Rutgers: gut bacteria molecule N-MNA restores NAD and repairs the intestinal lining in mice and flies
Rutgers researchers found that the bacterial molecule N-MNA is converted to NAD and promotes intestinal stem cell regeneration in mice and flies; human cells were tested in culture.
Researchers at Rutgers Health reported in Science Advances that some commensal gut bacteria, including specific probiotic species, produce (amide-)N-methylnicotinamide (N-MNA), a precursor of the coenzyme NAD. The experiments used fruit flies, mice and human cells. According to the authors, N-MNA promotes regeneration of the intestinal epithelium. science.org
Science Advancesscience.orgOpen source ↗ The first author is Jiangmeng Han; the senior authors include Nan Gao and Xiaoyang Su.
NAD levels decline with age and are associated with chronic and inflammatory diseases. N-MNA is a structural isomer of methylnicotinamide, a product of nicotinamide breakdown. Unlike that metabolite, N-MNA can be converted back into NAD.
How N-MNA becomes NAD
Stable isotope tracing showed that N-MNA is rapidly taken up and incorporated into NAD reactions by intestinal epithelial cells and other cells of flies, mice and humans. Genetic and pharmacological analyses suggest that the conversion goes through the Preiss-Handler pathway, independent of the salvage pathway. In human colon cells, N-MNA supplied about 22% of NAD within 24 hours. It also became NAD in human neurons, liver cells and kidney cells. According to the authors, unlike known NAD precursors, N-MNA brings a methyl group into host cells.
Gut repair in animals and patient samples
Cell-type-specific ablation or overexpression of SIRT1, an NAD-consuming enzyme, in Drosophila, together with intestinal stem cell lineage tracing in mice, indicated that systemic N-MNA supplementation promotes stem cell regeneration and epithelial repair. science.org
Science Advancesscience.orgOpen source ↗ In mice with inflamed and damaged colons, untreated animals lost 20% of body weight and died, while animals injected with N-MNA lost 5% and recovered. In flies with damaged guts, seven-day survival rose from 43% to 78%.
The team also analysed stool samples from 54 patients with inflammatory bowel disease and 20 healthy volunteers. Patients with gut dysbiosis and inflammation had reduced stool N-MNA, and those with low N-MNA had significantly higher levels of gut inflammation markers.
The work is preclinical. N-MNA was not tested as a treatment in patients with inflammatory bowel disease. The researchers also did not test whether probiotic strains that make it, including Lactobacilli, raise NAD in people. The human enzymes that process N-MNA have not yet been identified, and Gao's laboratory is mapping the bacterial genes that produce the molecule. Ching-On Wong, a senior author, said that this compound may be sufficient on its own, but that other, better compounds cannot be ruled out.
