The gastrointestinal (GI) tract is a dynamic interface between the outside world and our internal physiology and, as such, spans many functions that go beyond digestion and nutrient absorption. It houses a substantial part of our immunity, making the digestive and immune systems closely interconnected. The gut-immune axis refers to the bidirectional communication between the GI tract, especially the gut microbiota, and the immune system. The GI microbiome plays an important role in supporting healthy immune and inflammatory responses through mechanisms involving microbial metabolites, immune cell development, and gut barrier integrity.

The Role of the Gut-Associated Lymphoid Tissues (GALT)

The GI tract houses the greatest number and diversity of immune cells in the body, primarily organized within the gut-associated lymphoid tissues (GALT), which helps support frontline immune defense. GALT includes Peyer’s patches (lymphoid follicles in the mucosa of the small intestine sampling antigens from the gut lumen), the appendix (may function as an adaptive immune inductive site and a microbial reservoir), and isolated lymphoid follicles (estimated about 30,000 solitary follicles distributed throughout the small and large intestines). These structures work together to support mucosal immunity, detect incoming antigens, and coordinate the production of antibodies for early immune activation.

GALT supports several key adaptive immune responses through B cell activation and antibody production, especially the production of secretory IgA (sIgA) — the dominant antibody in the gut. SIgA plays an important role in neutralizing bacterial toxins, mitigating pathogen invasion, and supporting mucosal homeostasis. GALT also contributes to the maturation of innate-like marginal zone B cells, which circulate systemically and respond to polysaccharide antigens from opportunistic bacteria. Furthermore, GALT supports the propagation and selection of systemic B cells, indicating that its role extends beyond local mucosal immunity to broader adaptive immune functions.

The Role of Short-Chain Fatty Acids (SCFAs) 

The GI tract is home to trillions of microbes producing microbial metabolites, such as the short-chain fatty acids (SCFAs) butyrate, acetate, and propionate. SCFAs are the end-products of microbial fermentation of macronutrients, especially plant polysaccharides that cannot be digested by humans alone because our genomes do not encode the enzymes needed to cleave the glycosidic linkages present in these fibers. These “missing enzymes” are provided by the gut microbiome, where certain bacteria, including Faecalibacterium prausnitzii, Roseburia, and Anaerostipes ferment the polysaccharides, producing SCFAs as their metabolic end-products.

SCFAs support immune health by promoting the activation, recruitment, and differentiation of various immune cells, such as neutrophils, macrophages, dendritic cells, and T-lymphocytes. SCFAs have also been shown to interact with G-protein-coupled receptors (such as GPR43 and GPR41) on intestinal immune cells. Activation of these receptors supports healthy immune and inflammatory responses by promoting interleukin (IL)-10-secreting regulatory T cells (Tregs) and normalizing macrophage secretion of pro-inflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-alpha (TNF-α). 

The GI epithelial barrier also plays an important role in immune health by maintaining separation between microbes and immune cells and limiting potentially harmful substances from entering circulation. SCFAs have been shown to promote intestinal barrier integrity by supporting tight junctions and the mucus layer. For example, butyrate has been shown to support the production of MUC2, the predominant mucin glycoprotein in the colon. By promoting the production of mucus and antimicrobial peptides, SCFAs help create a physical and biochemical barrier against pathogens. SCFAs also promote the expression, localization, and function of key tight junction proteins, including occludin, zonula occludens-1 (ZO1), claudin-1, and claudin4, strengthening the connections between epithelial cells and limiting the potential entry of harmful substances into the bloodstream. 

Interestingly, SCFAs may further support immune health through epigenetic mechanisms, such as inhibiting histone deacetylases (HDACs) — key enzymes that regulate chromatin structure and gene expression. By suppressing HDAC activity, SCFAs have been shown to modulate T lymphocyte differentiation, including mitigating pro-inflammatory Th17 cell activity and promoting Treg generation, thus supporting healthy immune and inflammatory responses. This association between microbial metabolism and gene expression suggests an important role for the GI microbiome as a bridge between dietary intake and immune health.

Translational Evidence Supporting the Gut-Immune Connection

There is compelling evidence suggesting that gut and immune health are deeply interconnected. A systematic review of 188 studies summarized dietary and probiotic strategies with measurable effects on immune function through modulation of the GI microbiome. The authors concluded that high-fiber, plant-rich diets consistently supported microbial diversity, increasing beneficial genera (such as Bifidobacterium and Faecalibacterium), along with the production of health-promoting metabolites like SCFAs. In contrast, Western-style diets high in saturated fats, refined sugars, and processed foods were associated with reduced microbial diversity and an expansion of opportunistic, pro-inflammatory taxa, compromising gut barrier integrity and immune resilience. Importantly, this review underscored the role of the gut microbiome as a modulator of immune activity, influencing Tregs development, mucosal IgA production, and the balance between tolerance and inflammation across the gut-immune axis. 

A recent multi-cohort observational study (n = 120) further explored the functional relationship between the GI microbiome and immune health in the context of pediatric allergy and immune tolerance. It compared the microbiome of 90 children with food or respiratory allergies to that of 30 age-matched healthy controls. Specific microbial signatures in the gut microbiome of children with allergies exhibited a relative abundance of Ruminococcus gnavus and Faecalibacterium prausnitzii and a depletion of Bifidobacterium longum and fiber-degrading, SCFA-producing taxa, such as Roseburia and Anaerostipes species. This microbial profile corresponded with a pro-inflammatory potential, including elevated pathways for lipopolysaccharide and urease synthesis, suggesting that gut microbial composition and metabolism may influence immune health.

Finally, a randomized, double-blind, placebo-controlled trial (n = 106) examined whether targeted microbiome modulation could impact immune outcomes in healthy adults. Participants received either a synbiotic supplement (containing Bifidobacterium lactis HN019, Lactobacillus rhamnosus HN001, and fructo-oligosaccharides) or placebo for eight weeks. Compared to placebo, the synbiotic group demonstrated enrichment of beneficial taxa (e.g., Lactobacillus, Bifidobacterium, and Collinsella) and of pathways related to amino acids and SCFAs biosynthesis. These microbiome shifts correlated with significant increases in anti-inflammatory biomarkers (IL-10 and sIgA) and reductions in pro-inflammatory biomarkers (C-reactive protein and interferon-γ) in the synbiotic group, relative to the control. Collectively, these findings suggest that dietary and probiotic interventions that support the gut microbiome may also promote immune health.

Learn more about gut and immune health: 

The Microbiome-Allergy Connection: Probiotics in Clinical Practice

Recent Study Uncovers Mechanistic Link Between Poor Diet and Impaired Innate Immunity Within the Gut

Promoting Immune Health in Children Starts in the Gut

Recent Review Explores Potential Relationship Between Food Allergy and the Gut Microbiome

By Antonia Toupet, PhD