Journal of Nutritional Biochemistry最新文献

High-fat diet (HFD) induces metabolic disturbances, in which gut microbiota and metabolites play a critical role. Although leonurine (LE) has demonstrated lipid-lowering effects, whether it ameliorates metabolic disorders through gut microbiota modulation remains unclear. Using 16S rRNA sequencing and untargeted metabolomics, we systematically evaluated the effects of LE on metabolic phenotypes, organ inflammation, intestinal barrier integrity, and the microbiota-metabolite axis in HFD-fed mice. Our results showed that LE significantly suppressed HFD-induced weight gain, dyslipidemia, and elevations in serum pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), while alleviating tissue inflammation and damage in the heart, liver, and kidneys. Furthermore, LE ameliorated HFD-related colon shortening, jejunal villus blunting, and decreased expression of tight junction proteins (ZO-1, Occludin), thereby enhancing intestinal barrier function. Gut microbiota analysis revealed that LE reversed HFD-induced dysbiosis, reduced the Firmicutes/Bacteroidetes ratio, and increased the abundance of beneficial genera such as Bifidobacterium. Metabolomic analysis further indicated that LE reduced intestinal levels of lipid metabolites (fatty acids, glycerides, glycerophospholipids) and markedly increased the content of the microbiota-derived metabolite indole-3-propionic acid (IPA). Correlation network analysis suggested that IPA levels were closely associated with beneficial bacterial abundance and improvements in lipid profiles and inflammatory markers. Mechanistically, LE elevated both serum and intestinal IPA levels, increased expression of the aryl hydrocarbon receptor (AhR), and decreased phosphorylation of NF-κB. Collectively, this study elucidates a novel association in which LE ameliorates HFD-induced metabolic inflammation and organ damage by remodeling the gut microbiota-metabolite axis, with the IPA-AhR pathway potentially playing a central role.

Maternal supplementation with Bifidobacterium animalis subsp. lactis (B. lac) in mice improves influenza virus infection resolution. Transmission pathways from mother to neonate are not fully identified. Benefits may be linked to metabolic modulations in plasma of mothers and in milk metabolome. To examine how maternal supplementation with B. lac impact maternal and offspring metabolomic profiles, pregnant mice were orally supplemented with B. lac for the five last days of pregnancy and the three first days of lactation (n=8-10). Plasma from mothers and offsprings and gastric contents (digested milk) from the offspring's stomach, were collected and high-throughput non-targeted metabolomic assays were applied. Hierarchical All-against-All association (HAllA) based on Spearman's rank correlations was performed to correlate the significant metabolites modulated by the maternal B. lac supplementation between the different compartments. The level of short-chain fatty acids (SCFAs) isocaproate and caproate, enriched in digested milk, showed a strong positive correlation with the level of equol glucuronide, the most affected bioactive compound in neonatal plasma with maternal B. lac supplementation. Moreover, milk isocaproate abundance also correlated positively with another bioactive metabolite in plasma offspring, the cinnamoylglycine. Additionally, the reduction of secondary bile acids (SBAs) and increase of vitamin E in maternal plasma were negatively and positively associated with SCFAs in digested milk, respectively. We identified several correlated microbial metabolites in the mother-milk-neonate relationship under maternal probiotic supplementation providing some insights into interactions between interconnected biological systems during perinatal period. While correlation does not imply causation, these findings provide valuable leads for future hypothesis-driven studies.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) affected approximately 25% of the global population, resulting in a huge economic burden. Silymarin, a traditional European herbal remedy with known hepatoprotective properties, has not been fully explored for its therapeutic potential in MAFLD.

Methods: MAFLD mice fed with high-fat diet (HFD) and palmitic acid (PA)-induced HepG2 cells were used to investigate the mechanism of silymarin in vivo and in vitro. HE and Oil Red were utilized to determine the lipotoxic injury in liver. The levels of glutathione (GSH), Malondialdehyde (MDA), iron, and reactive oxygen species (ROS) were measured via corresponding kits to verify the status of ferroptosis. The target of silymarin was validated through western blot, qPCR, immunohistochemistry and immunofluorescence. Targeted amino acid metabolomics was applied to detect the amino acid alteration in liver by LC-MS/MS.

Results: Silymarin reduced the weight and fat accumulation in MAFLD mice. The decreased levels of MDA and ROS and the increased level of GSH indicated that silymarin diminished hepatic ferroptosis. xCT is the potent target of silymarin in MAFLD. Cystine deprivation experiment indicated that cystine played a critical role in silymarin therapy. And silymarin treatment also resulted in amino acid reprogramming in liver.

Conclusions: These results suggested that silymarin alleviated MAFLD by targeting xCT and inhibiting ferroptosis. The alteration in amino acid by silymarin provided new clues for MAFLD therapy.

Given the significant clinical and economic burden of metabolic dysfunction-associated steatohepatitis (MASH), there is an urgent imperative to develop effective preventive and therapeutic agents. In this study, we evaluated the preventive effects and potential mechanisms of plant-derived compounds inositols (INS) and inositol hexakisphosphate (IP6) against MASH, utilizing a mouse model induced by western diet combined with low doses of CCl₄ (WD/CCl₄). The results showed that pretreatment with IP6 or INS significantly reduced obesity, fibrosis and lipid accumulation, alleviated insulin resistance, and prevented hyperglycemia in MASH mice. Both IP6 and INS also alleviated free fatty acid (FFA)- induced lipid accumulation in HepG2 cells. Transcriptomics analysis of the liver revealed that IP6 and INS reversed MASH-related transcriptomic changes, suppressing the expression of pro-fibrotic, pro-inflammatory, and lipid-metabolic genes. Integrated metabolomics and lipidomics revealed that the preventive effect of IP6 and INS against MASH was mediated through the rectification of disordered glycerophospholipid metabolism. Notably, knockdown of PEMT expression abolished the inhibitory effects of IP6 and INS on lipid accumulation, as well as α-SMA and COL-1 expression, in in vitro assays. These findings provide evidence that both IP6 and INS can prevent the development of MASH by improving disorders in glycerophospholipid metabolism, at least partially through the upregulation of PEMT.

Glutamine (Gln) is the body's most abundant and versatile amino acid, playing a crucial role in immune responses. The liver, a highly vascularized and metabolically active organ, has a strong regenerative capacity and is vital for immune function, detoxification of xenobiotics, and maintaining metabolic balance. This study aimed to clarify the molecular mechanisms involved in Gln's regulation of liver functions. Dietary supplementation with 1% Gln for weaned Kele × Large White (Yorkshire) hybrid piglets (castrated male) was administered over a period of 28 days. Our findings indicate that Gln enhances liver development processes. Through mRNA sequencing, 444 differentially expressed genes (DEGs) were identified between the control group and the Gln group. Gene Ontology (GO) enrichment analysis of DEGs revealed that the top 2 enriched biological processes were the immune system and the immune response. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis highlighted several T cell-related immune pathways, including Th1 / Th2 cell differentiation, Th17 cell differentiation, and T cell receptor signaling pathway. Analysis of the KEGG pathway network and protein-protein interaction (PPI) network showed that DEGs encoding CD8 α-chain (CD8A), lymphocyte-specific protein tyrosine kinase (LCK), and linker for activation of T cells (LAT) occupy central hub positions, suggesting their critical role in immune regulation. Real-time quantitative PCR (RT-qPCR) results were consistent with the RNA sequencing data. Furthermore, Western blot analysis showed significantly increased protein expression of LCK and LAT in the Gln group, indicating the activation of the CD8A / LCK / LAT signaling axis. These results highlight Gln's immunomodulatory effects through hepatic T-cell signaling and establish a foundation for further investigation into Gln's impact on liver physiology.

Epidemiological studies describe a positive correlation between sugar consumption during pregnancy and the risk for atopic respiratory diseases in the progeny. In the present study we developed an experimental model to test whether the offspring born to and/or breastfed by mice exposed to liquid fructose would manifest changes in the allergic airway disease induced by sensitization and challenge with ovalbumin (OVA). Male mice born to mothers consuming fructose during pregnancy and/or lactation exhibited exacerbated infiltration of eosinophils and lymphocytes in the bronchoalveolar lavage (BAL) after challenge with OVA. Such changes were not detected in the female progeny. On the other hand, the OVA-challenged female progeny born to and breastfed by mothers consuming fructose exhibited higher concentrations of IL-4, IL-5 and TGF-β1 in the BAL and IgE in serum. Additional characteristics that were specifically programmed in the male progeny born to mothers exposed to fructose during pregnancy and lactation comprised increased BAL levels of IL-10, eosinophil infiltration in the lung parenchyma, lung collagen deposition and goblet cell numbers and ccl11, muc5b and receptor for advanced glycation endproducts expression in the lung. Altogether, our experimental approach reveals a previously undescribed causal relationship between maternal fructose consumption and changes in the allergic response in the offspring exposed to the OVA model. Such changes are sex-specific and while the female progeny exhibits higher IL-4, IL-5, TGF-β1 and IgE levels upon challenge with OVA, only the male offspring manifested exacerbated hallmarks of severe disease, including cellular infiltration, goblet cell hyperplasia, and collagen deposition.

Dietary (poly)phenols and methylxanthines may help lower the risk of developing neurodegenerative diseases. However, the relationship between (poly)phenols and methylxanthines and age-related cognitive impairment has not been fully explored, in particular (poly)phenol-rich diets using biomarkers. A cross-sectional analysis was conducted on 202 participants aged 60 - 80 diagnosed with mild cognitive impairment (MCI) or two or more cardiometabolic disorders (CMD). The associations between metabolic signature/metabolites, cognition, and cardiometabolic risk were assessed using linear models, adjusted for covariates and multiple testing (FDR < 0.05). The metabolic signature of (poly)phenol-rich diet score (PPS) was linked with Quality of Episodic Memory (QEM), sustained attention, attentional fluctuation and intensity in the subgroups with CMD or MCI (FDR-adjusted p < 0.05). In plasma, 8 (poly)phenol metabolites presented significant inverse associations with MCI diagnosis, with 4-O-caffeoylquinic acid showing the strongest association (odds ratio: 0.84 (95% CI: 0.72, 0.98)). In cerebrospinal fluid (CSF), 6 metabolites were significantly associated with 4 cognitive outcomes, including QEM (FDR-adjusted p < 0.05). As for cardiometabolic outcomes, 5 plasma metabolites were inversely associated with Framingham risk score, while (-)-epicatechin in CSF showed negative associations with LDL-C and TC (FDR-adjusted p < 0.05). Plasma methylxanthine showed favourable associations with cardiometabolic markers, including paraxanthine and HDL-C (stdBeta: 0.17 (0.15, 0.30)), and 3-methylxanthine and HbA1c (stdBeta: -0.25 (-0.43, -0.07)). The PPS signature and (poly)phenol/methylxanthine metabolites from plasma and CSF are significantly associated with favourable cognitive and cardiometabolic outcomes, highlighting the potential role of a (poly)phenol-rich diet, particularly phenolic acids, in promoting cognitive and cardiometabolic health.

Manganese (Mn) is involved in hepatic lipoprotein secretion, and dietary Mn supplementation has been proposed as a potential therapeutic strategy for hyperlipidemia. SLC30A10 is a unique transporter responsible for Mn efflux from hepatocytes and regulated by dietary fructose. However, whether direct manipulation of hepatic Mn levels through SLC30A10 can alter plasma lipid levels remains unclear. Here we demonstrate that SLC30A10 regulates hepatic Mn levels without affecting hepatic triglyceride secretion or plasma lipid homeostasis. Adeno-associated virus-mediated overexpression of SLC30A10 significantly decreased hepatic Mn concentrations without compromising VLDL secretion or changing plasma triglyceride or total cholesterol levels in mice on either standard chow or high-fat diet (HFD). Moreover, hepatocyte-specific deletion of Slc30a10 gene in mice led to a marked Mn accumulation in the liver and to a less extent in the plasma, while hepatic lipoprotein secretion or plasma lipid levels were unaffected under either chow or HFD feeding condition. Taken together, these results suggest that manipulation of hepatic manganese levels through the exporter SLC30A10 does not alter plasma lipid homeostasis.

Dietary methionine restriction (MR) improves metabolic health in various animals. Beneficial effects on mice include reduced obesity and improved metabolism associated with the appearance of multilocular uncoupling protein 1 (UCP1) positive adipocytes in white fat. This suggests that MR-induced UCP1 thermogenesis contributes significantly to metabolic health. To test this, we evaluated MR effects using unique UCP1-deficient mice on a hybrid (F1) background that is resistant to developing hypothermia upon acute cold exposure. F1.Ucp1^HET and F1.Ucp1^KO mice were fed high fat control diet (HF-CD) and then switched to a high fat MR diet (HF-MRD). Indirect calorimetry was used to monitor energy metabolism; and, serum hormones, metabolites, tissue gene expression, and histology were evaluated. While both genotypes showed improved metabolic parameters when fed HF-MRD, F1.Ucp1^KO mice exhibited further changes in iWAT morphology and more pronounced metabolic improvements in glucose tolerance, serum metabolic biomarker profiles and hepatic steatosis compared to F1.Ucp1^HET. Strikingly, F1.Ucp1^KO mice showed elevated fatty acid oxidation compared with F1.Ucp1^HET when fed HF-CD that was sustained after the switch to HF-MRD. We posit that F1.Ucp1^KO mice employ fatty acid oxidation for body temperature maintenance as at least a part of a mechanism that protects them from acute exposure to cold temperatures in addition to development of diet-induced obesity. Furthermore, our studies suggest that many of the metabolic benefits of MR in mice do not require functional UCP1 thermogenesis.

Long-chain polyunsaturated fatty acids (LCPUFA) promote immune development and improve obesity-related inflammation. This study determined the effects of LCPUFA-supplemented diets (age Wk3-10) fed to male and female rats on: 1) anthropometrics and glucose tolerance, 2) splenocyte membrane lipid composition, 3) systemic and intestinal immune function, and 4) systemic, subcutaneous (SAT) and visceral (VAT) adipose inflammation. Wistar rats were fed a high-fat diet (20% w/w fat) with 0% docosahexaenoic acid (DHA)+0% arachidonic acid (ARA) (control), 1%DHA+1%ARA (1%DHA), 2%DHA+1%ARA (2%DHA) or 1%DHA+1%ARA+1% eicosapentaenoic acid (EPA) (fish oil). Diets did not alter anthropometrics or glucose tolerance. Compared to control, all diets increased DHA in splenocyte phosphatidylethanolamine, 2%DHA also increased DHA in phosphatidylcholine; fish oil increased EPA in phosphatidylethanolamine and phosphatidylcholine (P<0.01). Experimental diets altered splenocyte phenotypes (P<0.05), including higher % of activated cytotoxic T cells (2%DHA), natural killer T cells (2%DHA, fish oil) and dendritic cells/macrophages expressing MHC-II complex (1%DHA) without altering ex vivo responses to mitogens. In mesenteric lymph nodes, experimental diets lowered IL-10 (1%DHA, 2%DHA, female-only) and increased IL-8 (2%DHA) production after mitogen stimulation (P<0.01). In plasma, experimental diets lowered IL-8 (1%DHA, male-only), CRP (2%DHA) and TGF-β (2%DHA, female-only) (P<0.02). In SAT, 2%DHA increased IL-10 (male-only, P<0.05). In VAT, all diets increased IL-10, 2%DHA also increased leptin (P<0.01). Collectively, compared to high-fat control, LCPUFA diets reduced systemic and adipose inflammation and altered the splenocyte phenotypes and MLN immune response in a sex-specific manner. These effects may indicate improved immune and adipose function and were more pronounced in rats fed the 2%DHA.