High-fat diet induces sarcopenic obesity in natural aging rats through the gut-trimethylamine N-oxide-muscle axis.

INTRODUCTION: The lack of suitable animal models for sarcopenic obesity (SO) limits in-depth research into the disease. Emerging studies have demonstrated that gut dysbiosis is involved in the development of SO. As the importance of microbial metabolites is starting to unveil, it is necessary to comprehend the specific metabolites associated with gut microbiota and SO. OBJECTIVES: We aimed to investigate whether high-fat diet (HFD) causes SO in natural aging animal models and specific microbial metabolites that are involved in linking HFD and SO. METHODS: Young rats received HFD or control diet for 80 weeks, and obesity-related metabolic disorders and sarcopenia were measured. 16S rRNA sequencing and non-targeted and targeted metabolomics methods were used to detect fecal gut microbiota and serum metabolites. Gut barrier function was evaluated by intestinal barrier integrity and intestinal permeability. Trimethylamine N-oxide (TMAO) treatment was further conducted for verification. RESULTS: HFD resulted in body weight gain, dyslipidemia, impaired glucose tolerance, insulin resistance, and systemic inflammation in natural aging rats. HFD also caused decreases in muscle mass, strength, function, and fiber cross-sectional area and increase in muscle fatty infiltration in natural aging rats. 16S rRNA sequencing and nontargeted and targeted metabolomics analysis indicated that HFD contributed to gut dysbiosis, mainly characterized by increases in deleterious bacteria and TMAO. HFD destroyed intestinal barrier integrity and increased intestinal permeability, as evaluated by reducing levels of colonic mucin-2, tight junction proteins, goblet cells and elevating serum level of fluorescein isothiocyanate-dextran 4. Correlation analysis showed a positive association between TMAO and SO. In addition, TMAO treatment aggravated the development of SO in HFD-fed aged rats through regulating the ROS-AKT/mTOR signaling pathway. CONCLUSION: HFD leads to SO in natural aging rats, partially through the gut-microbiota-TMAO-muscle axis.

Peripheral amyloid-ß clearance mediates cognitive impairment in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent risk factor for cognitive impairment. Cerebral amyloid-ß (Aß) accumulation, as an important pathology of cognitive impairment, can be caused by impaired Aß clearance in the periphery. The liver is the primary organ for peripheral Aß clearance, but the role of peripheral Aß clearance in NAFLD-induced cognitive impairment remains unclear. METHODS: We examined correlations between NAFLD severity, Aß accumulation, and cognitive performance in female Sprague-Dawley rats. The impact of NAFLD on hepatic Aß clearance and the involvement of low-density lipoprotein receptor-related protein 1 (LRP-1) were assessed in rat livers and cultured hepatocytes. Additionally, a case-control study, including 549 NAFLD cases and 549 controls (782 males, 316 females), investigated the interaction between NAFLD and LRP-1 rs1799986 polymorphism on plasma Aß levels. FINDINGS: The severity of hepatic steatosis and dysfunction closely correlated with plasma and cerebral Aß accumulations and cognitive deficits in rats. The rats with NAFLD manifested diminished levels of LRP-1 and Aß in liver tissue, with these reductions inversely proportional to plasma and cerebral Aß concentrations and cognitive performance. In vitro, exposure of HepG2 cells to palmitic acid inhibited LRP-1 expression and Aß uptake, which was subsequently reversed by a peroxisome proliferator-activated receptor α (PPARα) agonist. The case-control study revealed NAFLD to be associated with an increment of 8.24% and 10.51% in plasma Aß40 and Aß42 levels, respectively (both P < 0.0001). Moreover, the positive associations between NAFLD and plasma Aß40 and Aß42 levels were modified by the LRP-1 rs1799986 polymorphism (P for interaction = 0.0017 and 0.0015, respectively). INTERPRETATION: LRP-1 mediates the adverse effect of NAFLD on peripheral Aß clearance, thereby contributing to cerebral Aß accumulation and cognitive impairment in NAFLD. FUNDING: Major International (Regional) Joint Research Project, National Key Research and Development Program of China, National Natural Science Foundation of China, and the Angel Nutrition Research Fund.

The role of peripheral ß-amyloid in insulin resistance, insulin secretion, and prediabetes: in vitro and population-based studies.

Background: Previous experimental studies have shown that mice overexpressing amyloid precursor protein, in which ß-amyloid (Aß) is overproduced, exhibit peripheral insulin resistance, pancreatic impairment, and hyperglycemia. We aimed to explore the effects of Aß on insulin action and insulin secretion in vitro and the association of plasma Aß with prediabetes in human. Methods: We examined the effects of Aß40 and Aß42 on insulin-inhibited glucose production in HepG2 cells, insulin-promoted glucose uptake in C2C12 myotubes, and insulin secretion in INS-1 cells. Furthermore, we conducted a case-control study (N = 1142) and a nested case-control study (N = 300) within the prospective Tongji-Ezhou cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) for prediabetes were estimated by using conditional logistic regression analyses. Results: In the in vitro studies, Aß40 and Aß42 dose-dependently attenuated insulin-inhibited glucose production in HepG2 cells, insulin-promoted glucose uptake in C2C12 myotubes, and basal and glucose-stimulated insulin secretion in INS-1 cells. In the case-control study, plasma Aß40 (adjusted OR: 2.00; 95% CI: 1.34, 3.01) and Aß42 (adjusted OR: 1.94; 95% CI: 1.33, 2.83) were positively associated with prediabetes risk when comparing the extreme quartiles. In the nested case-control study, compared to the lowest quartile, the highest quartile of plasma Aß40 and Aß42 were associated with 3.51-fold (95% CI: 1.61, 7.62) and 2.75-fold (95% CI: 1.21, 6.22) greater odds of prediabetes, respectively. Conclusion: Elevated plasma Aß40 and Aß42 levels were associated with increased risk of prediabetes in human subjects, which may be through impairing insulin sensitivity in hepatocytes and myotubes and insulin secretion in pancreatic ß-cells.

Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis.

BACKGROUND: Gut microbiota plays a key role in the development of sarcopenia via the 'gut-muscle' axis, and probiotics-based therapy might be a strategy for sarcopenia. Fecal microbiota transplantation from young donors (yFMT) has attracted much attention because of its probiotic function. However, whether or not yFMT is effective for sarcopenia in old recipients is largely unknown. Thus, we aimed to investigate the effect and mechanism of yFMT on age-related sarcopenia. METHODS: The fecal microbiota of either young (12 weeks) or old (88 weeks) donor rats was transplanted into aged recipient rats for 8 weeks. Then, muscle mass, muscle strength, muscle function, muscle atrophy, and muscle regeneration capacity were measured. Analysis of fecal 16 s rRNA, serum non-targeted metabolomic, gut barrier integrity, and muscle transcriptome was conducted to elucidate the interaction between gut microbiota and skeletal muscles. RESULTS: As evaluated by magnetic resonance imaging examination, grip strength test (P < 0.01), rotarod test (P < 0.05), and exhaustive running test (P < 0.05), we found that yFMT mitigated muscle mass loss, muscle strength weakness, and muscle function impairment in aged rats. yFMT also countered age-related atrophy and poor regeneration capacity in fast- and slow-switch muscles, which were manifested by the decrease in slow-switch myofibres (both P < 0.01) and muscle interstitial fibrosis (both P < 0.05) and the increase in the cross-section area of myofibres (both P < 0.001), fast-switch myofibres (both P < 0.01), and muscle satellite cells (both P < 0.001). In addition, yFMT ameliorated age-related dysbiosis of gut microbiota and metabolites by promoting the production of beneficial bacteria and metabolites-Akkermansia, Lactococcus, Lactobacillus, γ-glutamyltyrosine, 3R-hydroxy-butanoic acid, and methoxyacetic acid and inhibiting the production of deleterious bacteria and metabolites-Family_XIII_AD3011_group, Collinsella, indoxyl sulfate, indole-3-carboxilic acid-O-sulphate, and trimethylamine N-oxide. Also, yFMT prevented age-related destruction of gut barrier integrity by increasing the density of goblet cells (P < 0.0001) and the expression levels of mucin-2 (P < 0.0001) and tight junctional proteins (all P < 0.05). Meanwhile, yFMT attenuated age-related impairment of mitochondrial biogenesis and function in fast- and slow-switch muscles. Correlation analysis revealed that yFMT-induced alterations of gut microbiota and metabolites might be closely related to mitochondria-related genes and sarcopenia-related phenotypes. CONCLUSIONS: yFMT could reshape the dysbiosis of gut microbiota and metabolites, maintain gut barrier integrity, and improve muscle mitochondrial dysfunction, eventually alleviating sarcopenia in aged rats. yFMT might be a new therapeutic strategy for age-related sarcopenia.

DHPPA, a major plasma alkylresorcinol metabolite reflecting whole-grain wheat and rye intake, and risk of metabolic syndrome: a case-control study.

PURPOSE: Whole-grain intake assessed through self-reported methods has been suggested to be inversely associated with the metabolic syndrome (MetS) risk in epidemiological studies. However, few studies have evaluated the association between whole-grain intake and MetS risk using objective biomarkers of whole-grain intake. The aim of this study was to examine the association between plasma 3-(3,5-Dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, and MetS risk in a Chinese population. METHODS: A case-control study of 667 MetS cases and 667 matched controls was conducted based on baseline data of the Tongji-Ezhou Cohort study. Plasma DHPPA concentrations were assessed by high-performance liquid chromatography-tandem mass spectrometry. The MetS was defined based on criteria set by the Joint Interim Statement. RESULTS: Plasma DHPPA was inversely associated with MetS risk. After adjustment for age, sex, body mass index, smoking status, alcohol drinking status, physical activity and education level, the odds ratios (ORs) for MetS across increasing quartiles of plasma DHPPA concentrations were 1 (referent), 0.86 (0.58-1.26), 0.77 (0.52-1.15), and 0.59 (0.39-0.89), respectively. In addition, the cubic spline analysis revealed a potential nonlinear association between plasma DHPPA and MetS, with a steep reduction in the risk at the lower range of plasma DHPPA concentration. CONCLUSION: Our study revealed that individuals with higher DHPPA concentrations in plasma had lower odds of MetS compared to those with lower DHPPA concentrations in plasma. Our findings provided further evidence to support health benefits of whole grain consumption.

Insoluble yeast ß-glucan attenuates high-fat diet-induced obesity by regulating gut microbiota and its metabolites.

Emerging evidence suggests that insoluble dietary fiber prevents obesity by regulating gut dysbiosis. However, whether insoluble yeast ß-glucan (IYG) has an anti-obesity effect is still unclear. Here, the impact and potential mechanism of long-term IYG supplementation on high-fat diet (HFD)-induced obesity were investigated. After 24 weeks of long-term supplementation, IYG ameliorated weight gain, dyslipidemia, systemic inflammation, glucose intolerance and insulin resistance in HFD-fed rats. In addition, HFD-induced gut dysbiosis and changed levels of short-chain fatty acids and lipopolysaccharide were restored by IYG. Meanwhile, HFD-induced downregulations of tight junction proteins and Mucin 2 as well as elevated gut permeability were recovered by IYG. IYG also mitigated HFD-induced colonic inflammation and oxidative stress. Moreover, antibiotic treatment abrogated the protective effect of IYG on obesity, indicating the important role of gut microbiota in IYG's effect. This study demonstrated that IYG, as a potential prebiotic, exhibited a protective effect on HFD-induced obesity.

Quercetin-3-O-Glucuronide Alleviates Cognitive Deficit and Toxicity in Aß1-42 -Induced AD-Like Mice and SH-SY5Y Cells.

SCOPE: Alzheimer's disease (AD) is characterized by amyloid-ß (Aß) related imbalance, Tau-hyperphosphorylation, and neuroinflammation, in which Aß and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome. METHODS AND RESULTS: AD mice model built through intracerebroventricular injection of Aß1-42 and AD cell model developed through the SH-SY5Y cell line and Aß1-42 are used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain insulin signaling pathway, and high-throughput pyrosequencing of 16S rRNA are assessed. Data show that Q3G attenuates neuroinflammation and brain IR in Aß1-42 -injected mice and relieves apoptosis in Aß1-42 -treated SH-SY5Y cells by interrupting the downstream insulin signaling. Q3G ameliorates Aß accumulation and Tau phosphorylation, restores CREB and BDNF levels in the hippocampus , and reverses Aß1-42 -induced cognitive impairment. Besides, Q3G restores Aß1-42 -induced reduction of short-chain fatty acids (SCFAs) and gut microbiota dysbiosis. CONCLUSION: Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aß1-42 -induced cognitive dysfunction.

Yeast ß-glucan alleviates cognitive deficit by regulating gut microbiota and metabolites in Aß1-42-induced AD-like mice.

Alzheimer's disease (AD) is a neurodegenerative disease that remarkably imposes a huge global public health burden. Yeast ß-glucans have been incorporated in functional foods and used in prophylactic applications owing to their biological effects. However, few studies had investigated the effects of yeast ß-glucans on neurodegenerative diseases. Here, gut microbiota and metabolites SCFAs were analyzed through high-throughput 16S rRNA gene sequencing and GC-MS, respectively. Results indicated that yeast ß-glucans could prominently shape the intestinal flora and produce SCFAs. Aß1-42-induced AD mice treated with small-molecular yeast ß-glucan (S-ß-Glu) or macro-molecular yeast ß-glucan (M-ß-Glu) exhibited evident alterations of the composition of the gut microbiota, especially in some beneficial bacteria and inflammatory-related bacteria such as Lactobacillus, Bifidobacterium, Desulfovibrio, Oscillibacter, Mucispirillum, Alistipes, Anaerotruncus, and Rikenella. M-ß-Glu regulated gut microbiota act as prebiotics better than S-ß-Glu. Correlation analysis demonstrated the key microbiota closely associated with AD-related pathologies and cognition. Moreover, M-ß-Glu and S-ß-Glu ameliorated neuroinflammation and brain insulin resistance (IR), which played a central role in the process of AD pathology. This study broadened the underlying applications of yeast ß-glucans as a novel dietary supplementation to prevent early-stage pathologies associated with AD by regulating gut microbiota and the potential mechanism might be ameliorating brain IR.

Association of plasma ß-amyloid 40 and 42 concentration with type 2 diabetes among Chinese adults.

AIMS/HYPOTHESIS: There is evidence for a bidirectional association between type 2 diabetes and Alzheimer's disease. Plasma ß-amyloid (Aß) is a potential biomarker for Alzheimer's disease. We aimed to investigate the association of plasma Aß40 and Aß42 with risk of type 2 diabetes. METHODS: We performed a case-control study and a nested case-control study within a prospective cohort study. In the case-control study, we included 1063 newly diagnosed individuals with type 2 diabetes and 1063 control participants matched by age (±3 years) and sex. In the nested case-control study, we included 121 individuals with incident type 2 diabetes and 242 matched control individuals. Plasma Aß40 and Aß42 concentrations were simultaneously measured with electrochemiluminescence immunoassay. Conditional logistic regression was used to evaluate the association of plasma Aß40 and Aß42 concentrations with the likelihood of type 2 diabetes. RESULTS: In the case-control study, the multivariable-adjusted ORs for type 2 diabetes, comparing the highest with the lowest quartile of plasma Aß concentrations, were 1.97 (95% CI 1.46, 2.66) for plasma Aß40 and 2.01 (95% CI 1.50, 2.69) for plasma Aß42. Each 30 ng/l increment of plasma Aß40 was associated with 28% (95% CI 15%, 43%) higher odds of type 2 diabetes, and each 5 ng/l increment of plasma Aß42 was associated with 37% (95% CI 21%, 55%) higher odds of type 2 diabetes. Individuals in the highest tertile for both plasma Aß40 and Aß42 concentrations had 2.96-fold greater odds of type 2 diabetes compared with those in the lowest tertile for both plasma Aß40 and Aß42 concentrations. In the nested case-control study, the multivariable-adjusted ORs for type 2 diabetes for the highest vs the lowest quartile were 3.79 (95% CI 1.81, 7.94) for plasma Aß40 and 2.88 (95% CI 1.44, 5.75) for plasma Aß42. The multivariable-adjusted ORs for type 2 diabetes associated with each 30 ng/l increment in plasma Aß40 and each 5 ng/l increment in plasma Aß42 were 1.44 (95% CI 1.18, 1.74) and 1.47 (95% CI 1.15, 1.88), respectively. CONCLUSIONS/INTERPRETATION: Our findings suggest positive associations of plasma Aß40 and Aß42 concentration with risk of type 2 diabetes. Further studies are warranted to elucidate the underlying mechanisms and explore the potential roles of plasma Aß in linking type 2 diabetes and Alzheimer's disease.

Procyanidins Extracted from Lotus Seedpod Ameliorate Amyloid-ß-Induced Toxicity in Rat Pheochromocytoma Cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is characterized by extracellular senile plaque deposits, intracellular neurofibrillary tangles, and neuronal apoptosis. Amyloid-ß (Aß) plays a critical role in AD that may cause oxidative stress and downregulation of CREB/BDNF signaling. Anti-Aß effect has been discussed as a potential therapeutic strategy for AD. This study aimed to identify the amelioration of procyanidins extracted from lotus seedpod (LSPC) on Aß-induced damage with associated pathways for AD treatment. Rat pheochromocytoma (PC12) cells incubated with Aß 25-35 serve as an Aß damage model to evaluate the effect of LSPC in vitro. Our findings illustrated that LSPC maintained the cellular morphology from deformation and reduced apoptosis rates of cells induced by Aß 25-35. The mechanisms of LSPC to protect cells from Aß-induced damage were based on its regulation of oxidation index and activation of CREB/BDNF signaling, including brain-derived neurotrophic factor (BDNF) and phosphorylation of cAMP-responsive element-binding (CREB), protein kinase B (also known as AKT), and the extracellular signal-regulated kinase (ERK). Of note, by high-performance liquid chromatography-tandem mass spectroscopy (LC-MS/MS), several metabolites were detected to accumulate in vivo, part of which could take primary responsibility for the amelioration of Aß-induced damage on PC12 cells. Taken together, our research elucidated the effect of LSPC on neuroprotection through anti-Aß, indicating it as a potential pretreatment for Alzheimer's disease.