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

## TL;DR

This study shows how the enzyme SIRT3 in intestinal cells affects immune responses in colorectal cancer and colitis through NAD+ synthesis.

## Contribution

The novel finding is that microbiota-derived quinolinic acid replenishes NAD+ in intestinal cells under SIRT3 deficiency, influencing immune function.

## Key findings

- SIRT3 deficiency in intestinal epithelial cells promotes TH1 and CTL differentiation through IL-1β-IL-1R1 signaling.
- Microbiota-derived 3-hydroxyaminobenzoic acid is a source of quinolinic acid for NAD+ synthesis in intestinal cells.
- Targeting intestinal epithelial cells via NAD+ regulation may offer new treatment approaches for immune-associated diseases.

## Abstract

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 (TH1) and cytotoxic T lymphocytes (CTLs) differentiation. IEC SIRT3 deficiency enhances the production of IL‐1β and promotes local TH1 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 TH1 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.

Microbiota‐derived quinolinic acid is used as an alternative source of replenishing the intracellular NAD+ pool induced by SIRT3 deficiency to regulate intestinal epithelial cell and T cell function, which has implications for targeting intestinal epithelial cells as an approach to the treatment of immune‐associated diseases, including colorectal cancer and colitis.