Short-chain fatty acid deficiency drives aberrant B cell differentiation in systemic lupus erythematosus

  • Clin Immunol. 2026 Jun:285:110706. doi: 10.1016/j.clim.2026.110706.
Ryuichiro Kanda  1 ,  Satoshi Kubo  1 ,  Kaoru Yamagata  1 ,  Shigeru Iwata  2 ,  Yasuyuki Todoroki  3 ,  Masanobu Ueno  1 ,  Atsushi Nagayasu  4 ,  Yurie Satoh-Kanda  1 ,  Ippei Miyagawa  3 ,  Koshiro Sonomoto  5 ,  Yoshiya Tanaka  3 ,  Shingo Nakayamada  6
Affiliations
  • 1. First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.
  • 2. Department of Rheumatology and Clinical Immunology, Wakayama Medical University, Japan.
  • 3. First Department of Internal Medicine, University of Occupational and Environmental Health, Japan; Department of Molecular Targeted Therapeutics, School of Medicine, University of Occupational and Environmental Health, Japan.
  • 4. First Department of Internal Medicine, University of Occupational and Environmental Health, Japan; Department of Infectious Disease Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.
  • 5. First Department of Internal Medicine, University of Occupational and Environmental Health, Japan; Department of Clinical Nursing, University of Occupational and Environmental Health, Japan.
  • 6. First Department of Internal Medicine, University of Occupational and Environmental Health, Japan. Electronic address: [email protected].
PMID: 41974394 DOI: 10.1016/j.clim.2026.110706
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive plasmablast differentiation, with gut dysbiosis considered a key environmental factor. Serum levels of butyrate, a short-chain fatty acid (SCFA) produced by the gut microbiota, were decreased in 35 untreated patients with active SLE compared with healthy controls (3.3 ± 1.0 vs 1.4 ± 0.7 μM, p < 0.001, Cohen's d = 2.40), and SCFAs regulated plasmablast differentiation via signaling through their specific receptor, G-protein-coupled receptor (GPR43). SCFAs inhibited plasmablast differentiation in human B cells, an effect reversed by a GPR43 antagonist. Butyrate or a GPR43 agonist activated β-arrestin 2, suppressing NF-κB phosphorylation and reducing NF-κB binding to the PRDM1 promoter. Serum SCFA levels are influenced by diet and gut environment, which were not evaluated. SCFAs may be a possible adjustable variable that should be clinically explored, highlighting the potential for fine-tuning GPR43 signaling as novel therapeutic strategies for SLE.

Keywords
Gut dysbiosis; Plasmablast; Short-chain fatty acids; Systemic lupus erythematosus.
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