Dietary lipoic acid alleviates autism-like behavior induced by acrylamide in adolescent mice: the potential involvement of the gut-brain axis.

Consuming fried foods has been associated with an increased susceptibility to mental health disorders. Nevertheless, the impact of alpha-lipoic acid (α-LA, LA) on fried food-induced autism-like behavior remains unclear. This study aimed to explore how LA affects autism-related behavior and cognitive deficits caused by acrylamide in mice, a representative food hazard found in fried foods. This improvement was accomplished by enhanced synaptic plasticity, increased neurotrophin expression, elevated calcium-binding protein D28k, and restored serotonin. Additionally, LA substantially influenced the abundance of bacteria linked to autism and depression, simultaneously boosted short-chain fatty acid (SCFA) levels in fecal samples, and induced changes in serum amino acid concentrations. In summary, these findings suggested that exposure to acrylamide in adolescent mice could induce the development of social disorders in adulthood. LA showed promise as a nutritional intervention strategy to tackle emotional disorders during adolescence.

Lactobacillus plantarum LLY-606 Supplementation Ameliorates the Cognitive Impairment of Natural Aging in Mice: The Potential Role of Gut Microbiota Homeostasis.

This work explored the effects of Lactobacillus plantarum LLY-606 (LLY-606) on cognitive function in aging mice. Our findings demonstrated that LLY-606 effectively prolonged the lifespan of mice and improved age-related cognitive impairments. Additionally, our study revealed that supplementation with LLY-606 resulted in the downregulation of inflammatory cytokine levels and the upregulation of antioxidant capacity. Furthermore, probiotic supplementation effectively mitigated the deterioration of the intestinal barrier function in aging mice. Amplicon analysis indicated the successful colonization of probiotics, facilitating the regulation of age-induced gut microbiota dysbiosis. Notably, the functional abundance prediction of microbiota indicated that tryptophan metabolism pathways, glutamatergic synapse pathways, propanoate metabolism pathways, and arginine and proline metabolism pathways were enriched after the LLY-606 intervention. In summary, LLY-606 emerged as a potential functional probiotic capable of influencing cognitive function in aging mice. This effect was achieved through the modulation of gut microbiota, the regulation of synaptic plasticity, and the enhancement of neurotrophic factor levels.

Stevioside Ameliorates Prenatal Obesity Induced Postpartum Depression: The Potential Role of Gut Barrier Homeostasis.

SCOPE: Postpartum depression and cognitive impairment are the common complications of prenatal obesity. Stevioside is a non-nutritive natural sweetener with antioxidant and anti-inflammatory. However, its effects on depression behaviors and cognitive impairment induced by a high-fat diet (HFD) remain unclear. METHODS AND RESULTS: An 8-week HFD is used to establish a prenatal obesity model in female C57BL/6J mice to explore the improvement effects of stevioside (0.5 mg mL-1 in drinking water) on maternal depression and cognitive dysfunction after weaning. The results demonstrated that stevioside improves behavioral performance of obese maternal mice, and inhibits neuronal damage and 5-hydroxytryptamine (5-HT) abnormality induced by HFD. In addition, stevioside inhibits oxidative stress by reducing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) and glutathione (GSH) activities in the brains of obese maternal mice. Additionally, stevioside improves gut barrier integrity and prevented lipopolysaccharide (LPS) extravasation, and alleviates neuroinflammation. Correlation analysis shows that gut barrier and serum LPS are closely related to behavioral performance and brain biochemical indicators. CONCLUSION: Stevioside is capable to prevent prenatal obesity-induced cognitive and mood disorders by restoring intestinal barrier damage and inhibiting inflammation.

Leucine-Restricted Diet Ameliorates Obesity-Linked Cognitive Deficits: Involvement of the Microbiota-Gut-Brain Axis.

Leucine restriction (LR) improves insulin resistance and promotes white adipose tissue browning. However, the effect of LR on obesity-associated cognitive impairment remains unclear. The present study found that an 8-week LR dramatically improved high-fat diet (HFD)-induced cognitive decline by preventing synaptic dysfunction, increasing the expressions of neurotrophic factors, and inhibiting neuroinflammation in memory-related brain regions. Moreover, LR notably reshaped the structure of gut microbiota, which was manifested by downregulating the Firmicutes/Bacteroidetes ratio, reducing the relative abundance of inflammation-related bacteria including Acetatifactor, Helicobacter, Mucispirillum, and Oscillibacter but increasing short-chain fatty acid (SCFA)-producing bacterial genera including Alistipes, Allobaculum, Odoribacter, and Olsenella. Notably, HFD-caused SCFA reduction, gut barrier damage, and LPS leakage were recovered by LR. Our findings suggested that LR could serve as an effective approach to attenuate obesity-induced cognitive deficits, which may be achieved by balancing gut microbiota homeostasis and enhancing SCFA production.

Lactobacillus plantarum LLY-606 supplementation ameliorates hyperuricemia via modulating intestinal homeostasis and relieving inflammation.

Gut microbiota is associated with hyperuricemia progression and can be regulated by Lactobacillus plantarum. However, the role of Lactobacillus plantarum in hyperuricemia is still unknown. Thus, we constructed the mouse model of hyperuricemia using potassium oxonate and hypoxanthine treatment to explore the effects of Lactobacillus plantarum LLY-606 supplementation on the development of hyperuricemia. The results showed that Lactobacillus plantarum LLY-606 significantly reduced the level of serum uric acid through inhibiting uric acid secretion and regulating uric acid transport. We also found that Lactobacillus plantarum LLY-606 supplementation inhibited the inflammatory response and the activation of the TLR4/MyD88/NF-κB signaling pathway in mice. Microbiome sequencing and analysis suggested the successful colonization of probiotics, which could regulate intestinal flora dysbiosis induced by hyperuricemia. The abundance of Lactobacillus plantarum was significantly negatively correlated with hyperuricemia-related indicators. Notably, the functional abundance prediction of microbiota indicated that lipopolysaccharide biosynthesis protein pathways and lipopolysaccharide biosynthesis pathways were inhibited after the probiotic intervention. In conclusion, Lactobacillus plantarum LLY-606 can serve as a potential functional probiotic to affect the development of hyperuricemia through modulating gut microbiota, downregulating renal inflammation, and regulating uric acid metabolism.

Tryptophan-rich diet ameliorates chronic unpredictable mild stress induced depression- and anxiety-like behavior in mice: The potential involvement of gut-brain axis.

Tryptophan, an essential amino acid, has been reported that it has the potential to regulate depression-like behavior. Meanwhile, Chronic stress-induced depression also has a close relationship with gut microbiota structure and composition. In the current research, we demonstrated that a tryptophan-rich diet (0.6% tryptophan w/w) significantly attenuated depression- and anxiety-like behaviors in a chronic unpredictable mild stress (CUMS)-treated mouse model. Tryptophan supplementation improved neuroinflammation, increased expression of BDNF, and improved mitochondrial energy metabolism in the brain of CUMS-treated mice. Besides, CUMS also enhanced the kynurenine pathway, but repressed the serotonin pathway and indole pathway of tryptophan metabolism, leading to a decrease in 5-HT and indole in serum, whereas tryptophan supplementation might shift the tryptophan metabolism more toward the serotonin pathway in CUMS-treated mice. The gut microbiome was restructured by increasing the relative abundance of Lachnospiracea, Clostridium, Lactobacillus, Bifidobacterium in tryptophan-treated depressive mice. Moreover, tryptophan administration inhibited stress-induced gut barrier damage and decreased inflammatory responses in the colon. Together, our study purports the gut-brain axis as a mechanism for the potential of tryptophan to improve depression and anxiety-related behavior.

Sesamol ameliorates dextran sulfate sodium-induced depression-like and anxiety-like behaviors in colitis mice: the potential involvement of the gut-brain axis.

Inflammatory bowel disease (IBD) is accompanied by some psychiatric disorders, including anxiety and depression. Sesamol has been reported to alleviate colitis symptoms and depression-like behaviors caused by chronic unpredictable mild stress, but its protective effect and underlying neurobiological mechanism on IBD induced by dextran sulfate sodium (DSS) accompanying depression-like and anxiety-like behaviors remains still unclear. Here, we found that a six-week sesamol treatment (100 mg per kg bodyweight per day) for DSS-induced mice predominantly prevented inflammatory response, epithelial barrier dysfunction and depression-like and anxiety-like behaviors via the gut-brain axis. Sesamol alleviated neuroinflammatory responses via suppressing the TLR-4/NF-κB pathway, protected against oxidative stress and upregulated the Nrf2 antioxidant signaling pathway. Moreover, sesamol treatment improved brain-derived neurotrophic factor (BDNF) by upregulating the BDNF/TrkB/CREB signaling pathway, restored synaptic impairments and enhanced norepinephrine (NE) and serotonin (5-HT) levels. Importantly, the correlation analysis showed that the gut barrier and lipopolysaccharide (LPS) content in the serum were highly associated with behavioral performance and the biochemical indexes of the brain. In summary, the present study indicates that sesamol is a novel nutritional intervention strategy for preventing IBD and its symptoms of anxiety and depression.

Dietary protein and amino acid restriction: Roles in metabolic health and aging-related diseases.

The prevalence of obesity is a worldwide phenomenon in all age groups and is associated with aging-related diseases such as type 2 diabetes, as well metabolic and cardiovascular diseases. The use of dietary restriction (DR) while avoiding malnutrition has many profound beneficial effects on aging and metabolic health, and dietary protein or specific amino acid (AA) restrictions, rather than overall calorie intake, are considered to play key roles in the effects of DR on host health. Whereas comprehensive reviews of the underlying mechanisms are limited, protein restriction and methionine (Met) restriction improve metabolic health and aging-related neurodegenerative diseases, and may be associated with FGF21, mTOR and autophagy, improved mitochondrial function and oxidative stress. Circulating branched-chain amino acids (BCAAs) are inversely correlated with metabolic health, and BCAAs and leucine (Leu) restriction promote metabolic homeostasis in rodents. Although tryptophan (Trp) restriction extends the lifespan of rodents, the Trp-restricted diet is reported to increase inflammation in aged mice, while severe Trp restriction has side effects such as anorexia. Furthermore, inadequate protein intake in the elderly increases the risk of muscle-centric health. Therefore, the restriction of specific AAs may be an effective and executable dietary manipulation for metabolic and aging-related health in humans, which warrants further investigation to elucidate the underlying mechanisms.

Development of astaxanthin-loaded layer-by-layer emulsions: physicochemical properties and improvement of LPS-induced neuroinflammation in mice.

Astaxanthin (AST) has been shown to have neuroprotective effects; however, its bioavailability in vivo is low due to its hydrophobic properties. In this study, lactoferrin (LF) was prepared by heat-treatment at different temperatures, and on this basis, a layer-by-layer self-assembly method was used to construct double-layer emulsions with LF as the inner layer and polysaccharide (beet pectin, BP or carboxymethyl chitosan, CMCS) as the outer layer. Then AST was encapsulated in the emulsions and their physiochemical properties and function were investigated. The results indicated that high temperature heated LF (95 °C) showed a more stable structure than the lower temperature one, and the exposed internal nonpolar groups of LF could give the emulsion an enhanced stability. The rheology results showed that compared with CMCS, the double-layer emulsion formed by BP had a higher viscosity. In addition, the 95 °C LF-AST-BP emulsion showed the best stability among all the bilayer emulsions. The best emulsion was then used as a model drug to investigate its effects on lipopolysaccharide (LPS)-induced neuroinflammation and learning-memory loss in C57BL/6J mice. Through animal behavioral experiments, it was found that dietary supplementation with the AST emulsion could effectively improve the brain cognitive and learning memory impairment caused by inflammation. Transmission electron microscopy, mRNA and western blotting results also illustrated that the AST emulsion could alleviate neuroinflammation caused by LPS. This study provides a feasible scheme for exploring an AST loaded system and may be suitable for food and drug applications.

High-fiber diet mitigates maternal obesity-induced cognitive and social dysfunction in the offspring via gut-brain axis.

Maternal obesity has been reported to be related to neurodevelopmental disorders in the offspring. However, the underlying mechanisms and effective interventions remain unclear. This cross-sectional study with 778 children aged 7-14 years in China indicated that maternal obesity is strongly associated with children's lower cognition and sociality. Moreover, it has been demonstrated that maternal obesity in mice disrupted the behavior and gut microbiome in offspring, both of which were restored by a high-fiber diet in either dams or offspring via alleviating synaptic impairments and microglial maturation defects. Co-housing and feces microbiota transplantation experiments revealed a causal relationship between microbiota and behavioral changes. Moreover, treatment with the microbiota-derived short-chain fatty acids also alleviated the behavioral deficits in the offspring of obese dams. Together, our study indicated that the microbiota-metabolites-brain axis may underlie maternal obesity-induced cognitive and social dysfunctions and that high dietary fiber intake could be a promising intervention.

Methylated Metabolites of Chicoric Acid Ameliorate Hydrogen Peroxide (H2O2)-Induced Oxidative Stress in HepG2 Cells.

Chicoric acid (CA) can display health benefits as a dietary polyphenol. However, as CA is widely metabolized in vivo, the actual compounds responsible for its bioactivities are not entirely known. Herein, the major methylated metabolites of CA were isolated from an in vitro co-incubation system, and their structures were elucidated. The antioxidant activities of the monomethylated metabolites (M1) and dimethylated metabolites (M2) of CA were evaluated against H2O2-induced oxidative stress damage in HepG2 cells and compared to CA. The results indicated that both M1 and M2 had better antioxidant capacities than CA by increasing cell viability, improving mitochondrial function, and balancing cellular redox status. These compounds also prevented oxidative stress by mediating the Keap1/Nrf2 transcriptional pathway and downregulating enzyme activity. The current research indicates that the methylated metabolites of CA could potentially be the candidates that are responsible for the biological efficacies attributed to CA.

Phosphatidylcholine Ameliorates LPS-Induced Systemic Inflammation and Cognitive Impairments via Mediating the Gut-Brain Axis Balance.

Systemic inflammation will cause an imbalance in the steady state of the gut-brain axis. Phosphatidylcholine (PC) is a phospholipid found in egg yolk that has anti-inflammatory and antioxidant properties. The present research proved that PC supplementation (60 mg/kg body weight) for 35 days prevented inflammatory responses and behavioral disturbances in lipopolysaccharide (LPS)-induced mice. PC could regulate the expression of neurotrophic factors and synaptic proteins, which effectively alleviated the nerve damage and synaptic dysfunction caused by LPS. In addition, PC supplementation ameliorated gut barrier damage, altered gut genes, and improved gut health by modulating the cell adhesion molecule (CAM) pathway. Furthermore, PC remodeled the gut microbiome structure in the mice of the LPS group by increasing the relative abundance of Rikenellaceae and Lachnospiraceae. PC also increased short-chain fatty acid (SCFA) production in LPS-induced mice, which in turn ameliorated brain inflammatory responses. In conclusion, PC supplementation may be a nutritional strategy for the prevention of systemic inflammation via the gut-brain axis.

Sesamol Supplementation Attenuates DSS-Induced Colitis via Mediating Gut Barrier Integrity, Inflammatory Responses, and Reshaping Gut Microbiome.

Sesamol, a liposoluble lignan extract, has already been proved to possess potent anti-inflammatory properties, and it could also regulate gut dysfunction. The purpose of the present research is to explore the protective effect of sesamol on colitis mice. In the current research, sesamol treatment (100 mg/kg bodyweight/day) for 6 weeks inhibited the dextran sulphate sodium (DSS)-induced bodyweight loss of mice. Transmission electron microscopy and hematoxylin and eosin staining results showed that the DSS-induced histopathological changes of mice were also recovered by sesamol supplementation. In addition, DSS-induced inflammatory responses were inhibited by sesamol supplementation via the NF-κB signaling pathway in mice colon. Moreover, sesamol treatment prevented gut barrier damages by enhancing the expression of tight junction proteins (occludin, claudin-1, and ZO-1) and recovering the loss of gut mucus layer. Furthermore, sesamol supplementation also increased the short-chain fatty acid (SCFAs) contents of acetate, propionate, and butyrate. Furthermore, sesamol supplementation changed the gut microbiome structure by enhancing the relative abundance of Coprococcuscus, Butyricicoccus, Odoribacter, and AF12 in colitis mice. In conclusion, sesamol could effectively ameliorate DSS-induced colitis by promoting gut microecology.

Methionine Restriction Regulates Cognitive Function in High-Fat Diet-Fed Mice: Roles of Diurnal Rhythms of SCFAs Producing- and Inflammation-Related Microbes.

SCOPE: Methionine restriction (MR) is known to potently alleviate inflammation and improve gut microbiome in obese mice. The gut microbiome exhibits diurnal rhythmicity in composition and function, and this, in turn, drives oscillations in host metabolism. High-fat diet (HFD) strongly altered microbiome diurnal rhythmicity, however, the role of microbiome diurnal rhythmicity in mediating the improvement effects of MR on obesity-related metabolic disorders remains unclear. METHODS AND RESULTS: 10-week-old male C57BL/6J mice are fed a low-fat diet or HFD for 4 weeks, followed with a full diet (0.86% methionine, w/w) or a methionine-restricted diet (0.17% methionine, w/w) for 8 weeks. Analyzing microbiome diurnal rhythmicity at six time points, the results show that HFD disrupts the cyclical fluctuations of the gut microbiome in mice. MR partially restores these cyclical fluctuations, which lead to time-specifically enhance the abundance of short-chain fatty acids producing bacteria, increases the acetate and butyric, and dampens the oscillation of inflammation-related Desulfovibrionales and Staphylococcaceae over the course of 1 day. Notably, MR, which protects against systemic inflammation, influences brain function and synaptic plasticity. CONCLUSION: MR could serve as a potential nutritional intervention for attenuating obesity-induced cognitive impairments by balancing the circadian rhythm in microbiome-gut-brain homeostasis.

Sea-Buckthorn Flavonoids Alleviate High-Fat and High-Fructose Diet-Induced Cognitive Impairment by Inhibiting Insulin Resistance and Neuroinflammation.

Sea-buckthorn flavonoids (SFs) have been used as functional food components for their bioactive potential in preventing metabolic complications caused by diet, such as obesity and inflammation. However, the protective effect of SFs on cognitive functions is not fully clear. In this study, a high-fat and high-fructose diet (HFFD)-induced obese mice model was treated with SFs for 14 weeks. It was found that the oral SF administration (0.06% and 0.31% w/w, mixed in diet) significantly reduced bodyweight gain and insulin resistance in the HFFD-fed mice. SFs significantly prevented HFFD-induced neuronal loss and memory impairment in behavioral tests. Additionally, SFs also suppressed the HFFD-induced synaptic dysfunction and neuronal damages by increasing the protein expressions of PSD-95. Furthermore, SF treatment activated the ERK/CREB/BDNF and IRS-1/AKT pathways and inactivated the NF-κB signaling and its downstream inflammatory mediator expressions. In conclusion, SFs are a potential nutraceutical to prevent high-energy density diet-induced cognitive impairments, which could be possibly explained by their mediating effects on insulin signaling and inflammatory responses in the brain.

Secoisolariciresinol diglucoside alleviates hepatic lipid metabolic misalignment involving the endoplasmic reticulum-mitochondrial axis.

Secoisolariciresinol diglucoside (SDG) has positive effects on obesity and its complications. We investigated the effects and mechanism of SDG on high-fat and high-fructose diet (HFFD)-induced hepatic lipid metabolic disorders. Supplementation with 40 mg kg-1 d-1 SDG for 12 weeks significantly reduced the body weight and the ratio of liver and adipose tissue to body weight in HFFD-fed mice. Serum and hepatic TG, TC, HDL-C, and LDL-C levels became normalized, and hepatic lipid metabolic disorders lessened because of the downregulation of lipid synthesis genes and upregulation of lipid oxidation genes. SDG also alleviated endoplasmic reticulum (ER) stress and mitochondrial dysfunction by regulating the ER stress factors Bip, IRE1α, Xbp1, Atf6, Perk, and Chop and mitochondrial function-related genes Cox5b, Cox7a1, Cox8b, and Cycs. Results with HepG2 cells confirmed that SDG regulated lipid metabolic disorders by the ER stress-Ca2+-mitochondrial-associated pathway. Our study provides a strategy for the treatment of obesity and its related comorbidities.

Effects of alternate-day fasting, time-restricted fasting and intermittent energy restriction DSS-induced on colitis and behavioral disorders.

Intermittent fasting (IF) has been reported to have beneficial effects on improving gut function via lowering gut inflammation and altering the gut microbiome diversity. In this study, we aimed to investigate the differential effects of three different common IF treatments, alternate day fasting (ADF), time-restricted fasting (TRF), and intermittent energy restriction (IER), on a dextran sodium sulfate (DSS)-induced colitis mouse model. The results indicated that TRF and IER, but not ADF improved the survival rates of the colitis mice. TRF and IER, but not ADF, reversed the colitis pathological development by improving the gut barrier integrity and colon length. Importantly, TRF and IER suppressed the inflammatory responses and oxidative stress in colon tissues. Interestingly, TRF and IER also attenuated colitis-related anxiety-like and obsessive-compulsive disorder behavior and alleviated the neuroinflammation and oxidative stress. TRF and IER also altered the gut microbiota composition, including the decrease of the enrichments of colitis-related microbes such as Shigella and Escherichia Coli, and increase of the enrichments of anti-inflammatory-related microbes. TRF and IER also improved the short chain fatty acid formation in colitis mice. In conclusion, the TRF and IER but not ADF exhibited the protective effects against colitis and related behavioral disorders, which could be partly explained by improving the gut microbiome compositions and preventing gut leak, and consequently suppressing the inflammation and oxidative damages in both colon and brain. The current research indicates that proper IF regimens could be effective strategies for nutritional intervention for the prevention and treatment of colitis.

Lycopene Alleviates DSS-Induced Colitis and Behavioral Disorders via Mediating Microbes-Gut-Brain Axis Balance.

Gut microbes play significant roles in colitis development. The current study was aimed to uncover the preventive effects of lycopene (LYC), a functional carotenoid component, on colitis and the accompanied behavior disorders. The current study demonstrated that LYC treatment (50 mg/kg body weight/day) for 40 days prevented the dextran sulfate sodium (DSS)-induced gut barrier damages and inflammatory responses in male mice. LYC improved DSS-induced depression and anxiety-like behavioral disorders by suppressing neuroinflammation and prevented synaptic ultrastructure damages by upregulating the expressions of neurotrophic factor and postsynaptic-density protein. Moreover, LYC reshaped the gut microbiome in colitis mice by decreasing the relative abundance of proteobacteria and increasing the relative abundance of Bifidobacterium and Lactobacillus. LYC also elevated the generation of short-chain fatty acids and inhibited the permeability of lipopolysaccharide in colitis mice. In conclusion, LYC ameliorate DSS-induced colitis and behavioral disorders via mediating microbes-gut-brain axis balance.

Protective Effects of Sesamol on Systemic Inflammation and Cognitive Impairment in Aging Mice.

Sesamol, a lignan in sesame, possesses several bioactivities, such as antioxidation, anti-inflammation, and neuroprotective capability. In this study, the effects of sesamol on aging-caused cognitive defects are investigated. Twelve-month-old mice were treated with sesamol (0.1%, w/w) as dietary supplementation for 12 weeks. Behavioral tests revealed that sesamol improved aging-associated cognitive impairments. Sesamol decreased aging-induced oxidative stress via suppression of malondialdehyde production and increased antioxidant enzymes. Histological staining showed that sesamol treatment improved aging-induced neuronal damage and synaptic dysfunction in the hippocampus. Furthermore, sesamol significantly reduced aging-induced neuroinflammation by inhibiting the microglial overactivation and inflammatory cytokine expressions. Meanwhile, the accumulation of Aß1-42 was reduced by sesamol treatment. Moreover, sesamol protected the gut barrier integrity and reduced LPS release, which was highly associated with its beneficial effects on behavioral and inflammatory changes. In conclusion, our findings indicated that the use of sesamol is feasible in the treatment of aging-related diseases.