These substances function as antioxidants but also have potent anti-inflammatory activity 19 , Some studies even show that high doses of antioxidants increase your risk of death 23 , For this reason, most health professionals advise people to avoid high-dose antioxidant supplements , although further studies are needed before solid conclusions can be reached.

Eating plenty of antioxidant-rich whole food is a much better idea. Studies indicate that foods reduce oxidative damage to a greater extent than supplements. For example, one study compared the effects of drinking blood-orange juice and sugar water, both of which contained equal amounts of vitamin C.

It found that the juice had significantly greater antioxidant power The best strategy to ensure adequate antioxidant intake is to follow a diet rich in various vegetables and fruits, alongside other healthy habits However, low-dose supplements, such as multivitamins, may be beneficial if you are deficient in certain nutrients or unable to follow a healthy diet.

Studies suggest that taking regular, high-dose antioxidant supplements may be harmful. If possible, get your daily dose of antioxidants from whole foods, such as fruits and vegetables.

Adequate antioxidant intake is essential to a healthy diet, although some studies suggest that high-dose supplements may be harmful. The best strategy is to get your daily dose of antioxidants from healthy plant foods, such as fruits and vegetables. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

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However, Bian et al. Although microbial diversity has been a parameter to describe a healthy microbiome, it must be as a starting point for further inquiry of ecological mechanisms The gut microbiota consisted of genera and families belonging to 22 phyla by 16S rRNA gene amplicon sequencing.

According to the results of species annotations Fig. S 1f—h , the phylum levels of gut microbiota mainly included Firmicutes , Bacteroidetes , and Proteobacteria Fig. Methanobacteriaceae , Akkermansiaceae , Muribaculaceae , Ruminococcaceae , Christensenellaceae , and Lactobacillaceae had a higher abundance in the Y centenarian group at the family level than in other groups.

Lachnospiraceae , Burkholderiaceae , and Bifidobacteriaceae were less abundant Fig. The potentially beneficial bacterial groups Akkermansiaceae , Lactobacillaceae , and Christensenellaceae were also found in the Y centenarian group.

Their abundance gradually increased with age, which followed previous reports 25 , At the genus level, Akkermansia , Methanobrevibacter , Klebsiella , Parabacteroides , Phascolarctobacterium , Barnosiella , Alisipes , Butyricimonas , Lachnoclostridium , and Blautia species exhibited a higher abundance in the Y centenarian group than in other groups Fig.

This is consistent with the results of Palmas et al. We analyzed the phylogenetic relationship of top species at the genus level, and clearly observed that relative abundances of Akkermansia , Methanobrevibacter , Klebsiella , Parabacteroides , Phascolarctobacterium , Barnosiella , Alisipes , Butyricimonas , Lachnoclostridium , and Blautia , etc.

gradually increases with age Fig. Studies have shown that Akkermansia can prolong the lifespan of prematurely aging mice and enhance the intestinal barrier 28 , Having well-characterized cohorts with diversity increase in gut microbiota, we next asked if we could identify age-associated human gut microbial characteristics among these cohorts.

Of note, we found that high levels of 13 genera in the older groups Y80, Y, Y These genera included the potential probiotics Lactobacillus , Akkermansia , the methanogenic Methanobrevibacter , Alistipes , Parabacteroides , uncl Erysipelotrichaceae , Butyrivibrio , Butyricimonas , Barnesiella , Phascolarctobacterium , gut butyrate-producing members Roseburia , and SCFA-producing species such as uncl Clostridiales , uncl Ruminococcaceae.

Thus, we defined these taxa as age-related core taxa with increased age, where were complex co-occurring network relationship Fig. Intriguingly, we found that age-related Barnesiellaceae were significantly inversely associated with metabolic profiles Fig. From the clinical parameters of each group, it can be observed that the body health index of the people in the longevity area was good Fig.

Of note, causal links between Akkermansia and host metabolic benefits have been demonstrated in mouse and human studies 30 , 31 , and a high abundance of Alistipes was reported to be associated with a low risk of atherosclerotic cardiovascular disease 32 , low TG levels or low BMI 33 , These data characterized the trajectory of gut microbiota with age.

b Co-occurrence network analysis of gut microbiota at the genus level. Different nodes represent different genera, the size of the node represents the average relative abundance of the genus, the nodes of the same phylum have the same color, and the thickness of the line between nodes is positively correlated with the absolute value of the correlation coefficient of species interaction.

The positive and negative correspondence between the color of the connection and the correlation red positive correlation, blue negative correlation. a Correlations between the relative abundance of selected bacterial family and clinical parameters.

Age years old, Hei height, Wei weight, BMI body mass index, NCE neck circumference, ACE abdominal circumference, WSBP systolic blood pressure, WDP diastolic blood pressure, CHO cholinesterase, ALB albumin, GLO globulin, γ-GPE γ-glutamyl transpeptidase, ALK alkaline phosphatase, AST aspartate aminotransferase, TBN total bilirubin, ALT alanine aminotransferase, Ca calcium, BUN urea nitrogen, UA uric acid, Cr creatinine, CHOL total cholesterol, TG triglycerides, HDL.

c high-density lipoprotein, LDL. c low-density lipoprotein. HBA1c glycated hemoglobin, PLC platelet count, WBCC white blood cell count, LAV absolute lymphocyte value, NAV absolute value of neutrophils, Hb hemoglobin concentration.

b Clinical parameters of all the groups. Changes in clinical indicators of different age groups. At the functional level, we observed that a large number of metabolism pathway by metagenomic sequencing, such as carbohydrate metabolism, amino acid metabolism, metabolism of cofactors and vitamins, glycan biosynthesis and metabolism, lipid metabolism, metabolism of other amino acids, biosynthesis of other secondary metabolites, metabolism of terpenoids and polyketides, and xenobiotics biodegradation and metabolism.

Compared to younger groups, the gut microbiota of older groups harbored higher abundances of a set of genes related to xenobiotics biodegradation and metabolism, which showing significant associations with increased age Fig.

Of note, we found that high levels of aminobenzoate degradation, atrazine degradation, benzoate degradation, caprolactam degradation, chlorocyclohexane and chlorobenzene degradation, dioxin degradation, ethylbenzene degradation, fluorobenzoate degradation, polycyclic aromatic hydrocarbon degradation, styrene degradation, toluene degradation, and xylene degradation significant associations with increased age Fig.

a Box plot and bar chart showing the gut microbial KEGG pathway annotation xenobiotics biodegradation and metabolism, amino acid metabolism, carbohydrate metabolism, lipid metabolism, biosynthesis of other secondary metabolites, metabolism of other amino acids, metabolism of cofactors and vitamins, glycan biosynthesis and metabolism, metabolism of terpenoids and polyketides.

P values were obtained from two-sided Wilcoxon rank-sum tests. For all box and whisker plots, the center line represents median. The bounds of box represent the first and third quartiles.

The upper whisker extends from the hinge to the largest value no further than 1. The lower whisker extends from the hinge to the smallest value at most 1. b Heatmap showing the gut microbial functions of RNA polymerase, dehydrogenase, methyltransferase, oxidoreductase, acetyltransferase betwween six age groups.

Box plot showing the changes of superoxide dismutase, glutathione stransferase, and catalase with age groups. c , d Correlations between the selected age-related bacterial genus and metabolic pathway and oxidoreductase. We also observed that a large number of oxidoreductase, methyltransferase, acetyltransferase, dehydrogenase in Y group, where superoxide dismutase, glutathione stransferase, catalase significant associations with increased age Fig.

Together, our results show that age-related gut functional characteristics, such as xenobiotics biodegradation and metabolism, and oxidoreductase significant associations with increased age. Of note, age-related gut microbiota and function also exhibited significant associations, where Akkermansia significant associationswith xenobiotics biodegradation and metabolism, glycan biosynthesis and metabolism, biosynthesis of other secondary metabolites, superoxide dismutase, and catalase; Lactobacillus significant associationswith xenobiotics biodegradation and metabolism, metabolism of terpenoids and polyketides, and superoxide dismutase Fig.

These data indicated age-related gut functional characteristics. Having well-characterized age-related gut microbiota and function, we next asked if we could targeted separate, and screen these age-related gut microbiota and function strains.

Indeed, we detected numerous significant associations between age and microbial diversity, the relative abundances of species or function in the Jiaoling, China World Longevity Township.

To verify the correlation between these age-related gut microbiota and function strains, we separated and purified strains, including Lactobacillus Since only a single medium was selected and cultured in an anaerobic environment, we did not isolate all the age-related strains analyzed by the above-mentioned big data.

Fortunately, we have isolated a large number of Lactobacillus , mainly including L. salivarius , L. fermentum , L.

plantarum , L. mucosae , L. gasseri , L. paragasseri , L. animalis , L. crispatus , etc Fig. The pie chart illustrating the proportion of all strains isolated from the fecal sample at the genus level, and a total of 2, strains were isolated. The bar graph showing the detailed composition of the top 6 genera isolated from the fecal sample, including Lactobacillus, Enterococcus, Escherichia, Weissella, Lactococcus, Pediococcus.

Next, some faecal isolation strains were selected for antioxidant probiotics screening. After preliminary screening bacteria suspension and re-screening bacteria suspension, extracellular substance, intracellular substance, and bacteria fragment , a strain with strong antioxidant activity, named Lactobacillus plantarum LP , was finally screened in vitro.

These results indicated that a strain with better antioxidant activity from gut microorganisms was isolated and screened in vitro and named it Lactobacillus plantarum Then the functions of genes were annotated by GO Gene Ontology database, and the pathways were annotated using KEGG Kyoto Encyclopedia of Genes and Genomes database.

Intriguingly, we found that a large number of biological process, molecular function, and cellular component genes including metabolic process, cellular process, catalytic activity, binding, transporter activity, antioxidant activity.

Finally, 12 antioxidant activity GO numbers and antioxidant activity genes number were found Fig. The oxidoreductase-related gene clusters are annotated, mainly including srlD : SDR family oxidoreductase EC We also found a large number of genes, such as carbohydrate metabolism, amino acid metabolism, energy metabolism, nucleotide metabolism, lipid metabolism, metabolism of other amino acids, and xenobiotics biodegradation and metabolism Fig.

S 4d and deposited it in the Culture Collection Center of the Institute of Microbiology, Guangdong Academy of Sciences, with the deposit number GDMCC Table S 4.

These results suggested that LP eprovided with a large of oxidoreductase-related genes in vivo. LP genome circle map and oxidoreductase related genes. The coding genes were annotated with National Center for Biotechnology Information NCBI NR database by BLAST.

From the outside to the inside: the first circle is the genome location information, the second circle is the GC content information, the third circle is the coding gene on the positive chain marked in red , and the fourth circle is the coding gene on the negative chain marked in green , the fifth circle is the ncRNA information on the positive strand marked in blue , the sixth circle is the ncRNA information on the negative strand marked in purple , and the seventh circle is the information of long repetitive sequences in the genome marked in orange , the eighth circle represents genes related to oxidoreductase.

To further test whether the gut-resident LP can also alleviate oxidative stress in animals, LP was intragastrically injected into mice Fig.

S 5k,l. The gut microbial profiles of recipient mice were analysed by 16S rRNA gene amplicon sequencing at 8 weeks Fig. S 5a—c. As expected, LP could regulate the composition and function of the gut microbiota of oxidatively damaged mice.

Moreover, at the functional level, we observed that a large number of carbohydrate metabolism amino acid metabolism, lipid metabolism, xenobiotics biodegradation, and metabolism in Lactobacillus.

These results revealed profound changes in the composition and function of the gut microbiota of the LP group, indicating the importance of LP in the development of gut microbes.

a Schematic of mice experimental design. b , e Mice liver and kidney antioxidant capacity determination, including glutathione peroxidase GSH-Px activity, superoxide dismutase SOD activity, thioredoxin reductase TrxR activity, total antioxidant T-AOC capacity, malondialdehyde MDA content, total carbonyl Carbonyl content.

c , f The relative expression of GSH-Px , SOD , Nrf2 , TrxR in liver and kidney tissues of oxidatively damaged mice. g Mice serum endotoxin determination. Glutathione peroxidase GSH-Px , superoxide dismutase SOD , thioredoxin reductase TrxR , total antioxidant capacity levels T-AOC , malondialdehyde MDA , carbonyl, and endotoxin ET are thought to play key roles in the pathophysiology of oxidative stress damage.

At 8 weeks, model mice exhibited significantly lower GSH-Px, SOD, TrxR, T-AOC, and higher MDA, carbonyl levels compared with control mice in the liver. Notably, LP mice were significantly higher GSH-Px, SOD, TrxR, T-AOC, and lower MDA, carbonyl levels compared with model mice Fig.

Similarly, the kidneys of LP mice also showed similar results to the liver Fig. We next examined alterations in genes GSH-Px , SOD , TrxR , and nuclear factor-erythroid 2-related factor 2 Nrf2 messenger expression in the liver and kidney.

Particularly, the levels of GSH-Px , SOD , TrxR , and Nrf2 mRNA were significantly increased in the LP group compared with those in the model group for mice Fig. To determine how LP affect the liver, kidney, we examined the structure of them.

Histomorphological analysis revealed a significant structural change of liver in model group compared with these in control group Fig. In addition, differences in kidney morphology were evident in the model group compared with control group Fig. The model mice exhibited some serious lesions in the liver and kidney.

However, in the LP group, liver and kidney morphology resem-bled that in controls. Furthermore, no visible histopathological abnormalities were observed in the LP and vitamin C Vc groups Fig.

These results showed that LP has the function of relieving oxidative stress in the liver and kidneys. Impaired body health responses in the intestine are known to be associated with gut barrier dysfunction We investigated if gut-resident LP affected gut barrier function.

LP markedly decreased plasma endotoxin levels in LP mice Fig. We next examined the effect of LP on intestinal histopathological changes. There was a significant structural change of intestine in model group compared with these in control group and no obvious difference in the morphology of the epithelium in LP mice compared with Vc group Fig.

These results demonstrated that LP has the function of protecting the intestinal barrier. To determine the mechanism by which gut-resident LP exerts antioxidant activity at a distance, we characterized the small-molecule substance present in the serum of LPtreated animals relative to model group by LC-MS.

Subsequent tandem mass spectrometry identified candidate small molecules that were significantly enriched in the serum of LPtreated animals, of which 2 were negatively identified as L-ascorbate and mesaconic acid Fig.

S 5d, g, i. Further analysis revealed that 15 metabolic pathways were involved in the above-mentioned metabolites with significant differences Fig. Fortunately, among these 7 significantly enriched small molecules, we have detected a very important metabolite L-ascorbate, which is well known to have a very strong antioxidant effect 36 , 37 , To corroborate these findings, we determined the oxidative activity of Vc L-ascorbate in vivo.

We observed a significantly higher levels in the liver and kidney of GSH-Px, SOD, TrxR, T-AOC, and lower MDA, carbonyl levels in Vc mice compared with model mice Fig.

Likewise, the expression levels in the liver and kidney of GSH-Px , SOD , TrxR , and Nrf2 mRNA were significantly increased in the Vc group compared with those in the model group for mice Fig. In addition, no obvious difference in the morphology of the epithelium in Vc mice compared with control group Fig.

a , b Features identified by ultra-high-resolution mass spectrometry of different metabolites significantly up-regulated and down-regulated in the LP group compared to the model group. The volcano chart can visually display the overall distribution of different metabolites.

The significantly up-regulated metabolites are represented by red dots, the significantly down-regulated metabolites are represented by green dots, and the size of the dot represents the VIP value. c KEGG pathway enrichment bubble chart. The larger the value of abscissa, the higher the enrichment of differential metabolites in the pathway.

The color of the dot represents the p -value of the hypergeometric test. The smaller the value, the greater the reliability of the test and the more statistically significant.

The size of the dot represents the number of different metabolites in the corresponding pathway. The larger the dot, the more differential metabolites in the pathway. d Correlation diagram of different metabolites the pos is the positive ion mode, the neg is the negative ion mode.

Positive correlation is red, and negative correlation is blue. e Diagram of related pathways of L-ascorbate. Finally, to determine whether the origin of L-ascorbate is produced by LP, we performed metabolomics analysis on it Table S 5 , 6.

Subsequent mass spectrometry showed an accumulation of L-ascorbate in LP culture supernatants Table S 5. Further analysis revealed that some metabolic pathways were involved in the L-ascorbate metabolites with ascorbate and aldarate metabolism, vitamin digestion and absorption, HIF-1 signaling pathway, glutathione metabolism.

Especially, L-ascorbate as a metabolite of fructose and mannose metabolism, amino suger and nucleotide suger metabolism showed in Fig. Together, these data demonstrate that the gut-resident Lactobacillus -derived small molecule L-ascorbate can act as effective substance involved in the antioxidant response.

Jiaoling, China, longevity township in the world has a high incidence of centenarians, a relatively single population, and a unique lifestyle and diet.

It is an ideal area for studying longevity. Therefore, an in-depth study of the gut microbiota of centenarians in Jiaoling, a town of longevity in the world, will help deepen our understanding of the mechanisms of longevity.

Although the gut microbiota is considered to be an important determinant of human health 39 , the structure of the gut microbiota and the mechanisms that influence longevity in long-lived populations are not fully understood.

Furthermore, how to thoroughly analyze the composition of the gut microbiota remains a great challenge. To the best of our knowledge, this was the first study to combine metagenomic sequencing of fecal microbes with large-scale culture omics in Jiaoling, a town of longevity in the world, to thoroughly explore the relationship between gut microbiota and healthy longevity.

We also demonstrate a previously underappreciated role of microbes in antioxidant responses. Furthermore, we identified Lactobacilli as mediators of this effect, in part because of their production of L-ascorbic acid, as we detected L-ascorbic acid in both the culture supernatant of in vitro cultures of Lactobacillus and in the serum of Lactobacillus plantarum gavage animals Fig.

The existence of age-related trajectories in the human gut microbiota, and that distinct gut microbiota and gut-resident as antioxidant systems may contribute to health and longevity.

In our study, the elderly, especially the centenarian group, showed higher gut microbial diversity than the younger group, compared with the general youth living in the same region. The gut microbiome structure and function of centenarians have unique characteristics.

However, studies have shown that centenarians are often characterized by reduced alpha diversity, decreased butyrate-producing bacteria eg, Faecalibacterium , Rosetella , Eubacterium , and Ruminococcus , and increased opportunistic pathogens This may be due to longer colonic transit times in middle-aged people than in younger adults 41 , 42 , and longer colonic transit times are associated with higher gut microbial diversity In addition, our study also found that the elderly population also has a higher abundance of some healthy bacterial species, such as Akkermansia , Lactobacillus and many SCFA-producing bacteria Fig.

Akkermansiaceae , Lactobacillaceae and Barnesiellaceae etc. were significantly correlated with clinical parameters. It is necessary for us to distinguish chronological aging from biological aging.

Generally, the environment, diet, life, and psychological factors should be considered. Biological age has been revealed as a better predictor than chronological age, and its measurement can facilitate the assessment of colonoscopy-related colorectal adenoma risk Dyslipidemia, Diabetes, Inflammaging are also age-associated conditions.

They could at least perform revalidate the age-associated taxonomic markers with these biomarkers. The extent of biological aging for individuals could be based on the age-associated residuals of these biomarkers and the taxonomic abundances of the above taxa could be associated with these age-adjusted residuals.

Meanwhile, the abundance of Methanobrevibacter also gradually increased with age. Loss of Akkermansia in older adults and its roles in the maintenance of colonic mucus thickness and anti-inflammatory immune status have been reported in mice Consistent with previous findings, age-related significantly increased abundances of Methanobrevibacter , methanogenic genes, and microbial diversity may be associated with prolonged colonic transit time, which was observed in older adults 47 , Methanobrevibacter is gradually enriched with age, which may have a role in longevity Our analyses revealed that older adults, especially the centenarians exhibited higher abundances of several health-promoting functions, including xenobiotics biodegradation and metabolism, and oxidoreductase significant associations with increased age.

Centenarians are long-lived individuals so they may have an important history of exposure to external pressure. In addition, because of their reduced mobility, these people spend more time in their homes than do younger people, and thus incur increased exposure to indoor pollutants.

Therefore, it is easy to speculate that their microbiome can better degrade these xenobiotics. This exposure and response could drive the accumulating xenobiotic-degrading ability in the gut microbiota of longevity people.

Here, we speculate that the ability of long-lived people to degrade xenobiotics may be the result of a top-down selection process related to the lifestyle habits of these particularly long-lived individuals. Previous studies found that the gut microbiota of Italian adults can also degrade xenobiotics 50 , which may be a functional response to exposure to these compounds Indeed, many systemic human diseases can be regulated by the collective microbial compositon within the gut This recognition has prompted attempts to modulate the microbiome therapeutically through the use of probiotics.

However, the possibly diverse mechanisms by which specific bacteria and their products elicit their distinct beneficial effects remain unknown.

Therefore, identification of molecular pathways affected by probiotics would allow for the more targeted use of probiotics or exploitation of microbial-derived small molecules.

Using in vitro large-scale culture techniques, we isolated strains from fecal samples and performed targeted isolation and screening of one Lactobacillus strain, identifying L-ascorbic acid as a small molecule derived from LP, though it is likely that many other small molecules in response to LP that we could not identify using our specific metabolomic platform.

This suggests that culturomics is an important complement to metagenomics for a comprehensive understanding of the gut microbiota. Although the number of strains of gut microbiota species retrieved by culturomics does not reflect the actual abundance of each species, the higher segregation rates of culturomics still indicate, to some extent, the relatively higher relative abundance of this species in feces.

These findings are consistent with previous literature reports on metagenomic data We found by culturomics that L. salivarius was the most abundant species of Lactobacillus. In order to ensure the accuracy of culturomics for Lactobacillus isolation, we analyzed the classification level of gut microbiota at the species level by metagenomics, and found that the top 20 species were L.

mucosae, L. salivarius, L. delbrueckii, L. fermentum, L. rogosae, L. johnsonii, L. amylovorus, L. reuteri, L. ruminis, L. equicursoris, L. murinus, L. gasseri, L. bifermentans, L. casei, L. ceti, L.

plantarum, L. crispatus, L. iners, L. ingluviei, L. Here we can clearly see that L. salivarius ranks second at the species level. This shows that the abundance of L.

salivarius in the gut microbiota is very high, so it is normal that we can isolate a large number of L. This result is also consistent with the results reported by Kristina et al.

regarding the presence of large amounts of Lactobacillus in the colon As we know, the vast majority of strains in the gut microbiota are unculturable. Metagenomic analysis has not been able to provide viable microorganisms for further strain characterization or functional assessment.

Culturomics seems to be able to fill this gap. Currently, culturomics and metagenomics exhibit a high degree of complementarity and a certain degree of mutual validation.

Therefore, culturomics contributes to further understanding of gut microbiota composition and highlights microbial dark matter. Combining culturomics and metagenomic data provides insight into the structure and function of gut bacterial communities.

Future studies examining transcriptomic, proteomic, and lipidomic studies in animals exposed to a range of functional strains will contribute to our comprehensive understanding of the causal relationship between gut microbiota and human health and longevity.

In conclusion, this study increases our understanding of the relationship between gut microbiota and human health and longevity. Furthermore, we establish Lactobacillus as a powerful driver of human health and add significant literature support for its potential as an antioxidant.

These data also suggest that the gut microbiota, in addition to its intrinsically encoded specific biocatalytic activity, can induce host bioprocessing pathways with potential effects on ingested foreign organisms. To elucidate age-related trajectories of the gut microbiota, as well as generational-related differences that cannot be captured in cross-sectional data, further controlled longitudinal human studies across a broad age range are needed.

Based on the national civil registration system, a total of participants were randomly drawn from eight towns. Participants were eligible based on the following criteria: 1 born in Jiaoling; 2 5 years or longer continuous residence in Jiaoling backtracking from the sampling point; 3 aged 0— years.

All enrolled participants signed an informed consent form before their physical examination and biomaterial collection. Subsequently, participants meeting the following additional criteria were selected for the metagenomic study: 1 with fecal and blood samples; 2 without antibiotic treatment in the past month before biomaterial collections; 3 without severe diseases end-stage cancer, renal or liver disease.

For age-related group comparison analyses, we divided subjects from the Jiaoling cohort into six age groups using a cutoff of 20 years. Clinical measurements, height, weight, and waist circumferences were measured by trained staff according to standardized protocols.

Blood pressure mm Hg was measured three times using an automatic manometer, and the mean of the measures was used in the analysis. Statistics of the factors are summarized in Table 1 , Table S 1 , and Fig. Microbial DNA was extracted using the QIAamp DNA stool mini kit QIAGEN, Hilden, Germany with additional bead-beating and heating steps using standard methods Using Cutadapt v1.

Uparse software v7. QIIME software v1. Theprincipal coordinates analysis PCoA diagrams were plotted using R software v2. The differences among groups of alpha diversity and beta diversity index were analysed using R software. Linear discriminant analysis effect size LEfSe was performed to explain the differences between groups A total of 3,, Eight to ten suspicious colonies with typical morphology was selected from each sample for identification.

We obtained isolates from fecal samples. Recently, it has been shown that the food derived antioxidant compounds might protect the host from intestinal oxidative stress via modulating the composition of beneficial microbial species in the gut.

The present review summarizes the impact of food antioxidants including antioxidant vitamins, dietary polyphenols, carotenoids, and bioactive peptides on the structure as well as function of host gut microbial communities. Several in vitro, animal model, and clinical studies indicates that food antioxidants might modify the host gut microbial communities and their health status.

Dietary components have an important role on the structure and function of host gut microbial communities. Even though, various dietary components, such as carbohydrates, fats, proteins, fibers, and vitamins, have been studied in depth for their effect on gut microbiomes, little attention has been paid regarding the impact of several food antioxidants on the gut microbiome.

The long-term exposure to reactive oxygen species ROS can cause microbial dysbiosis which leads to numerous intestinal diseases such as microbiota dysbiosis, intestinal injury, colorectal cancers, enteric infections, and inflammatory bowel diseases.

Recently, it has been shown that the food derived antioxidant compounds might protect the host from intestinal oxidative stress via modulating the composition of beneficial microbial species in the gut.

The present review summarizes the impact of food antioxidants including antioxidant vitamins, dietary polyphenols, carotenoids, and bioactive peptides on the structure as well as function of host gut microbial communities. Out of 21, organizations, only 16 met the threshold criteria, i.

These constituted 5 clusters Supplemental Fig. This analysis shows that the microbiology laboratory at Wageningen University in the Netherlands published the most articles 18 , followed by the State key laboratory of animal nutrition at China Agricultural University in Beijing, which published 17 papers.

Both are among the top institutions working on anthocyanin and gut microbiota Supplemental Fig. On the other hand, when we performed the independent analysis of the same organizations, out of 21, fulfilled the criteria. The results reveal the same observations, even with no linkages Supplemental Fig.

On visualizing the year-wise work of organizations, it depicted that most of the collaborative studies were carried out in the — year by top working institutes, and independent research was carried out in recent years Supplemental Fig.

Edible parts of plants carry several health promoting compounds like, proteins, minerals, vitamins and coloured anthocyanins 70 , 71 , Numerous studies have discovered the health-promoting properties of anthocyanin-rich foods.

Anthocyanins have anti-obesity properties, as they help to maintain energy balance and satiety while inhibiting the accumulation of body fat and the development of insulin resistance, dyslipidemia, and inflammation 73 , A diet of anthocyanin-rich fruits and vegetables substantially influences the gut flora 13 , After being consumed, anthocyanins have limited bioavailability in the body due to their resistance to complete absorption.

Five percent to ten percent of total polyphenol consumption is absorbed in the small intestine. More importantly, most dietary anthocyanins arrive intact in the colon, where they may interact with the microbiota and undergo biotransformation before being absorbed via the intestinal mucosa This finding was supported by studies carried out after cut off time limit of this studies 77 , 78 , 79 , 80 , Several studies have shown that obesity is associated with the gut microbiome, which differs between obese and lean animals.

The impact was more pronounced when the anthocyanin-rich diet was followed for a more extended period and at larger dosages. Our data analysis from rodent models will also help future investigators with the utility of rodent research in understanding the effect of anthocyanins on human models and planning such clinical trials.

Gut health biomarker SCFAs also have significant relevance in human gut microbiota composition. The healthy gut microbiota metabolizes indigestible dietary components to SCFAs 82 , The present meta-analysis of laboratory studies on rodents found that anthocyanin-rich diet interventions efficiently improved the gut's SCFAs, including acetic, propionic, and butyric acid profiles.

Here also, the longer duration of the anthocyanin-rich diet intervention was more efficient in enhancing the levels of all three main SCFAs. Similarly, the higher dosage of the anthocyanin-rich food intervention was more effective. Aside from that, anthocyanins had more significant impacts on the concentrations of all SCFAs in high-fat diet-induced obesity models than in other disease models.

During meta-analysis, it was observed that a few studies with wider cumulative interval values had more influence on the overall results than a large number of normal studies. Therefore, additional analysis was carried out after removing such studies.

Thus, all the analyses were carried out without such studies, and we recommend the same. This improved the outcomes of the meta-analysis. We also noticed substantial methodological and experimental variances in the research. Animal care procedures, oral dosing, and water purification protocols are some examples of unbiased observed variables that must be recorded.

Since these factors significantly affect therapy outcomes 9. Publication bias is an important parameter in meta-analysis. It includes time lag, duplication, outcome reporting, linguistics, etc. Many electronic databases are examined to eliminate the likelihood of publication bias.

To eliminate data supply bias, we employ individual searches and extractions. Participant differences, as well as the intervention's intensity and duration, all contributed to variability.

The individuals' health, other therapies they were receiving simultaneously, supplement doses and contents, follow-up durations, treatment modalities, and so on all differed significantly among the trials. These variations may have had a significant role in the funnel plot's original asymmetry.

The appearance of an asymmetrical funnel plot is purely coincidental 84 , The Trim-Fill correction method made minor changes to all studies, and associated funnel plots revealed a symmetrical distribution of SE and SMD with p -values greater than 0. The funnel plot indicated that the studies chosen for our research are not biased.

It has also been observed that the discrepancy displayed by the GRADE tool is significant only when it affects confidence in the results concerning a specific decision. Even if the inconsistency is significant, it may still maintain confidence in the conclusion of a particular decision The variability is significant, but the disparities between small and large treatment effects could be the source of the substantial heterogeneity.

Bibliographic coupling analysis of leading researchers and institutes indicated that most research work relevant to anthocyanin and gut studies had recently been carried out in animal models, i.

It is envisaged that several such human studies will be published in the near future to validate that current finding. However, some important qualifiers to this study should be mentioned.

As a limitation, PROSPERO, a central international database platform that helps to eliminate data duplication and reduces the chance for reporting bias by permitting comparison of the finished review with what was planned in the protocol, was not notified that this study was being conducted.

Furthermore, the substantial amount of missing data for published studies and the exclusion of studies with incomplete data diminish the statistical power of our meta-analysis. The data we used can be found in the references listed and also given in the attached supplementary files.

All the figures represented in this manuscript have been produced by authors itself. Gutiérrez-Del-Río, I. et al. Terpenoids and polyphenols as natural antioxidant agents in food preservation.

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Meta-analysis reveals reproducible gut microbiome alterations in response to a high-fat diet. Cell Host Microbe 26 2 , — Jandhyala, S. Role of the normal gut microbiota. World J. Bibbò, S. The role of diet on gut microbiota composition. Google Scholar. Anhê, F.

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Download references. The authors are thankful to Dr. Humira Sonah for providing valuable data analysis advice. Authors are also thankful to Computational Biology Lab Facility provided by NABI-CDAC collaboration and DeLcO library facility. Authors are also thankful to National Agri-Food Biotechnology Institute Mohali, DBT, GOI for providing fellowships.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

National Agri-Food Biotechnology Institute, Mohali, Punjab, , India. Department of Biochemistry, Panjab University, Chandigarh, India.

If the trial included standard errors SE , the SE was converted to SD by multiplying the SE by the square root of the sample size. The standardized mean difference SMD was calculated using Hedges' adjusted g.

The Forest plots were created to display the SMDs and CIs, which represent each study's observed effect, confidence interval, and weight Statistical tests for heterogeneity I 2 , Chi 2 , and Tau 2 were used to assess the consistency of the study's results.

The treatment groups receiving low and high doses of anthocyanin were chosen for dose comparison through meta-analysis. In studies with more than two anthocyanin treatments or anthocyanin-rich food interventions, each treatment group was compared to the control group Subgroup analyses were performed to identify potential contributory variables equal to and more than ten weeks , dose higher and lower doses as per respective studies , an animal model type High fat diet-induced obesity, diabetes, and other diseases.

For SCFA analysis, studies were classified similarly into subgroups based on the duration less than four weeks vs. equal to and more than 4 weeks , dose, and animal model type. The RevMan 5. GRADEprofiler GRADEpro tool was used for the analysis of data quality.

For systematic reviews and recommendations in healthcare, the Grading of Recommendations Assessment, Development, and Evaluation GRADE provides a transparent and structured approach for creating and presenting evidence summaries, including the quality of that evidence Using GRADE, we classified the quality of our meta-analysis results into two categories: higher and lower.

Begg's and Egger's regression asymmetry tests were used for estimating publication bias in various forms, such as time-lag bias caused by delayed publication , duplicate or multiple publications, outcome reporting bias only reporting good results , and language bias.

Egger test used linear regression to test asymmetry with numbers by examining the relationship between the standardized effect estimates and the standard error Begg's test assessed the significance of the correlation between the ranks of the effect estimates and the ranks of their variances The publications were downloaded in the Medline file format.

After selection, visualization of the thematic contiguity of the articles was carried out using the Vos Viewer tool, which enabled the network charts. The network visualization consists of multiple-colored bubbles.

Moreover, the number of links between two bubbles depicted the level of interaction between the items under consideration. Detailed information on the search strategy and the process followed for the meta-analysis has been displayed in the PRISMA flowchart Fig.

We identified articles using various search engines through a literature survey. Of these articles, were review articles, and were research articles.

From the total research articles selected for the study, were duplicates and therefore removed. Afterward, article abstracts and the full text of articles were read thoroughly and checked to determine whether they met the eligibility criteria. Thirty-four studies met the eligibility criteria. Figure 1 shows the flow and data extraction of the current study.

To pass the test, you should aim for a kappa score of 0. Near-perfect agreement in the selection and filtering of studies was observed, with values over 0. Of the total studies, 14 investigated the impact of the intervention of anthocyanins from various berry fruits.

The remaining studies included interventions from other sources like cereals and pulses Table 1. Seventeen studies were conducted on males, one was conducted on female mice models, and two were performed on male rats. Study characteristics examining the effect of anthocyanins on SCFA profile acetic, propionic, and butyric acid were mentioned in Table 2.

Ten studies were conducted on male mice, one on female mice, and three on male rats. Twelve studies that looked at the effect of the anthocyanins-rich diet intervention on the concentration of SCFAs in the cecal matter of the different subjects looked at the effect of berries, and one study each looked at the effect of black rice and purple sweet potatoes.

The meta-analysis result also obtained sufficient heterogeneity, as indicated by I 2 values. Regarding the contribution of individual studies, some showed non-significant results, and others had a relatively higher influence on overall value than others.

Four studies, including Diez-Echave et al. Heterogeneity was quantified by I 2 , inverse variance and standardised mean difference [SMD]. Similar meta-analyses, i. Forest plots in Supplemental Figs. The meta-analyses results indicated that intervention duration of the more extended period, i.

There was no effect of the type of study model. Finalized data quality was evaluated by Grade Tool Supplemental Fig. Forest plot of studies investigating the effect of anthocyanin supplementation on the SCFA profile, sub-grouped by short chain fatty acid type.

Pooled effect estimates are shown by diamonds after removing highly influencing studies. The meta-analyses showed a significant effect of the anthocyanin-rich diet intervention on acetic, propionic, and butanoic acid concentration Table 4 , Fig.

Of the three SCFAs, the highest impact was observed on the acetic acid SMD High heterogeneity was obtained, as indicated by I 2 values. Each short-chain fatty acid was sub-grouped based on intervention duration, anthocyanin dose, and model type.

Table 5 and Supplemental Figs. The intervention of anthocyanin at a higher dose imparted a remarkable impact on acetic acid SMD: 2. We have found a higher rise in the butanoic acid concentration for a more extended period of study duration SMD: 1. Also, the butanoic acid concentration was significantly higher in the subjects taking a higher dose of anthocyanins SMD: 3.

The study subjects showed a remarkable rise in butanoic acid concentration in the high-fat diet-induced obesity model SMD: 3. A remarkable rise in propionic acid was observed in the studies followed for a longer period i.

The study subjects showed a significant rise in propionic acid when a higher dose was supplemented SMD: 4. The propionic acid levels were significantly increased in the subjects with high-fat diet-induced obesity SMD: 4.

The data quality of the SCFA meta-analysis was also evaluated by Grade Tool Supplemental Fig. The funnel plot for Figure S1 shows no evidence of publication bias. To depict the active collaborations in anthocyanin, gut microbiota, and SCFA research, we tried to detect the network level among the authors Supplemental Fig.

We selected authors with minimum criteria of 10 articles in the chosen field and observed 14 clusters represented in the author network. Out of 46, authors, fulfilled the minimum criteria. Supplemental Fig. It indicates that Chen, and Zhang, are the leading researcher in anthocyanin, gut microbiota, and SCFA-related studies, with 37 and 35 articles.

Most research work relevant to anthocyanin and gut studies has been carried out recently, i. We also attempted to track the institution and department collaborations through visualization analysis Supplemental Fig.

Out of 21, organizations, only 16 met the threshold criteria, i. These constituted 5 clusters Supplemental Fig. This analysis shows that the microbiology laboratory at Wageningen University in the Netherlands published the most articles 18 , followed by the State key laboratory of animal nutrition at China Agricultural University in Beijing, which published 17 papers.

Both are among the top institutions working on anthocyanin and gut microbiota Supplemental Fig. On the other hand, when we performed the independent analysis of the same organizations, out of 21, fulfilled the criteria.

The results reveal the same observations, even with no linkages Supplemental Fig. On visualizing the year-wise work of organizations, it depicted that most of the collaborative studies were carried out in the — year by top working institutes, and independent research was carried out in recent years Supplemental Fig.

Edible parts of plants carry several health promoting compounds like, proteins, minerals, vitamins and coloured anthocyanins 70 , 71 , Numerous studies have discovered the health-promoting properties of anthocyanin-rich foods.

Anthocyanins have anti-obesity properties, as they help to maintain energy balance and satiety while inhibiting the accumulation of body fat and the development of insulin resistance, dyslipidemia, and inflammation 73 , A diet of anthocyanin-rich fruits and vegetables substantially influences the gut flora 13 , After being consumed, anthocyanins have limited bioavailability in the body due to their resistance to complete absorption.

Five percent to ten percent of total polyphenol consumption is absorbed in the small intestine. More importantly, most dietary anthocyanins arrive intact in the colon, where they may interact with the microbiota and undergo biotransformation before being absorbed via the intestinal mucosa This finding was supported by studies carried out after cut off time limit of this studies 77 , 78 , 79 , 80 , Several studies have shown that obesity is associated with the gut microbiome, which differs between obese and lean animals.

The impact was more pronounced when the anthocyanin-rich diet was followed for a more extended period and at larger dosages. Our data analysis from rodent models will also help future investigators with the utility of rodent research in understanding the effect of anthocyanins on human models and planning such clinical trials.

Gut health biomarker SCFAs also have significant relevance in human gut microbiota composition. The healthy gut microbiota metabolizes indigestible dietary components to SCFAs 82 , The present meta-analysis of laboratory studies on rodents found that anthocyanin-rich diet interventions efficiently improved the gut's SCFAs, including acetic, propionic, and butyric acid profiles.

Here also, the longer duration of the anthocyanin-rich diet intervention was more efficient in enhancing the levels of all three main SCFAs. Similarly, the higher dosage of the anthocyanin-rich food intervention was more effective. Aside from that, anthocyanins had more significant impacts on the concentrations of all SCFAs in high-fat diet-induced obesity models than in other disease models.

During meta-analysis, it was observed that a few studies with wider cumulative interval values had more influence on the overall results than a large number of normal studies. Therefore, additional analysis was carried out after removing such studies.

Thus, all the analyses were carried out without such studies, and we recommend the same. This improved the outcomes of the meta-analysis. We also noticed substantial methodological and experimental variances in the research.

Animal care procedures, oral dosing, and water purification protocols are some examples of unbiased observed variables that must be recorded. Since these factors significantly affect therapy outcomes 9. Publication bias is an important parameter in meta-analysis. It includes time lag, duplication, outcome reporting, linguistics, etc.

Many electronic databases are examined to eliminate the likelihood of publication bias. To eliminate data supply bias, we employ individual searches and extractions.

Participant differences, as well as the intervention's intensity and duration, all contributed to variability. The individuals' health, other therapies they were receiving simultaneously, supplement doses and contents, follow-up durations, treatment modalities, and so on all differed significantly among the trials.

These variations may have had a significant role in the funnel plot's original asymmetry. The appearance of an asymmetrical funnel plot is purely coincidental 84 , The Trim-Fill correction method made minor changes to all studies, and associated funnel plots revealed a symmetrical distribution of SE and SMD with p -values greater than 0.

The funnel plot indicated that the studies chosen for our research are not biased. It has also been observed that the discrepancy displayed by the GRADE tool is significant only when it affects confidence in the results concerning a specific decision. Even if the inconsistency is significant, it may still maintain confidence in the conclusion of a particular decision The variability is significant, but the disparities between small and large treatment effects could be the source of the substantial heterogeneity.

Bibliographic coupling analysis of leading researchers and institutes indicated that most research work relevant to anthocyanin and gut studies had recently been carried out in animal models, i.

It is envisaged that several such human studies will be published in the near future to validate that current finding. However, some important qualifiers to this study should be mentioned. As a limitation, PROSPERO, a central international database platform that helps to eliminate data duplication and reduces the chance for reporting bias by permitting comparison of the finished review with what was planned in the protocol, was not notified that this study was being conducted.

Furthermore, the substantial amount of missing data for published studies and the exclusion of studies with incomplete data diminish the statistical power of our meta-analysis. The data we used can be found in the references listed and also given in the attached supplementary files.

All the figures represented in this manuscript have been produced by authors itself. Gutiérrez-Del-Río, I. et al. Terpenoids and polyphenols as natural antioxidant agents in food preservation. Article CAS Google Scholar. Vauzour, D. Polyphenols and human health: Prevention of disease and mechanisms of action.

Nutrients 2 , — Mattioli, R. Anthocyanins: A comprehensive review of their chemical properties and health effects on cardiovascular and neurodegenerative diseases.

Molecules 25 17 , Pavlos, S. Medicinal plants against obesity: A met-analysis of literature. Article Google Scholar. Roy, S. Anthocyanin food colorant and its application in pH-responsive color change indicator films. Food Sci. Li, D. Purified anthocyanin supplementation reduces dyslipidemia, enhances antioxidant capacity, and prevents insulin resistance in diabetic patients.

Naseri, R. Anthocyanins in the management of metabolic syndrome: A pharmacological and biopharmaceutical review. Front Pharmacol. Jayarathne, S. Protective effects of anthocyanins in obesity-associated inflammation and changes in gut microbiome.

Food Res. Bisanz, J. Meta-analysis reveals reproducible gut microbiome alterations in response to a high-fat diet. Cell Host Microbe 26 2 , — Jandhyala, S.

Role of the normal gut microbiota. World J. Bibbò, S. The role of diet on gut microbiota composition. Google Scholar. Anhê, F. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp.

population in the gut microbiota of mice. Gut 64 , — Jamar, G. Contribution of anthocyanin-rich foods in obesity control through gut microbiota interactions. BioFactors 43 4 , — Bravo, J. Communication between gastrointestinal bacteria and the nervous system.

Carding, S. Dysbiosis of the gut microbiota in disease. Health Dis. Young, V. The role of the microbiome in human health and disease: An introduction for clinicians.

BMJ , j j Armougom, F. Monitoring bacterial community of human gut microbiota reveals an increase in lactobacillus in obese patients and methanogens in anorexic patients. PLoS ONE 4 9 , e Article ADS CAS Google Scholar.

Ley, R. Microbial ecology: Human gut microbes associated with obesity. Nature , — Ghosh, S. Enterobacter hormaechei bac from the gut of flathead grey mullet as probable aquaculture probiont.

Chambers, E. Role of gut microbiota-generated short-chain fatty acids in metabolic and cardiovascular health. Hamer, H. Butyrate modulates oxidative stress in the colonic mucosa of healthy humans.

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Other dietary food compounds, such as the phytochemicals in plants, are believed to have greater antioxidant effects than vitamins or minerals. These are called the non-nutrient antioxidants and include phytochemicals, such as lycopenes in tomatoes and anthocyanins found in cranberries.

A diet high in antioxidants may reduce the risk of many diseases including heart disease and certain cancers. Antioxidants scavenge free radicals from the body cells and prevent or reduce the damage caused by oxidation. The protective effect of antioxidants continues to be studied around the world.

For instance, men who eat plenty of the antioxidant lycopene found in red fruits and vegetables such as tomatoes, apricots, pink grapefruit and watermelon may be less likely than other men to develop prostate cancer. Lycopene has also been linked to reduced risk of developing type 2 diabetes mellitus.

Lutein, found in spinach and corn, has been linked to a lower incidence of eye lens degeneration and associated vision loss in the elderly. Research also suggests that dietary lutein may improve memory and prevent cognitive decline. Studies show that flavonoid-rich foods prevent some diseases, including metabolic-related diseases and cancer.

Apples, grapes, citrus fruits, berries, tea, onions, olive oil and red wine are the most common sources of flavonoids. Plant foods are rich sources of antioxidants. They are most abundant in fruits and vegetables, as well as other foods including nuts, wholegrains and some meats, poultry and fish.

Good sources of specific antioxidants include:. There is increasing evidence that antioxidants are more effective when obtained from whole foods, rather than isolated from a food and presented in tablet form.

Research shows that some vitamin supplements can increase our cancer risk. For example, vitamin A beta-carotene has been associated with a reduced risk of certain cancers, but an increase in others — such as lung cancer in smokers if vitamin A is purified from foodstuffs.

A study examining the effects of vitamin E found that it did not offer the same benefits when taken as a supplement. A well-balanced diet, which includes consuming antioxidants from whole foods, is best.

If you need to take a supplement, seek advice from your doctor or dietitian and choose supplements that contain all nutrients at the recommended levels.

Research is divided over whether antioxidant supplements offer the same health benefits as antioxidants in foods. To achieve a healthy and well-balanced diet , it is recommended we eat a wide variety from the main 5 food groups every day:.

To meet your nutritional needs, as a minimum try to consume a serve of fruit and vegetables daily. Although serving sizes vary depending on gender, age and stage of life, this is roughly a medium-sized piece of fruit or a half-cup of cooked vegetables.