Project description:Background & Aims:Intestinal dysbiosis contributes to the pathogenesis of metabolic-associated fatty liver disease (MAFLD), though precise bacterial targets and mechanisms remain incompletely elucidated. This study investigated whether the depletion of Alistipes putredinis (AP) in adolescents obesity-associated MAFLD is causally linked to disease progression and aimed to delineate its downstream signaling pathway.Methods:Fecal samples from 29 obese adolescents with MAFLD and 17 healthy controls in Hainan Province were analyzed by metagenomic sequencing. A high-fat diet–induced MAFLD mouse model was established and randomized into control, MAFLD, and AP-gavaged groups (12 weeks). Untargeted metabolomics and targeted short-chain fatty acid profiling were performed on fecal, hepatic, and AP culture supernatant samples. Liver transcriptomics, Western blot, and co-immunoprecipitation were employed to identify and validate involved molecular pathways.Results:AP abundance was significantly lower in MAFLD patients compared with controls. AP supplementation ameliorated hepatic lipid accumulation in MAFLD mice. Metabolomic analysis identified acetate as the principal mediator of AP’s protective effects. Acetate derived from AP activated the GPR43 receptor on hepatic neutrophils, inhibiting intracellular Ca²⁺ flux and NADPH oxidase 2 (NOX2) activity, thereby reducing reactive oxygen species (ROS) generation. Reduced ROS levels attenuated JNK phosphorylation, decreased LXRα binding to the SREBP-1c promoter, and suppressed proteolytic activation of SREBP-1c, leading to downregulation of key lipogenic enzymes ACC1 and FASN.Conclusion:Alistipes putredinis ameliorates MAFLD via acetate-mediated activation of the GPR43 receptor on hepatic neutrophils, which suppresses the Ca²⁺-NOX2-ROS signaling cascade and inhibits ROS-dependent SREBP-1c activation and lipogenic gene expression. These findings reveal a previously unrecognized gut microbiota–neutrophil signaling axis as a potential therapeutic target in MAFLD.

Project description:The aim of this research is to reveal the cellular crosstalk in fibrosis liver using transgenic pigs (TG) expressing humanized risk genes (PNPLA3I148M-GIPRdn-hIAPP) as a MAFLD model. The study uses single-nucleus sequencing to reveal the differentiation and interaction characteristics of various cell populations in the liver during the development of MAFLD. Compared to wild-type pigs (WT), the model pigs showed significantly increased plasma levels of neurotensin and phosphatidylserine, along with insulin resistance and significantly decreased HDL-c levels. After 6 months of high-fat high-sucrose diet induction, the model pigs exhibited obvious liver pathological features, including fat deposition, inflammatory cell aggregation, fibrosis, and blocked insulin signaling pathways. Single-nucleusl transcriptome sequencing identified six main cell types in the liver, and correlation analysis showed similar liver cell clusters, zones, and functions between pigs and humans. Liver cells near the central vein and liver sinusoidal endothelial cells (LSECs) were sensitive to metabolic changes and exhibited impaired function and reduced numbers first. Fibrosis-related pathways and the Rap1 pathway were activated in hepatic stellate cells of the model pigs, while retinol metabolism decreased, and the number of activated hepatic stellate cells increased. The differentiation direction of macrophages in the model pig's liver was markedly different from that in the WT pigs; the former differentiated toward the M1 phenotype, showing high expression of MHC-II antigen presentation molecules, various cytokines, phagosomes, and lysosomal-related genes. In contrast, the macrophages in the WT pig's liver primarily differentiated toward the M2 phenotype and expressed genes related to immune regulation and injury repair. There was active cell interaction between hepatic stellate cells, endothelial cells, and M1-type macrophages, promoting the development of chronic inflammation and fibrosis through interactions of receptors such as FGFs-FGFRs, PDGFs-PDGFRs, EFNA1-EPHRs, and CXCL12-CXCR4/CXCR7.In conclusion, the transgenic pig model of MAFLD exhibits liver pathological features consistent with MAFLD patients. The receptor interactions between hepatic stellate cells, endothelial cells, and macrophages play a key role in regulating metabolic inflammation and fibrosis development. Remarkable changes in receptor interactions hold promise for application in MAFLD drug development.

Project description:Objective:Metabolic associated fatty liver disease (MAFLD) affects approximately 25% of the global population, posing a serious threat to public health, and its pathogenesis remains largely unknown. Gut fungi play a significant role in the development of liver diseases, but the gut microbial community and its functions in MAFLD patients are not yet clear.Methods:We performed fungal ITS sequencing on fecal samples from 107 MAFLD patients and 120 healthy control (HC), matched for region, ethnicity, age, and sex. A high-fat diet-induced MAFLD mouse model was established and multi-omics techniques such as Liver transcriptome sequencing, qPCR, Western blot, and immunofluorescence were employed to validate the molecular mechanisms of key gut fungi involved in MAFLD. Results:MAFLD patients exhibited reduced species richness and diversity compared to HC. The gut microbiome of MAFLD patients was characterized by an increase in the harmful fungal genus Rhizopus, specifically the harmful fungi Rhizopus microsporus var. rhizopodiformis and Rhizopus microsporus var. chinensis, which positively correlated with the degree of steatosis and BMI. Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas B amphotericin (AMP) administration alleviated disease progression. Gavage with Rhizopus microsporus var. rhizopodiformis significantly exacerbates gut microbiota dysbiosis and metabolic disorders, disrupted the intestinal barrier and activated liver SREBP-1c, thereby upregulating key lipid synthesis enzymes ACC1 and FASN. This activation occurred through a pro-inflammatory cascade involving the liver macrophage LPS-TLR4-NF-κB axis, amplification of inflammatory signals, and neutrophil degranulation.Conclusion:Rhizopus microsporus var. rhizopodiformis promotes hepatic lipid synthesis by upregulating hepatic neutrophil degranulation and facilitating SREBP-1c activation pathway.

			Action	DRS
	a_MTBLS13232_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13232_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13232.txt	Txt

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Metabolic Characteristics of Schisantherin B in Mice with Metabolic-Associated Fatty Liver Disease

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