The Role of Host Genetics and Gut Microbiota Interaction in Immune System Regulation: A Systematic Review and Meta-Analysis

Abstract

Context: The interaction between host genetics and the gut microbiota plays a vital role in immune regulation; however, existing evidence lacks integrated quantification and methodological coherence. Therefore, we conducted a systematic review and meta-analysis of quantitative studies to test explicitly whether microbial metabolites mediate the association between host genetics and immune function. Evidence Acquisition: A systematic search was conducted in PubMed, Scopus, Web of Science, Embase, and the Cochrane Library through December 2025. Of 1,245 identified records, 14 quantitative studies met the inclusion criteria. Study quality was assessed using design-specific tools (NOS, STROBE-MR, JBI). Analyses were performed using random-effects models, meta-regression, and meta-analytic path analysis. The protocol was not registered in PROSPERO, and all analyses were exploratory. Results: The NOD2–Enterobacteriaceae interaction was associated with inflammatory bowel disease severity (OR = 2.34, 95% CI: 1.78 - 3.08, P < 0.001, I2 = 38%). Evidence from Mendelian randomization studies suggested that the microbiota may have a causal effect on inflammatory cytokines (OR = 1.52, 95% CI: 1.28 - 1.81, P < 0.001, I2 = 48%). Microbial metabolites mediated approximately 56 - 63% of the effects (k = 3, exploratory findings). Disease status, ethnicity, BMI, and diet explained a substantial proportion of the between-study heterogeneity. Publication bias assessment of 8 studies in the dysbiosis–cytokine analysis showed no statistically significant evidence of bias (Egger's test: P = 0.082; Begg's test: P = 0.114). Conclusions: Our findings suggest that metabolite-dependent pathways represent the primary intersection between host genetics and the gut microbiota in immune regulation. However, several caveats warrant consideration: the exploratory design, unregistered protocol, underpowered subgroup analyses, and European-centric populations mean that our conclusions should be viewed as hypothesis-generating rather than definitive, pending validation in prospective cohorts and trials. Accordingly, any clinical recommendations based on these findings should be made cautiously and treated as hypotheses for future research.