GENETIC VARIATION IN INNATE IMMUNE GENES SHAPES GUT MICROBIOTA COMPOSITION AND HOST-MICROBE INTERACTIONS: A REVIEW

Abstract

The gut microbiota is a critical determinant of host immune, metabolic, and epithelial homeostasis, yet the host genetic factors governing inter-individual variation in microbial composition remain incompletely defined. Beyond environmental influences, genetic variation in innate immune pathways has emerged as a key regulator of host-microbiome interactions. Variants in pattern recognition receptors, inflammasome components, antimicrobial peptide genes, and immune-regulatory cytokines modulate microbial sensing, antimicrobial defense, inflammatory tone, and barrier integrity, thereby exerting selective pressures on gut microbial communities. This review systematically synthesizes evidence from human genome-microbiome association studies, twin cohorts, population-based analyses, and mechanistic experimental models to delineate how genetic variation in innate immune genes shapes gut microbiota composition and function. We focus on major innate pathways, including Toll-like receptors, NOD-like receptors, inflammasomes, defensins, and cytokine signaling networks, and summarize their documented effects on microbial diversity, taxonomic structure, and disease-associated dysbiosis. Key methodological challenges such as small genetic effect sizes, environmental confounding, population specificity, and limited causal inference are critically evaluated. Finally, we outline future directions emphasizing longitudinal study designs, multi-omics integration, functional validation, and genotype-stratified interventions. Elucidating innate immune genetic control of the gut microbiota will be essential for advancing precision microbiome medicine and for developing targeted therapeutic strategies for inflammatory, metabolic, and immune-mediated diseases.