Dataset Information

Circadian disruption exacerbates MASH in mice by reducing intestinal Akkermansia muciniphila abundance via the FXR-CYP7A1-bile acid axis_Targeting Bile Acids

ABSTRACT:

Circadian disruption has emerged as a significant public health issue and is increasingly recognized as a contributor to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms remain poorly understood. In this study, we established a mouse model combining continuous light exposure and a western diet to investigate how circadian disruption exacerbates metabolic dysfunction-associated steatohepatitis (MASH). Our results demonstrated that circadian disturbance aggravated hepatic inflammation, lipid accumulation, and intestinal barrier impairment. Through integrated 16S rRNA sequencing and metabolomic analyses, we identified a marked reduction in Akkermansia muciniphila abundance and an elevation in CDCA-3S. Supplementation with A. muciniphila, taurine, or the FXR agonist obeticholic acid restored microbial and metabolic homeostasis, subsequently alleviating MASH pathology. Mechanistically, our data suggest these beneficial effects may involve the FXR–CYP7A1 signaling pathway. Our findings indicate that circadian disruption aggravates MASH potentially through reducing A. muciniphila abundance in a process associated with the FXR–CYP7A1–bile acid axis , and highlight the potential of microbial and metabolic interventions as novel therapeutic strategies for individuals with sleep-related circadian disorders.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS13845 | MetaboLights | 2026-02-05

REPOSITORIES: MetaboLights

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	a_MTBLS13845_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13845_LC-MS_alternating_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13845.txt	Txt

Items per page:

1 - 4 of 4

Similar Datasets

Project description:Background: The farnesoid X receptor (FXR) is a leading therapeutic target for MASH-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease. Methods: Leptin-deficient ob/ob mice were fed a MASH-inducing diet for 15 weeks prior to study start. After baseline liver biopsy and stratification, mice were allocated to INT-767 (10 mg/kg/day) or vehicle treatment for 8 weeks, either alongside ongoing MASH diet (progression) or following conversion to normal chow (reversal). Effects on extracellular matrix remodelling were analyzed histologically and by RNA-sequencing. Serum fibrosis biomarkers were measured longitudinally. Human liver samples were investigated using bulk and single-cell RNA-sequencing, histology, and cell culture assays. Results: INT-767 treatment was antifibrotic during MASH progression but not reversal, attenuating accumulation of type I collagen and basement membrane proteins (type IV collagen, laminin). Circulating levels of PRO-C4, a type IV collagen formation marker, were reduced by INT-767 treatment and correlated with fibrosis. Expression of basement membrane constituents also correlated with fibrosis severity and adverse clinical outcomes in human MASH. Single-cell RNA-sequencing analysis of mouse and human livers, and immunofluorescence staining colocalized FXR and basement membrane expression to myofibroblasts within the fibrotic niche. Treatment of culture-activated primary human hepatic stellate cells with INT-767 decreased expression of basement membrane components. Conclusion: These findings highlight the importance of basement membrane remodelling in MASH pathobiology and as a source of circulating biomarkers. Basement membrane deposition by activated hepatic stellate cells is abrogated by INT-767 treatment and measurement of basement membrane molecules should be included when determining the therapeutic efficacy of FXR agonists.

Dataset Information

Circadian disruption exacerbates MASH in mice by reducing intestinal Akkermansia muciniphila abundance via the FXR-CYP7A1-bile acid axis_Targeting Bile Acids

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets