The field of mucosal immunology explores the dynamic interactions between the gut epithelium, resident and infiltrating immune cells, and the commensal microbial communities that together maintain intestinal homeostasis. Disruptions in this integrated network underlie many chronic inflammatory disorders, such as inflammatory bowel disease (IBD), and facilitate the evolution of a microenvironment that supports tumor initiation and progression. Recent advances using organoid cultures, single-cell multi-omics, and sophisticated animal models have revealed the nuanced roles of immune subsets and barrier function but have also exposed significant gaps. Chief among these are the mechanisms by which microbial and stromal cues instruct immune tolerance or drive inflammation, the plasticity of mucosal circuits, and the contribution of these processes to cancer risk.

Despite expanding insight into epithelial-immune-microbiome interactions, key questions remain unanswered. How do mucosal immune cells sense and respond to antigens under homeostatic versus inflammatory or tumorigenic conditions? What is the nature of stromal-immune interplay governing barrier integrity, tolerance, and repair? Which microbial signals or metabolites tip the balance toward chronic inflammation or, conversely, mucosal healing? There is also an urgent need to clarify how immune dysregulation and persistent inflammation set the stage for colorectal carcinogenesis, and how these mechanisms might be targeted for personalized therapy. Although recent studies have begun to map these complex networks, translating such findings into effective therapeutics remains a core challenge in the field.

This Topic aims to elucidate the cellular and molecular mechanisms underpinning gut mucosal immunity, with a focus on the intricate dialogue among epithelial cells, immune effectors, and the microbiota. We invite contributions that dissect immune regulation during health, inflammation, and cancer; investigate the roles of diverse mucosal immune populations; uncover signaling pathways governing barrier biology, tolerance, or reactivity; and leverage cutting-edge models or computational systems to integrate multi-dimensional data. Our objective is to drive mechanistic and translational advances that inform the development of immunomodulatory and microbial-targeted interventions to restore mucosal homeostasis and prevent disease.

This Research Topic will encompass original research, reviews, and perspectives within the following boundaries: studies should center on gut mucosal immunity—from tissue biology and immunology to clinical and translational aspects—and address mechanisms relevant to health, chronic inflammation, or cancer progression. The following themes are especially encouraged:

-Epithelial barrier integrity, antigen uptake, and stem cell–immune interactions
-Microbiome-driven modulation of immune function and metabolite-mediated signaling
-Cellular and molecular circuits of chronic inflammation, mucosal healing, and fibrosis
-Mechanisms linking inflammation to colorectal cancer initiation and progression
-Development and evaluation of therapeutics targeting gut mucosal immunity, including microbial and immunomodulatory strategies
-Integration of human datasets, organoid models, single-cell or multi-omics technologies
-Computational or systems biology approaches to mapping gut-immune networks

The topic editors declare no conflict of interest

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Disruption of integrated network with immune system at the gut interface in local inflammation and cancer development