NAD+ metabolism influences TGF-β–associated transcriptional programs and the gut microbiota in murine models of colitis

Abstract

NAD + metabolism plays an important role in maintaining cellular homeostasis and has been implicated in fibrosis-related diseases, including inflammatory bowel disease (IBD). However, the molecular and system-level mechanisms linking NAD + metabolism to fibrosis remain incompletely understood. Here, we investigated the effects of nicotinamide mononucleotide (NMN), a key NAD + precursor, on transforming growth factor β (TGF-β)-associated transcriptional programs. In mouse embryonic fibroblasts, NMN partially restored a subset of TGF-β-associated transcriptional changes, including alterations in Lgr5 and Naprt expression, and affected the expression of fibrosis-associated genes such as Nt5e and Enpp1 , suggesting an association between NMN metabolism and TGF-β-associated transcriptional programs. In a prophylactic DSS-induced mouse model of colitis, NMN supplementation was associated with similar transcriptional changes in vivo , including increased expression of regeneration-associated genes and reduced fibrosis- and immune-related pathways. Microbiome analysis revealed NMN-associated shifts in bacterial communities. Long-term NMN administration was associated with altered colonic immune transcriptional signatures, including alterations in TGF-β-associated and IgA-related pathways, without detectable changes in B-cell or plasma-cell abundance. In a colitis-associated cancer model, NMN administration did not significantly affect tumor number but was associated with changes in TGF-β-related immune pathways within tumors. These findings indicate that NMN supplementation is associated with changes in TGF-β-associated transcriptional and immunological networks across cellular, microbial, and tissue contexts, providing insights into the potential contribution of NAD + metabolism in preventive approaches for fibrosis-related inflammatory conditions.