A delicate interplay between the immune system and nutrient metabolism
A new study has uncovered a critical mechanism that drives the inflammatory bowel disease (IBD), shedding light on the intricate connection between the immune system and nutrient metabolism. Researchers at the National Institute of Immunology in New Delhi have identified how a signaling pathway in immune cells called dendritic cells disrupts the conversion of vitamin A into its active form, retinoic acid, fueling chronic inflammation in the gut.
The study, led by Dr. Soumen Basak and published in the EMBO Journal, focuses on the noncanonical NF-κB signaling pathway. While this pathway has been at times linked to inflammatory processes, its role in gut health has remained underexplored. Now, the researchers have shown how its overactivation in dendritic cells in IBD patients and mouse models of colitis contributes to immune dysfunction and microbial imbalances.
A Pathway Gone Awry
Dendritic cells are vital immune regulators. But in people with IBD, these cells appear to malfunction due to heightened activity in the noncanonical NF-κB signaling pathway. This disrupts the production of retinoic acid by interfering with the production of the enzyme retinaldehyde dehydrogenase 2 (Raldh2), which converts dietary vitamin A into this key metabolite.
“Retinoic acid is essential for maintaining a balanced immune response and supporting a healthy gut microbiome. When its production is hindered, inflammation spirals out of control, leading to chronic gut conditions,” explain the lead authors.
From Mouse Models to Hopeful Treatment
To unravel this mechanism, the researchers used single-cell and bulk RNA sequencing, as well as biochemical and flow cytometry-based analyses, to study gut cells from mice with chemically induced colitis. They also experimented with genetically modified mice in which the noncanonical NF-κB pathway was disabled specifically in dendritic cells using the Cre-lox technique.
The results were striking. The mice showed significant improvements in gut inflammation, with healthier immune cell populations, elevated levels of protective antibodies, and improved microbial balance in their guts. The pathway’s role in disrupting vitamin metabolism ties directly to the worsening of gut inflammation and turning it off leads to remarkable recovery.
A New Therapeutic Frontier
The findings open the door to novel treatments for IBD that focus on the noncanonical NF-κB pathway. Unlike the canonical NF-κB pathway, which has been a traditional target for inflammatory conditions but is involved in a wide range of physiological processes, the noncanonical pathway plays a more specialized role. This makes it a more attractive target for therapies with potentially fewer side effects.
The study also suggests the potential for combining targeted treatments with dietary interventions. By restoring vitamin A metabolism and boosting retinoic acid production, it may be possible to enhance the immune system’s ability to manage inflammation without resorting to broad immunosuppressive drugs.
Bridging Immune Signaling and Nutrient Metabolism
This research highlights a previously underappreciated connection between immune regulation and micronutrient metabolism in the gut. “By linking the noncanonical NF-κB pathway to vitamin metabolism, we’ve opened a new therapeutic horizon for managing IBD,” says Dr. Basak.
For millions of people living with IBD, this discovery represents a potential turning point. With further research, targeting this pathway may lead to therapies that are not only more effective but also gentler on the body, offering hope for better outcomes and improved quality of life.
This breakthrough underscores the complexity of gut health and its reliance on the delicate interplay between the immune system and nutrients—a partnership that, when disrupted, can wreak havoc but also presents opportunities for innovative solutions.
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)
Written by Banya Kar