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Multi-omics profiling identifies a putative Akkermansia–HK3–lactate immunometabolic link associated with JPZS treatment in lupus nephritis

Year: 2026

Type: article

Abstract: Background Lupus nephritis (LN) is associated with aberrant glycolytic reprogramming in renal immune cells, yet its relationship with gut microbial alterations remains poorly defined. Hexokinase 3 (HK3) has emerged as a candidate metabolic node in myeloid activation, while the relationship between gut Akkermansia abundance and renal HK3-associated metabolic changes in LN remains unclear. We used Qihuang Jianpi Zishen decoction (JPZS), an herbal formula used as an adjunct in clinical practice, as an experimental probe to investigate this putative gut–immunometabolic connection through integrated multi-omics. Methods Female MRL/lpr mice ( n = 6 per group) received JPZS (6.305, 12.61, or 25.22 g/kg/day) or vehicle for 8 weeks, with C57BL/6 mice serving as a healthy reference group. Renal function, autoantibodies, histopathology, and glomerular IgG deposition were assessed across treatment groups. Integrated multi-omics profiling—fecal 16S rRNA sequencing, untargeted plasma metabolomics, and renal RNA sequencing—was performed in the matched control, model, and high-dose JPZS groups. Renal lactate and pyruvate were quantified, and HK3 and Ldhal6b mRNA and their corresponding proteins were evaluated by qPCR and western blotting. HK3/F4/80 dual immunofluorescence was additionally performed to examine the spatial localization of HK3 relative to renal macrophages. Results JPZS reduced proteinuria, serum creatinine, glomerular IgG deposition, and renal histopathological injury in MRL/lpr mice. Gut microbiome profiling showed marked enrichment of Akkermansia and altered community composition, without significant recovery of Chao1 or Shannon diversity, accompanied by reductions in Klebsiella and Enterococcus . Plasma metabolomics revealed remodeling of amino-acid and central carbon metabolism, while renal transcriptomics identified immune-related differences and an exploratory glycolysis/gluconeogenesis enrichment signal. JPZS reduced renal lactate accumulation and the lactate/pyruvate ratio and decreased renal HK3 expression at both the mRNA and protein levels. Dual immunofluorescence showed increased HK3 and F4/80 fluorescence in model kidneys, with overlapping signals evident in merged images; both signals were lower following JPZS-H treatment. Cross-layer correlation analyses linked gut genera, circulating metabolites, and renal gene expression; targeted assays separately characterized renal lactate/pyruvate status. Conclusion JPZS ameliorated renal injury while inducing coordinated changes in the gut microbiome, circulating metabolome, and renal immunometabolic profile in MRL/lpr mice. Integrated multi-omics and targeted validation identified a putative Akkermansia –HK3–lactate immunometabolic link associated with JPZS treatment. These findings provide a hypothesis-generating framework for gut–kidney immunometabolic crosstalk in LN and warrant future causal validation through microbiota- and HK3-targeted approaches.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1873518

Authors: Ming Li, Lijun Pang, Yunfei Li, Shuangshuang Shang, Chuanbing Huang

Institution: Anhui University of Traditional Chinese Medicine

Language: English

Topic: Systemic Lupus Erythematosus Research

Subfield: Rheumatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801