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GPR109a-AMPK Axis Mediates the Attenuation of Uric Acid-Induced M1 Macrophage Polarization by β-hydroxybutyrate from Lacticaseibacillus rhamnosus M2b

ABSTRACT:

Hyperuricemia (HUA) is a metabolic disorder marked by increased blood uric acid (UA) levels, closely linked to conditions such as gout. UA-induced macrophage M1 polarization fundamentally exacerbates inflammatory pathophysiology, but current HUA-specific immunoregulatory treatments are inadequate. We investigated β-hydroxybutyrate (BHB), a UA-degrading metabolite generated from Lacticaseibacillus rhamnosus M2b, for its ability to inhibit UA-induced macrophage M1 polarization through the activation of the GPR109a-AMPK axis, uncovering new targets for the intervention of HUA inflammation. BHB was identified as a significant molecule by untargeted metabolomics in conjunction with CCK8 and ELISA assays. Subsequently, the M1 polarization model was developed by activating RAW264.7 cells with 1mM UA, establishing the Control group, UA group, UA+BHB group, and UA+M2b sterile supernatant group (UA+M2b_CM group). The findings indicated that both BHB and M2b_CM markedly suppressed UA-induced M1 polarization, reduced the expression levels of IL-1β, IL-6, TNF-α, and iNOS, and stimulated AMPK phosphorylation (enhanced the ratio of p-AMPK/AMPK) (P<0.05). The transcriptome analysis of the GEO database verified that the AMPK pathway was markedly enhanced by BHB intervention. Functional validation experiments showed that specific silencing of GPR109a expression through siRNA interference or intervention with AMPK inhibitors (Compound C) completely eliminated the anti-inflammatory effects of BHB. These data offer substantial evidence that GPR109a functions as the principal molecular target facilitating the anti-inflammatory effects of BHB. In summary, Lacticaseibacillus rhamnosus M2b-derived BHB suppressed UA-induced macrophage M1 polarization via the activation of the GPR109a-AMPK signaling pathway, presenting a novel approach for utilizing intestinal microbiota metabolites to address HUA-related inflammation.

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

PROVIDER: MTBLS13224 | MetaboLights | 2026-01-26

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13224_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13224_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13224_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13224_LC-MS_alternating_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Aim: To investigate the effect and mechanism of Sitagliptin phosphate on inflammation and macrophage polarization in a mouse model of type 2 diabetes. Methods: In vitro, Raw264.7 cells were cultured with a high concentration of glucose (HG) and sitagliptin phosphate (SIG). The levels of inflammatory factors and the regulation of macrophage polarization were investigated, and the differentially expressed genes between HG and HG+SIG intervention were analyzed and enriched through transcriptomics. In vivo, C57BL/6J male mice were treated with HFD+STZ to establish a type 2 diabetes mouse model were investigated the effects of regulation of macrophage polarization in the pancreas and visceral adipose tissue. Results:In vitro cell experiments and transcriptomics showed that Sitagliptin phosphate decreased the secretion of inflammatory factors IL-6 and TNF-α induced by high-glucose, and increased secretion of anti-inflammatory factor IL-10 by enhancing macrophage polarization. In vivo, the body weight and abdominal visceral fat weight, the ratio of visceral fat weight to body weight and fasting blood glucose were significantly increased in the DM group compared with the Control (P<0.05), Sitagliptin phosphate treatments reversed the changes in the DM group. Moreover, histological analysis showed that compared with the Control group, the size of visceral adipocytes, hepatocyte lipid deposition and the ratio of M1/M2 macrophage were higher in the DM group, which were reversed by Sitagliptin phosphate treatments (P<0.05), insulin treatments did not have a significant effect(P＞0.05).Mechanistically, Western blot showed that compared with the normal group, HG upregulated the expression of mTORc1 protein, P-65 phosphorylation and P-65 protein expression in Raw264.7 cells (P<0.05), downregulated the expression of IKKβ (P<0.05) and PPAR-γ proteins (P<0.05), Sitagliptin phosphate and insulin treatments rescued these changes. Conclusion: These results indicated that Sitagliptin phosphate reduced high glucose-induced inflammation by improving the imbalance of macrophage polarization via modulating the mTORc1/ PPAR-γ/NF-κB in vitro and in vivo.

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GPR109a-AMPK Axis Mediates the Attenuation of Uric Acid-Induced M1 Macrophage Polarization by β-hydroxybutyrate from Lacticaseibacillus rhamnosus M2b

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