances and resulted in improved denaturing gradient gel electrophoresis (DGGE) profiles, which is indicative of a more complete lysis and representation of microbial diversity present in such samples.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Sex hormones strongly influence body fat distribution and adipocyte differentiation. Estrogens and testosterone differentially affect adipocyte physiology, but the importance of estrogens in the development of metabolic diseases during menopause is disputed. Estrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism. Disturbances of this metabolic signal lead to the development of metabolic syndrome and a higher cardiovascular risk in women. The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation. However, influence of the absence of these hormones and its relationship to higher obesity in women during menopause are not clear. This systematic review discusses of the role of estrogens and estrogen receptors in adipocyte differentiation, and its control by the central nervous systemn and the possible role of estrogen-like compounds and endocrine disruptors chemicals are discussed. Finally, the interaction between the decrease in estrogen secretion and the prevalence of obesity in menopausal women is examined. We will consider if the absence of estrogens have a significant effect of obesity in menopausal women.
Our understanding of the microbial involvement in inflammatory bowel disease (IBD) pathogenesis has increased exponentially over the past decade. The development of newer molecular tools for the global assessment of the gut microbiome and the identification of nucleotide-binding oligomerization domain-containing protein 2 in 2001 and other susceptibility genes for Crohn's disease in particular has led to better understanding of the aetiopathogenesis of IBD. The microbial studies have elaborated the normal composition of the gut microbiome and its perturbations in the setting of IBD. This altered microbiome or "dysbiosis" is a key player in the protracted course of inflammation in IBD. Numerous genome-wide association studies have identified further genes involved in gastrointestinal innate immunity (including polymorphisms in genes involved in autophagy: ATG16L1 and IGRM), which have helped elucidate the relationship of the local innate immunity with the adjacent luminal bacteria. These developments have also spurred the search for specific pathogens which may have a role in the metamorphosis of the gut microbiome from a symbiotic entity to a putative pathogenic one. Here we review advances in our understanding of microbial involvement in IBD pathogenesis over the past 10 years and offer insight into how this will shape our therapeutic management of the disease in the coming years.
TLR4 is the main recognition receptor of bacterial lipopolysaccharides, which play an important role in innate and adaptive immunity. We used real-time PCR to analyze the tissue expression profile and differential expression of TLR4 in 4 pig populations (Escherichia coli F18-resistant Sutai, E. coli F18-sensitive Sutai, Large White, Meishan), in order to determine the role that the TLR4 gene plays in resistance to E. coli F18. We found that TLR4 expressed consistently in the 4 populations, with relatively high levels in immune tissues and the highest level in the lung. Generally, the expression of TLR4 in E. coli F18-sensitive individuals was the highest, followed by that in E. coli F18-resistant, Large White and Meishan. In the spleen, lung, kidney, lymph nodes, and thymus gland, TLR4 expression is significantly higher in the E. coli F18-sensitive than in the other 3 populations; there were no significant differences among E. coli F18-resistant Sutai, Large White, and Meishan. In addition, Gene Ontology and pathway analysis showed that TLR4 takes part in the inflammatory response. We found that porcine TLR4 has consistent tissue specificity in each breed, and downregulation of expression of the TLR4 gene is related to resistance to E. coli F18 in weaning piglets.
Profiling phylogenetic marker genes, such as the 16S rRNA gene, is a key tool for studies of microbial communities but does not provide direct evidence of a community's functional capabilities. Here we describe PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states), a computational approach to predict the functional composition of a metagenome using marker gene data and a database of reference genomes. PICRUSt uses an extended ancestral-state reconstruction algorithm to predict which gene families are present and then combines gene families to estimate the composite metagenome. Using 16S information, PICRUSt recaptures key findings from the Human Microbiome Project and accurately predicts the abundance of gene families in host-associated and environmental communities, with quantifiable uncertainty. Our results demonstrate that phylogeny and function are sufficiently linked that this 'predictive metagenomic' approach should provide useful insights into the thousands of uncultivated microbial communities for which only marker gene surveys are currently available.
Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.
Antimicrobial peptides are secreted by the intestinal epithelium to defend from microbial threats. The role of human β defensin-1 (hBD-1) is notable because its gene (beta-defensin 1 (DEFB1)) is constitutively expressed and its antimicrobial activity is potentiated in the low-oxygen environment that characterizes the intestinal mucosa. Hypoxia-inducible factor (HIF) is stabilized even in healthy intestinal mucosa, and we identified that epithelial HIF-1α maintains expression of murine defensins. Extension to a human model revealed that basal HIF-1α is critical for the constitutive expression of hBD-1. Chromatin immunoprecipitation identified HIF-1α binding to a hypoxia response element in the DEFB1 promoter whose importance was confirmed by site-directed mutagenesis. We used 94 human intestinal samples to identify a strong expression correlation between DEFB1 and the canonical HIF-1α target GLUT1. These findings indicate that basal HIF-1α is critical for constitutive expression of enteric DEFB1 and support targeting epithelial HIF for restoration and maintenance of intestinal integrity.Mucosal Immunology advance online publication 6 March 2013; doi:10.1038/mi.2013.6.
The aim of this study was to evaluate the effects of green tea Camellia sinensis extract on proinflammatory molecules and lipolytic protein levels in adipose tissue of diet-induced obese mice. Animals were randomized into four groups: CW (chow diet and water); CG (chow diet and water + green tea extract); HW (high-fat diet and water); HG (high-fat diet and water + green tea extract). The mice were fed ad libitum with chow or high-fat diet and concomitantly supplemented (oral gavage) with 400 mg/kg body weight/day of green tea extract (CG and HG, resp.). The treatments were performed for eight weeks. UPLC showed that in 10 mg/mL green tea extract, there were 15 μg/mg epigallocatechin, 95 μg/mg epigallocatechin gallate, 20.8 μg/mg epicatechin gallate, and 4.9 μg/mg gallocatechin gallate. Green tea administered concomitantly with a high-fat diet increased HSL, ABHD5, and perilipin in mesenteric adipose tissue, and this was associated with reduced body weight and adipose tissue gain. Further, we observed that green tea supplementation reduced inflammatory cytokine TNFα levels, as well as TLR4, MYD88, and TRAF6 proinflammatory signalling. Our results show that green tea increases the lipolytic pathway and reduces adipose tissue, and this may explain the attenuation of low-grade inflammation in obese mice.
BACKGROUND #ENTITYSTARTX00026;
While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet.
C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high-fat (60 kcal % fat) diet (HFD) for 8 weeks.
HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice.
HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.
Sex differences in obesity-induced complications such as type 2 diabetes have been reported. The aim of the study was to pinpoint the mechanisms resulting in different outcome of female and male mice on a high-fat diet (HFD). Mice fed control or HFD were monitored for weight, blood glucose, and insulin for 14 weeks. Circulating chemokines, islet endocrine function and blood flow, as well as adipose tissue populations of macrophages and regulatory T-lymphocytes (T(reg)) were thereafter assessed. Despite similar weight (43.8±1.0 and 40.2±1.5 g, respectively), male but not female mice developed hyperinsulinemia on HFD as previously described (2.5±0.7 and 0.5±0.1 pmol/l, respectively) consistent with glucose intolerance. Male mice also exhibited hypertrophic islets with intact function in terms of insulin release and blood perfusion. Low-grade, systemic inflammation was absent in obese female but present in obese male mice (IL-6 and mKC, males: 77.4±17 and 1795±563; females: 14.6±4.9 and 240±22 pg/ml), and the population of inflammatory macrophages was increased in intra-abdominal adipose tissues of high-fat-fed male but not female mice. In contrast, the anti-inflammatory T(reg) cell population increased in the adipose tissue of female mice in response to weight gain, while the number decreased in high-fat-fed male mice. In conclusion, female mice are protected against HFD-induced metabolic changes while maintaining an anti-inflammatory environment in the intra-abdominal adipose tissue with expanded T(reg) cell population, whereas HFD-fed male mice develop adipose tissue inflammation, glucose intolerance, hyperinsulinemia, and islet hypertrophy.
16S ribosomal RNA gene (rDNA) amplicon analysis remains the standard approach for the cultivation-independent investigation
of microbial diversity. The accuracy of these analyses depends strongly on the choice of primers. The overall coverage and
phylum spectrum of 175 primers and 512 primer pairs were evaluated in silico with respect to the SILVA 16S/18S rDNA non-redundant reference dataset (SSURef 108 NR). Based on this evaluation a selection
of ‘best available’ primer pairs for Bacteria and Archaea for three amplicon size classes (100–400, 400–1000, ≥1000 bp) is provided. The most promising bacterial primer pair (S-D-Bact-0341-b-S-17/S-D-Bact-0785-a-A-21),
with an amplicon size of 464 bp, was experimentally evaluated by comparing the taxonomic distribution of the 16S rDNA amplicons
with 16S rDNA fragments from directly sequenced metagenomes. The results of this study may be used as a guideline for selecting
primer pairs with the best overall coverage and phylum spectrum for specific applications, therefore reducing the bias in
PCR-based microbial diversity studies.
Obesity is characterized by adipose tissue (AT) macrophage (ATM) accumulation, which promotes AT inflammation and dysfunction. Toll-like receptor 4 (TLR4) deficiency attenuates AT inflammation in obesity but does not impede the accumulation of ATMs. The purpose of the current study was to determine whether TLR4 deficiency alters ATM polarization. TLR4(-/-) and wild-type mice were fed a low-fat, high-monounsaturated fat (HF(MUFA)), or a high-saturated fat (HF(SFA)) diet for 16 weeks. Further, we used a bone marrow transplant model to determine the influence of hematopoietic cell TLR4 signaling. The metabolic and inflammatory responses to high-fat feeding and ATM phenotype were assessed. Global and hematopoietic cell TLR4 deficiency, irrespective of recipient genotype, produced a shift in ATM phenotype toward an alternatively activated state, which was accompanied by reduced AT inflammation. Despite the observed shift in ATM phenotype, neither global nor hematopoietic cell TLR4 deficiency influenced systemic insulin sensitivity after high-fat feeding. Results of the current study suggest that TLR4 directly influences ATM polarization but question the relevance of TLR4 signaling to systemic glucose homeostasis in obesity.
For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the
analysis of scientific images. We discuss the origins, challenges and solutions of these two programs,
and how their history can serve to advise and inform other software projects.
The short chain fatty acids (SCFAs) acetate (C(2)), propionate (C(3)) and butyrate (C(4)) are the main metabolic products of anaerobic bacteria fermentation in the intestine. In addition to their important role as fuel for intestinal epithelial cells, SCFAs modulate different processes in the gastrointestinal (GI) tract such as electrolyte and water absorption. These fatty acids have been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of GPCRs (GPR41 and GPR43) and inhibiton of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions including production of cytokines (TNF-α, IL-2, IL-6 and IL-10), eicosanoids and chemokines (e.g., MCP-1 and CINC-2). The ability of leukocytes to migrate to the foci of inflammation and to destroy microbial pathogens also seems to be affected by the SCFAs. In this review, the latest research that describes how SCFAs regulate the inflammatory process is presented. The effects of these fatty acids on isolated cells (leukocytes, endothelial and intestinal epithelial cells) and, particularly, on the recruitment and activation of leukocytes are discussed. Therapeutic application of these fatty acids for the treatment of inflammatory pathologies is also highlighted.
Nonalcoholic steatohepatitis (NASH) is characterized by oxidative stress and inflammatory responses that exacerbate liver injury. The objective of this study was to determine whether the antioxidant and antiinflammatory activities of green tea extract (GTE) would protect against NASH in a model of diet-induced obesity. Adult Wistar rats were fed a low-fat (LF) diet or high-fat (HF) diet containing no GTE or GTE at 1% or 2% (HF+2GTE) for 8 wk. The HF group had greater (P ≤ 0.05) serum alanine (ALT) and aspartate aminotransferases and hepatic lipids than the LF group. Both GTE groups had lower ALT and hepatic lipid than the HF group. In liver and epididymal adipose, the HF group had lower glutathione as well as greater mRNA and protein expression of TNFα and monocyte chemoattractant protein-1 (MCP-1) and NFκB binding activity than the LF group. Compared to the HF group, the HF+2GTE group had greater glutathione and lower protein and mRNA levels of inflammatory cytokines in both tissues. NFκB binding activities at liver and adipose were also lower, likely by inhibiting the phosphorylation of inhibitor of NFκB. NFκB binding activities in liver and adipose (P ≤ 0.05; r = 0.62 and 0.46, respectively) were correlated with ALT, and hepatic NFκB binding activity was inversely related to liver glutathione (r = -0.35). These results suggest that GTE-mediated improvements in glutathione status are associated with the inhibition of hepatic and adipose inflammatory responses mediated by NFκB, thereby protecting against NASH.
The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle--including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake--may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders.
Dietary phenolic compounds are often transformed before absorption. This transformation modulates their biological activity. Different studies have been carried out to understand gut microbiota transformations of particular polyphenol types and identify the responsible microorganisms. Although there are potentially thousands of different phenolic compounds in the diet, they are typically transformed to a much smaller number of metabolites. The aim of this review was to discuss the current information about the microbial degradation metabolites obtained from different phenolics and their formation pathways, identifying their differences and similarities. The modulation of gut microbial population by phenolics was also reviewed in order to understand the two-way phenolic-microbiota interaction. Clostridium and Eubacterium genera, which are phylogenetically associated, are other common elements involved in the metabolism of many phenolics. The health benefits from phenolic consumption should be attributed to their bioactive metabolites and also to the modulation of the intestinal bacterial population.
In this study, we investigated the effects of the major green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), on high-fat-induced obesity, symptoms of the metabolic syndrome, and fatty liver in mice. In mice fed a high-fat diet (60% energy as fat), supplementation with dietary EGCG treatment (3.2 g/kg diet) for 16 wk reduced body weight (BW) gain, percent body fat, and visceral fat weight (P < 0.05) compared with mice without EGCG treatment. The BW decrease was associated with increased fecal lipids in the high-fat-fed groups (r(2) = 0.521; P < 0.05). EGCG treatment attenuated insulin resistance, plasma cholesterol, and monocyte chemoattractant protein concentrations in high-fat-fed mice (P < 0.05). EGCG treatment also decreased liver weight, liver triglycerides, and plasma alanine aminotransferase concentrations in high-fat-fed mice (P < 0.05). Histological analyses of liver samples revealed decreased lipid accumulation in hepatocytes in mice treated with EGCG compared with high-fat diet-fed mice without EGCG treatment. In another experiment, 3-mo-old high-fat-induced obese mice receiving short-term EGCG treatment (3.2 g/kg diet, 4 wk) had decreased mesenteric fat weight and blood glucose compared with high-fat-fed control mice (P < 0.05). Our results indicate that long-term EGCG treatment attenuated the development of obesity, symptoms associated with the metabolic syndrome, and fatty liver. Short-term EGCG treatment appeared to reverse preexisting high-fat-induced metabolic pathologies in obese mice. These effects may be mediated by decreased lipid absorption, decreased inflammation, and other mechanisms.
To investigate the association between consumption of green tea and various serum markers in a Japanese population, with special reference to preventive effects of green tea against cardiovascular disease and disorders of the liver.
Cross sectional study.
Yoshimi, Japan.
1371 men aged over 40 years resident in Yoshimi and surveyed on their living habits including daily consumption of green tea. Their peripheral blood samples were subjected to several biochemical assays.
Increased consumption of green tea was associated with decreased serum concentrations of total cholesterol (P for trend < 0.001) and triglyceride (P for trend = 0.02) and an increased proportion of high density lipoprotein cholesterol together with a decreased proportion of low and very low lipoprotein cholesterols (P for trend = 0.02), which resulted in a decreased atherogenic index (P for trend = 0.02). Moreover, increased consumption of green tea, especially more than 10 cups a day, was related to decreased concentrations of hepatological markers in serum, aspartate aminotransferase (P for trend = 0.06), alanine transferase (P for trend = 0.07), and ferritin (P for trend = 0.02).
The inverse association between consumption of green tea and various serum markers shows that green tea may act protectively against cardiovascular disease and disorders of the liver.
The gut and the liver are closely linked to each other, as changes in the gut microbiota can play a significant role in the development of many liver diseases. Gut bacteria respond rapidly to changes in diet and thus can affect the liver through their metabolites. The impact of a high lipid diet on the liver in the presence of an altered gut flora modulated by ampicillin was investigated. The study was performed on 30 male Western albino rats randomly divided into 3 groups: control (phosphate buffered saline treated), group II (ampicillin 50 mg/kg for three weeks to induce microbiota alterations and fed on standard diet) and group III (same dose of ampicillin and fed on a lipid rich diet). Stool samples were collected for qualitative determination of bacteria. Serum hepato-specific markers, in addition to Glutathione (GSH), Lipid peroxidase (MDA), Glutathione-S- transferase(GST), and vitamin C in liver tissues, were measured. Altered gut microbiota significantly increased the level of the hepato-specific marker MDA and reduced the GST, GSH and vitamin C levels. However, animals fed a lipid rich diet displayed a more significant shift in hepatic markers and antioxidants. Moreover, a new switch in composition of the gut bacteria was observed by feeding the lipid rich diet. Our study showed that bacterial overgrowth in the gut can be associated with liver dysfunction and that a high lipid diet can promote the overgrowth of some liver damaging microflora during antibiotic treatment.
The incidence of nonalcoholic fatty liver disease (NAFLD) has risen along with the ongoing obesity epidemic. Green tea extract (GTE) inhibits intestinal lipid absorption and may regulate hepatic lipid accumulation. The objective of this study was to determine whether GTE protects against hepatic lipid accumulation during the development of NAFLD in an obese mouse model. Five-wk-old ob/ob (obese) mice and their lean littermates (8 mice·genotype⁻¹·dietary treatment⁻¹) were fed GTE at 0, 1, or 2% (wt:wt) for 6 wk. The body weights of obese mice and lean littermates fed diets containing GTE were 23–25% and 11–20% lower (P < 0.05) than their respective controls fed no GTE. Histologic evaluation showed a significant reduction in hepatic steatosis in GTE-fed obese mice only and histologic scores were correlated with hepatic lipid concentration (r = 0.84; P < 0.05), which was reduced dose dependently by GTE. GTE protected against hepatic injury as suggested by 30–41% and 22–33% lower serum alanine aminotransferase and aspartate aminotransferase activities, respectively. Hepatic α-tocopherol was 36% higher in obese mice than lean mice. GTE tended (P = 0.06) to lower hepatic α-tocopherol, which was not fully explained by the GTE-mediated reduction in hepatic lipid. Hepatic ascorbic acid was lower in obese mice than in lean mice (P < 0.05) and was unaltered by GTE. Obese mice had lower serum adiponectin than lean mice and this was not affected by GTE. The results suggest that GTE protects against NAFLD by limiting hepatic lipid accumulation and injury without affecting hepatic antioxidant status and adiponectin-mediated lipid metabolism. Further study is underway to define the events by which GTE protects against obesity-triggered NAFLD.
In the present study, polyphenols from green tea (GTP), oolong tea (OTP) and black tea (BTP) were prepared by extraction with hot water and polyamide column chromatography. In antioxidant assay in vitro, each tea polyphenols exhibited potential activity; the intestinal absorption of GTP, OTP and BTP was investigated individually by Caco-2 transwell system, and each sample was poorly transported, illustrating a low transport rate for tea polyphenols through cell monolayers. The effects of GTP, OTP and BTP on human intestinal microbiota were also evaluated, and each sample induced the proliferation of certain beneficial bacteria and inhibited Bacteroides–Prevotella and Clostridium histolyticum. Moreover, the short-chain fatty acids (SCFA) produced in cultures with tea polyphenols were relatively higher. Together, these results suggested GTP, OTP and BTP may modulate the intestinal flora and generate SCFA, and contribute to the improvements of human health.
Inflammatory bowel disease (IBD) is a common chronic intestinal disorder characterised by a loss of epithelial barrier function leading to the unregulated movement of luminal antigenic material into mucosal tissue with resultant inflammation. In IBD, multiple components of the inflammatory response lead to tissue hypoxia. Mucosal hypoxia leads to the inactivation of prolyl hydroxylase domain-containing (PHD) enzymes which in turn leads to the stabilization of the hypoxia-inducible factor (HIF) which induces the expression of barrier protective genes. Furthermore, pharmacologic hydroxylase inhibition has been shown to be protective in colitis, at least in part through enhancing intestinal epithelial barrier function through HIF-1-dependent barrier-protective gene expression. Therefore, targeting hypoxia-sensitive pathways represents a new and promising therapeutic approach in IBD. This article is protected by copyright. All rights reserved.
Green tea extract (GTE) reduces NFκB-mediated inflammation during nonalcoholic steatohepatitis (NASH). We hypothesized that its anti-inflammatory activities would be mediated in a Toll-like receptor 4 (TLR4)-dependent manner. Wild-type (WT) and loss-of-function TLR4-mutant (TLR4m) mice were fed a high-fat diet containing GTE at 0 or 2% for 8 weeks before assessing NASH, NFκB-mediated inflammation, TLR4 and its adaptor proteins MyD88 and TRIF, circulating endotoxin, and intestinal tight junction protein mRNA expression. TLR4m mice had lower (P<.05) body mass compared with WT mice but similar adiposity, whereas body mass and adiposity were lowered by GTE regardless of genotype. Liver steatosis, serum alanine aminotransferase, and hepatic lipid peroxidation were also lowered by GTE in WT mice, and were similarly lowered in TLR4m mice regardless of GTE. Phosphorylation of the NFκB p65 subunit and pro-inflammatory genes (TNFα, iNOS, MCP-1, MPO) were lowered by GTE in WT mice, and did not differ from the lowered levels in TLR4m mice regardless of GTE. TLR4m mice had lower TLR4 mRNA, which was also lowered by GTE in both genotypes. TRIF expression was unaffected by genotype and GTE, whereas MyD88 was lower in mice fed GTE regardless of genotype. Serum endotoxin was similarly lowered by GTE regardless of genotype. Tight junction protein mRNA levels were unaffected by genotype. However, GTE similarly increased claudin-1 mRNA in the duodenum and jejunum and mRNA levels of occludin and zonula occluden-1 in the jejunum and ileum. Thus, GTE protects against inflammation during NASH, likely by limiting gut-derived endotoxin translocation and TLR4/MyD88/NFκB activation.
Oligodendrocyte progenitor cells (OPCs) are present throughout the adult brain and spinal cord and can replace oligodendrocytes lost to injury, aging, or disease. Their differentiation, however, is inhibited by myelin debris, making clearance of this debris an important step for cellular repair following demyelination. In models of peripheral nerve injury, TLR4 activation by lipopolysaccharide (LPS) promotes macrophage phagocytosis of debris. Here we tested whether the novel synthetic TLR4 agonist E6020, a Lipid A mimetic, promotes myelin debris clearance and remyelination in spinal cord white matter following lysolecithin-induced demyelination. In vitro, E6020 induced TLR4-dependent cytokine expression (TNFα, IL1β, IL-6) and NF-κB signaling, albeit at ∼10-fold reduced potency compared to LPS. Microinjection of E6020 into the intact rat spinal cord gray/white matter border induced macrophage activation, OPC proliferation, and robust oligodendrogenesis, similar to what we described previously using an intraspinal LPS microinjection model. Finally, a single co-injection of E6020 with lysolecithin into spinal cord white matter increased axon sparing, accelerated myelin debris clearance, enhanced Schwann cell infiltration into demyelinated lesions, and increased the number of remyelinated axons. In vitro assays confirmed that direct stimulation of macrophages by E6020 stimulates myelin phagocytosis. These data implicate TLR4 signaling in promoting repair after CNS demyelination, likely by stimulating phagocytic activity of macrophages, sparing axons, recruiting myelinating cells, and promoting remyelination. This work furthers our understanding of immune-myelin interactions and identifies a novel synthetic TLR4 agonist as a potential therapeutic avenue for white matter demyelinating conditions such as spinal cord injury and multiple sclerosis.
In recent years, studies in the gastrointestinal (GI) mucosa have taught us a number of important lessons related to tissue oxygenation and metabolism in health and disease. The highly vascularized mucosa lies immediately adjacent to an anaerobic lumen containing trillions of metabolically active microbes (i.e. the microbiome) that results in one of the more austere tissue microenvironments in the body. These studies have also implicated a prominent role for oxygen metabolism and hypoxia in inflammation, so called “inflammatory hypoxia”, that results from the activation of multiple oxygen consuming enzymes. Inflammation-associated shifts in the composition of the microbiome and microbial-derived metabolites have revealed a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of key target genes that promote inflammatory resolution. Analyses of these pathways have provided a multitude of opportunities for understanding basic mechanisms of both homeostasis and disease mechanisms that have defined new targets for intervention. Here, we review recent advances in our understanding of metabolic influences on host-microbe interactions in the GI mucosa.
A compelling set of links between the composition of the gut microbiota, the host diet, and host physiology has emerged. Do these links reflect cause-and-effect relationships, and what might be their mechanistic basis? A growing body of work implicates microbially produced metabolites as crucial executors of diet-based microbial influence on the host. Here, we will review data supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs). SCFAs can directly activate G-coupled-receptors, inhibit histone deacetylases, and serve as energy substrates. They thus affect various physiological processes and may contribute to health and disease.
Intestinal epithelial cells (IECs) are exposed to profound fluctuations in oxygen tension and have evolved adaptive transcriptional responses to a low-oxygen environment. These adaptations are mediated primarily through the hypoxia-inducible factor (HIF) complex. Given the central role of the IEC in barrier function, we sought to determine whether HIF influenced epithelial tight junction (TJ) structure and function. Initial studies revealed that short hairpin RNA-mediated depletion of the HIF1β in T84 cells resulted in profound defects in barrier and nonuniform, undulating TJ morphology. Global HIF1α chromatin immunoprecipitation (ChIP) analysis identified claudin-1 (CLDN1) as a prominent HIF target gene. Analysis of HIF1β-deficient IEC revealed significantly reduced levels of CLDN1. Overexpression of CLDN1 in HIF1β-deficient cells resulted in resolution of morphological abnormalities and restoration of barrier function. ChIP and site-directed mutagenesis revealed prominent hypoxia response elements in the CLDN1 promoter region. Subsequent in vivo analysis revealed the importance of HIF-mediated CLDN1 expression during experimental colitis. These results identify a critical link between HIF and specific tight junction function, providing important insight into mechanisms of HIF-regulated epithelial homeostasis.
Obesity is caused by an imbalance between caloric intake and energy expenditure and accumulation of excess lipids in adipose tissues. Recent studies have demonstrated that green tea and its processed products (e.g., oolong and black tea) are introduced to exert beneficial effects on lipid metabolism. Here, we propose that fermented green tea (FGT) extract, as a novel processed green tea, exhibits antiobesity effects. FGT reduced body weight gain and fat mass without modifying food intake. mRNA expression levels of lipogenic and inflammatory genes were downregulated in white adipose tissue of FGT-administered mice. FGT treatment alleviated glucose intolerance and fatty liver symptoms, common complications of obesity. Notably, FGT restored the changes in gut microbiota composition (e.g., the Firmicutes/Bacteroidetes and Bacteroides/Prevotella ratios), which is reported to be closely related with the development of obesity and insulin resistance, induced by high-fat diets. Collectively, FGT improves obesity and its associated symptoms and modulates composition of gut microbiota; thus, it could be used as a novel dietary component to control obesity and related symptoms.
Abstract Green tea extract (GTE) protects against nonalcoholic steatohepatitis (NASH) by decreasing hepatic steatosis and nuclear factor kappa B (NFκB) activation. We hypothesized that hypolipidemic and anti-inflammatory activities of GTE would protect against NASH by reducing cyclooxygenase-2 (COX-2), an NFκB-dependent enzyme, and prostaglandin E2 (PGE2) in a dietary fat-induced obese model. Male Wistar rats were fed a low-fat diet containing no GTE or a high-fat (HF) diet containing GTE at 0%, 1%, or 2% for 8 weeks. Insulin resistance and total hepatic fatty acids increased following HF feeding (P<.05) and these were normalized by GTE at 1-2%. GTE (1-2%) normalized hepatic malondialdehyde without affecting cytochrome P450 2E1 mRNA expression, which was otherwise increased by HF feeding. HF-mediated increases in hepatic COX-2 protein and activity as well as PGE2 concentrations were normalized by GTE (1-2%). COX-2 activity and PGE2 were correlated to each other, and to serum alanine aminotransferase (ALT) and hepatic NFκB-binding activity (P<.05; r=0.28-0.49). GTE attenuated HF-mediated increases in total hepatic n-6 and n-3, without affecting the n-6/n-3 ratio. GTE did not affect HF-mediated increases in n-6 in nonesterified fatty acid (NEFA) and phospholipid pools, whereas n-3 and n-6/n-3 in both pools were unaffected by GTE and HF feeding. GTE decreased total hepatic arachidonic acid without affecting HF-mediated increases in arachidonic acid in NEFA or phospholipid pools. Thus, GTE attenuates lipid peroxidation and PGE2 accumulation by decreasing COX-2 activity independent of arachidonic acid availability and supports an additional mechanism by which GTE protects against liver injury during NASH in an HF-feeding model.
STAMP is a graphical software package that provides statistical hypothesis tests and exploratory plots for analysing taxonomic
and functional profiles. It supports tests for comparing pairs of samples or samples organized into two or more treatment
groups. Effect sizes and confidence intervals are provided to allow critical assessment of the biological relevancy of test
results. A user-friendly graphical interface permits easy exploration of statistical results and generation of publication-quality
plots.
Availability and implementation: STAMP is licensed under the GNU GPL. Python source code and binaries are available from our website at: http://kiwi.cs.dal.ca/Software/STAMP
Contact: donovan.parks{at}gmail.com
Supplementary information: Supplementary data are available at Bioinformatics online.
Green tea is one of the most popular beverages in the world. Its beneficial health effects and components have been extensively reviewed. However, little is known about the influence of green tea consumption on the human intestinal microbiota (HIM), which plays a crucial role in human health. Ten volunteers who did not usually consume green tea, drank it for 10 days and then stopped drinking it for 7 days. Their fecal samples were collected at three time points: before beginning the 10-day green-tea regime, at the conclusion of that 10 days, and 7 days after stopping the regime. Their fecal samples were analyzed by terminal restriction fragment length polymorphism with specific primer-restriction enzyme systems for HIM and by using a real-time PCR method for the Bifidobacterium species. Although the HIM of each subject was relatively stable, the proportion of Bifidobacterium species played an important role in the classification of their fecal microbiota. Although there were inter-individual differences in the Bifidobacterium species, an overall tendency for the proportion of bifidobacteria to increase because of green tea consumption was noted. However, little change was observed in the composition of Bifidobacterium species in each sample. This suggests that the change in proportion was induced, not by an inter-species transition, but by an intra-species increase and/or decrease. In conclusion, green tea consumption might act as a prebiotic and improve the colon environment by increasing the proportion of the Bifidobacterium species.
Previous efforts to forecast future trends in obesity applied linear forecasts assuming that the rise in obesity would continue unabated. However, evidence suggests that obesity prevalence may be leveling off.
This study presents estimates of adult obesity and severe obesity prevalence through 2030 based on nonlinear regression models. The forecasted results are then used to simulate the savings that could be achieved through modestly successful obesity prevention efforts.
The study was conducted in 2009-2010 and used data from the 1990 through 2008 Behavioral Risk Factor Surveillance System (BRFSS). The analysis sample included nonpregnant adults aged ≥ 18 years. The individual-level BRFSS variables were supplemented with state-level variables from the U.S. Bureau of Labor Statistics, the American Chamber of Commerce Research Association, and the Census of Retail Trade. Future obesity and severe obesity prevalence were estimated through regression modeling by projecting trends in explanatory variables expected to influence obesity prevalence.
Linear time trend forecasts suggest that by 2030, 51% of the population will be obese. The model estimates a much lower obesity prevalence of 42% and severe obesity prevalence of 11%. If obesity were to remain at 2010 levels, the combined savings in medical expenditures over the next 2 decades would be $549.5 billion.
The study estimates a 33% increase in obesity prevalence and a 130% increase in severe obesity prevalence over the next 2 decades. If these forecasts prove accurate, this will further hinder efforts for healthcare cost containment.
Nonalcoholic fatty liver disease (NAFLD) is a constellation of progressive liver disorders that are closely related to obesity, diabetes, and insulin resistance and may afflict over 70 million Americans. NAFLD may occur as relatively benign, nonprogressive liver steatosis, but in many individuals it may progress in severity to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure or hepatocellular carcinoma. No validated treatments currently exist for NAFLD except for weight loss, which has a poor long-term success rate. Thus, dietary strategies that prevent the development of liver steatosis or its progression to nonalcoholic steatohepatitis are critically needed. Green tea is rich in polyphenolic catechins that have hypolipidemic, thermogenic, antioxidant, and anti-inflammatory activities that may mitigate the occurrence and progression of NAFLD. This review presents the experimental evidence demonstrating the hepatoprotective properties of green tea and its catechins and the proposed mechanisms by which these targeted dietary agents protect against NAFLD.
The prevalence of obesity has been rising steadily over the last several decades and is currently at unprecedented levels: more than 68% of US adults are considered overweight, and 35% are obese (Flegal et al., JAMA 303:235-241, 2010). This increase has occurred across every age, sex, race, and smoking status, and data indicate that segments of individuals in the highest weight categories (i.e., BMI > 40 kg/m(2)) have increased proportionately more than those in lower BMI categories (BMI < 35 kg/m(2)). The dramatic rise in obesity has also occurred in many other countries, and the causes of this increase are not fully understood (Hill and Melanson, Med Sci Sports Exerc 31:S515-S521, 1999).
Proinflammatory adipose tissue macrophages (ATMs) contribute to obesity-associated disease morbidity. We will provide an update of the current state of knowledge regarding the phenotypic and functional diversity of ATMs in lean and obese mice and humans.
The phenotypic diversity of ATMs is now known to include more than two types requiring an expansion of the simple concept of an M2 to M1 shift with obesity. Potential functions for ATMs now include the regulation of fibrosis and response to acute lipolysis in states of caloric restriction. Novel pathways that can potentiate ATM action have been identified, which include inflammasome activation and the response to lipodystrophic adipose tissue. Studies provide a new appreciation for the ability of ATMs to respond dynamically to the adipose tissue microenvironment.
ATMs play a key role in shaping the inflammatory milieu within adipose tissue, and it is now apparent that ATM heterogeneity is acutely shaped by the adipose tissue environment. To account for the new findings, we propose a new nomenclature for ATM subtypes that takes into account their diversity.
The intestinal microflora is a complex ecosystem containing over 400 bacterial species. Anaerobes outnumber facultative anaerobes. The flora is sparse in the stomach and upper intestine, but luxuriant in the lower bowel. Bacteria occur both in the lumen and attached to the mucosa, but do not normally penetrate the bowel wall .
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
N-Acetylglucosamine (GlcNAc) and N-acetylneuraminic acid (NANA) are good carbon sources for Escherichia coli K-12, whereas N-acetylmannosamine (ManNAc) is metabolized very slowly. The isolation of regulatory mutations which enhanced utilization of ManNAc allowed us to elucidate the pathway of its degradation. ManNAc is transported by the manXYZ-encoded phosphoenolpyruvate-dependent phosphotransferase system (PTS) transporter producing intracellular ManNAc-6-P. This phosphorylated hexosamine is subsequently converted to GlcNAc-6-P, which is further metabolized by the nagBA-encoded deacetylase and deaminase of the GlcNAc-6-P degradation pathway. Two independent mutations are necessary for good growth on ManNAc. One mutation maps to mlc, and mutations in this gene are known to enhance the expression of manXYZ. The second regulatory mutation was mapped to the nanAT operon, which encodes the NANA transporter and NANA lyase. The combined action of the nanAT gene products converts extracellular NANA to intracellular ManNAc. The second regulatory mutation defines an open reading frame (ORF), called yhcK, as the gene for the repressor of the nan operon (nanR). Mutations in the repressor enhance expression of the nanAT genes and, presumably, three distal, previously unidentified genes, yhcJIH. Expression of just one of these downstream ORFs, yhcJ, is necessary for growth on ManNAc in the presence of an mlc mutation. The yhcJ gene appears to encode a ManNAc-6-P-to-GlcNAc-6-P epimerase (nanE). Another putative gene in the nan operon, yhcI, likely encodes ManNAc kinase (nanK), which should phosphorylate the ManNAc liberated from NANA by the NanA protein. Use of NANA as carbon source by E. coli also requires the nagBA gene products. The existence of a ManNAc kinase and epimerase within the nan operon allows us to propose that the pathways for dissimilation of the three amino sugars GlcNAc, ManNAc, and NANA, all converge at the step of GlcNAc-6-P.