A recent study has uncovered a key mechanism behind gut inflammation, focusing on immune cells called dendritic cells. Dr. Soumen Basak and his team of researchers at the National Institute of Immunology, New Delhi discovered that these cells, which help regulate the immune system, can malfunction in inflammatory bowel disease (IBD), a chronic gut inflammatory disorder.

Leveraging single-cell and bulk RNA sequencing data from humans and mice, the study revealed that a specific signaling pathway, known as noncanonical NF-κB signaling, is significantly active in dendritic cells from patients with IBD and mice with colitis. Nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-kB) is a family of transcription factors that play diverse roles in regulating immune responses and the development of immune organs. Using biochemical and flow cytometry-based analyses, they surprisingly found that this pathway disrupts the production of retinoic acid, a crucial molecule derived from Vitamin A that helps maintain a balanced immune response in the gut. By interfering with the accessibility of Vitamin A metabolites in the gut, the noncanonical NF-κB signaling leads to an increase in inflammation and worsens gut conditions. When researchers disrupted this signalling pathway specifically in dendritic cells by the Cre-lox method, the mice showed significant improvements in gut inflammation symptoms. They had more beneficial immune cells and higher levels of protective antibodies in their gut, promoting a healthy gut microbiome.

This research promises a possible shift in treating IBD by focusing on the noncanonical NF-κB pathway and micronutrient supplementation. While the canonical NF-κB pathway has traditionally been considered for therapeutic targeting in inflammatory ailments, pharmacological inhibition of this pathway causes undesirable side effects due to its broad involvement in various physiological processes and increases the risk of infections. On the other hand, the noncanonical NF-κB pathway plays a role in a limited set of biological processes. This study published in the EMBO Journal identifies a rather unknown role of the noncanonical NF-κB pathway in tuning vitamin metabolism in the gut, paving the way for novel treatment regimes.

Reference:

Deka A, Kumar N, Basu S, Chawla M, Bhattacharya N, Ali SA, Bhawna, Madan U, Kumar S, Das B, Sengupta D, Awasthi A, Basak S. Non-canonical NF-κB signaling limits the tolerogenic β-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies. EMBO J. 2024 Jul 25. doi: 10.1038/s44318-024-00182-6. Epub ahead of print. PMID: 39060515. (https://doi.org/10.1038/s44318-024-00182-6)