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The Shocking Link Between Your Liver and Your Feet: 12 Things Your Feet Can Tell YouResveratrol and liver health -
At the genus level, more changes could be observed. Compared with the NC group, decreases in Barnesiella and Parasutterella and increases Intestinimonas and Enterorhabdus were observed in both the RSV and HFD groups.
Additionally, HFD increased the relative abundance of Oscillibacter , Clostridium IV , Pseudoflavonifractor , Anaerotruncus , Clostridium XlVb , and Peptococcus , and RSV increased that of Olsenella and Hydrogenoanaerobacterium. Compared with the HFD group, RSV had an increasing effect on Allobaculum and Enterorhabdus and a decreasing effect Intestinimonas , Clostridium IV , Anaerotruncus , Flavonifractor , and Clostridium XlVb Figures 3D,F,G.
In the high dose RSV experiment, at the phylum level, Firmicutes were significantly increased and Bacteroidetes were significantly decreased in both the HFD and HRSV groups compared with the NC group, and high dose RSV further increased the Firmicutes compared with HFD group Supplementary Figures 3A,C.
At the family level, compared with the NC group, Porphyromonadaceae was decreased and Erysipelotrichaceae was increased in both other groups Supplementary Figures 3B,E. Compared with the NC group, decreases in Barnesiella and increases in Allobaculum were observed in both the HRSV and HFD groups.
Additionally, HRSV increased that of Olsenella compared with the NC group, and can further promote Allobaculum compared with the HFD group Supplementary Figures 3D,F. Figure 3. RSV caused significant changes in the gut microbiota at the phylum, family, and genus levels.
A Changes in the composition of the gut microbiota in different groups at the phylum level; stacked bar charts represent the relative abundance of major taxa. B The relative abundance of bacteria differed in the three groups at the phylum level.
C Composition of the gut microbiota at the family level. D Composition of the gut microbiota at the genus level. E The relative abundance of bacteria differed in the three groups at the family level.
F,G The relative abundance of bacteria differed in the three groups at the genus level. PICRUSt is a tool for predicting microbial community function based on 16S rRNA gene sequencing.
We compared our data with existing 16S rDNA sequencing databases to analyze the functional differences between different samples and groups. The obtained prediction results were used to enrich gene families by KEGG analysis.
NAFLD was highly relevant to various metabolic pathways, so we used the linear discriminant analysis LDA effect size LEfSe to analyze the differences in metabolic pathways between the three groups Figure 4A. As a result, changes in amino acid, carbohydrate, energy, glycan, and lipid metabolism were observed.
Most carbohydrate metabolic pathways, including fructose and mannose metabolism, glycolysis gluconeogenesis, galactose metabolism and the pentose phosphate pathway, were enriched in the RSV group; most of the glycan biosynthesis pathways were enriched in the NC group; and lipid metabolic pathways such as fatty acid biosynthesis were enriched in the HFD group.
Bray—Curtis-based PCoA also revealed a significant difference in gene function in the three groups Figure 4B. Subsequently, we listed some glucose and lipid metabolism modules, including pyruvate metabolism, fatty acid biosynthesis, butanoate metabolism, glycan biosynthesis and metabolism, that were significantly increased in the HFD groups and decreased in the RSV group Figure 4C , indicating that RSV may exert effects through these pathways.
Figure 4. RSV changed the function of the gut microbiota in HFD-fed mice. B Principle coordinate analysis PCoA showed the Bray—Curtis distance of the predicted KEGG pathways in the three groups. C Glucose and lipid metabolic pathways that were altered between groups. Data are shown as the mean ± SEM, the Kruskal—Wallis and Wilcoxon tests were performed in LEfSe, ANOSIM was used for similarities in PCoA.
Tight junctions in the intestinal epithelium are an important barrier for preventing harmful substances from entering the gut-liver axis. To determine whether tight junctions experienced changes during the development of the disease, we measured the protein and mRNA expression levels of the tight junction proteins zo-1 and occludin in the colon Figures 5A—C.
We found that in the HFD group, the protein expression levels of zo-1 and occludin decreased but could be restored after RSV treatment. Additionally, the gene expression of zo-1 decreased in the HFD group and was upregulated in the RSV group.
There was no change in the gene expression of occludin. Subsequently, we examined the signaling pathways related to the immune response in the liver, the gene expression of inflammatory factors Figure 5D , and the level of oxidative stress in the liver Figures 5E,F and found that immune signaling molecules such as TLR4 and MyD88, and inflammatory factors such as IL-1 and TNF-α were increased in the HFD group and that these changes were reversed in the RSV group.
The above results suggest that RSV can repair the damage to tight junctions in the intestine caused by HFD and simultaneously reduce the liver immune response, inflammatory factor levels and the oxidative stress level.
Figure 5. RSV restored the loss of tight junctions caused by HFD in the gut and ameliorated liver inflammation and oxidative stress. A Protein levels of the tight junction factors zo-1, occludin in the colon among different groups.
B Statistical analysis of protein levels. C Relative mRNA expression of zo-1 and occludin in the mouse colon. D Relative mRNA expression of inflammatory factors MyD88, TLR-4, IL-1, and TNF-α in the liver. E Total liver GSH level. The insulin signaling pathway plays an important role in fatty acid metabolism.
Our study indicated that RSV is beneficial for improving insulin resistance, so we tested the key molecules of the insulin signaling pathway and genes related to lipogenesis, fatty acid oxidation, and fatty acid uptake. We found that both irs1 and p-irs1 were decreased in the HFD group and recovered in the RSV group, while mTor and p-mTor both increased in the HFD group and decreased after RSV treatment.
Among fatty acid metabolism genes, we found that some lipogenesis-related genes, such as Gpat1, Mogat, and Pparg, were inhibited by RSV treatment Figure 6C.
Although we did not find that HFD caused increased expression of liver fatty acid uptake-related genes in our experiments, RSV did suppress genes such as Fabp2 and Fabp1 Figure 6D.
We also noted that fatty acid oxidation-related genes Cpt1, Acox1 showed increases in expression in the HFD group and that these increases were abolished after the administration of RSV Figure 6E. The above results indicated that RSV can restore the expression of genes related to lipid metabolism to normal levels.
Figure 6. Effects of resveratrol on the insulin signaling pathway and fatty acid-related genes in fatty liver mice. A Western blotting was used to detect the protein levels of key molecules in the insulin signaling pathway irs1, p-irs1. mTor, and p-mTor in the liver among the different groups.
B Statistical analysis of the protein levels. The relative expressions of genes related to C lipogenesis, D fatty acid uptake, and E fatty acid oxidation were assessed by qRT-PCR. We found that the gut microbiota was mainly related to body weight, fat weight, fasting blood glucose, HOMA-IR, oil red O staining, and liver TG.
Furthermore, we calculated the correlation coefficient of the gut microbiota and previously detected signaling molecules Figure 7B and found that most of the molecules exhibiting changes after RSV treatment presented a significant correlation with the gut microbiota.
It is worth mentioning that mTor, p-mTor, p-irs1, and pparg were related to similar components of the microbiota Hydrogenoanaerobacterium , Anaerotruncus , Flavonifractor , Oscillibacter , Ruminococcaceae , Intestinimonas , and Clostridium XlVb ; mTor, p-mTor, and pparg were positively related to these groups, while p-irs1 was negatively related to them.
The above data showed that many metabolic indicators and molecules that were recovered by RSV treatment were related to the gut microbiota, suggesting that the gut microbiota is an important factor in the anti-NAFLD effect of RSV. Figure 7.
Red represents a positive correlation; blue represents a negative correlation. Deeper color indicates an increased correlation coefficient.
To verify whether RSV had the ability to directly change the gut microbiota, we cultured the gut microbiota in GAM and then fermented the microbiota with RSV dissolved in ethanol RSV group , with an equal dose of ethanol control group or with no additional treatment empty group.
The fermented samples were collected at 48 h, after which 16S rRNA sequencing was performed. The results showed that the sequence numbers had no significance in all the groups Figure 8A and that the Shannon indexes of control and rsv groups were lower than those of the empty group Figure 8B.
At the same time, we measured the β diversity by PCoA and found that RSV significantly changed the community composition during fecal fermentation Figure 8C.
Subsequently, we analyzed the changes in taxa at different levels between the control and RSV groups Figures 8D,E. At the phylum level, RSV increased the relative abundance of Firmicutes and decreased that of Bacteroidetes.
At the family level, we observed decreasing abundance of Porphyromonadaceae, Bacterioidaceae, Enterococcaceae, Streptococcaceae. The above results confirmed that RSV can independently change the composition of the gut microbiota in vitro. Figure 8.
RSV changed the composition of the gut microbiota in vitro. Representative alpha diversity analysis factors: A Observed sequence numbers.
B Shannon index. Representative β-diversity analysis factor: C Principle coordinate analysis PCoA of the microbiome at the OTU level. D Changes in the composition of the microbiome at the genus level; stacked bar charts represent the relative abundance of taxa.
E The relative abundance of the microbiome differed between the control and RSV groups at the phylum, families, and genus levels.
Currently, there is no reliable medical treatment for non-alcoholic fatty liver Sumida and Yoneda, In our study, we verified the therapeutic effect of RSV on NAFLD mice and explored the underlying mechanism.
The results showed that RSV can significantly improve liver steatosis and insulin resistance in mice. We also observed a downward trend in body weight and blood indicators after RSV treatment, suggesting that RSV exerted a specific effect on improving NAFLD.
The gut microbiota is a new emerging target of RSV. We detected the gut microbiota of the three groups by 16S rRNA sequencing and observed significant changes.
In terms of α-diversity, we noted that the Shannon index was increased in the HFD group and decreased in both low and high dose RSV group. However, some studies have indicated that patients with NAFLD exhibit lower α-diversity Murphy et al. Subsequently, we analyzed the specific differences in taxa among the gut microbiota and evaluated their correlation with metabolic indicators.
However, other studies have suggested that RSV can restore Firmicutes and Bacteroidetes Zhao et al. These differences may be caused by the timing of the medication. In our study, mice were treated with RSV after NAFLD model is established to verify the therapeutic effect, other previous studies treated mice with RSV at the beginning of HFD feeding, and the duration of medication is different between the studies.
In the low dose RSV experiment, RSV caused a significantly increase in the Actinobacteria phylum, along with the Olsenella and Enterorhabdus genera Coriobacteriaceae family. Olsenella can produce SCFAs, which are related to the tight junctions of the intestinal barrier.
One study showed that pectin can increase Olsenella and ameliorate fatty liver Li et al. We found that most of the altered genera belonged to Firmicutes , but the correlation with metabolic indicators differed among genera.
Allobaculum Erysipelotrichaceae family was negatively correlated with the oil red O staining area and fasting blood glucose. RSV could increase the proportion of Allobaculum. Previous studies have proven that increases in Allobaculum are beneficial to HFD mice Raza et al. Allobaculum shows increases when dietary fiber is taken and is negatively related to the concentration of leptin Ravussin et al.
In contrast, the Lachnospiraceae family Clostridium XlVb genus and Ruminococcaceae family Anaerotruncus , Clostridium IV , Flavonifractor , Intestinimonas , and Oscillibacter genus were all positively correlated with the severity of the disease, and RSV caused decreases in these genera.
Clostridium XlVb is an anaerobic bacterium that was found to be reduced in mice receiving fruit extracts rich in polyphenols. It is related to the improvement of the obesity phenotype Xu et al.
Many experiments have shown that the Ruminococcaceae family is downregulated in NAFLD Safari and Gérard, ; Chen et al. The members of the Anaerotruncus and Oscillibacter genera are conditional pathogenic bacteria that in in high-fat and high-sugar diet-fed mice Kong et al.
Clostridium IV is positively correlated with a high-carbohydrate diet Yamaguchi et al. Flavonifractor has also shown a positive correlation with TG levels in some studies Li et al. Intestinimonas is believed to increase in obese rats and is related to an increase in deoxycholic acid Lin et al.
In the high dose RSV study, we still observed the composition of microbiota is totally different in the three groups, however, the altered microbiota were not totally in consistent with the low dose group, the interaction between microbiota is very complex, we always seen various results in studies using different dosage and duration of RSV Charytoniuk et al.
However, we still notice some similar changes, the Allocaculum were increased in different dose group compared with the HFD group, and Olsenella genus were increased in different dose group compared with NC group, indicating these two genus might be an important target of RSV.
Our data confirmed that RSV supplementation can indeed alter the gut microbiota of NAFLD mice. According to the correlation analysis, the altered gut microbiota is associated with the phenotype of NAFLD, and such alterations in the gut microbiota have been proven to cause beneficial changes in NAFLD in previous studies.
Due to the limitation of sequencing depth, we can only distinguish the genera related to the disease, and more advanced sequencing is needed to identify the relevant functional species. To further explore the underlying mechanisms, we tested tight junction proteins zo-1 and occludin in the colon and found that RSV can repair the damage to tight junctions caused by HFD.
Previous studies have shown that changes in the composition and metabolites of the gut microbiota directly affect tight junctions Lee et al. Our results also suggested that RSV modifies the intestinal immune response. It is generally believed that gut microbiota triggers innate and adaptive immunity and maintains the stability of the intestine Hooper and Macpherson, In previous studies about Inflammatory Bowel Disease and Diabetic Nephropathy, the transplantation of fecal microbiota from RSV gavage mice directly affected the intestinal inflammation and gut barrier of the recipient mice Alrafas et al.
We also observed reductions in liver inflammation and oxidative stress after RSV treatment. According to previous studies, the gut microbiota produces numerous immunogens, such as LPS, during metabolic processes.
Damage to tight junctions causes excessive levels of LPS and other immunogens to enter the liver, stimulates the immune response, produces excessive inflammatory factors, and increases oxidative stress Zhang et al.
Another study demonstrated that HFD-induced damage to intestinal permeability leads to insulin resistance Cani et al. Similar to a previous study, our experiments showed the recovery of fasting blood glucose and insulin levels, and the enrichment of glucose metabolic pathways was impaired after RSV treatment; therefore, we examined the insulin signaling pathway.
The results showed that the effects on IRS1, p-IRS1, mTor and p-mTor resulting from HFD feeding can be repaired by RSV treatment. This may result from a decrease in liver inflammation because the inflammatory state of the liver can affect the insulin signaling pathway Tilg and Moschen, In addition, we conducted correlation analysis and found that the tight junction and insulin signaling pathways were significantly related to the altered gut microbiota.
In accordance with our results, previous studies have shown that RSV ameliorates insulin resistance in obese mice fed a high-fat and high-sugar diet; when the gut microbiota was transferred from RSV-treated mice to non-treated mice, the normalization of insulin resistance was observed in recipient mice, indicating that gut microbiota mediates the effects of RSV Abbasi Oshaghi et al.
Furthermore, we detected fatty acid metabolism genes and found that RSV reduced the expression of lipogenesis and fatty acid uptake genes, which can directly prevent steatosis. Previous studies had found that RSV can regulate fatty acid metabolism in the liver and adipose tissue Alberdi et al.
The specific mechanisms need further studies. These results suggest that RSV may benefit NAFLD by repairing tight junctions and improving the insulin signaling pathway.
Although many studies have focused on the effects of RSV on the gut microbiota in various diseases Chaplin et al. Previous studies showed RSV can direct affect specific bacteria in vitro Dos Santos et al.
The results showed that RSV can significantly change the composition of the gut microbiota in vitro. Although there are many differences in the in vitro and in vivo culture environments, we observed that some of the same changes, such as increases in the Firmicutes phylum were observed in the in vitro study and in vivo HRSV group, the low dose RSV group also have a trend to increase it.
the Allocaculum genus were upregulated by both low dose and high dose studies, and the in vitro study also showed high amount of Allocaculum in the rsv group.
Olsenella genus were increased in both three studies, but controversial results still existed. The contradictions may have resulted from the interaction between the gut microbiota and disease. As previous studies have reported, RSV can also ameliorate NAFLD in other ways, and the state of the disease may in turn influence the gut microbiota Charytoniuk et al.
The above results confirmed that RSV is an independent influencing factor of the gut microbiota. At present, some clinical studies found that RSV had beneficial effects on various metabolic-related diseases. In type 2 diabetes researches, RSV was capable of decreasing blood glucose and improving insulin resistance Brasnyo et al.
Meanwhile, RSV increased serum adiponectin and inhibited atherothrombotic signals in patients with coronary heart disease Tome-Carneiro et al. Previous studies also found that RSV could lower cardiovascular risk by reducing cholesterol, systolic blood pressure, and diastolic blood pressure in obese people Huang et al.
As for the clinical studies of NAFLD, some results suggested that RSV was able to alleviate liver steatosis, downregulated the BMI and serum bilirubin Faghihzadeh et al.
Considering that the efficiency of the drug can be influenced by gut microbiota Wilson and Nicholson, , the diversity of human gut microbiota might be an important factor Lozupone et al. Exploring the effect of RSV on the gut microbiota can help it to become a therapeutic drug for NAFLD.
Although we found that RSV exerted an obvious therapeutic effect on NAFLD and changed the composition of the gut microbiota, to further explore the effect of the altered gut microbiota on NAFLD, fecal microbiota transplantation FMT experiments are needed.
Our research group is currently conducting FMT-related experiments. Additionally, there are numerous different species belonging to each genus, and individual species often have different functions Walker et al.
Hence, we will also need more advanced sequencing methods, such as metagenomics, to study the relationship between species and NAFLD.
In conclusion, this article verified the potential of RSV as a therapeutic regimen for NAFLD. Moreover, RSV can change the gut microbiota, and the altered microbiota is significantly related to improved liver steatosis and insulin resistance.
Our study provides new evidence regarding the potential use of RSV as an effective medical treatment for NAFLD. The datasets presented in this study can be found in online repositories. The animal study was reviewed and approved by Laboratory Aniamal Welfare and Ethic Committe of Fujian Medical University.
FD, RH, FC, and XW: conceptualization. ZC and YH: methodology. RH, XY, XH, and BZ: formal analysis. FD, DL, and YW: investigation.
RH: resources. FD: data curation. FD and RH: writing—original draft preparation. FC and XW: writing—review and editing. All authors have read and agreed to the published version of the manuscript.
This work was supported by Startup Fund for scientific research from Fujian Medical University No. C [Min Wei Jiao Ke hao]. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Figure 1 High dose RSV had the same therapeutic effects on HFD-induced fatty liver and metabolic parameters in mice. Supplementary Figure 2 High dose RSV modulated the diversity of the gut microbiota in NAFLD mice. Supplementary Figure 3 High dose RSV caused significant changes in the gut microbiota at the phylum, family, and genus levels.
Supplementary Figure 4 CMC had no effects on metabolic parameters in mice. Supplementary Table 1 Primers used in the quantitative real-time PCR.
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Exclusive news, data and analytics for financial market professionals Learn more about Refinitiv. NEW YORK Reuters Health - Resveratrol, an antioxidant abundant in grapes, red wine, peanuts -- and, according to a new study, dark chocolate and cocoa -- may prevent and treat the build-up of fat in the liver caused by chronic alcohol drinking.
In experiments with mice, resveratrol reduced the amount of fat produced in the liver of mice fed alcohol and increased the rate at which liver fat was broken down. Chronic heavy alcohol drinking causes fat to accumulate in the liver and can lead to cirrhosis, fibrosis, and other liver diseases.
Previous work has shown that chronic alcohol ingestion inhibits two proteins -- AMPK and SIRT1 -- that play a key role in the breakdown of fats in the liver. When alcohol inhibits these two proteins, it allows fat to accumulate. By activating AMPK and SIRT1, resveratrol helps to clear fat from the liver, the new study indicates.
In the study, mice were maintained on a low-fat diet and some were fed resveratrol alone, alcohol alone, or the combination of resveratrol plus alcohol. Tests on the animals showed that resveratrol treatment boosted levels of SIRT1 and stimulated the activity of AMPK in the livers of mice fed alcohol.
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Eco-friendly packaging the Resverayrol of the liveg grape, this article sheds Resverafrol on the Detoxifying body organs benefits of resveratrol, a Seasonal vegetable harvest compound found in red wine. Detoxifying body organs, we delve into helth intriguing connection between resveratrol and liver health, presenting current research findings, dietary considerations, and potential risks. Explore the multifaceted benefits of resveratrol further as it extends beyond liver wellness to potentially enhance lifespan and support the management of chronic conditions such as diabetes. Understanding the synergy between resveratrol and gut health is also essential, as a balanced gut biome is vital for overall well-being. Moreover, the compound's influence on cardiovascular health, particularly its role in maintaining healthy blood pressure levelshighlights its importance as part of a heart-healthy lifestyle.
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