Microbiota-Associated Metabolites as Immunometabolic Regulators of Glomerular Inflammation: Disease-Specific Mechanisms and Therapeutic Opportunities.
- 1School of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People's Republic of China.
- 2Nephrology and Rheumatology Immunology Diagnosis and Treatment Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, People's Republic of China.
- 3Beijing Institute of Chinese Medicine, Beijing, 100010, People's Republic of China.
Abstract
Background
Immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) are immune-mediated glomerular diseases in which dysregulated adaptive immunity converges with innate inflammatory and filtration-barrier injury. Clinical relapse and incomplete recovery despite upstream immune control motivate investigation of additional injury modifiers.Main body
This review evaluates five microbiota-associated metabolite families-short-chain fatty acids (SCFAs), tryptophan-derived metabolites, aromatic amino acid-derived uremic solutes, trimethylamine N-oxide (TMAO), and bile acids-across three modules: immune-tolerance failure, innate inflammatory amplification, and filtration-barrier disruption. In IgAN, multi-omics data showing preserved or elevated systemic acetate with reduced glomerular free fatty acid receptor 2/3 (FFAR2/FFAR3)-associated signaling suggest impaired renal SCFA sensing, but do not establish receptor competence as the dominant target. In MN, disease-specific studies support podocyte injury mediated by complement C3a and its receptor (C3a/C3aR) and complement-associated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) pyroptosis as related injury processes, whereas proposed SCFA-regulatory T cell (Treg)-B-cell and SCFA-inflammasome interactions remain largely hypothesis-generating; experimental Lactobacillus-indole-aryl hydrocarbon receptor (AhR) data provide preliminary evidence. In LN, microbiota-dependent tryptophan pathway perturbation and treatment-associated metabolomic changes support the kynurenine-to-tryptophan ratio as a readily measurable candidate biomarker requiring prospective validation. Across diseases, interpretation requires separating microbial production from renal retention, metabolite abundance from receptor signaling competence, and total from unbound exposure for protein-bound solutes.Conclusion
Microbiota-associated metabolites constitute a plausible immunometabolic layer rather than established causal pathways in immune-mediated glomerular disease. Priorities include disease-specific longitudinal phenotyping, compartment-resolved metabolite measurement, target-engagement studies, and biomarker-embedded clinical trials before therapeutic claims are advanced.
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BibTeX
@article{hou2026microbiotaassociated,
title = {{Microbiota-Associated Metabolites as Immunometabolic Regulators of Glomerular Inflammation: Disease-Specific Mechanisms and Therapeutic Opportunities.}},
author = {Fanyu Hou and Liuxiao Yang and Wu Liu and Wen Liu and Yanyu Cui and Hongliang Rui and Baoli Liu},
journal = {Journal of inflammation research},
year = {2026},
month = oct,
doi = {10.2147/jir.s641770},
url = {https://europepmc.org/article/MED/42921202},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Microbiota-Associated Metabolites as Immunometabolic Regulators of Glomerular Inflammation: Disease-Specific Mechanisms and Therapeutic Opportunities.
AU - Fanyu Hou
AU - Liuxiao Yang
AU - Wu Liu
AU - Wen Liu
AU - Yanyu Cui
AU - Hongliang Rui
AU - Baoli Liu
PY - 2026
DA - 2026/10/19
JO - Journal of inflammation research
DO - 10.2147/jir.s641770
UR - https://europepmc.org/article/MED/42921202
AB - Background Immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) are immune-mediated glomerular diseases in which dysregulated adaptive immunity converges with innate inflammatory and filtration-barrier injury. Clinical relapse and incomplete recovery despite upstream immune control motivate investigation of additional injury modifiers.Main body This review evaluates five microbiota-associated metabolite families-short-chain fatty acids (SCFAs), tryptophan-derived metabolites, aromatic amino acid-derived uremic solutes, trimethylamine N-oxide (TMAO), and bile acids-across three modules: immune-tolerance failure, innate inflammatory amplification, and filtration-barrier disruption. In IgAN, multi-omics data showing preserved or elevated systemic acetate with reduced glomerular free fatty acid receptor 2/3 (FFAR2/FFAR3)-associated signaling suggest impaired renal SCFA sensing, but do not establish receptor competence as the dominant target. In MN, disease-specific studies support podocyte injury mediated by complement C3a and its receptor (C3a/C3aR) and complement-associated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) pyroptosis as related injury processes, whereas proposed SCFA-regulatory T cell (Treg)-B-cell and SCFA-inflammasome interactions remain largely hypothesis-generating; experimental Lactobacillus-indole-aryl hydrocarbon receptor (AhR) data provide preliminary evidence. In LN, microbiota-dependent tryptophan pathway perturbation and treatment-associated metabolomic changes support the kynurenine-to-tryptophan ratio as a readily measurable candidate biomarker requiring prospective validation. Across diseases, interpretation requires separating microbial production from renal retention, metabolite abundance from receptor signaling competence, and total from unbound exposure for protein-bound solutes.Conclusion Microbiota-associated metabolites constitute a plausible immunometabolic layer rather than established causal pathways in immune-mediated glomerular disease. Priorities include disease-specific longitudinal phenotyping, compartment-resolved metabolite measurement, target-engagement studies, and biomarker-embedded clinical trials before therapeutic claims are advanced.
SN - 1178-7031
ER -