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Royal jelly and 10-hydroxy-2-decenoic acid mitigate alcoholic fatty liver disease in mice via the gut-microbiota-metabolite axis

ABSTRACT:

Royal jelly (RJ) and its signature bioactive compound, 10-hydroxy-2-decenoic acid (10-HDA), are believed to possess hepatoprotective properties. However, their protective effects and underlying mechanisms against alcoholic fatty liver disease (AFLD) remain unclear. In the present study, we integrated 16S rRNA sequencing, untargeted metabolomics, and molecular biology analyses to evaluate their therapeutic potential in an AFLD mouse model. The results demonstrated that RJ and 10-HDA significantly improved alcohol-induced liver injury by reducing lipid accumulation and mitigating dyslipidemia, inflammation, and oxidative stress. The 16S rRNA sequencing revealed that RJ and 10-HDA ameliorated alcohol-induced gut microbiota disruption. In particular, supplementation with beneficial doses of RJ (200 mg/kg/day) and 10-HDA (100 mg/kg/day) reduced the abundance of Pseudomonadota and Escherichia, and increased the abundance of Verrucomicrobiota (e.g., Akkermansia) and Lactobacillus. Untargeted metabolomics further indicated that the host metabolic regulation involved key pathways such as serotonergic synapse, bile secretion, and tryptophan metabolism. Moreover, RJ and 10-HDA activated the adenosine monophosphate-activated protein kinase (AMPK) pathway, promoting fatty acid β-oxidation while suppressing lipogenesis. Notably, integrated correlation analysis revealed that the beneficial faecal metabolites restored by the intervention were closely associated with the activation of the hepatic AMPK pathway. In contrast, alcohol-enriched deleterious metabolites exhibited the opposite trend, linking luminal metabolic shifts to upstream hepatic lipid regulation. Collectively, these findings suggest that RJ and 10-HDA mitigate AFLD by modulating the gut-microbiota-metabolite axis and activating the AMPK signaling pathway, supporting their potential use as dietary supplements in strategies aimed at managing AFLD and promoting liver health.

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

PROVIDER: MTBLS14067 | MetaboLights | 2026-05-14

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14067_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS14067_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14067_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS14067_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Individuals with Urea Cycle Disorders (UCD) cannot remove ammonia, a waste product, from the blood. At present there is little information on the use of sodium phenylbutyrate (Buphenyl™) in children with argininosuccinic aciduria (ASA). It is hoped that this drug may help lower ammonia and argininosuccinic acid levels in patients with ASA. Through this study we hope to learn whether the use of sodium phenylbutyrate (Buphenyl™) in patients with ASA, in addition to diet and arginine therapy, will decrease liver damage and the number of periods during which ammonia levels are high. The primary study objective is to determine if the treatment of ASA patients with sodium phenylbutyrate (Buphenyl™) in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production. Twelve patients with ASA will be studied using a randomized, cross-over design. Medical records will be reviewed to confirm the diagnosis prior to enrollment. Patients will be on the each arm of the study for one week each preceded by a three day washout period. Patients will come to the Baylor College of Medicine General Clinical Research Center in Texas Children's Hospital for an inpatient hospitalization. This hospitalization is for diet control, clinical evaluation, and stable isotope infusions for measurement of in vivo rates of ureagenesis and nitric oxide production. During the washout periods Buphenyl™ or other alternative route medications, e.g., benzoate, will be discontinued and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/m2. Following randomization, subjects will be maintained on either high-dose arginine (500 mg/kg/day or 10 grams/m2) alone, or the alternative of low-dose arginine (100 mg/kg/d or 2 grams/m2) along with sodium phenylbutyrate (500 mg/kg/day or 10 grams/m2). For the second week they will be crossed over to the other arm of the study preceded by another three day washout. Previous medications and dietary protein intake (0.6 g/kg/day or current metabolic diet) will be continued during both arms of the study. The two arms may be performed as separate ten-day admissions. The decision to design the study with two arms, high-dose arginine and low-dose arginine/Buphenyl™, was reached after weighing several considerations. First, the current accepted practice for treatment of ASA is high-dose arginine. Based on metabolic flux studies, we have quantified the effects of this dose of arginine as compared to standard doses of Buphenyl™/phenylacetate on ureagenesis. Since the study is not designed or intended to address the independent effects of Buphenyl™ as compared to arginine alone, Buphenyl™ was added for safety reasons to accommodate loss of clearance of nitrogen by decreasing the arginine dose. Moreover, based on our experience with recruiting for previous versions of this study, most ASA patients with liver dysfunction are on an alternative route ammonia scavenger medication in addition to arginine. We found that this has in fact become an accepted practice. Hence, when considering study design from both a safety and recruitment perspective, it was most reasonable to design the study to investigate specifically the hypothesis that the production and presence of argininosuccinic acid leads to liver dysfunction. Since both low-dose arginine with Buphenyl™ and high-dose arginine alone lead to a decreased production of argininosuccinic acid, and both are currently accepted therapies in ASA and UCDs in general, the need to address their effects distinctly is not being investigated at this time. Sodium phenylbutyrate dosage will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients. Daily dosage will be given in equally divided doses 4 times per day. In order to ensure that the study remains double-blind to investigators, study staff and subjects, the Investigational Pharmacy Service at Texas Children's Hospital will dispense both the Buphenyl™ and arginine in powder form which is compounded into capsules or will be mixed with syrpalta (up to 5 grams will dissolve in 10cc liquid) and administered orally or through nasogastric or gastrostomy tube. No nasogastric tube should be placed or gastrostomy performed solely for the purpose of inclusion in this study. Because the reported adverse effects of sodium phenylbutyrate include gastritis, participants will be started on a standard dose of ranitidine (Zantac™), or comparable drug, during both arms of the study.

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Royal jelly and 10-hydroxy-2-decenoic acid mitigate alcoholic fatty liver disease in mice via the gut-microbiota-metabolite axis

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