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New Study Shows NAD+ Supplement Improves Alcohol-Induced Intestinal Dysfunction

Alcohol degrades protein complexes – tight junctions – in the intestines that block bacteria and toxic metabolites from crossing into blood circulation, yet nicotinamide riboside (NR) restores them in mice.

By Bennett M. Sherman

Key Points

  • Excess alcohol consumption contributes to a porous intestinal lining (epithelium) mediated by tight junction degradation, but the NAD+ booster NR restores this lining in mice.
  • NR increases the mitochondrial production of energy molecules (adenosine triphosphate [ATP]) in human intestinal epithelial cells treated with alcohol.
  • NR stimulates Sirtuin1 proteins – activators of mitochondria production – to restore cell energy and tight junction protein stability in human intestinal epithelial cells.

Alcohol consumption, especially when excessive, can damage multiple organs, including the brain, liver, and intestines. The primary point of alcohol absorption occurs in the intestines, making this organ susceptible to alcohol-induced damage and injury. Moreover, intestinal injury from alcohol precipitates the crossover of toxic bacteria and metabolites from the gut into blood circulation. Research indicates that alcohol consumption damages mitochondria and reduces cell energy production in the heart, skeletal muscle, and liver, but whether mitochondrial damage contributes to alcohol-driven intestinal dysfunction remains unclear.

Published in Nutrients, Yang and colleagues from Sun Yat-sen University in China show that treating mice with the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) alleviates alcohol-driven intestinal epithelium degradation. Their data suggests NR restores diminished mitochondrial function from alcohol use as shown with increased human intestine cell ATP levels. They show that NR-mediated increased ATP levels come from elevated mitochondrial production (biogenesis) mediated by the protein Sirtuin1 in intestine epithelial cells. The increased cell energy production from NR promotes the restoration of tight junction proteins that help to seal the intestinal epithelium. These findings provide evidence that NR prevents intestinal barrier damage from excess alcohol consumption by restoring mitochondrial function.

NR Preserves the Intestinal Lining with Excessive Alcohol Consumption

Yang and colleagues sought confirmation that NR promotes the structural integrity of the intestinal lining. They fed mice ample amounts of alcohol, which degraded the intestinal lining, but NR partially restored it. These findings suggested that, somehow, NR preserves the gut’s intestinal lining to prevent bacteria and toxic metabolites from spilling into the body’s circulation.

(Li et al., 2022 | Nutrients) NR restores the intestinal lining following excess alcohol consumption. The images depict the intestine. In healthy mice (CTRL), the proteins (pink) and DNA (blue) are uniform and not porous, whereas the alcohol-fed mice (EtOH) have DNA in disarray and porous proteins. Treatment with NR (EtOH+NR) alleviates the disarrangement of DNA and proteins.

Studies have shown that maintaining the intestinal epithelial lining requires copious amounts of cell energy. For this reason, Yang and colleagues measured whether NR restores cellular ATP levels in human intestinal cells treated with alcohol. The researchers found that, as expected, alcohol exposure lowered the abundance of ATP but that NR facilitated higher ATP levels. Because mitochondria produce ATP molecules for cell energy, Yang and colleagues’ findings suggest that NR restores mitochondrial function.

(Li et al., 2022 | Nutrients) NR restores ATP production in human intestinal epithelial cells treated with alcohol. Compared to healthy cells (CTRL), those treated with alcohol (EtOH) exhibit a ~50% decline in ATP levels, however, NR treatment (EtOH+NR) almost completely restores ATP.

Yang and colleagues had the idea that NR increases ATP levels by increasing mitochondrial production. They utilized a mitochondria-specific protein stain to see whether NR supplemented to human intestine epithelial cells could increase the abundance of mitochondria in the presence of alcohol. The researchers also genetically removed Sirtuin1 proteins to find whether NR could stimulate an upsurge of mitochondria without Sirtuin1. They found that NR substantially increased mitochondrial abundance but not without the Sirtuin1 protein. These results indicate that NR stimulates the Sirtuin1 protein which then mediates the production of mitochondria.

Because it takes a lot of cell energy to maintain the intestinal epithelium, Yang and colleagues measured tight junction protein levels – zonula occludens-1 (ZO-1) and occludin proteins – in human intestinal epithelial cells. The researchers found that NR increased the abundance of the tight junction proteins, however, when they used a genetic manipulation to remove Sirtuin1 proteins, this effect disappeared. These findings support that NR stimulates Sirtuin1 proteins to drive mitochondrial production and elevate cell ATP levels, which triggers the stability and maintenance of tight junctions in the intestines.

(Li et al., 2022 | Nutrients) NR stimulates mitochondrial production in a Sirtuin1-dependent manner. Normal cells treated with alcohol (Scramble siRNA+EtOH) show less mitochondrial abundance (red stain) than those with added NR (Scramble siRNA+EtOH+NR). Genetically manipulating the cells to eliminate Sirtuin1 proteins confers no difference between alcohol-treated cells with and without NR (Sirt1 siRNA+EtOH and Sirt1 siRNA+EtOH+NR, respectively).

“Our data indicate that boosting NAD by NR prevents ethanol-induced intestinal dysfunction by activation of epithelial mitochondrial function,” said Yang and colleagues. “NR acts as a good NAD precursor without side effects and is able to regulate mitochondrial function via activating the [Sirtuin1] signaling pathway, maintain [tight junctions] stability and ultimately reverse ethanol-induced damage to the intestinal epithelial barrier.”

Supplementing NAD+ Could Be a Means to Preserve the Gut

This study provides the first piece of evidence that supplementing with an NAD+ precursor can preserve the intestinal lining under conditions of excessive alcohol consumption. A previous study has shown that boosting NAD+ levels preserves the intestines with chemotherapeutic cisplatin treatment. By showing that NR drives mitochondrial production to help maintain tight junction protein stability and thus improve the intestinal lining with excess alcohol consumption, Yang and colleagues’ research points to another NAD+ precursor benefit.

Model and Dosage

Model: C57BL/6J mice

Dosage: 400 mg/kg of NR by oral gavage

Source

Li W, Zhou Y, Pang N, Hu Q, Li Q, Sun Y, Ding Y, Gu Y, Xiao Y, Gao M, Ma S, Pan J, Fang EF, Zhang Z, Yang L. NAD Supplement Alleviates Intestinal Barrier Injury Induced by Ethanol Via Protecting Epithelial Mitochondrial Function. Nutrients. 2022 Dec 30;15(1):174. doi: 10.3390/nu15010174. PMID: 36615829; PMCID: PMC9823589.

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