A variety of diseases are related to the loss of gut epithelial integrity, including inflammatory bowel disease, colon cancer, diabetes, and rheumatoid arthritis. The gut innate immune system mediates processes that are responsible for gut tissue integrity, epithelial repair, and microbial homeostasis. For example, tissue-resident Th17 cells are responsible for the induction of protective antibodies, innate lymphoid cells regulate intestinal stem cell regeneration, and tissue-resident γδ T cells promote tissue repair and dampen pro-inflammatory responses. Transcription factors are involved in an intricate network of interactions with other partner proteins and are key regulators of immune cell phenotype and tissue repair. While the binding of transcription factors to DNA is well studied, our understanding of transcription factor protein-protein interactions in the regulation of gene expression remains limited. We are studying transcription factor protein-protein interactions that promote gut tissue integrity and are developing small molecules that target these interactions as immune-modulating therapeutics.