NAD ⁺ ‐Dependent Enzyme SIRT3 Limits Intestinal Epithelial Cell Functions Through NAD ⁺ Synthesis Pathway in Colorectal Cancer

Intestinal epithelial cells (IEC) are crucial for regulating intestinal local immunity to potentiate mucosal barrier function, but the mechanism remains unclear. In this study, we showed that the nicotinamide adenine dinucleotide (NAD⁺)-dependent enzyme SIRT3 in IECs is required for local T cell differentiation in colorectal cancer and colitis. Modest IEC SIRT3 overexpression reduces the secretion of proinflammatory cytokine IL-1β and inhibits IFNγ-producing CD4⁺T cells (T_H1) and cytotoxic T lymphocytes (CTLs) differentiation. IEC SIRT3 deficiency enhances the production of IL-1β and promotes local T_H1 and CTL differentiation in limiting colorectal cancer growth and aggravating colitis. Mechanistically, SIRT3 deficiency promotes IEC functions through quinolinic acid (QA)-mediated NAD⁺ synthesis for limiting tumor growth. Microbiota-derived 3-hydroxyaminobenzoic acid is the source of intracellular QA in IECs. IL-1β-IL-1R1 signaling is required for IEC SIRT3 deficiency-induced T_H1 and CTL differentiation in cancer. Thus, our findings showed that microbiota-derived QA is used as an alternative source of replenishing the intracellular NAD⁺ pool induced by SIRT3 deficiency to regulate IEC and T cell function, which has implications for targeting IECs as an approach to the treatment of immune-associated diseases, including colorectal cancer and colitis.