Rong Xiao

Introduction: Adolescence is a crucial period for youth development. However, many teenagers consume diets high in sugar and fat but low in essential nutrients, which can impair growth and increase the risk of obesity and metabolic diseases. This study developed a knowledge graph-based system that generates personalised menus for adolescents by combining structured nutrition data with individual dietary profiles, and evaluated its effects in a school setting. Methods: An adolescent dietary knowledge graph was built to integrate 339 dishes, 246 ingredients, 30 nutrients and 26 adolescent nutrient problems. This framework was enriched with 300 individual dietary profiles capturing physiological traits, health risks and taste preferences. Furthermore, a rule-based engine generated daily menus, aiming to meet nutrient targets. This was assessed using diet-quality indicators and a three-month randomised controlled trial involving 400 adolescents (intervention: n = 200; control: n = 200). Results: Recommended menus consistently showed higher scores on the Chinese Healthy Diet Index, Dietary Diversity Score and Food Variety Score than the non-intervention meals ( P < 0.0001). Following the intervention, the personalised menu group demonstrated significantly lower increases in body weight, body mass index and body fat index compared to the control group ( P < 0.05). Height gain did not differ significantly between groups ( P = 0.088). Conclusion: These results suggest that knowledge graph-based personalised recommendation systems can translate established nutritional guidelines into structured, individualised dietary guidance for adolescents. This integrated approach provides a feasible digital framework for implementing guideline-concordant meal planning in school settings and may help bridge the gap between general recommendations and the diverse needs of growing teenagers.

The epigenetic regulation of genes involved in cholesterol and oxysterol homeostasis is an emerging field with significant potential for elucidating the association between sterol homeostasis and diseases. DNA, RNA, histone modifications, as well as non-coding RNA, regulate cholesterol and oxysterol homeostasis by coordinating pathways involved in cholesterol synthesis, uptake, efflux, and alterations in metabolites. Therefore, dysregulation of epigenetic modifications may have important implications for the pathogenesis of cholesterol and oxysterol metabolism disorders. Here, we review recent advances in the function and mechanism of the interaction between cholesterol/oxysterol metabolism regulation and epigenetic modifications to discuss how each of the 4 parts of cholesterol metabolism is executed and regulated with the participation of epigenetic modification.

Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals. Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group). EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs accounted for the majority and were mainly accompanied by downregulated mRNAs, which was consistent with the downregulated expression of the m6A writer methyltransferase-like 4 (METTL4). 27-OHC and 24S-OHC combined with various gut metabolites significantly distinguished between MCI subgroups from healthy controls (EMCI/Control: AUC = 0.877; LMCI/Control: AUC = 0.952). Heatmap revealed the correlation between Phorbol myristate and differentially m6A-methylated mRNAs. Differentially expressed gut metabolites and methylated mRNAs were commonly enriched in 34 KEGG metabolic pathways, including cholesterol metabolism and neurodegenerative disease-related pathways. Our study explored the altered oxysterols, gut metabolites, and m6A methylation and their associations in different stages of MCI. The potential function of aberrant gut metabolites in oxysterols and m6A methylation driving MCI progression warrants further mechanistic investigation.

Background/Objectives: Alterations of oxysterols and gut microbiota have been recognized as indicators affecting mild cognitive impairment (MCI) and sarcopenia, respectively, whereas their association with co-dysfunction has not been investigated. Methods: In this study, a total of 1035 individuals were divided into Control (n = 264), MCI (n = 435), and MCI with possible sarcopenia (MPS, n = 336) groups. Cognition and muscle indexes, serum oxysterols, and gut microbiota were measured. Spearman’s rank coefficients were calculated to determine their correlations. Results: Performances of global and multidimensional cognitive tests was successively worse in the Control, MCI, and MPS groups. Longer duration of five-time chair stand test, lower 6-meter walk speed, and handgrip strength were observed in the MPS group, along with increased 27-hydroxycholesterol (27-OHC) and 5α,6α-epoxycholesterol and decreased 5α-Cholest-8(14)-ene-3β,15α-diol (15-HC). Higher concentrations of amyloid precursor protein (APP), neurofilament, and C-terminal agrin fragment (CAF) were discovered in the MCI and MPS groups. The α-diversity of gut microbiota in the MCI and MPS group was remarkably decreased, followed by a shifted abundance of microbial taxa, such as Alistipes and Rikenellaceae. Multiple significant correlations were found between cognition and muscle indexes and with oxysterols. Conclusions: Our study indicates that oxysterols and gut microbiota are prominently involved in the co-dysfunction of cognition and muscle.

Gut microbiota and microRNAs (miRNAs) have been proved to be intimately involved in dementia. Our previous studies have showed that oxysterols and the subsequent neurotoxic effects contributed to the pathogenesis of cognitive decline. However, the exact mechanism linking dietary oxysterol-induced cognitive changes, gut microbiota, and miRNAs remains elusive. Here, two sets of experiments were conducted on male C57BL/6J mice treated with mixed-oxysterol diet or 27-hydroxycholesterol (27-OHC) combined with antibiotic cocktails and miRNA antagonists. Neurobehavioral tests were conducted to assess learning and memory of mice. 16S ribosomal DNA gene sequencing was performed to evaluate microbial diversity and community composition. Oxysterol levels were detected using HPLC–MS. Western blotting and RT-qPCR were used to detect the expression of the intestinal barrier-related factors. We found that a 0.05% mixed-oxysterol diet altered the gut microbiota, damaged the intestinal barrier, upregulated the expression of miR-144-3p, and resulted in learning and memory impairment, while depleting the gut microbiota with antibiotic cocktails partly alleviated these injuries. Moreover, there were enhanced Aβ deposition, as well as higher 27-OHC and its metabolite in the brain of oxysterols-treated mice, which could be reduced by sterol 27-hydroxylase inhibitor-anastrozole, indicating that 27-OHC might be the key regulator of oxysterol-induced brain pathological changes. Additionally, by antagonizing miR-144-3p, microbiota dysbiosis-related Aβ deposition, oxysterol load, and cognitive decline were significantly ameliorated. Taken together, our study demonstrates that dietary oxysterols impair cognitive function through 27-OHC causing microbiota dysbiosis and intestinal barrier dysfunction, targeting miR-144-3p might be a promising strategy against cognitive impairment. Graphical Abstract

Oxysterols, as metabolites of cholesterol, play a key role in cholesterol homeostasis, autophagosome formation, and regulation of immune responses. Disorders in oxysterol metabolism are closely related to the pathogenesis of neurodegenerative diseases. To systematically investigate the profound molecular regulatory mechanisms of neurodegenerative diseases, it is necessary to quantify oxysterols and their metabolites in central and peripheral biospecimens simultaneously and accurately. However, there are a lot of unsolved problems with the existing methods, such as the hindrance of applying a single method to different biological specimens or the challenge of simultaneous quantification due to differential groups on the ends of the oxysterol side chains. Herein, according to the physicochemical properties and structure of oxysterols, an optimized liquid chromatography-tandem mass spectrometry method for the quantification of oxysterols was established by optimizing the sample preparation process, chromatographic conditions, mobile phase pH, and solvent selection. Seven oxysterols were detected by this method, including 27-hydroxycholesterol, 7α-hydroxycholesterol, 7α,27-dihydroxycholesterol, 7-dehydrocholesterol, 7α-hydroxy-3-oxo-4-cholestenoic acid, 3-hydroxy-5-cholestenoic acid, and 24(S)-hydroxycholesterol. Non-derivatization extraction with methyl tert-butyl ether was used for different biospecimens, followed by simultaneous chromatographic separation of oxysterols on a phenyl hexyl column. By repeated validation, this method exhibited satisfactory linearity, precision, recovery, sensitivity, repeatability, and stability, and it was successfully applied to the detection of oxysterols in the plasma, cerebral cortex, and liver of mouse. In summary, our optimized method enables concurrent analysis and quantification of oxysterols and their metabolites in various biospecimens, presenting a broad range of applicability.

To investigate the effect of vitamin D3 (VD3) combined with folic acid (FA) intervention on the cognitive function among patients with mild cognitive impai

Gut microbiome dysbiosis has been widely implicated in cognitive impairment, but the identity of the specific bacterial taxa and mechanisms are not fully elucidated. Brain glucose hypometabolism coincides with the cognitive decline. This study explored the link among cognition, gut microbiota and glucose uptake based on the fecal microbiota transplantation from mild cognitive impairment individuals (MCI-FMT) and investigated whether similar mechanisms were involved in 27-hydroxycholesterol (27-OHC)-induced cognitive decline. Our results showed that the MCI-FMT mice exhibited learning and memory decline and morphological lesions in the brain and colon tissues. There were reduced ¹⁸F-fluorodeoxyglucose uptake, downregulated expression of glucose transporters (GLUT1,3,4) and upregulated negative regulator of glucose uptake (TXNIP) in the brain. MCI-FMT altered the bacterial composition and diversity of the recipient mice, and the microbial signatures highlighted by the increased abundance of Bacteroides recapitulated the negative effects of MCI bacterial colonization. However, inhibiting Bacteroidetes or TXNIP increased the expression of GLUT1 and GLUT4, significantly improving brain glucose uptake and cognitive performance in 27-OHC-treated mice. Our study verified that cognitive decline and abnormal cerebral glucose uptake were associated with gut microbiota dysbiosis; we also revealed the involvement of Bacteroidetes and molecular mechanisms of TXNIP-related glucose uptake in cognitive deficits caused by 27-OHC.

Background: Cognitive impairment is associated with dysregulated immune responses. Emerging evidence indicates that Th17 cells and their characteristic cytokine-IL-17 are receiving growing interest in the pathogenesis of cognitive decline. Here, we focus on the involvement of Th17 cells in mild cognitive impairment (MCI) and the possible mechanism of cholesterol metabolite-27-hydroxycholesterol (27-OHC). Methods: 100 individuals were recruited into the nested case–control study who completed cognition assessment and the detection of oxysterols and Th17-related cytokines in serum. In addition, mice were treated with 27-OHC and inhibitors of RORγt and Foxp3 (Th17 and Treg transcription factors), and the factors involved in Th17/Treg balance and amyloidosis were detected. Results: Our results showed there was enhanced 27-OHC level in serum of MCI individuals. The Th17-related cytokines homeostasis was altered, manifested as increased IL-17A, IL-12p70, IL-23, GM-CSF, MIP-3α and TNF-α but decreased IL-13, IL-28A and TGF-β1. Further, in vivo experiments showed that 27-OHC induced higher immunogenicity, which increased Th17 proportion but decreased Treg cells in peripheral blood mononuclear cells (PBMCs); Th17 proportions in hippocampus, and IL-17A level in serum and brain were also higher than control mice. The fluorescence intensity of amyloid-β (Aβ) and the precursor of amyloid A amyloidosis–serum amyloid A (SAA) was increased in the brain of 27-OHC-treated mice, and worse learning and memory performance was supported by water maze test results. While by inhibiting RORγt in 27-OHC-loaded mice, Th17 proportions in both PBMCs and hippocampus were reduced, and expressions of IL-17A and TGF-β1 were down- and up-regulated, respectively, along with a decreased amyloidosis in brain and improved learning and memory decline. Conclusions: Altogether, our results demonstrate that excessive 27-OHC aggravates the amyloidosis and leads to cognitive deficits by regulating RORγt and disturbing Th17/Treg balance.