Nicotinamide N-methyltransferase mediates redox regulation and colonic epithelial barrier impairment by SIRT1/PPAR-γ/NLRP6/NRF2 axis in inflammatory bowel disease.

INTRODUCTION

Inflammatory bowel disease (IBD) involves a complicated systemic inflammatory immune response that is characterized by epithelial barrier failure and mucosal immune response dysregulation. Nicotinamide N-methyltransferase (NNMT) catalyzes nicotinamide adenine dinucleotide (NAD+) turnover and sustains pro-inflammatory signals in the niacin and nicotinamide metabolic pathways. However, the expression and function of NNMT in IBD is still unknown.

OBJECTIVES

This study aims to explore the expression, role and mechanism of NNMT in IBD, provide a theoretical basis for the clinical application of immunometabolic therapy, and provide a new direction for the treatment of IBD.

RESULTS

Here, we found NNMT expression was higher in colonic tissues and sera of IBD patients than healthy people, and serum NNMT levels were linked with inflammatory activity. The inhibition of NNMT raised NAD+ levels, regulated the SIRT1/PPAR-γ/NLRP6/NRF2 axis, decreased oxidative stress and mitochondrial damage in colonic epithelial cells (CECs), thus repaired colonic epithelial barrier, and attenuated inflammation in IBD.

CONCLUSIONS

Our data proposed that NNMT was involved in the pathogenesis and progression of IBD, and NNMT was a potential biomarker to assess the inflammatory activity of IBD, and inhibition of NNMT and targeting NAD+ immunometabolic processes could be used as a new treatment direction for IBD to repair the colonic epithelial barrier and inhibit oxidative stress.