Tolerogenic dendritic cells attenuate collagen-induced arthritis through a mucosal immunity–gut microbiota–butyrate axis

Background Tolerogenic dendritic cells (TolDCs) are being developed to restore antigen-specific immune tolerance in autoimmune diseases. However, whether their therapeutic effects in autoimmune arthritis involve modulation of the gut–joint axis remains unclear. Methods TolDCs generated using an NF-κB decoy oligodeoxynucleotide were loaded with bovine type II collagen and administered to rats with collagen-induced arthritis (CIA). Arthritis severity was assessed clinically and histologically. Antibiotic-mediated microbiota depletion and fecal microbiota transplantation (FMT) were used to assess microbiota involvement. Colonic tight-junction protein expression, mesenteric lymph node Treg/Th17 balance, fecal microbial communities, PICRUSt2-predicted short-chain fatty acid (SCFA)-related metabolic functions based on 16S rRNA sequencing data, serum SCFAs, and the effects of sodium butyrate supplementation were also evaluated. Results TolDCs reduced paw swelling and arthritis scores and ameliorated ankle-joint pathology. In the concurrent antibiotic-depletion experiment, TolDC-associated improvements in arthritis outcomes did not reach statistical significance, whereas FMT from TolDC-treated donors partially transferred protection to antibiotic-pretreated CIA recipients. TolDC treatment increased colonic ZO-1 and occludin expression, shifted the mesenteric lymph node Treg/Th17 balance toward a regulatory profile, altered gut microbial community structure and composition, and was accompanied by higher predicted abundances of selected butyrate-associated MetaCyc pathways and KEGG Orthology (KO) functional groups, along with increased serum butyrate concentrations. Sodium butyrate supplementation partially reproduced the protective phenotype. Conclusion These findings support a microbiota-dependent component of TolDC-mediated protection and suggest that a coordinated mucosal immunity–gut microbiota–butyrate axis may contribute to arthritis control.