Summary:
Inflammatory bowel disease is a chronic condition of the gastrointestinal tract driven by interactions between genetics, environmental factors, and disrupted immune responses. A key feature of the disease is the loss of immune tolerance to the gut microbiome. Current treatments target inflammation but do not directly address the underlying immune-microbiome imbalance, highlighting the need for approaches that restore immune regulation. Immunoglobulins, particularly IgA and IgG, play an important role in shaping interactions between the immune system and gut bacteria. IgA supports microbial balance and intestinal homeostasis, while IgG is more closely linked to inflammation. In people with inflammatory bowel disease, increased binding of these antibodies to gut bacteria has been associated with disease activity, suggesting that modification of these responses may be clinically relevant. Vitamin D has been identified as a regulator of both immune function and the gut microbiome. It influences cell activity, reduces inflammatory immune responses, and has been associated with greater microbial diversity. These factors suggest that vitamin D may help restore immune tolerance to gut bacteria. This paper is an interventional clinical trial that examined the effects of 12 weeks of vitamin D supplementation in patients with inflammatory bowel disease and low vitamin D levels. The study assessed changes in immune responses, antibody-bacteria interactions, and gut microbiota composition. The findings showed that vitamin D supplementation was associated with reduced disease activity and inflammation. It also shifted immune responses, increasing IgA binding and reducing IgG binding to gut bacteria, alongside changes in specific bacterial groups. In addition, vitamin D positively influenced immune cells. In conclusion, this study suggests that vitamin D may help regulate immune-microbiome interactions and promote immune tolerance in inflammatory bowel disease, indicating a potential therapeutic role beyond its commonly known functions.
Abstract:
Loss of immune tolerance to the gut microbiome plays a pathogenic role in inflammatory bowel disease (IBD). How dietary factors alter host immune-gut microbiome interactions in IBD is unclear. Here, we apply multi-omics (immunoglobulin A or G and 16S rRNA sequencing [IgA-seq, IgG-seq], blood single-cell RNA sequencing [scRNA-seq], and immune repertoire sequencing) to investigate the effects of 12 weeks of vitamin D on host immune microbe interactions in patients with IBD. Vitamin D treatment associates with decreased disease activity and inflammatory markers and increased IgA-bound and decreased IgG-bound gut microbiota. Vitamin D alters the profiles of IgA-bound (increased Lachnospiraceae, Blautia) and IgG-bound (decreased Proteobacteria, Enterococcaceae) gut bacteria. Vitamin D increases B cell activating factor (BAFF) signaling between plasmacytoid dendritic cells and B cells, alters BCR and TCR clonotypes that associate with Ig-bound gut microbiota, and increases α4β7+ B and T regulatory cells. Our results demonstrate that vitamin D promotes immune tolerance to gut microbiota in patients with IBD. Clinical trial is registered under NCT04828031.
Article Publication Date: 26/06/2026
DOI: 10.1016/j.xcrm.2026.102703
