Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-c) was a strong risk factor for incident cardiovascular diseases and proved to be a better target of lipid-lowering therapies. Recently, gut microbiota has been implicated in the regulation of host metabolism. However, its causal role in the variation of non-HDL-c remains unclear. METHODS: Microbial species and metabolic capacities were assessed with fecal metagenomics, and their associations with non-HDL-c were evaluated by Spearman correlation, followed by LASSO and linear regression adjusted for established cardiovascular risk factors. Moreover, integrative analysis with plasma metabolomics were performed to determine the key molecules linking microbial metabolism and variation of non-HDL-c. Furthermore, bi-directional mendelian randomization analysis was performed to determine the potential causal associations of selected species and metabolites with non-HDL-c. FINDINGS: Decreased Eubacterium rectale but increased Clostridium sp CAG_299 were causally linked to a higher level of non-HDL-c. A total of 16 microbial capacities were found to be independently associated with non-HDL-c after correcting for age, sex, demographics, lifestyles and comorbidities, with the strongest association observed for tricarboxylic acid (TCA) cycle. Furthermore, decreased 3-indolepropionic acid and N-methyltryptamine, resulting from suppressed capacities for microbial reductive TCA cycle, functioned as major microbial effectors to the elevation of circulating non-HDL-c. INTERPRETATION: Overall, our findings provided insight into the causal effects of gut microbes on non-HDL-c and uncovered a novel link between non-HDL-c and microbial metabolism, highlighting the possibility of regulating non-HDL-c by microbiota-modifying interventions. FUNDING: A full list of funding bodies can be found in the Sources of funding section.

Enhanced interactions among gut mycobiomes with the deterioration of glycemic control.

BACKGROUND: The gut mycobiome is closely linked to health and disease; however, its role in the progression of type 2 diabetes mellitus (T2DM) remains obscure. Here, a multi-omics approach was employed to explore the role of intestinal fungi in the deterioration of glycemic control. METHODS: 350 participants without hypoglycemic therapies were invited for a standard oral glucose tolerance test to determine their status of glycemic control. The gut mycobiome was identified through internal transcribed spacer sequencing, host genetics were determined by genotyping array, and plasma metabolites were measured with untargeted liquid chromatography mass spectrometry. FINDINGS: The richness of fungi was higher, whereas its dissimilarity was markedly lower, in participants with T2DM. Moreover, the diversity and composition of fungi were closely associated with insulin sensitivity and pancreatic ß-cell functions. With the exacerbation of glycemic control, the co-occurrence network among fungus taxa became increasingly complex, and the complexity of the interaction network was inversely associated with insulin sensitivity. Mendelian randomization analysis further demonstrated that the Archaeorhizomycetes class, Fusarium genus, and Neoascochyta genus were causally linked to impaired glucose metabolism. Furthermore, integrative analysis with metabolomics showed that increased 4-hydroxy-2-oxoglutaric acid, ketoleucine, lysophosphatidylcholine (20:3/0:0), and N-lactoyl-phenylalanine, but decreased lysophosphatidylcholine (O-18:2), functioned as key molecules linking the adverse effect of Fusarium genus on insulin sensitivity. CONCLUSIONS: Our study uncovers a strong association between disturbance in gut fungi and the progression of T2DM and highlights the potential of targeting the gut mycobiome for the management of T2DM. FUNDINGS: This study was supported by MOST and NSFC of China.

Alistipes indistinctus-derived hippuric acid promotes intestinal urate excretion to alleviate hyperuricemia.

Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.

The association between depression during perimenopause and progression of chronic conditions and multimorbidity: results from a Chinese prospective cohort.

PURPOSE: The association between perimenopausal depression and many chronic conditions among women has been well-established. However, the role of depression during perimenopause in the progression of multiple chronic conditions (multimorbidity) remains poorly understood. MATERIAL AND METHODS: A total of 1,216 community-dwelling women in their perimenopause period between 2010 and 2016 were enrolled in our analysis, and followed up for the progression of multimorbidity. Depression, as well as its severity, was evaluated by the Center for Epidemiologic Studies Depression 10-item scale (CES-D-10). Progression of multimorbidity was defined as the first report of two or more chronic conditions for participants without multimorbidity or the new report of one or more conditions for those with multimorbidity. Univariable and multivariable Cox proportional hazards model and the restricted cubic spline regression model were performed to assess the prospective association between perimenopausal depression and the progression of multimorbidity. RESULTS: A total of 480 (39.5%) women reported depression during perimenopause, and 529 (43.5%) women progressed to multimorbidity. After adjusting for socio-demographic and lifestyle factors, perimenopausal depression was independently associated with the progression of multimorbidity (hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.13 to 1.60). Moreover, the severity of depression was positively and linearly associated with the progression of multimorbidity (P < 0.05). CONCLUSIONS: Our finding reveals a prospective association between perimenopausal depression and the progression of multimorbidity, indicating interventions targeting perimenopausal depression may reduce the burden of chronic diseases and multimorbidity in women's post-menopausal life.

RBP4-based Multimarker Score: A Prognostic Tool for Adverse Cardiovascular Events in Acute Coronary Syndrome Patients.

CONTEXT: Retinol binding protein 4 (RBP4) has been implicated in the progression of cardiovascular diseases. However, its association with major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) remains obscure. OBJECTIVE: Here, we examined the prognostic value of baseline RBP4 and its derived multimarker score for MACEs in ACS patients. METHODS: A total of 826 patients with ACS were consecutively recruited from the department of cardiology and prospectively followed up for a median of 1.95 years (interquartile range, 1.02-3.25 years). Plasma RBP4 was measured using enzyme-linked immunosorbent assay. Adjusted associations between RBP4 and its derived multimarker score (1 point was assigned when RBP4 ≥ 38.18µg/mL, left ventricular ejection fraction [LVEF] ≤ 55%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥ 450 ng/L, estimated glomerular filtration rate [eGFR] ≤ 90 mL/min/1.73 m2, and age ≥60) with MACEs were analyzed. RESULTS: In total, 269 ACS patients (32.57%) experienced MACEs. When patients were grouped by multimarker score (0-1, n = 315; 2-3, n = 406; 4-5, n = 105), there was a significant graded association between RBP4-based multimarker score and risk of MACEs (intermediate score (2-3): HRadj: 1.80; 95% CI, 1.34-2.41; high score (4-5): HRadj: 3.26; 95% CI, 2.21-4.81) and its components (P < .05 for each). Moreover, the prognostic and discriminative value of the RBP4-derived multimarker score remained robust in ACS patients with various high-risk anatomical or clinical characteristics. CONCLUSION: The RBP4-derived 5-item score serves as a useful risk stratification and decision support for secondary prevention in patients with ACS.

Cardiometabolic benefits of Lacticaseibacillus paracasei 8700:2: A randomized double-blind placebo-controlled trial.

BACKGROUND & AIMS: Modulating microbial metabolism via probiotic supplementation has been proposed as an attractive strategy for the prevention of cardiometabolic diseases. Recently, Lacticaseibacillus paracasei (L. paracasei) was reported to alleviate metabolic disorders in murine models, however, its beneficial effects in humans remain to be determined. This study evaluated whether L. paracasei supplementation could improve endothelial function and cardiometabolic health in subjects with metabolic syndrome (MetS). METHODS: In this randomized, double-blind and placebo-controlled trial among 130 participants with MetS, subjects were randomly assigned to placebo or L. paracasei 8700: 2 (10 billion CFU) daily for 12 weeks. Endothelial function was measured by flow-mediated slowing, and cardiometabolic health was determined by both components and severity of MetS. Ideal compliance was defined as consumption no less than 70% of the capsules. RESULTS: 130 individuals (mean [SD] age, 45.97 [7.11] years; 95 men [73.1%]) were enrolled and randomized to L. paracasei (n = 66) or placebo control (n = 64). Compared to placebo, L. paracasei supplementation led to a greater reduction in remnant cholesterol (-0.16 mmol/L, 95%CI: -0.29 mmol/L to -0.02 mmol/L; P = 0.024). Such a reduction in remnant cholesterol was significantly associated with improvement in endothelial function (r = -0.23, P = 0.027). In subjects with an ideal compliance with trial protocol, L. paracasei treatment additionally lowered triglycerides, alleviated MetS severity and delayed weight gain. On the contrary, no obvious effect on insulin sensitivity or pancreatic beta-cell function was observed after L. paracasei intervention. Moreover, regarding safety and tolerability, no significant between-group difference in protocol-specified adverse events of interest was observed. CONCLUSIONS: L. paracasei supplementation enhanced endothelial function potentially through downregulating remnant cholesterol levels. Our study provides a feasible and safe strategy for the prevention of cardiometabolic diseases in subjects with severe dyslipidemia and endothelial dysfunction. REGISTERED: Under ClinicalTrails.gov identifier NCT05005754.

Flavonifractor plautii Protects Against Elevated Arterial Stiffness.

BACKGROUND: Dysbiosis of gut microbiota plays a pivotal role in vascular dysfunction and microbial diversity was reported to be inversely correlated with arterial stiffness. However, the causal role of gut microbiota in the progression of arterial stiffness and the specific species along with the molecular mechanisms underlying this change remain largely unknown. METHODS: Participants with elevated arterial stiffness and normal controls free of medication were matched for age and sex. The microbial composition and metabolic capacities between the 2 groups were compared with the integration of metagenomics and metabolomics. Subsequently, Ang II (angiotensin II)-induced and humanized mouse model were employed to evaluate the protective effect of Flavonifractor plautii (F plautii) and its main effector cis-aconitic acid. RESULTS: Human fecal metagenomic sequencing revealed a significantly high abundance and centrality of F plautii in normal controls, which was absent in the microbial community of subjects with elevated arterial stiffness. Moreover, blood pressure only mediated part of the effect of F plautii on lower arterial stiffness. The microbiome of normal controls exhibited an enhanced capacity for glycolysis and polysaccharide degradation, whereas, those of subjects with increased arterial stiffness were characterized by increased biosynthesis of fatty acids and aromatic amino acids. Integrative analysis with metabolomics profiling further suggested that increased cis-aconitic acid served as the main effector for the protective effect of F plautii against arterial stiffness. Replenishment with F plautii and cis-aconitic acid improved elastic fiber network and reversed increased pulse wave velocity through the suppression of MMP-2 (matrix metalloproteinase-2) and inhibition of MCP-1 (monocyte chemoattractant protein-1) and NF-κB (nuclear factor kappa-B) activation in both Ang II-induced and humanized model of arterial stiffness. CONCLUSIONS: Our translational study identifies a novel link between F plautii and arterial function and raises the possibility of sustaining vascular health by targeting gut microbiota.

Bidirectional association between physical multimorbidity and subclinical depression in Chinese older adults: Findings from a prospective cohort study.

BACKGROUND: Both physical multimorbidity and subclinical depression pose a significant threat to aging population worldwide. The association between these conditions appeared to be in a bidirectional way, however the joint causal relationship yet to be fully understood in elderly Chinese population. METHODS: A total of 4605 Chinese elders from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2015) were included for the present study. Physical multimorbidity was defined as having two or more self-reported chronic physical conditions. Subclinical depression was defined by ≥ 12 scores assessed using the 10-item Centre for Epidemiological Studies Depression Scale. The bidirectional association between physical multimorbidity and subclinical depression was examined using multivariable logistic regression models, adjusting for covariates. RESULTS: During study period, 23.99% of participant reported incident episode of subclinical depression and 21.36% reported physical multimorbidity. In fully adjusted model, those with physical multimorbidity were two times more likely to have subclinical depression (OR = 2.05, 95% CI: 1.71-2.46). Besides that, subclinical depression was associated with physical multimorbidity (OR = 1.84, 95% CI: 1.50-2.46), but in slightly less magnitude. Furthermore, the bidirectional association remains statistically significant across different subgroups. LIMITATIONS: Chronic conditions were all self-reported and we couldn't adjust for all confounders, which may be subject to measurement error. CONCLUSIONS: Physical multimorbidity and subclinical depression was associated in a bidirectional way in elderly Chinese population, which highlights the necessary of covering a broad spectrum of aspects of clinical management among adults with physical multimorbidity or subclinical depression.

A panel of platelet-associated circulating long non-coding RNAs as potential biomarkers for colorectal cancer.

Evidence has suggested the potential of tumor-educated platelets as a biomarker trove for cancer diagnostics, but the difficulty in isolation limits its application. Since most of the circulating RNAs are derived from platelets, the change of RNA profile in platelets may lead to altered RNA expression in serum. Here, we identified a panel of platelet-associated long non-coding RNAs (lncRNAs) and evaluated its diagnostic capacity in serum of colorectal cancer (CRC) patients. Four lncRNAs, LNCAROD, SNHG20, LINC00534, and TSPOAP-AS1, were upregulated in both platelets and serum of CRC patients. A binary logistic model derived from them has validated area under roc curve of 0.78 indicating great performance. Furthermore, the expression levels of LNCAROD and TSPOAP-AS1 were correlated with cancer staging and tumor location. Together, our results add novel lncRNA biomarkers to the list of blood tests for CRC diagnostics and provide molecular evidence for the cross-talk between CRC platelets and serum.

Programmed cell death of Chlamydomonas reinhardtii induced by three cyanobacterial volatiles ß-ionone, limonene and longifolene.

ß-Ionone, limonene and longifolene are 3 main components in cyanobacterial volatile organic compounds, which are formed through different pathways and can poison and even kill other algae. To uncover their toxic mechanism from programmed cell death (PCD), the photosynthetic pigments, chlorophyll fluorescence, caspase-like activities, cell size, nuclear variations and DNA ladders were investigated in Chlamydomonas reinhardtii treated with ß-ionone (0.2 mM), limonene (0.2 mM) and longifolene (0.4 mM) at lethal concentration during 24 h. In the treatments with the 3 compounds, the photosynthetic pigments in C. reinhardtii cells gradually degraded, and Fv/Fm gradually decreased and disappeared at 24 h, suggesting that the cell death might be a PCD, due to the physiological activities gradually disappearing. During the cell death, the activities of caspase-9-like and caspase-3-like significantly increased, with the highest at 1 h. With prolonging the treatment time, C. reinhardtii cells gradually shrank, and the nuclei concentrated firstly following by a broken process, with moving to the cell edge. For DNA, obvious ladders were detected at 1 h, and then they gradually degraded to fragments of 100-250 bp at 24 h. These hallmarks suggested that ß-ionone, limonene and longifolene may poison other algae by inducing PCD.

The role of ATF3 in ZnO nanoparticle-induced genotoxicity and cytotoxicity in bronchial epithelial cells.

ZnO nanoparticle (ZnO NP) exposure causes oxidative stress in the respiratory system, leading to pulmonary damage. Activating transcription factor 3 (ATF3) participates in a variety of cellular stress responses. However, the role of ATF3 in ZnO NP genotoxicity and cytotoxicity remains to be explored. Here we reported that ZnO NP treatment dramatically induced the expression of ATF3 in human bronchial epithelial (HBE) cells, which was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2). ATF3 was required for the repair of ZnO NP-induced DNA damage as gamma foci number increased when endogenous ATF3 was silenced. Moreover, ATF3 also contributed to ZnO NP-induced cell apoptosis. Mechanistic study revealed that ATF3 interacted with the p53 protein and upregulated its expression under ZnO NP treatment. Collectively, our findings demonstrated ATF3 as an important regulator of epithelial homeostasis by promoting both DNA repair and the death of damaged cells under ZnO NP-induced genotoxic stress.

Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis.

BACKGROUND: Upregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis. METHODS: The effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET). RESULTS: Triptolide reduced both tumor number and tumor size in adenomatous polyposis coli (Apc) mutated (ApcMin/+) mice as well as AOM/DSS-induced mice. Moreover, triptolide effectively inhibited colorectal cancer cell proliferation, colony formation, and organoid growth in vitro, which was associated with decreased Pol III target genes. Mechanistically, triptolide treatment blocked TBP/Brf1interaction, leading to the reduced formation of TFIIIB at the promoters of tRNAs and 5S rRNA. CONCLUSIONS: Together, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.