Gut microbiota–immune crosstalk in intestinal inflammation and enteric infection: mechanisms and therapeutic frontiers

The mammalian gastrointestinal tract harbors a dense and dynamic microbial community that co-evolved with the host immune system over millennia. Far from serving as passive bystanders, commensal microorganisms are active architects of intestinal immunity, continuously calibrating epithelial barrier integrity, innate immune sensing, and adaptive immune programming to maintain homeostasis. Pattern recognition receptors expressed by epithelial and immune cells distinguish commensal signals from pathogen-associated molecular patterns, enabling tolerogenic responses to the resident microbiota while mounting rapid antimicrobial defenses against enteric pathogens. Microbial metabolites, including short-chain fatty acids, secondary bile acids, tryptophan derivatives, and polyamines, serve as critical immunomodulatory mediators that influence innate immune cell activation, T helper cell differentiation, IgA class switching, and mucus layer composition. Perturbations to this ecosystem, whether through enteric infection, antibiotic exposure, dietary shifts, or host genetic susceptibility, can unravel the finely tuned balance between tolerance and defense, driving pathological outcomes including intestinal inflammation and increased susceptibility to infection.

Despite major advances in cataloguing the gut microbiome and profiling mucosal immune responses, fundamental mechanistic questions remain unanswered. How do specific commensal species and their metabolites instruct distinct innate and adaptive immune programs in a tissue- and context-dependent manner? What molecular mechanisms underlie colonization resistance, the ability of a healthy microbiome to directly exclude or suppress enteric pathogens, and how do successful pathogens subvert this defense? How do pathogens co-opt or disrupt commensal–immune circuits to establish infection and promote systemic spread? How do inflammatory conditions such as IBD alter host susceptibility to enteric infection, and how does infection, in turn, precipitate or exacerbate intestinal inflammation? Addressing these questions is critical to understanding gut immune homeostasis and to developing the next generation of microbiota-targeted and immune-modulating therapies. This collection is deliberately focused on the mechanistic and translational immunology of commensal–host–pathogen interactions in the intestinal compartment, and is distinct from broader topics addressing non-gut microbiome–immune crosstalk in systemic autoimmunity or non-communicable disease.

This Research Topic aims to consolidate and advance mechanistic understanding of how gut microbiota–immune interactions shape intestinal inflammation and enteric infection. We welcome Original Research, Systematic Reviews, and Perspective articles addressing, but not limited to, the following themes:

-Innate immune sensing of commensal and pathogenic signals at the intestinal mucosa: pattern recognition, tolerogenic versus inflammatory signaling, and epithelial–immune crosstalk.
-Commensal-mediated colonization resistance and its disruption: microbial competition, metabolite-mediated exclusion of pathogens, and immune-reinforced barrier defense.
-Microbial metabolites as immunological effectors: mechanisms by which SCFAs, bile acids, tryptophan catabolites, and other metabolites modulate mucosal immune cell identity and function.
-Pathogen strategies for microbiota disruption and immune evasion: how enteric pathogens alter microbial ecology and co-opt host immune pathways to establish and sustain infection.
-Epithelial barrier dysfunction in infection and inflammation: tight junction regulation, mucus dynamics, antimicrobial peptide production, and secretory IgA responses.
-Adaptive immune responses at the intestinal mucosa: IgA class switching and affinity maturation, T helper and regulatory T cell polarization by commensal and pathogenic antigens, and tissue-resident memory formation.
-Immunometabolic reprogramming of intestinal immune cells: nutrient sensing, mTOR and HIF pathways, and mitochondrial dynamics in infection-driven inflammation.
-Microbiota-targeted interventions against intestinal inflammation and enteric infection: probiotics, prebiotics, postbiotics, fecal microbiota transplantation, and phage-based approaches — with emphasis on immune mechanisms of action.

We welcome Original Research, Systematic Reviews, and Perspective articles focused on the mechanistic and translational immunology of gut microbiota–host–pathogen interactions. Submissions should address how commensal and pathogenic signals shape mucosal immunity, epithelial barrier function, colonization resistance, or microbiota-targeted therapeutics. Manuscripts centred on systemic autoimmunity or non-gut microbiome interactions fall outside the scope of this collection.

The topic editors declare no conflict of interest

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• Case Report
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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Editorial
• FAIR² Data
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Gut microbiota–immune interactions, Intestinal mucosal immunity, Colonization resistance, Epithelial barrier function, Microbial metabolites immunomodulation, Enteric pathogen immune evasion, Pattern recognition receptors, Inflammatory bowel disease, Regu

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