Modulation of Intestinal Immunity by ATG16L1 T300A and Ffar2

Abstract

The mucosal immune system is essential for maintaining homeostasis between the host and the gut microbiota. When this delicate balance is perturbed, an overactive immune response against gut microbes can lead to inflammatory bowel disease (IBD) and contribute to the growth and spread of colorectal cancer (CRC). IBD encompasses Crohn’s disease (CD) and ulcerative colitis (UC) and afflicts over 3 million individuals in the U.S. CRC is the third most incident cancer globally and the second most deadly. Both CRC and IBD have significant unmet medical needs and tremendous diagnostic, preventative, and therapeutic opportunities in microbiome sciences and immunology. This thesis explores the pathogenesis of IBD and CRC and aims to uncover how the gut microbiota and immune system may be harnessed for novel diagnostic and therapeutic options to prevent intestinal disease. To elucidate CD pathogenesis, we utilized mice that harbor the CD risk allele ATG16L1 T300A (T300A). Using gnotobiotic T300A mice in combination with fecal transfers from humans with T300A and IBD, we uncovered a role for T300A in regulating the gut microbiota and intestinal T cell responses. These microbial and CD4+ T-helper type 1 and 17 cell changes occurred before disease onset, suggesting that alterations arise prior to disease symptoms. The gut microbiota generates metabolites that affect the host immune system. One such example is short-chain fatty acids (SCFA). Ffar2, a G protein-coupled receptor expressed by epithelial and immune cells, recognizes SCFA and can modulate colon tumor progression. We found that loss of Ffar2 potentiates tumorigenesis by a “two-hit” model, first by gut barrier breach and then by dendritic cell (DC) dysfunction. Loss of Ffar2 increased both IL-27+ DCs and exhausted CD8+ T cells in tumors. We found that il27p28 expression was upregulated in human CRC tissue, suggesting a pro-tumorigenic role for IL-27. IL-27 neutralization or Ffar2 agonism reduced tumor burden in mice, supporting their potential as CRC therapeutics. Overall, this thesis elucidates two distinct mechanisms whereby host genes regulate homeostasis between the immune system and the gut microbiota to reduce susceptibility to IBD and CRC.