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<p>Hyperuricemia (HUA) is a metabolic disorder characterized by elevated blood uric acid (UA) levels, closely associated with conditions such as gout. UA-induced macrophage M1 polarization fundamentally exacerbates inflammatory pathophysiology, but current HUA-specific immunoregulatory treatments are inadequate. This study investigates whether β-hydroxybutyrate (BHB), a UA-degrading metabolite produced by <i>Lacticaseibacillus rhamnosus</i> M2b, can suppress UA-induced M1 macrophage polarization and promote M2 polarization via activation of the GPR109a–AMPK signaling axis, aiming to identify novel targets for intervening in HUA-related inflammation. Using untargeted metabolomics combined with CCK-8 and ELISA assays, BHB was identified as the key active molecule. An M1 polarization model was established by stimulating RAW264.7 cells with 1 mM UA. Experimental groups included control, UA, UA + BHB, and UA + M2b-conditioned medium (UA + M2b_CM) groups. Results showed that both BHB and M2b_CM significantly inhibited UA-induced M1 polarization, as indicated by reduced levels of IL-1β, IL-6, TNF-α, and iNOS. Concurrently, they promoted M2 polarization markers CD163 and IL-10 expression, and enhanced AMPK phosphorylation (increased p-AMPK/AMPK ratio) (<i>P &lt; 0.05</i>). It was confirmed by transcriptomic analysis that BHB intervention could significantly enhance the activity of the AMPK signaling pathway. Functional validation experiments demonstrated that either silencing GPR109a expression with small interfering RNA (siRNA) or inhibiting AMPK with Compound C completely abolished the anti-inflammatory effects of BHB. Conversely, overexpression of GPR109a enhanced the anti-inflammatory efficacy of BHB. This result confirms that GPR109a is the primary molecular target mediating the effects of BHB, and that GPR109a participates in this mediating process through the AMPK signaling pathway. In conclusion, BHB derived from <i>Lacticaseibacillus rhamnosus</i> M2b inhibits UA-induced M1 macrophage polarization and promotes M2 polarization by activating the GPR109a–AMPK signaling pathway. These findings provide a new strategic perspective for utilizing gut microbiota metabolites in the treatment of HUA-related inflammation.</p>

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GPR109a-AMPK axis mediates the Attenuation of uric acid-induced M1 macrophage polarization by β-hydroxybutyrate from Lacticaseibacillus rhamnosus M2b

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Manxi Du,
  • Yi He,
  • Yuqiu Zhu,
  • Wujin Chen,
  • Xiaoyu Chen,
  • Dan Yang,
  • Qingqing Yang,
  • Bei Zhang,
  • Yuping Sun

摘要

Hyperuricemia (HUA) is a metabolic disorder characterized by elevated blood uric acid (UA) levels, closely associated with conditions such as gout. UA-induced macrophage M1 polarization fundamentally exacerbates inflammatory pathophysiology, but current HUA-specific immunoregulatory treatments are inadequate. This study investigates whether β-hydroxybutyrate (BHB), a UA-degrading metabolite produced by Lacticaseibacillus rhamnosus M2b, can suppress UA-induced M1 macrophage polarization and promote M2 polarization via activation of the GPR109a–AMPK signaling axis, aiming to identify novel targets for intervening in HUA-related inflammation. Using untargeted metabolomics combined with CCK-8 and ELISA assays, BHB was identified as the key active molecule. An M1 polarization model was established by stimulating RAW264.7 cells with 1 mM UA. Experimental groups included control, UA, UA + BHB, and UA + M2b-conditioned medium (UA + M2b_CM) groups. Results showed that both BHB and M2b_CM significantly inhibited UA-induced M1 polarization, as indicated by reduced levels of IL-1β, IL-6, TNF-α, and iNOS. Concurrently, they promoted M2 polarization markers CD163 and IL-10 expression, and enhanced AMPK phosphorylation (increased p-AMPK/AMPK ratio) (P < 0.05). It was confirmed by transcriptomic analysis that BHB intervention could significantly enhance the activity of the AMPK signaling pathway. Functional validation experiments demonstrated that either silencing GPR109a expression with small interfering RNA (siRNA) or inhibiting AMPK with Compound C completely abolished the anti-inflammatory effects of BHB. Conversely, overexpression of GPR109a enhanced the anti-inflammatory efficacy of BHB. This result confirms that GPR109a is the primary molecular target mediating the effects of BHB, and that GPR109a participates in this mediating process through the AMPK signaling pathway. In conclusion, BHB derived from Lacticaseibacillus rhamnosus M2b inhibits UA-induced M1 macrophage polarization and promotes M2 polarization by activating the GPR109a–AMPK signaling pathway. These findings provide a new strategic perspective for utilizing gut microbiota metabolites in the treatment of HUA-related inflammation.