Regulation of gut microbiota by vitamin C, vitamin E and ß-carotene.

Vitamin C (VC), vitamin E (VE) and ß-carotene (ßC) are representative dietary antioxidants, which exist in daily diet and can increase the antioxidant capacity of body fluids, cells and tissues. The health benefits of vitamins like VC, VE and ßC are widely demonstrated. Given that the strong associations between the gut microbiota and host health or a range of diseases has been extensively reported, it is important to explore the modulatory effects of known vitamins on the gut microbiota. Herein, this article reviews the effects of VC, VE and ßC on the gut microbiota. Totally, 19 studies were included, of which eight were related to VC, nine to VE, and six to ßC. Overall, VC, VE and ßC can provide health benefits to the host by modulating the composition and metabolic activity of the gut microbiota, improving intestinal barrier function and maintaining the normal function of the immune system. Two perspectives are proposed for future studies: i) roles of known antioxidant activity of vitamins in regulating the gut microbiota and its molecular mechanism need to be further studied; ii) causal relationships between the regulatory effects of vitamins on gut microbiota and host health still remains to be further verified.

Microbially produced vitamin B12 contributes to the lipid-lowering effect of silymarin.

Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, we investigate the contributions of the gut microbiota to the improvement of liver lipid metabolism by silymarin. We find i) strong and significant microbial shifts upon silymarin but not silibinin treatment; ii) over 60% variations of liver fat are explained by silymarin-induced bacterial B12 production in male rats but not in male germ-free mice; iii) fecal microbiota transplantation confirms their protective roles against liver fat accumulation; iv) upregulation of one-carbon metabolism and fatty acid degradation pathways are observed based on the liver transcriptome analyses; and v) in humans the delta changes of serum B12 associate negatively with the fluctuations of serum triglycerides. Overall, we reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities.

Phytosterols as bioactive food components against nonalcoholic fatty liver disease.

Phytosterols are bioactive food components widely present in cell membranes of plants, especially in nuts and oilseeds. In recent years, many studies have shown that phytosterols possess therapeutic potentials for nonalcoholic fatty liver disease (NAFLD). This review summarizes the effects of phytosterols from in vitro and in vivo studies to lower the levels of total cholesterol (TC) and triglycerides (TG), and the evidence supporting the potential of phytosterols against NAFLD. The potential mechanisms by which phytosterols improve NAFLD may include (i) competition with cholesterol; (ii) regulation of key factors involved in cholesterol and TG metabolism; and (iii) inhibition of liver inflammation and (iv) regulation of liver fatty acid composition. In summary, phytosterols are potential natural ingredients with good safety profile against NAFLD, which deserve more future studies.

Modulation of gut microbiota by glycyrrhizic acid may contribute to its anti-NAFLD effect in rats fed a high-fat diet.

AIMS: Glycyrrhizic acid is a natural anti-non-alcoholic fatty liver disease (NAFLD) compound isolated from licorice, while its action mechanism deserves to be fully elucidated. MATERIALS AND METHODS: Enlightened by the widely discovered associations between the NAFLD and gut microbiota, this study aimed to explore whether glycyrrhizic acid, licorice flavonoids, and licorice extract can regulate the gut microbiota of rats fed a high-fat diet. KEY FINDINGS: It was found that glycyrrhizic acid, licorice flavonoids, and licorice extract could significantly reduce the level of triglycerides in the liver of NAFLD model rats, and the effect of glycyrrhizic acid was stronger than licorice flavonoids and licorice extract. Moreover, they caused significant changes in the structural composition of the gut microbiota. Correlation analysis showed that the regulation of hepatic total cholesterol and triglyceride levels by glycyrrhizic acid treatment was closely related to the decrease of the relative abundances of Lachnospiraceae, Coriobacteriaceae, Blautia, and Collinsella and the increase of the relative abundances of Romboutsia and Turicibacter on the gut microbiota. Meanwhile, the functional predictive analysis of the gut microbiota indicated that the function of carbohydrate transport and metabolism was significantly decreased by drugs treatment, which might contribute to the decrease of fat accumulation in the liver of rats. SIGNIFICANCE: In conclusion, this study revealed the ameliorating effects of glycyrrhizic acid, licorice flavonoids, and licorice extract on NAFLD, and suggested that the effect of glycyrrhizic acid on NAFLD may be related to the improvement of the dysbiosis of gut microbiota.

Are micronutrient levels and supplements causally associated with the risk of Alzheimer's disease? A two-sample Mendelian randomization analysis.

The potential of micronutrients, including vitamins and minerals, to prevent Alzheimer's disease (AD) has attracted much attention. However, the causal associations between micronutrient levels or supplements and AD risk remain unclear. We performed a two-sample Mendelian randomization (2SMR) analysis to evaluate the causal associations between micronutrient levels and supplements and AD risk. A total of 60 genome-wide association studies (GWAS) related to five types of vitamins (vitamins A, B, C, D, and E) and seven types of minerals (magnesium, calcium, iron, copper, zinc, selenium, and phosphorus) were included. For vitamins, using the data source provided by two GWAS, the analysis of 2SMR indicated that the vitamin D level was causally associated with a decreased risk of AD (IVW, OR: 0.474, 95%CI: 0.269-0.834, P-value = 0.010; OR: 0.857, 95%CI: 0.748-0.982, P-value = 0.027), while no effect of vitamin D supplement was observed. Currently, available data do not support the causal associations between the other four types of vitamins/supplements and AD risk. As for minerals, the copper level acted as a causal protective factor for AD risk (IVW, OR: 0.865, 95%CI: 0.751-0.998, P-value = 0.046). In conclusion, the present analysis indicated that among the vitamins and minerals, vitamin D and copper levels exhibited negative causal associations with AD risk, which may help in better use of micronutrients to prevent AD and require further verification by further studies.

Causal association evaluation of diabetes with Alzheimer's disease and genetic analysis of antidiabetic drugs against Alzheimer's disease.

BACKGROUND: Despite accumulating epidemiological studies support that diabetes increases the risk of Alzheimer's disease (AD), the causal associations between diabetes and AD remain inconclusive. The present study aimed to explore: i) whether diabetes is causally related to the increased risk of AD; ii) and if so, which diabetes-related physiological parameter is associated with AD; iii) why diabetes drugs can be used as candidates for the treatment of AD. Two-sample Mendelian randomization (2SMR) was employed to perform the analysis. RESULTS: Firstly, the 2SMR analysis provided a suggestive association between genetically predicted type 1 diabetes (T1D) and a slightly increased AD risk (OR = 1.04, 95% CI = [1.01, 1.06]), and type 2 diabetes (T2D) showed a much stronger association with AD risk (OR = 1.34, 95% CI = [1.05, 1.70]). Secondly, further 2SMR analysis revealed that diabetes-related physiological parameters like fasting blood glucose and total cholesterol levels might have a detrimental role in the development of AD. Thirdly, we obtained 74 antidiabetic drugs and identified SNPs to proxy the targets of antidiabetic drugs. 2SMR analysis indicated the expression of three target genes, ETFDH, GANC, and MGAM, were associated with the increased risk of AD, while CPE could be a protective factor for AD. Besides, further PPI network found that GANC interacted with MGAM, and further interacted with CD33, a strong genetic locus related to AD. CONCLUSIONS: In conclusion, the present study provides evidence of a causal association between diabetes and increased risk of AD, and also useful genetic clues for drug development.

Probiotics as potential therapeutic options for Alzheimer's disease.

The steadily increasing prevalence of Alzheimer's disease (AD) worldwide and the lack of effective therapeutic agent attract novel therapeutic approach in recent years. In view of the close relationships between gut microbiota and AD, probiotics have been suggested as potential therapeutic options for AD in recent years. The present review discussed the research progresses concerning the effects of probiotics administration to combat AD. A total of 35 studies, including 26 animal model studies and 9 human studies, were included herein. Among the 26 animal model studies, 24 used mice model, and 2 used Caenorhabditis elegans and Drosophila melanogaster AD models, respectively. As for probiotics, a total of 13 studies employed single-strain probiotic, and the rest studies used multi-strain probiotics (ranged from 2 to 9 probiotic strains), 4 used probiotic-fermented milk or probiotic-fermented soybean, 2 studies used engineered probiotic strain, and 4 studies focused on the combined effect of probiotics with AD drug memantine, selenium, or exercise. Bifidobacterium and Lactobacillus species were the most frequently used probiotics in the included studies. Overall, currently available studies showed that probiotic administration conferred neuroprotective benefits and could attenuate cognitive deficits and modulate gut microbiota dysbiosis, which may be related to oxidative and inflammatory pathways. Several perspectives on future studies on this topic are proposed. Thus, probiotics seem to be an attractive approach to combat AD, which deserves to be further studied by well-designed large-scale clinical studies. KEY POINTS: •We discussed the recent progresses concerning the effects of probiotics administration to combat AD. •A total of 35 associated studies consisted of 26 animal model studies and 9 human studies were included. •Most studies found that probiotic administration conferred neuroprotective benefits and could attenuate cognitive deficits.

Myricetin supplementation decreases hepatic lipid synthesis and inflammation by modulating gut microbiota.

The relationship between poor in vivo bioavailability and effective pharmacological activity are not yet fully clarified for many flavonoids. The analysis of flavonoids-induced alterations in the gut microbiota represents a promising approach to provide useful clues to elucidate the mechanism of action. Here, we investigate the effect of myricetin supplementation on high-fat-diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) in rats and explore the associations with the gut microbiota through high-throughput analyses. The 12-week myricetin supplementation and fecal microbiota transplantation outcomes suggest that myricetin significantly slows the development of NAFLD. Meanwhile, the anti-NAFLD effects of myricetin are associated with the modulation of the gut microbiota composition. Myricetin reduces hepatic lipid synthesis and inflammation through modulations in fecal butyric-acid-related gut microbiota and protection of the gut barrier function. This study may facilitate the elucidation of the action mechanism of flavonoids with low bioavailability.

Anti-inflammatory effect of luteolin is related to the changes in the gut microbiota and contributes to preventing the progression from simple steatosis to nonalcoholic steatohepatitis.

Increasing intestinal barrier function is one of the basic methods to suppress inflammation in the progression from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). Luteolin exists widely in vegetables, fruits and natural herbs and has various biological activities, including benefits on nonalcoholic fatty liver disease (NAFLD). However, its regulatory effects on the gut microbiota and involvement in its biological activities remain to be investigated. We fed rats a high-fat diet containing 0.5% luteolin for 12 weeks and determined the effects of luteolin on lipid metabolism, inflammation, and the gut microbiota. Supplementation with luteolin for 12 weeks significantly reduced blood lipids and hepatic lipid levels and improved liver fat accumulation and inflammation. Moreover, supplementation with luteolin led to the significant enrichment of more than 10% of gut bacterial species, which contributed to increase the abundance of ZO-1, reduce intestinal permeability, reduce plasma lipopolysaccharide, and inhibit the TLR4/NF-κB pathway. In summary, the anti-inflammatory effect of luteolin might be related to changes in the gut microbiota and contribute to preventing the progression from SS to NASH. Our research provides new insights into the anti-inflammatory mechanism of luteolin and supports its use as a dietary supplement for NAFLD patients.

Comparative analysis of heparin affecting the biochemical properties of chicken and murine prion proteins.

The conversion of cellular prion protein (PrPC) to disease-provoking conformer (PrPSc) is crucial in the pathogenesis of prion diseases. Heparin has been shown to enhance mammalian prion protein misfolding. As spontaneous prion disease has not been reported in non-mammalian species, such as chicken, it is interesting to explore the influence of heparin on the conversion of chicken prion protein (ChPrP). Herein, we investigated the influences of heparin on biochemical properties of full-length recombinant ChPrP, with murine prion protein (MoPrP) as control. The results showed that at low heparin concentration (10 µg/mL), a great loss of solubility was observed for both MoPrP and ChPrP using solubility assays. In contrast, when the concentration of heparin was high (30 µg/mL), the solubility of MoPrP and ChPrP both decreased slightly. Using circular dichroism, PK digestion and transmission electron microscopy, significantly increased ß-sheet content, PK resistance and size of aggregates were observed for MoPrP interacted with 30 µg/mL heparin, whereas 30 µg/mL heparin-treated ChPrP showed less PK resistance and slight increase of ß-sheet structure. Therefore, heparin can induce conformational changes in both MoPrP and ChPrP and the biochemical properties of the aggregates induced by heparin could be modified by heparin concentration. These results highlight the importance of concentration of cofactors affecting PrP misfolding.

Associations Between Obesity and Alzheimer's Disease: Multiple Bioinformatic Analyses.

BACKGROUND: Identifying modifiable risk factors, such as obesity, to lower the prevalence of Alzheimer's disease (AD) has gained much interest. However, whether the association is causal remains to be evaluated. OBJECTIVE: The present study was designed: 1) to make a quantitative assessment of the association between obesity and AD; 2) to validate whether there was a causal association between them; and 3) to provide genetic clues for the association through a network-based analysis. METHODS: Two-sample Mendelian randomization (2SMR) analysis, meta-analysis, and protein-protein interaction (PPI) network analysis, were employed. RESULTS: Firstly, the meta-analysis based on 9 studies comprising 6,986,436 subjects indicated that midlife obesity had 33%higher AD odds than controls (OR = 1.33, 95%CI = [1.03, 1.62]), while late-life obesity were inversely associated with AD risk (OR = 0.57, 95%CI = [0.47, 0.68]). Secondly, 2SMR analysis indicated that there was no causal association between them. Thirdly, CARTPT was identified to be shared by the anti-obesity drug targets and AD susceptibility genes. Further PPI network analysis found that CARTPT interacted with CD33, a strong genetic locus linked to AD. Finally, 2SMR analysis showed that CNR1 could be a protective factor for AD. CONCLUSION: Multiple bioinformatic analyses indicated that midlife obesity might increase the risk of AD, while current evidence indicated that there was no causal association between them. Further, CARTPT might be an important factor linking the two disease conditions. It could help to better understand the mechanisms underlying the associations between obesity and AD.

Regulatory effects of transition metals supplementation/deficiency on the gut microbiota.

Transition metal ions are essential micronutrients for all living organisms and exert a wide range of effects on human health. The uptake of transition metal ions occurs primarily in the gastrointestinal tract, which is colonized by trillions of bacterial cells. In recent years, increasing studies have indicated that transition metals have regulatory effects on the gut microbiota. In view of the significant effect of the gut microbiota on human health and involvement in the pathogenesis of a wide range of diseases, in this paper, we provide a comprehensive discussion on the regulatory effects of four kinds of transition metal ions on the gut microbiota. A total of 20 animal model and human studies concerning the regulatory effects of four types of transition metal ions (i.e., iron, copper, zinc, and manganese) on gut microbiota were summarized. Both the deficiency and supplementation of these transition metal ions on the gut microbiota were considered. Furthermore, the potential mechanisms governing the regulatory effects of transition metal ions on the gut microbiota were also discussed. KEY POINTS : • Regulatory effects of iron, copper, zinc, and manganese on gut microbiota were reviewed. • Both deficiency and supplementation of metal ions on gut microbiota were considered. • Mechanisms governing effects of metal ions on gut microbiota were discussed.

AlzRiskMR database: an online database for the impact of exposure factors on Alzheimer's disease.

In view of great difficulties in the pathogenesis analysis of Alzheimer's disease (AD) presently, profiling the modifiable risk factors is crucial for early detection and intervention of AD. However, the causal associations among them have yet to be identified, and the effective integration and application of these data also remain considerable challenges due to the lack of efficient collection and analysis procedures. To address this issue, we performed comprehensive analyses by two-sample Mendelian randomization (2SMR) and established the AlzRiskMR database (https://github.com/SDBMC/RiskFactors2AD). Four 2SMR analysis methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode, were used for the complementary calculation to test the reliability of the results. The database currently comprises 1870 sets of data of Genome-Wide Association Studies (GWAS) from the MR-Base and NHGRI-EBI GWAS Catalog database. AlzRiskMR database not only estimates causal associations between modifiable risk factors and AD but also offers a useful and timely resource for early intervention of AD development incidence.

Type 2 Diabetes Mellitus Drugs for Alzheimer's Disease: Current Evidence and Therapeutic Opportunities.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) represent two major health burdens with steadily increasing prevalence and accumulating evidence indicates a close relationship between the two disorders. In view of their similar pathogenesis, the potential of T2DM drugs for the treatment of AD has attracted considerable attention in recent years, with inspiring outcomes. Here, we provide a comprehensive overview of the effects of a total of 14 individual drugs (among which are seven T2DM drug types) against AD. Further, we discuss the potential action mechanisms of these T2DM drugs against AD. We argue that these findings may open novel avenues for AD drug discovery, drug target identification, and cotreatment of the two disorders.

Impact of modifiable risk factors on Alzheimer's disease: A two-sample Mendelian randomization study.

With the steadily increasing prevalence of Alzheimer's disease (AD) and great difficulties encountered for AD drug development presently, much interest has been devoted to identifying modifiable risk factors to lower the risk of AD, while the causal associations between risk factors and AD remain inconclusive. The present study conducted a comprehensive evaluation of the causal associations between risk factors and AD development by taking the recent advancements of Mendelian randomization (MR). Inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation. A total of 45 risk factors and corresponding studies were covered in the study. This two-sample MR (2SMR) analysis provided a suggestive association between genetically predicted higher years of schooling and reduced risks of AD, and each standard deviation (3.71 years) increased in years of schooling was associated with a 41% reduction in the risk of AD (IVW, OR: 0.59, 95% CI: 0.45-0.77). At the same time, it was genetically predicted that urate might be a risk factor in AD, and it was found that each standard deviation increase in urate levels (1.33 mg/dL) was associated with a 0.09-fold increase in the risk of AD (IVW, OR: 1.09, 95% CI: 1.01-1.18). To summarize, the 2SMR analysis indicated a suggestive association between genetically predicted higher years of schooling and reduced risks of AD, and between genetically predicted higher urate levels and increased risks of AD. The findings provide useful clues to help combat AD and warrants future studies.

Bidirectional interactions between curcumin and gut microbiota in transgenic mice with Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with increasing prevalence worldwide, while there are no effective drugs at present. Curcumin, a natural polyphenolic substance isolated from turmeric, is a promising natural compound to combat AD, but its pharmacology remains to be fully understood for its poor in vivo bioavalibility. Inspired by the recently reported associations between gut microbiota and AD development, the present study investigated the interactions of curcumin with gut microbiota of APP/PS1 double transgenic mice from two directions: (i) curcumin influences gut microbiota, and (ii) gut microbiota biotransform curcumin. It was found that curcumin administration tended to improve the spatial learning and memory abilities and reduce the amyloid plaque burden in the hippocampus of APP/PS1 mice. On the one hand, curcumin administration altered significantly the relative abundances of bacterial taxa such as Bacteroidaceae, Prevotellaceae, Lactobacillaceae, and Rikenellaceae at family level, and Prevotella, Bacteroides, and Parabacteroides at genus level, several of which have been reported to be key bacterial species associated with AD development. On the other hand, a total of 8 metabolites of curcumin biotransformed by gut microbiota of AD mice through reduction, demethoxylation, demethylation and hydroxylation were identified by HPLC-Q-TOF/MS, and many of these metabolites have been reported to exhibit neuroprotective ability. The findings provided useful clues to understand the pharmacology of curcumin and microbiome-targeting therapies for AD.

Impact of cooking on the antioxidant activity of spice turmeric.

Curcuminoids, as the main ingredient of turmeric, are popularly used in food additives and condiments, and are widely accepted to be beneficial for human health for their antioxidant activity. However, curcuminoids are highly susceptible in terms of thermal-induced degradation, and curry is usually boiled, roasted, or fried in the use of food additives and condiments. Thus, it is interesting to explore the effect of cooking on the antioxidant activity of curcuminoids. In the present study, the total antioxidant capacity (T-AOC) of cooked curcuminoids (boiled curcuminoids, roasted curcuminoids, and fried curcuminoids) processed through three heating conditions, and their protective effects against oxidative damage to rat pheochromocytoma (PC12) cells, a well-established neuronal model, were evaluated. It was found that cooking slightly lowered the T-AOC of curcuminoids, with boiled curcuminoids being relatively stronger than roasted curcuminoids, and fried curcuminoids being the weakest form. Both boiled and roasted curcuminoids could significantly improve cell viability, mitigate intracellular accumulation of reactive oxygen species and reduce malondialdehyde activity, reduce caspase-3 and caspase-9 protein expression, and increase superoxide dismutase activity of PC12 cells compared with the control group. In comparison with parent curcuminoids, the protective effects of cooked curcuminoids got relatively lower overall, with boiled curcuminoids being relatively stronger than roasted curcuminoids. In conclusion, the cooked curcuminoids, including boiled and roasted forms, still have antioxidant and neuroprotective activity.

Regulation of gut microbiota in Alzheimer's disease mice by silibinin and silymarin and their pharmacological implications.

The newly reported associations between Alzheimer's disease (AD) and gut microbiota indicate the potential of gut microbiota regulation-based therapeutic intervention for AD. Silymarin and its main active component, silibinin, are promising natural agents against AD, while their acting mechanisms remain to be explored. The present study investigated the effects of silibinin and silymarin administration on behavioral and histological manifestations, and regulation on the gut microbiota of transgenic APP/PS1 mice. First, silibinin and silymarin administration could alleviate memory deficits and reduce the amyloid plaque burden in the brain of APP/PS1 mice in comparison with controls. Second, silibinin and silymarin administration tended to decrease the microbiota diversity and exhibited regulative effect in abundances on several key bacterial species associated with AD development. This implied that gut microbiota regulation by silibinin and silymarin might be involved in their effects against AD. Further studies are warranted to fully elucidate the molecular mechanisms.

Astragalus alters gut-microbiota composition in type 2 diabetes mice: clues to its pharmacology.

Background: Astragalus possesses therapeutic effects for type 2 diabetes (T2D), while its action mechanisms remain to be elucidated. In view of the pathogenic associations between gut microbiota and T2D, we explored the effect of astragalus on gut-microbiota composition of T2D mice. Materials and methods: Modulation effects of astragalus on gut microbiota of T2D-model mice were assessed by 16S rRNA gene sequencing. Results: Inhibited blood-glucose and body-weight levels of T2D mice by astragalus were accompanied by gut microbiota-composition alteration. Astragalus administration significantly increased gut-microbiota richness and diversity in T2D mice and significantly altered the abundance of several bacterial taxa, inducing increased abundance of Lactobacillus and Bifidobacterium. PICRUSt software revealed the relationship between astragalus and T2D. Conclusion: Due to previously reported decreased gut-microbiota richness and diversity and reduced abundance of key species of Lactobacillus and Bifidobacterium, more studies are encouraged to explore the contribution of gut-microbiota alteration by astragalus to its anti-T2D effect.

Associations Between Gut Microbiota and Alzheimer's Disease: Current Evidences and Future Therapeutic and Diagnostic Perspectives.

Developing novel agents for unexplored targets to combat Alzheimer's disease (AD) represents an urgent task due to its increasing prevalence worldwide. The present paper summarizes the latest studies emerged in the past few years investigating the associations between the "forgotten organ" gut microbiota and AD from the following two aspects: 1) the associations between gut microbiota and AD development by animal models and human studies; and 2) the effects of gut microbiota modulation-based intervention for AD. Then, we propose future perspectives in two promising research areas: 1) developing gut microbiota modulation-based intervention; and 2) developing gut microbiota-associated diagnostic biomarkers for AD. Knowledge gaps and potential barriers to overcome towards these two goals are also discussed.