Scientists at Rutgers Health have discovered a molecule produced by "good" gut bacteria that rapidly heals the intestinal lining, protecting against severe inflammatory diseases and triggering increased production of a coenzyme whose levels diminish with age.
In tests in mice, flies and human cells, researchers found evidence that the breakthrough molecule – called (amide-)N-methylnicotinamide, or N-MNA – has the potential to treat inflammatory bowel disease and other chronic gut disorders in humans by activating a coenzyme called nicotinamide adenine dinucleotide, or NAD, whose decline is thought to be a major driver of aging.
The study was published in Science Advances.
Tests showed that N-MNA, a precursor molecule, activated NAD, thereby speeding the repair of damaged guts by stimulating stem cell regeneration.
Some species of gut bacteria, including one available in dietary supplements, also produce a precursor of NAD, fueling a market for products meant to bolster it. Because NAD cannot enter cells directly, scientists have been seeking precursors that can be taken up by cells and converted into NAD.
N-MNA is a near twin of a molecule human cells make when they dispose of excess NAD building blocks, but N-MNA, unlike the molecule humans make themselves, can be converted back into NAD.
"Humans do not appear to make this exact precursor molecule N-MNA, but some of the bacteria living in our gut do," said senior study author Nan Gao , a professor of pharmacology, physiology and neuroscience at Rutgers New Jersey Medical School and an expert in fly genetics.
"The molecules animal cells and bacteria make are almost identical, but a tiny difference allows the creation of the bacterial compound back into NAD itself," said another senior study author, Xiaoyang Su , associate professor of medicine at Rutgers Robert Wood Johnson Medical School . Su is also co-director of the Metabolomics Shared Resource at Rutgers Cancer Institute , New Jersey's only National Cancer Institute-designated Comprehensive Cancer Center, together with RWJBarnabas Health.
Jiangmeng Han, the first author of the study and a doctoral degree student in biological sciences at Rutgers University-Newark , tracked the molecule into human colon cells, where it supplied about 22% of their NAD within 24 hours. It also became NAD in human neurons, liver cells and kidney cells and in the bodies and heads of fruit flies given it.
In mice with inflamed and damaged colons, untreated animals lost 20% body weight and died, while those injected with N-MNA lost 5% and recovered. In fruit flies with damaged guts, N-MNA raised seven-day survival from 43% to 78%.
As for humans, in stool samples from 54 patients with inflammatory bowel disease (IBD) and 20 healthy volunteers, patients with low N-MNA had significantly higher levels of gut inflammation markers.
"Patients with low levels of this metabolite showed a higher inflammatory activity," said Gao.
He added that a stool test might eventually help identify patients likely to benefit from probiotics, though that is probably some years away.
"Right now, we're still trying to understand the fundamentals, and this requires a multidisciplinary team of a biochemist, geneticist, and intestinal biologist," Gao said.
Researchers involved in the study didn't test N-MNA treatment in the IBD patients, nor did they test whether consuming probiotic strains that make N-MNA, including Lactobacilli in yogurt and oral supplements, raises NAD in people.
"This compound itself may be sufficient, but we cannot rule out the possibility that there are other, better compounds," said Ching-On Wong, an assistant professor of biological sciences at Rutgers-Newark and a senior author of the study.
This discovery is a product of cross-unit collaborations among doctoral degree students and postdoctoral fellows in different Rutgers campuses and departments.
The team has received a five-year, $3.6 million National Institutes of Health grant to identify the still-unknown human enzymes that process N-MNA. Wong's lab is testing whether the molecule supports brain cell health and longevity, and Gao's lab is mapping the bacterial genes that produce it.
Rutgers has filed a provisional patent application on uses of N-MNA, with Han, Ferraris, Su and Gao named as inventors.
This research was funded by the National Center for Complementary and Integrative Health, National Institutes of Health, grant number R01AT013333. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
