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

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.