Increased small intestinal permeability has recently been described as an integral element, along with genetic makeup and environmental triggers, in the pathogenesis of chronic inflammatory diseases (CIDs). We identified zonulin as a master regular of intercellular tight junctions, and both our group and others have linked the zonulin pathway to the development of several CIDs. We further characterized zonulin as the precursor of haptoglobin (Hp)-2. In this dissertation, my aim is to study the role of zonulin-mediated small intestinal permeability in the pathogenesis of CIDs by using a zonulin transgenic mouse model as well as zonulin genotyping and disease modeling in several CIDs. Zonulin transgenic Hp2 mice (Ztm) were subjected to dextran-sodium-sulfate (DSS) treatment, and their morbidity and mortality compared to C57Bl/6 (WT) mice. We observed increased morbidity (more severe body weight loss and colonic inflammation) and mortality at 11 days post DSS treatment in zonulin transgenic Hp2 mice compared to WT. Ztm had increased small intestinal permeability at baseline compared to WT, which was exacerbated by DSS treatment and associated with upregulation of the zonulin gene in the small intestine. Treatment with the zonulin inhibitor AT1001 prevented the DSS-induced increased small intestinal permeability and completely reversed mortality rates. We went on to study the risk Hp genotypes in disease development by using a combination of HLA and Hp genotypes to predict disease outcome. We observed increased HP2 allele frequency in several CIDs studied. Additionally, the HP2 allele (both in homozygosity and heterozygosity) seems to increase the risk of early age of onset of Type 1 diabetes (T1D). Using the combination of HLA and Hp genotypes, we were able to create accurate positive predictive models for celiac disease (CD) and T1D. Taken together, these data show that the zonulin gene can be mechanistically linked to increased small intestinal permeability that leads to a break of tolerance with subsequent development of CIDs. Additionally, the use of the Hp genotype, either alone or in addition to other genetic markers, may be a useful tool to create predictive models for disease development for precision and preventive medicine approaches.