$2.6M Grant Awarded by NIH to Identify Possible Targets for Treating Alcohol-Related Organ Damage

Dr. Cresci will explore how increasing levels of two molecules commonly depleted as a result of chronic alcohol exposure may help to rescue pathologies of alcohol use disorder, including bacterial imbalances, leaky gut and increased circulating toxins.

09/18/2020

The National Institute of Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, has awarded Gail Cresci, PhD, RD, a five-year, $2.6 million grant to investigate potential therapies for organ damage due to chronic alcohol use, which is responsible for significant disease and death worldwide.

While previous research, including by Dr. Cresci, has suggested that chronic alcohol (ethanol) exposure is associated with an imbalance of good and bad bacteria in the gut (dysbiosis) and leaky intestinal barriers that cause harmful inflammation throughout the body, scientists are still searching for how long-term exposure to ethanol induces this damage.

“Identifying the specific signaling mechanisms that connect ethanol exposure with gut dysbiosis and intestinal permeability will prove very important to developing therapies to treat or prevent alcohol-related organ damage,” said Dr. Cresci, a staff member in the Department of Inflammation and Immunity and nutritionist in the Department of Pediatric Gastroenterology, Hepatology and Nutrition. “That is what we aim to uncover with this new award.”

These latest funds mark Dr. Cresci’s first R01 award, a major milestone in a scientist’s path towards research independence. She was previously awarded two mentored research grants, also from NIAAA, for a related project.

Amplifying intestinal-generated immune nutrients

One known side effect of gut dysbiosis is significantly reduced levels of the short-chain fatty acid butyrate, which is important for intestinal health.

In earlier studies, Dr. Cresci and her team found that treating preclinical models of chronic-binge ethanol exposure with tributryin, an oral butyrate analogue, improved intestinal integrity and prevented inflammation in the liver.

“We were encouraged to see that targeting butyrate levels may be a viable approach for treating and preventing alcohol-related liver injury,” said Dr. Cresci. “The next phase of research, which we are getting ready to embark on, will be to interrogate why and how, on a cellular level, butyrate conferred these benefits.”

Dr. Cresci and her team will study how ethanol-induced gut dysbiosis and associated low butyrate levels affect endothelial cell integrity in the intestines, as breakdown between the proteins that hold endothelial cells together is a major cause of leaky intestinal barriers.

In addition to butyrate levels, chronic ethanol exposure also lowers levels of all-trans retinoic acid (atRA), a metabolic byproduct of immune-supporting vitamin A. Like butyrate, another intestinally-generated immune nutrient, atRA is known to promote barrier function and immune regulation. Here, Dr. Cresci’s team will study how altering atRA and butyrate levels modulate ethanol’s effect on various immune cell functions within the intestines and, as a result, microvascular endothelial cell regulation.

“Microvascular endothelial cells are critical for mucosal immune function in the gut. When intestinal epithelial barrier integrity breaks down, as is a result of ethanol exposure, increased toxins can ultimately cause severe microvascular endothelial cell and immune dysfunction,” explained Dr. Cresci. “Importantly, though, intestinal microvascular endothelial cells have never been studied in the context of ethanol, butyrate and atRA.”

Dr. Cresci says she is hopeful their investigation into these associations may reveal novel targets for treating or preventing alcohol-related intestinal damage that often progresses to other organ injury.

Image: Excessive ethanol disrupts gut microbiome, butyrate and retinoic acid levels, intestinal epithelium and intestinal microvascular endothelium, causing increased inflammation and dysregulated immunity.



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