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Synergistic modulation of the gutmicrobiome-liver-hostmetabolome axis associates withthe therapeutic efficacy ofDanlou tablet against metabolicsyndrome

ABSTRACT: Background: Obesity drives chronic diseases such as cardiovascular disease anddiabetes. Danlou tablet (DLT), a traditional Chinese medicine formula, is used totreat coronary heart disease by regulating lipid metabolism, suggesting potentialfor addressing obesity-related metabolic dysfunction. However, its role in obesityand insulin resistance remains unexplored. Objectives: We investigated the efficacy and mechanisms of DLT against high-fatdiet (HFD)-induced obesity and insulin resistance. Methods: C57BL/6N mice were fed an HFD for 22 weeks and treated with DLT. Acomprehensive phenotypic assessment was conducted, including body weight,glucose tolerance, insulin sensitivity, serum biochemistry, and histopathologyof key tissues. To elucidate the therapeutic mechanism, we integrated 16S rRNAgene sequencing of gut microbiota, serum metabolomics (UPLC-Q-TOF- MS),and hepatic transcriptomics. Results: DLT treatment counteracted HFD-induced metabolic dysfunction,reducing body weight, adiposity, dyslipidemia, and insulin resistance, while ame-liorating hepatic steatosis, inflammation, and oxidative stress. At the microbiallevel, DLT restored gut microbial diversity, corrected the Firmicutes/Bacteroidotaratio, and modulated key genera. Metabolomics linked these changes to restoredfatty acid B-oxidation. In the liver, transcriptomics showed that DLT reversed HFDinduced gene expression, suppressed inflammatory pathways and enhancedfatty acid oxidation and xenobiotic metabolism. Integrated multi-omics analy-sis revealed a strong correlative relationship that DLT's therapeutic benefits areassociated with the modulation of the gut-liver axis, where remodeling of thegut microbiome is closely linked to the reprogramming of hepatic metabolicpathways. Conclusion: DLT counteracts HFD-induced obesity and insulin resistance via amulti-level regulatory mechanism that is closely associated with the modulationof the gut-liver axis, which involves suppressing pathogenic gut microbes, restor-ing fatty acid metabolism, and enhancing hepatic lipid catabolism and antioxidantdefense. This comprehensive preclinical evidence supports the clinical translationof DLT as a novel therapeutic option for obesity and type 2 diabetes mellitus.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14750 | MetaboLights | 2026-06-12

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14750_LC-MS_negative_reverse-phase.txt	Txt
	a_MTBLS14750_LC-MS_positive_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14750_LC-MS_negative_reverse-phase_v2_maf.tsv	Tabular
	m_MTBLS14750_LC-MS_positive_reverse-phase_v2_maf.tsv	Tabular

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Project description:An 8-week high fat palm oil diet causes obesity and insulin resistance in C57BL/6J mice, but induces only small changes in the muscle transcriptome. Introduction: The metabolic syndrome (MS) is a cluster of metabolic abnormalities linked to an increased risk of type 2 diabetes and cardiovascular diseases. Two major characteristics of the MS are obesity and insulin resistance. In the present study we investigated the effect of obesity and insulin resistance on the mouse muscle transcriptome. Methods: C57BL/6J mice were fed a palm oil-based low fat diet (LFD) or high fat diet (HFD) for eight weeks. Microarray analysis was performed by using two complementary strategies: (1) 8-week HFD transcriptome versus 8-week LFD transcriptome and (2) transcriptome of mice sacrificed at the start of the intervention versus 8-week LFD transcriptome and 8-week HFD transcriptome, respectively. Results: HFD mice develop obesity and whole-body insulin resistance. Despite these metabolic disturbances we found that HFD induces relatively small changes in gene expression (< 1.3 fold). Only the up-regulation of FA oxidation and the down-regulation of the MAPK cascade were specific for the HFD intervention. Eight-weeks of aging induced more changed gene expression levels than the HFD, including genes involved in cell-cell interaction and development. Conclusion: Eight weeks of aging induce more pronounced changes in the muscle transcriptome than an HFD. Since only one strategy revealed the transcriptional down-regulation of the MAPK cascade, whereas both strategies showed the up-regulation of FA oxidation we suggest the use of complementary analysis strategies by the genome-wide search of gene expression changes induced by mild interventions, such as an HFD. Keywords: diet intervention and time course In this study, C57BL/6J mice were fed a high fat (HF) diet for 8 weeks to induce obesity and insulin resistance. Plasma levels of the adipokines leptin and adiponectin were measured. To investigate how these metabolic disturbances will influence the skeletal muscle transcriptome we performed whole-genome microarray analysis. Functional implications were assessed by analyses of predefined gene sets based on Gene Ontology, biochemical, metabolic and signaling pathways.

Project description:Background & Aims: In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, the main determinant of NASH-associated mortality. The short chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remains unclear. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.

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Synergistic modulation of the gutmicrobiome-liver-hostmetabolome axis associates withthe therapeutic efficacy ofDanlou tablet against metabolicsyndrome

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