Type 3 resistant starch from Canna edulis reduce lipid levels in patients with mild hyperlipidemia through altering gut microbiome: A double- blind randomized controlled trial.

Type 3 resistant starch from Canna edulis (Ce-RS3) is an insoluble dietary fiber which could improve blood lipids in animals, but clinically robust evidence is still lacking. We performed a double-blind randomized controlled trial to assess the effects of Ce-RS3 on lipids in mild hyperlipidemia. One hundred and fifteen patients were included followed the recruitment criteria, and were randomly allocated to receive Ce-RS3 or placebo (native starch from Canna edulis) for 12 weeks (20 g/day). In addition to serum lipids, complete blood counts, serum inflammatory factors, antioxidant indexes, and dietary survey, 16 S rRNA sequencing technique was utilized to analyze the gut microbiota alterations. Targeted quantitative metabolomics (TQM) was used to detect metabolite changes. Compared with the placebo, Ce- RS3 significantly decreased levels of total cholesterol, lowdensity lipoprotein cholesterol, and non-high-density lipoprotein cholesterol, and increased the glutathione peroxidase. Based on the 16 S rRNA sequencing, TQM, the correlation analysis, as well as the Kyoto Encyclopedia of Genes (KEGG) and Genomes and Human Metabolome Database (HMDB) analysis, we found that Ce-RS3 could increase the abundances of genera Faecalibacterium and Agathobacter, while reduce the abundances of genera norank_f_Ruminococcaceae and Christensenellaceae_R-7_ group to regulate phenylalanine metabolism, which could reduce the fatty acid biosynthesis and fatty acid elongation in the mitochondria to lower blood lipids. Conclusively, we firstly confirmed the feasibility of Ce-RS3 for clinical application, which presents a novel, effective therapy for the mild hyperlipidemia. (Chictr. org. cn. Clinical study on anti-mild hyperlipidemia of Canna edulis RS3 resistant starch, ID Number: ChiCTR2200062871).

Oral challenge with Streptococcus sanguinis induces aortic inflammation and accelerates atherosclerosis in spontaneously hyperlipidemic mice.

Atherosclerosis is exacerbated by periodontal pathogens, which induce vascular inflammation after entering the bloodstream. Among oral indigenous bacteria, Streptococcus sanguinis and S. anginosus are related to systemic disorders, such as infective endocarditis and abscess, and are sometimes detected in human atherosclerotic plaques or blood. Thus, these oral streptococci may contribute to the progression of atherosclerosis. To test this hypothesis, apolipoprotein E-deficient spontaneously hyperlipidemic mice were intraorally challenged with S. sanguinis or S. anginosus. Atherosclerotic plaque formation increased significantly in the S. sanguinis-challenged group compared with the carboxymethylcellulose-treated control group. Expression levels of mRNAs of proinflammatory cytokines in the aorta and levels of atherosclerosis-related mediators in blood increased upon S. sanguinis challenge. Adaptor molecule TNF receptor-associated factor 6 was also enhanced in the aorta when mice were challenged with S. sanguinis. Furthermore, challenge with S. anginosus induced systemic inflammation, but inflammation-related mRNA expression levels in the aorta only increased slightly and were accompanied by minimal expansion of the lesion area. By contrast, with the exception of IL-1α, the expression levels of inflammation-related genes did not change in gingival tissues of both bacteria- and sham-challenged groups. These results reveal that S. sanguinis causes aortic inflammation that leads to accelerated progression of atherosclerosis.

Akebia Saponin D Regulates the Metabolome and Intestinal Microbiota in High Fat Diet-Induced Hyperlipidemic Rats.

Hyperlipidemia is a major component of metabolic syndrome, and regarded as one of the main risk factors causing metabolic diseases. We have developed a therapeutic drug, akebia saponin D (ASD), and determined its anti-hyperlipidemia activity and the potential mechanism(s) of action by analyzing the metabolome and intestinal microbiota. Male Sprague-Dawley rats were fed a high fat diet to induce hyperlipidemia, and then given ASD orally for 8 weeks. Lipid levels in serum were determined biochemically. Metabolites in serum, urine and feces were analyzed by UPLC-Q/TOF-MS, and the structure of the intestinal microbiota was determined by 16S rRNA sequencing. The ASD treatment significantly decreased the levels of TC, TG and LDL-c and increased the serum level of HDL-c. Metabolomics analysis indicated that the ASD treatment mainly impacted seven differential metabolites in the serum, sixteen differential metabolites in the urine and four differential metabolites in feces compared to the model group. The ASD treatment significantly changed eight bacteria at the genus level compared to the model group. In conclusion, ASD treatment can significantly alleviate HFD-induced hyperlipidemia and the hypolipidemic effect of ASD treatment is certainly associated with a systematic change in the metabolism, as well as dynamic changes in the structure of the intestinal microbiota.

The role of small intestinal bacterial overgrowth in the pathogenesis of hyperlipidemia.

OBJECTIVE: Introduction: Small intestinal bacterial overgrowth may cause the hyperlipidemia appearance by enterohepatic circulation disturbance which evolves on the background of the early bile acids deconjugation with further endotoxin production and oxidative stress in the liver with hyperproduction of cholesterol and atherogenic lipoproteins. The aim: the determination of prevalence and features of SIBO in a series of patients with hyperlipidemia and in control subjects. PATIENTS AND METHODS: Materials and methods: Nineteen patients with hyperlipidemia and ten control subjects were studied. Small intestinal bacterial overgrowth was assessed by a lactulose breath test. Such biochemical markers as CRP, ALT, AST, GGTP, apolipoprotein B, bilirubin, cholesterol and lipid profile were determined. Except the routine interpretation of lactulose breath test, which contains the SIBO detection, small intestinal transit time and hydrogen level evaluation with next comparison between groups of patients was realized. RESULTS: Results: Small intestinal bacterial overgrowth was present in 78.9% of patients with hyperlipidemia and 40% in control subjects. The maximal dose of H2 was particularly higher in patients with hyperlipidemia in comparison with control group (94,7±13,69 vs. 36,13±5,4). There was a strong correlation between AST level and SIBO existence in both groups (r=1). Positive connection between LDL, TG, VLDL and the dose of exhaled hydrogen on 120 minute (r=0.6, r= 0.62, r=0.7 respectively) and strong negative correlation between HDL and 120 minute dose (r=-0.74) in main group was marked. CONCLUSION: Conclusions: Patients with hyperlipidemia have a higher prevalence of small intestinal bacterial overgrowth and there is a relationship between H2 rate and LDL, TG, VLDL.

Aspirin eugenol ester regulates cecal contents metabolomic profile and microbiota in an animal model of hyperlipidemia.

BACKGROUND: Hyperlipidemia, with an increasing of prevalence, has become one of the common metabolic diseases in companion animal clinic. Aspirin eugenol ester (AEE) is a novel compound that exhibits efficacious anti-hyperlipidemia activities. However, its mechanisms are still not completely known. The objective of present study was to investigate the intervention effects of AEE on cecal contents metabonomics profile and microbiota in hyperlipidemia rats. RESULTS: Three groups of rats were fed with a control diet, or high fat diet (HFD) containing or not AEE. The results showed the beneficial effects of AEE in HFD-fed rats such as the reducing of aspartate aminotransferase (AST) and total cholesterol (TCH). Distinct changes in metabonomics profile of cecal contents were observed among control, model and AEE groups. HFD-induced alterations of eight metabolites in cecal contents mainly related with purine metabolism, linoleic acid metabolism, glycerophospholipid metabolism, sphingolipid metabolism and pyrimidine metabolism were reversed by AEE treatment. Principal coordinate analysis (PCoA) and cluster analysis of microbiota showed altered patterns with distinct differences in AEE group versus model group, indicating that AEE treatment improved the negative effects caused by HFD on cecal microbiota. In addition, the correction analysis revealed the possible link between the identified metabolites and cecal microbiota. CONCLUSIONS: This study showed regulation effects of AEE on cecal contents metabonomics profile and microbiota, which could provide information to reveal the possible underlying mechanism of AEE on hyperlipidemia treatment.

Western diet feeding influences gut microbiota profiles in apoE knockout mice.

BACKGROUND: Gut microbiota plays an important role in many metabolic diseases such as diabetes and atherosclerosis. Apolipoprotein E (apoE) knock-out (KO) mice are frequently used for the study of hyperlipidemia and atherosclerosis. However, it is unknown whether apoE KO mice have altered gut microbiota when challenged with a Western diet. METHODS: In the current study, we assessed the gut microbiota profiling of apoE KO mice and compared with wild-type mice fed either a normal chow or Western diet for 12 weeks using 16S pyrosequencing. RESULTS: On a western diet, the gut microbiota diversity was significantly decreased in apoE KO mice compared with wild type (WT) mice. Firmicutes and Erysipelotrichaceae were significantly increased in WT mice but Erysipelotrichaceae was unchanged in apoE KO mice on a Western diet. The weighted UniFrac principal coordinate analysis exhibited clear separation between WT and apoE KO mice on the first vector (58.6%) with significant changes of two dominant phyla (Bacteroidetes and Firmicutes) and seven dominant families (Porphyromonadaceae, Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae, Helicobacteraceae, Erysipelotrichaceae and Veillonellaceae). Lachnospiraceae was significantly enriched in apoE KO mice on a Western diet. In addition, Lachnospiraceae and Ruminococcaceae were positively correlated with relative atherosclerosis lesion size in apoE KO. CONCLUSIONS: Collectively, our study showed that there are marked changes in the gut microbiota of apoE KO mice, particularly challenged with a Western diet and these alterations may be possibly associated with atherosclerosis.

Effect of Marine Microalga Chlorella pyrenoidosa Ethanol Extract on Lipid Metabolism and Gut Microbiota Composition in High-Fat Diet-Fed Rats.

Effects of marine microalga Chlorella pyrenoidosa 55% ethanol extract (CPE55) on lipid metabolism, gut microbiota and regulation mechanism in high fat diet-fed induced hyperlipidaemia rats were investigated. Structure characterizations of major compounds in CPE55 were determined by ultra-performance liquid chromatography-quadrupole/time of flight mass spectrometry (UPLC-Q-TOF-MS/MS). The compositions of gut microbiota in rats were analyzed by high-throughput next-generation 16S rRNA gene sequencing. Oral administration with CPE55 markedly alleviated dyslipidemia through improving adverse blood lipid profile and inhibiting hepatic lipid accumulation and steatosis. CPE55 has downregulated the gene expression levels of acetyl CoA carboxylase, sterol regulatory element-binding transcription factor-1c, and 3-hydroxy-3-methyl glutaryl coenzyme A reductase and upregulated adenosine 5'-monophosphate-activated protein kinase-α. It has also improved the abundance of bacteria Alistipes, Prevotella, Alloprevotella, and Ruminococcus1 and decreased the abundances of Turicibacter and Lachnospira. Turicibacter and Lachnospira were both positive correlations of metabolic phenotypes. The findings above illustrated that CPE55 might be developed as food ingredients to ameliorate lipid metabolic disorders and hyperlipidaemia.

[Preliminary Study on Association Between Intestine Microbiota and Blood Glucose,Blood Lipid Metabolism in Middle-aged and Elderly People in Chengdu].

OBJECTIVE: To investigate the possible relationship between the gut microbiota and hyperlipidemia,hyperglycemia in middle-aged and elderly people in Chengdu. METHODS: 51 of middle-aged and elderly people participated in this study. The concentration of blood glucose and lipid,and the other physiological parameters of the subjects were analyzed,and their fecal microbiota was also profiled by Illumina high-throughput sequencing technique. RESULTS: The fecal microbiota in the middle-aged and elderly were mainly Firmicutes,Bacteroidetes,Proteobacteria,Fusobacteria,Actinobacteria,Verrucomicrobia. The diversity offecalmicrobiota was significantly lower in the subjects with higher blood glucose (P<0.05),while it did not exhibited relationship with changes in blood lipids. At the bacterial phyla: Proteobacteria and Bacteroidetes were respectively significantly higher in middle-aged and elderly women with higher blood glucose (P<0.05). At the bacterial genus: Faecalibacterium was significantly lower in the hyperglycemic subjects (P<0.05),its abundance and blood glucose levels were negatively correlated (r=⁻0.278,P=0.048); Prevotella and Paraprevotella were significantly lower in the high blood lipids group (P<0.05),and both of them were negatively correlated with blood lipid levels (r=⁻0.357,P=0.10; r=⁻0.365,P=0.008). CONCLUSION: The fecal microbiota in the tested middle-aged and elderly subjects varied with blood glucose and blood lipid concentration. Intestinal microbes might posses close relationship with blood glucose and lipid metabolism in middle-aged and elderly people.

Rhizoma Coptidis alkaloids alleviate hyperlipidemia in B6 mice by modulating gut microbiota and bile acid pathways.

It is hypothesized that Rhizoma Coptidis (RC) alkaloids exert their hypolipidemic effects primarily by targeting the gastrointestinal tract and liver. Thus, this study was conducted to evaluate the antihyperlipidemic mechanisms of RC alkaloids (at a daily dose of 140mg/kg for 35days) in high-fat and high-cholesterol induced hyperlipidemic B6 mice. After treatment, serum lipid parameters were determined, the expression of lipid metabolism related genes and pathways such as the sterol regulatory element binding proteins (SREBPs) and bile acid signaling in mice were also investigated. Meanwhile, Illumina sequencing was used to investigate the differences in gut microbiota of B6 mice. The results indicated that RC alkaloids reduced the body weight gain and serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), total bile acids (TBA) and lipopolysaccharide of B6 mice. Liver fat deposition and epididymal adipose cell size were also deceased in therapy group. RC alkaloids feeding significantly promoted the abundance of Sporobacter termitidis, Alcaligenes faecalis, Akkermansia muciniphila in the gut of mice, whereas, the abundance of Escherichia coli, Desulfovibrio C21_c20, Parabacteroides distasonis was suppressed. The observed antihyperlipidemic effects of RC alkaloids can also be attributed to their action as agonists of FXR and TGR5, activators for SREBP2, LDLR, UCP2 and CYP7A1, inhibitors of HMGCR, TXNIP, TLR4 and JNK. Therefore, this study expands current knowledge on hypolipidemic mechanisms of RC alkaloids and presents new evidence supporting a key role for RC alkaloids as regulators of lipid homeostasis by modulation gut microbiota and hepatic lipid metabolism.

Effect of prebiotics of Agave salmiana fed to healthy Wistar rats.

BACKGROUND: Inulin and other fructans are synthesized and stored in mezcal agave (Agave salmiana). Fructans provide several health benefits and have excellent technological properties, but only few data report their physiological effect when added in the diet. RESULTS: Here, we studied the physiological effects of fructans obtained from A. salmiana when added in the diet of Wistar rats. Results showed favorable changes on Wistar rats when the fructans was added to their diet, including the decrease of the pH in the feces and the increase of the number of lactic acid bacteria (CFU g-1 ) (Lactobacillus spp. and Bifidobacterium spp.), even these changes were enhanced with the synbiotic diet (fructans plus B. animalis subsp. lactis). Synbiotic diet, developed changes in the reduction of cholesterol and triglycerides concentrations in serum, with statistical differences (P < 0.05). Histological analysis of colon sections showed that synbiotic diet promoted colon cells growth suggesting that fructans from A. salmiana confer beneficial health effects through gut microbiota modulation. CONCLUSION: Our data underline the advantage of targeting the gut microbiota by colonic nutrients like specific structure of fructans from A. salmiana, with their beneficial effects. More studies are necessary to define the role of fructans to develop more solid therapeutic solutions in humans. © 2016 Society of Chemical Industry.

Effects of two whole-grain barley varieties on caecal SCFA, gut microbiota and plasma inflammatory markers in rats consuming low- and high-fat diets.

Mixed-linkage ß-glucans are fermented by the colon microbiota that give rise to SCFA. Propionic and butyric acids have been found to play an important role in colonic health, as well as they may have extraintestinal metabolic effects. The aim of the present study was to investigate how two whole-grain barley varieties differing in dietary fibre and ß-glucan content affected caecal SCFA, gut microbiota and some plasma inflammatory markers in rats consuming low-fat (LF) or high-fat (HF) diets. Barley increased the caecal pool of SCFA in rats fed the LF and HF diets compared with those fed the control diet, and the effect was generally dependent on fibre content, an exception was butyric acid in the LF setting. Furthermore, whole-grain barley reduced plasma lipopolysaccharide-binding protein and monocyte chemoattractant protein-1, increased the caecal abundance of Lactobacillus and decreased the Bacteroides fragilis group, but increased the number of Bifidobacterium only when dietary fat was consumed at a low level. Fat content influenced the effects of barley: rats fed the HF diets had a higher caecal pool of acetic and propionic acids, higher concentrations of amino acids and higher amounts of lipids in the portal plasma and liver than rats fed the LF diets; however, less amounts of butyric acid were generally formed. Interestingly, there was an increase in the caecal abundance of Akkermansia and the caecal pool of succinic acid, and a decrease in the proportion of Bifidobacterium and the Clostridium leptum group. In summary, whole-grain barley decreased HF diet-induced inflammation, which was possibly related to the formation of SCFA and changes in microbiota composition. High ß-glucan content in the diet was associated with reduced plasma cholesterol levels.

Structural and functional alteration of the gut microbiota in elderly patients with hyperlipidemia.

Objective: To investigate the structure, composition, and functions of the gut microbiota in elderly patients with hyperlipidemia. Methods: Sixteen older patients diagnosed with hyperlipidemia (M group) and 10 healthy, age-matched normal volunteers (N group) were included. These groups were further subdivided by sex into the male normal (NM, n = 5), female normal (NF, n = 5), male hyperlipidemia (MM, n = 8), and female hyperlipidemia (MF, n = 8) subgroups. Stool samples were collected for high-throughput sequencing of 16S rRNA genes. Blood samples were collected for clinical biochemical index testing. Results: Alpha- and beta-diversity analyses revealed that the structure and composition of the gut microbiota were significantly different between the M and N groups. The relative abundances of Bacteroides, Parabacteroides, Blautia, Peptococcus, and Bifidobacterium were significantly decreased, while those of Lactobacillus, Helicobacter, and Desulfovibrio were significantly higher in the M group. There were also significant sex-related differences in microbial structure between the NM and NF groups, and between the MM and MF groups. Through functional prediction with PICRUSt 2, we observed distinct between-group variations in metabolic pathways associated with the gut microbiota and their impact on the functionality of the nervous system. Pearson's correlation coefficient was used as a distance metric to build co-abundance networks. A hypergeometric test was used to detect taxonomies with significant enrichment in specific clusters. We speculated that modules with Muribaculaceae and Lachnospiraceae as the core microbes play an important ecological role in the intestinal microbiota of the M group. The relative intestinal abundances of Agathobacter and Faecalibacterium in the M group were positively correlated with serum triglyceride and low-density lipoprotein levels, while the relative abundance of Bifidobacterium was negatively correlated with the serum lipoprotein a level.

Microbiota based personalized nutrition improves hyperglycaemia and hypertension parameters and reduces inflammation: a prospective, open label, controlled, randomized, comparative, proof of concept study.

Background: Recent studies suggest that gut microbiota composition, abundance and diversity can influence many chronic diseases such as type 2 diabetes. Modulating gut microbiota through targeted nutrition can provide beneficial effects leading to the concept of personalized nutrition for health improvement. In this prospective clinical trial, we evaluated the impact of a microbiome-based targeted personalized diet on hyperglycaemic and hyperlipidaemic individuals. Specifically, BugSpeaks®-a microbiome profile test that profiles microbiota using next generation sequencing and provides personalized nutritional recommendation based on the individual microbiota profile was evaluated. Methods: A total of 30 participants with type 2 diabetes and hyperlipidaemia were recruited for this study. The microbiome profile of the 15 participants (test arm) was evaluated using whole genome shotgun metagenomics and personalized nutritional recommendations based on their microbiota profile were provided. The remaining 15 participants (control arm) were provided with diabetic nutritional guidance for 3 months. Clinical and anthropometric parameters such as HbA1c, systolic/diastolic pressure, c-reactive protein levels and microbiota composition were measured and compared during the study. Results: The test arm (microbiome-based nutrition) showed a statistically significant decrease in HbA1c level from 8.30 (95% confidence interval (CI), [7.74-8.85]) to 6.67 (95% CI [6.2-7.05]), p < 0.001 after 90 days. The test arm also showed a 5% decline in the systolic pressure whereas the control arm showed a 7% increase. Incidentally, a sub-cohort of the test arm of patients with >130 mm Hg systolic pressure showed a statistically significant decrease of systolic pressure by 14%. Interestingly, CRP level was also found to drop by 19.5%. Alpha diversity measures showed a significant increase in Shannon diversity measure (p < 0.05), after the microbiome-based personalized dietary intervention. The intervention led to a minimum two-fold (Log2 fold change increase in species like Phascolarctobacterium succinatutens, Bifidobacterium angulatum, and Levilactobacillus brevis which might have a beneficial role in the current context and a similar decrease in species like Alistipes finegoldii, and Sutterella faecalis which have been earlier shown to have some negative effects in the host. Overall, the study indicated a net positive impact of the microbiota based personalized dietary regime on the gut microbiome and correlated clinical parameters.

Effect of lotus seed resistant starch on small intestinal flora and bile acids in hyperlipidemic rats.

Ordinary and hyperlipidemic rats were gavaged with lotus seed resistant starch (LRS), and the structure of the small intestinal flora and bile acids composition were determined for four groups of rats to construct a relationship network diagram between different bacterial genera, bile acids and blood lipid profiles, revealing a microbial mechanism for the lipid-lowering effect of LRS in hyperlipidemic rats. LRS inhibited the growth of Romboutsia, Bacillus, Blautia, norank_f__Muribaculaceae and norank_f__Eubacterium_coprostanoligenes_group in hyperlipidemic rats. Meanwhile LRS promoted the production of primary bile acids (CA, CDCA, ß-MCA) and secondary bile acids (LCA, UDCA), and reduced the contents of TCA, Dehydro-LCA, isoLCA, LCA-3-S and THDCA in hyperlipidemic rats. Furthermore, Blautia, norank_f__Muribaculaceae and norank_f__Eubacterium_coprostanoligenes_group were positively correlated with Dehydro-LCA, isoLCA, TCA, LCA-3-S, TCHO, TG and LDL-C. In summary, LRS improves blood lipid levels by regulating small intestinal flora and accelerating the breakdown of cholesterol into bile acids in the liver.

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study.

Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.

Increased inflammation, impaired bacterial clearance, and metabolic disruption after gram-negative sepsis in Mkp-1-deficient mice.

MAPKs are crucial for TNF-alpha and IL-6 production by innate immune cells in response to TLR ligands. MAPK phosphatase 1 (Mkp-1) deactivates p38 and JNK, abrogating the inflammatory response. We have previously demonstrated that Mkp-1(-/-) mice exhibit exacerbated inflammatory cytokine production and increased mortality in response to challenge with LPS and heat-killed Staphylococcus aureus. However, the function of Mkp-1 in host defense during live Gram-negative bacterial infection remains unclear. We challenged Mkp-1(+/+) and Mkp-1(-/-) mice with live Escherichia coli i.v. to examine the effects of Mkp-1 deficiency on animal survival, bacterial clearance, metabolic activity, and cytokine production. We found that Mkp-1 deficiency predisposed animals to accelerated mortality and was associated with more robust production of TNF-alpha, IL-6 and IL-10, greater bacterial burden, altered cyclooxygenase-2 and iNOS expression, and substantial changes in the mobilization of energy stores. Likewise, knockout of Mkp-1 also sensitized mice to sepsis caused by cecal ligation and puncture. IL-10 inhibition by neutralizing Ab or genetic deletion alleviated increased bacterial burden. Treatment with the bactericidal antibiotic gentamicin, given 3 h after Escherichia coli infection, protected Mkp-1(+/+) mice from septic shock but had no effect on Mkp-1(-/-) mice. Thus, during Gram-negative bacterial sepsis Mkp-1 not only plays a critical role in the regulation of cytokine production but also orchestrates the bactericidal activities of the innate immune system and controls the metabolic response to stress.

The Impact of Microbial Composition on Postprandial Glycaemia and Lipidaemia: A Systematic Review of Current Evidence.

Postprandial hyperglycaemia is associated with increased risk of cardiovascular disease. Recent studies highlight the role of the gut microbiome in influencing postprandial glycaemic (PPG) and lipidaemic (PPL) responses. The authors of this review sought to address the question: "To what extent does individual gut microbiome diversity and composition contribute to PPG and PPL responses?". CINAHL Plus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from January 2010 to June 2020. Following screening, 22 studies were eligible to be included in the current review. All trials reported analysis of gut microbiome diversity and composition and PPG and/or PPL. Results were reported according to the 'Preferred Reporting Items for Systematic Reviews and Meta-Analysis' (PRISMA) statement. Individual microbiota structure was found to play a key role in determining postprandial metabolic responses in adults and is attributed to a complex interplay of diet, microbiota composition, and metagenomic activity, which may be predicted by metagenomic analysis. Alterations of gut microbiota, namely relative abundance of bacterial phylum Actinobacteria and Proteobacteria, along with Enterobacteriaceae, were associated with individual variation in postprandial glycaemic response in adults. The findings of the current review present new evidence to support a personalised approach to nutritional recommendations and guidance for optimal health, management, and treatment of common metabolic disorders. In conclusion, personalised nutrition approaches based on individual microbial composition may improve postprandial regulation of glucose and lipids, providing a potential strategy to ameliorate cardiometabolic health outcomes.

Enterococcus faecium R0026 Combined with Bacillus subtilis R0179 Prevent Obesity-Associated Hyperlipidemia and Modulate Gut Microbiota in C57BL/6 Mice.

Bacillus subtilis and Enterococcus faecium are commonly used probiotics. This study aimed to identify the effect of live combined Bacillus subtilis R0179 and Enterococcus faecium R0026 (LCBE) on obesityassociated hyperlipidemia and gut microbiota in C57BL/6 mice. Forty male C57BL/6 mice were divided into four groups: normal group (N group), model group (M group), low-dose group (L group), and high-dose group (H group). Mice were gavaged with LCBE at 0.023 g/mice/day (L group) or 0.23 g/mice/day (H group) and fed with a high-fat diet for 8 weeks. In vitro E. faecium R0026 showed an ability to lower the low-concentration of cholesterol by 46%, and the ability to lower the highconcentration of cholesterol by 58%. LCBE significantly reduced the body weight gain, Lee index, brown fat index and body mass index of mice on a high-fat diet. Moreover, LCBE markedly improved serum lipids (including serum triglyceride, total cholesterol, low-density lipoprotein and highdensity lipoprotein) while also significantly reducing liver total cholesterol. Serum lipopolysaccharide and total bile acid in L and H groups decreased significantly compared with M group. PCR-DGGE analysis showed that the composition of gut microbiota in the treatment groups was improved. Akkermansia muciniphila was found in H group. The PCA result indicated a similar gut microbiota structure between LCBE treatment groups and normal group while the number of bands and Shannon diversity index increased significantly in the LCBE treatment groups. Finally, qPCR showed Bifidobacterium spp. increased significantly in H group compared with M group, LCBE alleviated liver steatosis and improved brown adipose tissue index.

Periodontitis induces endothelial dysfunction in mice.

The treatment of periodontitis has numerous positive effects on established chronic health conditions, including cardiovascular disease and diabetes. However, ethical considerations do limit the establishment of human trials to investigate whether periodontitis promotes the early stages of chronic conditions. Therefore, the aim of this study was to investigate whether periodontitis induces endothelial dysfunction in hyperlipidemic apolipoprotein E gene-deficient (ApoE-/-) mice. Forty-five 8-week-old ApoE-/- mice were challenged by oral lavage with Porphyromonas gingivalis and Streptococcus gordonii for 4 weeks. A subgroup of animals (n = 15-17/group) was placed in a metabolic chamber immediately before euthanasia at 4 weeks to measure VO2/CO2 concentrations and voluntary locomotion. In infected and control animals alveolar bone levels were measured by x-ray imaging and endothelial function was determined by measuring endothelial-dependent vasorelaxation of aortic rings. The mRNA expression levels of serum amyloid A and tumor necrosis factor were determined in liver tissues by qRT PCR and protein concentrations in serum by ELISA. Caecal contents were analysed by sequencing to determine changes to the gut microbiota to investigate linkages between microbiome and systemic changes. The results showed that oral lavage of P. gingivalis and S. gordonii for 4 weeks, initiated periodontitis in ApoE-/- mice, similar to the human situation. The oral inflammation was accompanied by a significant increase in mRNA expression of pro-inflammatory mediators serum amyloid A1 and tumor necrosis factor in the liver. Mice with periodontitis also exhibited impaired endothelial-dependent vasorelaxation responses to acetylcholine. This systemic response was connected to increased energy expenditure, locomotion and respiratory quotient. No differences were detected in caecal microbiota between the infected and control animals. Overall, this is the first report that provide evidence that periodontitis induces endothelial dysfunction in mice. Other systemic responses observed in response to the local reaction need further investigation. The study suggests that early prevention of periodontitis may help limit the early stages of endothelial dysfunction that is linked to atherogenesis in humans.

Integrated Metagenomics and Metabolomics to Reveal the Effects of Policosanol on Modulating the Gut Microbiota and Lipid Metabolism in Hyperlipidemic C57BL/6 Mice.

The aim of the study was to investigate the regulatory effects of policosanol on hyperlipidemia, gut microbiota and metabolic status in a C57BL/6 mouse model. A total of 35 C57BL/6 mice were assigned to 3 groups, chow (n=12), high fat diet (HFD, n=12) and HFD+policosanol (n=11), then treated for 18 weeks. Policosanol supplementation significantly reduced serum triglycerides and total cholesterol, as well as the weight of brown adipose tissue (BAT) (p<0.05), without affecting body weight in HFD-fed mice (p>0.05). Combined 16S rRNA gene sequencing and untargeted metabolomic analysis demonstrated that policosanol had regulatory effects on gut microbiota and serum metabolism in mice. In obese mice, policosanol increased the proportion of Bacteroides, decreased the proportion of Firmicutes, and increased the ratio of Bacteroides to Firmicutes (p<0.05). Policosanol promoted lipolysis and thermogenesis process, including tricarboxylic acid (TCA) cycle and pyruvate cycle, correlated with the increasing level of Bacteroides, Parasutterella, and decreasing level of Lactobacillus and Candidatus_Saccharimonas. Moreover, policosanol decreased fatty acid synthase (FAS) in the iWAT of obese mice. Policosanol also increased peroxisome proliferators-activated receptor-γ (PPARγ), uncoupling Protein-1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PR domain containing 16 (PRDM16) in brown adipose tissue (BAT) obese mice (p<0.05). This study presents the new insight that policosanol may inhibit the synthesis of fatty acids, and promote lipolysis, thermogenesis related gene expression and regulate gut microbiota constituents, which provides potential for policosanol as an antihyperlipidemia functional food additive and provide new evidence for whole grain food to replace refined food.