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Supplementation with non-absorbable antibiotics or curcumin improves Western diet induced intestinal barrier dysfunction. Ten week old LDLR2/2 mice were fed ad libitum High Fat High Cholesterol containing Western type diet (TD 88137, WD) for 16 weeks. Experimental groups either received non-absorbable antibiotics (100 mg/L Neomycin and 10 mg/L Polymyxin B) in drinking water or were gavaged daily with Curcumin (100 mg/kg in 0.5% carboxymethylcellulose). Panel A: Fasting plasma was collected at the time of necropsy and circulating LPS levels (EU/ml) were determined. Data are presented as Mean 6 SEM, n = 6-9 per group. Panel B: Overnight fasted mice were gavaged with FITC-dextran 4 kDa and plasma samples were collected after 4 h. Appearance of FITC-dextran in plasma was monitored and the data (Mean6SEM, n = 6-9, per group) are presented as FITC concentration (ng/ml). Panel C: Intestinal Alkaline Phosphatase activity was determined and Specific activity (nmoles PNP released/h/ mg protein) expressed as % chow-fed controls is shown (Mean 6 SEM, n = 6-9 per group). P,0.0001 by One way ANOVA with Bonferroni posthoc correction; Dissimilar letters above the bars indicate significant differences between groups (P,0.05). doi:10.1371/journal.pone.0108577.g001
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Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as Type 2 Diabetes and atherosclerosis) has shifted the focus from Western diet-induced changes in gut microbiota per se to release of gut bacteria-derived products into circulation as the possible mechanism for the chronic inflammatory state underlying the develo...
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... curcumin (1.5160.39) ( Figure 1A). LPS is continuously generated in the lumen of the intestine by the gut bacteria and an intact intestinal barrier prevents the release of even trace yet pathological amounts of LPS into the circulation. ...
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... 1.1360.15) further establishing an improvement in intestinal barrier function by these two interventions ( Figure 1B). In addition to intestinal barrier function which restricts the release of LPS that is continuously produced in the intestinal lumen, intestinal alkaline phosphatase (IAP) associated with the brush border detoxifies LPS by dephosphorylation of the Lipid A moiety (the primary source of the endotoxic effects) and is considered as an important gut mucosal defense factor. ...
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... translocation of bacteria/bacterial products is ob- served in IAP2/2 mice along with increased obesity [19] emphasizing the role of IAP not only in maintaining the intestinal barrier function but also in metabolic diseases. Western diet feeding significantly reduced IAP activity (,Q75%) and this decrease was attenuated by supplementation with antibiotics (,Q25%) ( Figure 1C). Notably, curcumin supplementation significantly increased IAP activity compared to chow diet fed control mice (,2 fold increase). ...
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... significant improvement in glucose tolerance was observed by antibiotic ( Figure 3A) or curcumin supplementation ( Figure 3B); the initial rise in blood glucose and levels at all-time points were significantly lower in mice given antibiotics or curcumin. Area under the curve, AUC, was calculated and a significant decrease was observed in mice treated with antibiotics ( Figure 3C, 3940068000 vs 3020065800) or curcumin (Fig- ure 3D, 36800612000 vs 2800067000). ...
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... studies will examine the effects of curcumin on other components of the intestinal barrier to further advance our current understanding and to develop curcumin as a dietary supplement to attenuate multiple inflammation-linked diseases. Figure 1C). Luminal LPS- induced decrease in the expression of tight junction proteins ZO-1 and Claudin -1 ( Figure 3G) increases the paracellular transport of LPS into circulation ( Figure 1A). ...
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... 1C). Luminal LPS- induced decrease in the expression of tight junction proteins ZO-1 and Claudin -1 ( Figure 3G) increases the paracellular transport of LPS into circulation ( Figure 1A). Trace yet pathological doses of LPS along with Western diet-induced increase in circulating lipids (e.g., fatty acids) enhance macrophage activation and induce NF-kB-driven gene expression ( Figure 3A) resulting in increased secretion of pro-inflammatory cytokines and chemokines ( Figure 3C and D). ...
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Background: Ulcerative colitis (UC) is characterized by altered chromogranin-A (CHGA), alternatively activated macrophages (M2) and intestinal epithelial cells (IECs). We previously demonstrated that CHGA is implicated in colitis progression by regulating the macrophages. Here, we investigated the interplay between CHGA, M2, tight junctions (TJ) an...
Citations
... In vivo assessments in rat models further affirmed curcumin's efficacy, improving tight junction structure, suppressing serum TNF-α and LPS concentrations, and positively modulating occludin expression in the intestinal mucosa [170]. Another study corroborated these findings, demonstrating that curcumin significantly enhanced intestinal barrier function by restoring alkaline phosphatase activity and the expression of tight junction proteins ZO-1 and claudin-1 [171]. ...
In the aging process, physiological decline occurs, posing a substantial threat to the physical and mental well-being of the elderly and contributing to the onset of age-related diseases. While traditional perspectives considered the maintenance of life as influenced by a myriad of factors, including environmental, genetic, epigenetic, and lifestyle elements such as exercise and diet, the pivotal role of symbiotic microorganisms had been understated. Presently, it is acknowledged that the intestinal microbiota plays a profound role in overall health by signaling to both the central and peripheral nervous systems, as well as other distant organs. Disruption in this bidirectional communication between bacteria and the host results in dysbiosis, fostering the development of various diseases, including neurological disorders, cardiovascular diseases, and cancer. This review aims to delve into the intricate biological mechanisms underpinning dysbiosis associated with aging and the clinical ramifications of such dysregulation. Furthermore, we aspire to explore bioactive compounds endowed with functional properties capable of modulating and restoring balance in this aging-related dysbiotic process through epigenetics alterations.
... IAP possesses the capability to neutralize the bacterial endotoxin lipopolysaccharide [70]. Research indicates that administering curcumin orally can increase IAP activity threefold and reduce the levels of circulating endotoxin lipopolysaccharide (LPS) [71], thereby directly demonstrating curcumin's regulatory impact on the intestinal barrier's initial layer [72]. The intestinal mucosal layer, constituting the second layer, is crucial in separating luminal contents from epithelial cells and preventing pathogenic bacteria from entering. ...
Curcumin (CUR) is a lipophilic natural polyphenol that can be isolated from the rhizome of turmeric. Studies have proposed that CUR possesses a variety of biological activities. Due to its anti-inflammatory and antioxidant properties, CUR shows promise in the treatment of inflammatory bowel disease, while its anti-obesity effects make it a potential therapeutic agent in the management of obesity. In addition, curcumin’s ability to prevent atherosclerosis and its cardiovascular benefits further expand its potential application in the treatment of cardiovascular disease. Nevertheless, owing to the limited bioavailability of CUR, it is difficult to validate its specific mechanism of action in the treatment of diseases. However, the restricted bioavailability of CUR makes it challenging to confirm its precise mode of action in disease treatment. Recent research indicates that the oral intake of curcumin may lead to elevated levels of residual curcumin in the gastrointestinal system, hinting at curcumin’s potential to directly influence gut microbiota. Furthermore, the ecological dysregulation of the gut microbiota has been shown to be critical in the pathogenesis of human diseases. This review summarizes the impact of gut dysbiosis on host health and the various ways in which curcumin modulates dysbiosis and ameliorates various diseases caused by it through the administration of curcumin.
... Some of these fragments are lipopolysaccharides (LPS) and glycolipids that lead to endotoxemia, thereby activating macrophages and NK cells [48]. In addition, saturated SCFAs are associated with the differentiated composition of the intestinal microbiome and are ligands for TLR4 receptors [49]. When binding to the TLR4/CD14 receptors in macrophages, they induce a cascade of pro-inflammatory cytokines (mainly IL-6 and TNF-a), thereby initiating an immune response. ...
In recent years, the increasing number of studies on the relationship between the gut microbiota and atherosclerosis have led to significant interest in this subject. The gut microbiota, its metabolites (metabolome), such as TMAO, and gut dysbiosis play an important role in the development of atherosclerosis. Furthermore, inflammation, originating from the intestinal tract, adds yet another mechanism by which the human ecosystem is disrupted, resulting in the manifestation of metabolic diseases and, by extension, cardiovascular diseases. The scientific community must understand and elucidate these mechanisms in depth, to gain a better understanding of the relationship between atherosclerosis and the gut microbiome and to promote the development of new therapeutic targets in the coming years. This review aims to present the knowledge acquired so far, to trigger others to further investigate this intriguing topic.
... The disruption of the intestinal barrier loses the ability to limit the release of LPS from bacteria into circulation . Curcumin inhibited LPS-induced translocation of [ 3 H]-mannitol and FITC dextran by increasing the activity of intestinal mucosal defense factor intestinal alkaline phosphatase (IAP), which in turn improved intestinal barrier function (Ghosh et al., 2014). The mechanism by which curcumin inhibits AS may be through reducing the release of LPS and inhibiting the release of proinflammatory factors such as IL-6 and MCP-1 after excessive activation of macrophages, and reducing the expression of pro-inflammatory transcription factor NF-κB. ...
Atherosclerosis (AS) is a chronic inflammatory reaction that primarily affects large and medium-sized arteries. It is a major cause of cardiovascular disease and peripheral arterial occlusive disease. The pathogenesis of AS involves specific structural and functional alterations in various populations of vascular cells at different stages of the disease. The immune response is involved throughout the entire developmental stage of AS, and targeting immune cells presents a promising avenue for its treatment. Over the past 2 decades, studies have shown that gut microbiota (GM) and its metabolites, such as trimethylamine-N-oxide, have a significant impact on the progression of AS. Interestingly, it has also been reported that there are complex mechanisms of action between GM and their metabolites, immune responses, and natural products that can have an impact on AS. GM and its metabolites regulate the functional expression of immune cells and have potential impacts on AS. Natural products have a wide range of health properties, and researchers are increasingly focusing on their role in AS. Now, there is compelling evidence that natural products provide an alternative approach to improving immune function in the AS microenvironment by modulating the GM. Natural product metabolites such as resveratrol, berberine, curcumin, and quercetin may improve the intestinal microenvironment by modulating the relative abundance of GM, which in turn influences the accumulation of GM metabolites. Natural products can delay the progression of AS by regulating the metabolism of GM, inhibiting the migration of monocytes and macrophages, promoting the polarization of the M2 phenotype of macrophages, down-regulating the level of inflammatory factors, regulating the balance of Treg/Th17, and inhibiting the formation of foam cells. Based on the above, we describe recent advances in the use of natural products that target GM and immune cells crosstalk to treat AS, which may bring some insights to guide the treatment of AS.
... We discovered that infection with SGIV interfered with intestinal barrier function, as evidenced by elevated serum DAO levels and increased intestinal permeability, which might be attributable to the disruption of intestinal tight-binding protein expression and organization. Previously, oral supplementation with curcumin could lead to a twofold augmentation in intestinal alkaline phosphatase activity, resulting in a direct favorable impact on intestinal health [36]. Alternatively, the advantageous impacts of curcumin on the intestinal barrier have been demonstrated to enhance the function of the intestinal barrier through the conservation of ZO-1 and claudin-1 levels within the intestinal epithelium or mend the structure of the intestinal epithelium by decreasing the damage caused by lipopolysaccharides (LPS) to ZO-1, claudin-1, and claudin-7 [37]. ...
Singapore grouper iridovirus (SGIV) is a new ranavirus species in the Iridoviridae family, whose high lethality and rapid spread have resulted in enormous economic losses for the aquaculture industry. Curcumin, a polyphenolic compound, has been proven to possess multiple biological activities, including antibacterial, antioxidant, and antiviral properties. This study was conducted to determine whether curcumin protected orange-spotted grouper (Epinephelus coioides) from SGIV-induced intestinal damage by affecting the inflammatory response, cell apoptosis, oxidative stress, and intestinal microbiota. Random distribution of healthy orange-spotted groupers (8.0 ± 1.0 cm and 9.0 ± 1.0 g) into six experimental groups (each group with 90 groupers): Control, DMSO, curcumin, SGIV, DMSO + SGIV, and curcumin + SGIV. The fish administered gavage received DMSO dilution solution or 640 mg/L curcumin every day for 15 days and then were injected intraperitoneally with SGIV 24 h after the last gavage. When more than half of the groupers in the SGIV group perished, samples from each group were collected for intestinal health evaluation. Our results showed that curcumin significantly alleviated intestine damage and repaired intestinal barrier dysfunction, which was identified by decreased intestine permeability and serum diamine oxidase (DAO) activity and increased expressions of tight junction proteins during SGIV infection. Moreover, curcumin treatment suppressed intestinal cells apoptosis and inflammatory response caused by SGIV and protected intestinal cells from oxidative injury by enhancing the activity of antioxidant enzymes, which was related to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Moreover, we found that curcumin treatment restored the disruption of the intestinal microbiota caused by SGIV infection. Our study provided a theoretical basis for the functional development of curcumin in aquaculture by highlighting the protective effect of curcumin against SGIV-induced intestinal injury.
... To investigate how the diurnal change in indigenous bacteria affects the transcriptome of PP and the ordinary tissue in the ileum, we impaired the indigenous bacteria using 1-day treatment with an antibiotics cocktail in drinking water: vancomycin (0.5 g/L; FUJIFILM Wako Pure Chemical) and polymyxin B (0.1 g/L; FUJIFILM Wako Pure Chemical), which are known to be poorly absorbed (Ghosh et al. 2014;Rao et al. 2011;Zanvit et al. 2015) and are frequently used to induce gut dysbiosis (Hayashi et al. 2017;Ran et al. 2020). Thirty-two male Wistar rats aged 7 weeks were equally divided into a control group and an antibioticstreated (Abx) group. ...
Our previous study revealed the diurnal change in the indigenous bacteria settling on the terminal region of the rat ileum. In the present study, we investigated the diurnal change in indigenous bacteria on the most distal ileal Peyer’s patch (PP) and surrounding ileal mucosa and explored how stimulation from indigenous bacteria for a day affects the intestinal immune system at the beginning of the light phase. Histological measurement revealed that bacteria adjacent to the follicle-associated epithelium of PP and to the villous epithelium of the surrounding ileal mucosa are more abundant at zeitgeber time (ZT)0 and ZT18 than at ZT12. On the other hand, tissue-section 16S rRNA amplicon sequencing revealed no significant difference between ZT0 and ZT12 in the bacterial composition on the ileal tissue including the PP. One-day treatment with an antibiotic (Abx) successfully impaired the settlement of bacteria around the ileal PP. In transcriptome analysis, 1-day Abx treatment led to the downregulation of several chemokines in both PP and ordinary ileal mucosa at ZT0. Histological analysis of the 1-day Abx group revealed decreases in both CD68⁺ macrophages in PP and naphthol AS-D chloroacetate esterase stain-positive mast cells in the ileal villi. Together, these findings suggest that the colonies of indigenous bacteria on the distal ileal PP and surrounding mucosa expand during the dark phase, which might lead to the expression of genes to regulate the intestinal immune system and contribute to the homeostasis of at least macrophages in PP and mast cells in the ileal mucosa.
... Pretreatment with CUR prevents this LPS-induced disorganization of ZO-1, claudin-1, claudin-7, and actin filaments [34]. Previous research had verified the increase in tight junction protein mRNA in mice and jejunal mucosal occludin and ZO-1 mRNA and protein levels in ducks after CUR supplementation [35,36], indicating that CUR enhanced the integrity of the intestinal epithelium. In the present study, CUR supplementation had no significant effect on the tight junction proteins in the jejunum, probably because CUR is not absorbed and utilized in the jejunum, which is consistent with the findings of intestinal morphology in the small intestine showing that CUR increased VH/CD in the duodenum but not in the jejunum. ...
The current study was carried out to examine the effects of pueraria extract (PE) and curcumin (CUR) on growth performance, antioxidant capacity and intestinal integrity in broiler chickens. A complete randomized design with a 2 × 2 factorial arrangement of treatments was employed to assign 200 one-day-old Ross-308 broilers to four groups, each including five replicates of ten birds. Chickens in the control group (CON) were fed the basal diet, while the PE, CUR and PE+CUR groups were supplemented with 200 mg/kg PE or 200 mg/kg CUR or 200 mg/kg PE+ 200 mg/kg CUR. This trial lasted for 28 days. The PE supplementation decreased the average daily gain during the whole period (p < 0.05). The PE+CUR group had a higher feed conversion ratio than that of the PE and CUR groups during days 14–28 and 1–28 (p < 0.05). Dietary CUR supplementation increased duodenal T-SOD activity (p < 0.05). Compared with the CON group, the other three groups increased the duodenal GSH-Px activity, the PE+CUR group reduced the duodenal H2O2 level, and the CUR and PE groups elevated the ileal GSH-Px activity and the ratio of jejunal villus height to crypt depth, respectively (p < 0.05). The addition of PE decreased crypt depth and increased villus area and mucin-2 mRNA level in the jejunum (p < 0.05). Overall, dietary supplementation with PE, CUR, or a combination of these, enhanced the antioxidant status and intestinal integrity of broilers.
... mice on a chow diet. A: The results are shown for 17 genes whose expression was previously reported to have decreased in the jejunum of Ldlr −/− mice fed a WD(22): intestinal alkaline phosphatase (Alp1)(34)(35)(36)(37)(38)(39); apolipoprotein A-I (ApoA-I)(40,41); atonal homolog 1 (Atoh1)(27)(28)(29); defensin 4 (Defb4)(42,43); delta-like canonical notch ligand 4 (Dll4)(44); growth factor independent protein 1 (Gfi1)(30); interleukin 22 (Il22)(31,45); interleukin 23 (Il23)(31,46,47); interleukin 36γ (Il36γ) (31); lysozyme (Lyz) (48); mucin 2 (Muc2)(49); notch receptor 1 (Notch1) (33); notch receptor 2 (Notch2) (31); regenerating islet-derived 3b (Reg3b) (50); regenerating islet-derived 3g (Reg3g)(51); surfactant A (Sftpa1) (52); and defensin 3 (Defb3)(53,54). B: The results are shown for two genes whose expression was previously reported to have increased in the jejunum of Ldlr −/− mice fed a WD(22): LPS-binding protein (Lbp)(55,56); secreted phosphoprotein 1 (Spp1)(57,58). ...
Conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously reported that feeding Ldlr-/- mice standard mouse chow supplemented with unsaturated LPA or LPC qualitatively mimicked the dyslipidemia and atherosclerosis induced by feeding a Western diet (WD). Here we report that adding unsaturated LPA to standard mouse chow also increased the content of reactive oxygen species (ROS) and oxidized phospholipids (OxPL) in jejunum mucus. To determine the role of intestinal autotaxin, enterocyte specific Ldlr-/-/Enpp2 knockout (iKO) mice were generated. In control mice, the WD increased enterocyte Enpp2 expression and raised autotaxin levels. Ex vivo, addition of OxPL to jejunum from Ldlr-/- mice on a chow diet induced expression of Enpp2. In control mice, the WD raised OxPL levels in jejunum mucus, and decreased gene expression in enterocytes for a number of peptides and proteins that affect antimicrobial activity. On the WD, the control mice developed elevated levels of LPS in jejunum mucus and plasma, with increased dyslipidemia and increased atherosclerosis. All of these changes were reduced in the iKO mice. We conclude that the WD increases the formation of intestinal OxPL, which i) induce enterocyte Enpp2 and autotaxin resulting in higher enterocyte LPA levels; that ii) contribute to the formation of ROS that help to maintain the high OxPL levels; iii) decrease intestinal antimicrobial activity; and iv) raise plasma LPS levels that promote systemic inflammation and enhance atherosclerosis.
... These ameliorative effects of such natural mixtures on intestinal barrier structure and inflammatory parameters are likely to be ascribed to the strengthening properties and anti-inflammatory abilities of Curcuma L. and Cassia M., respectively. Indeed, it has been demonstrated that the treatment with curcumin can significantly reduce the circulating LBP levels and improve IEB integrity by upregulating intestinal ZO-1, occludin and claudin-1 expression in murine models of sepsis, intestinal ischemia-reperfusion injury and type 2 diabetes mellitus [42][43][44]. In parallel, treatment with Cassia mimosoides normalized the inflammatory parameters, reducing circulating IL-1β and TNF levels in a HFD mouse model [36]. ...
Intestinal epithelial barrier (IEB) impairment and enteric inflammation are involved in the onset of obesity and gut-related dysmotility. Dietary supplementation with natural plant extracts represents a useful strategy for the management of body weight gain and systemic inflammation associated with obesity. Here, we evaluate the efficacy of a food supplement containing the dry extract of Curcumin, Emblica and Cassia in counteracting enteric inflammation and motor abnormalities in a mouse model of obesity, induced by a high-fat diet (HFD). Male C57BL/6 mice, fed with standard diet (SD) or HFD, were treated with a natural mixture (Curcumin, Emblica and Cassia). After 8 weeks, body weight, BMI, liver and spleen weight, along with metabolic parameters and colonic motor activity were evaluated. Additionally, plasma LBP, fecal calprotectin, colonic levels of MPO and IL-1β, as well as the expression of occludin, TLR-4, MYD88 and NF-κB were investigated. Plant-based food supplement administration (1) counteracted the increase in body weight, BMI and metabolic parameters, along with a reduction in spleen and liver weight; (2) showed strengthening effects on the IEB integrity; and (3) reduced enteric inflammation and oxidative stress, as well as ameliorated the colonic contractile dysfunctions. Natural mixture administration reduced intestinal inflammation and counteracted the intestinal motor dysfunction associated with obesity.
... Included in these 19 were the phytochemical berberine and plant-derived traditional Chinese medicines. Six of the included papers either did not assess either atherosclerosis [77,78] or the gut microbiome [79,80] or found no reduction [81,82] with the intervention. Of note, our gallic acid paper only observed a reduction in males, but not females [75]. ...
... There are seven polyphenol studies [75,79,89,96,98,102,103] that examined plaque burden in correlation with gut microbiome changes. These studies included a mix of sex and animal model types. ...
... Two studies by Ghosh et al. and Zhang et al. [79,105] assessed the efficacy of curcumin in atherosclerosis and gut health in mice. The study by Ghosh et al. was excluded as it did not assess gut bacteria changes. ...
Gut microbiome alterations have recently been linked to many chronic conditions including cardiovascular disease (CVD). There is an interplay between diet and the resident gut microbiome, where the food eaten affects populations of certain microbes. This is important, as different microbes are associated with various pathologies, as they can produce compounds that are disease-promoting or disease-protecting. The Western diet negatively affects the host gut microbiome, ultimately resulting in heightened arterial inflammation and cell phenotype changes as well as plaque accumulation in the arteries. Nutritional interventions including whole foods rich in fiber and phytochemicals as well as isolated compounds including polyphenols and traditional medicinal plants show promise in positively influencing the host gut microbiome to alleviate atherosclerosis. This review investigates the efficacy of a vast array of foods and phytochemicals on host gut microbes and atherosclerotic burden in mice. Reduction in plaque by interventions was associated with increases in bacterial diversity, reduction in the Firmicutes/Bacteroidetes (F/B) ratio, and upregulation of Akkermansia. Upregulation in CYP7 isoform in the liver, ABC transporters, bile acid excretion, and the level of acetic acid, propionic acid, and butyric acid were also noted in several studies reducing plaque. These changes were also associated with attenuated inflammation and oxidative stress. In conclusion, an increase in the abundance of Akkermansia with diets rich in polyphenols, fiber, and grains is likely to reduce plaque burden in patients suffering from CVD.
