Clostridium butyricum and its metabolites regulate macrophage polarization through miR-146a to antagonize gouty arthritis

Abstract

Introduction: Gut microbiota modulation has recently been identified as a prospective avenue for the exploration of novel therapeutic strategies for the management of gout. Nevertheless, the application of a single specific strain or bacterial metabolite for gout intervention has rarely been explored and the underlying regulatory mechanism remains elusive.

Objectives: To ascertain the potential role and the molecular mechanism of Clostridium butyricum and butyrate in the management of gouty arthritis.

Methods: A Uox-KO mouse model of gouty arthritis was developed and the composition of the gut microbiota was analyzed. C. butyricum and butyrate were supplemented to assess functional recovery and intestinal homeostasis. NanoString analysis identified miRNA variations. GC/MS measured butyric acid levels and qPCR detected the abundance of butyrate-producing enzymes and bacteria. Flow cytometry analyzed macrophage polarization and ELISA measured pro-inflammatory cytokine production. Agomir and antagomir were transfected and dual-luciferase reporter assay was adapted for validation of miRNA target binding. siRNA and rescue experiments were performed to validate the role of SOCS7 in macrophage polarization. In addition, a cohort of patients with gouty arthritis were assembled for the purpose of validating the molecular mechanism.

Results: The results of our study demonstrated that a reduction of butyrate levels, resulting from a deficiency of butyrate-producing bacteria, leads to aberrant miR-146a expression. This, in turn, induces an imbalance in macrophage polarization and the onset of gouty arthritis. The administration of C. butyricum and butyrate demonstrated considerable anti-inflammatory efficacy by restoring intestinal homeostasis, modulating miR-146a expression, and skewing macrophage polarization. The SOCS7/JAK2-STAT3 signaling pathway was identified as a pivotal mediator in the skewing of macrophage polarization induced by miR-146a.

Conclusion: Our findings enrich the understanding of the regulatory mechanisms underlying macrophage polarization in gouty arthritis and highlight the potential applications of probiotics and their metabolites in clinical gout treatment.

Keywords: Clostridium butyricum; Gouty arthritis; Macrophage polarization; SOCS7/JAK2-STAT3 pathway; miR-146a.