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: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.

Project description:Population based studies have established that androgen deficiency in males correlates with type 2 diabetes, visceral adiposity, and metabolic syndrome. Androgen therapy has been investigated as a possible treatment regime to combat these disorders. However, the molecular mechanism of androgen effects on these diseases still remain poorly understood. The zucker diabetic fatty (ZDF) rat, containing a mutation in the leptin receptor, is a well-investigated model of obesity and type 2 diabetes. Male rats are characterized as androgen deficient and spontaneously develop obese, hyperlipidemia, hyperglycemia and hyperinsulinemia. In this study, we used ZDF male rats as a model of metabolic syndrome to investigate the effects of testosterone administration on the development of the metabolic conditions. Methods: Male ZDF rats at six week of age were randomly divided into two groups and administered testosterone undecanoate(TU) or vehicle alone every three days for three weeks. After three weeks, overnight fasted blood glucose and insulin concentrations were significantly higher and glucose tolerance and insulin sensitivity were impaired in TU treated ZDF rats compared to vehicle controls. Moreover, increased serum triglycerides and VLDL were observed in TU treated rats. To further explore the observed metabolic changes in TU treated ZDF rats, whole-genome microarray analysis were performed on isolated liver mRNA. Results: Array analysis revealed that many hepatic lipogenic genes were increased in male ZDF rat livers treated with TU. Interestingly, SREBP-1c, a key transcriptional activator of lipogenic genes and PGC-1 , an activator of SREBP-1c were induced while small heterodimer partner, a transcriptional inhibitor of lipogenic genes was suppressed by TU treatment. Exploring signaling pathways for these effects, we observed that the hepatic activated forms of STAT3 and AMPK, two known inhibitors of hepatic lipogenesis, were decreased in TU treated rat. Moreover, we observed that DHT could block the induction of STAT3 and AMPK phosphorylation in treated primary human hepatocytes. Preliminarily, in the leptin receptor positive zucker diabetic lean male rats, we observed that TU treatment has an oppose effect on the hepatic lipogenic genes, suggesting that hepatic leptin signaling may influence androgen signaling. Further insight into the relationship between androgen deficiency and the leptin system may help improve treatment of the metabolic syndrome. Population based studies have established that androgen deficiency in males correlates with type 2 diabetes, visceral adiposity, and metabolic syndrome. Androgen therapy has been investigated as a possible treatment regime to combat these disorders. However, the molecular mechanism of androgen effects on these diseases still remain poorly understood. The zucker diabetic fatty (ZDF) rat, containing a mutation in the leptin receptor, is a well-investigated model of obesity and type 2 diabetes. Male rats are characterized as androgen deficient and spontaneously develop obese, hyperlipidemia, hyperglycemia and hyperinsulinemia. In this study, we used ZDF male rats as a model of metabolic syndrome to investigate the effects of testosterone administration on the development of the metabolic conditions. Two-condition experiment. (1) lean ZDF rats (control) vs. lean ZDF rats (testosterone treated). (2) obese ZDF rats (control) vs. obese ZDF rats (testosterone treated). Biological replicates: 4 control replicates, 4 treated replicates.

			Action	DRS
	a_MTBLS13694_GC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13694_GC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13694.txt	Txt

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Alistipes putredinis Alleviates Metabolic-Associated Fatty Liver Disease via the Acetate-GPR43 Axis by Suppressing Neutrophil ROS Generation

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