Researchers at the UCSD School of Medicine have determined that alcohol interferes with intestinal defense mechanisms by decreasing levels of naturally occurring antimicrobials. In a study published in “Cell Host & Microbe” on Feb. 10, biologists discovered that bacteria left unchecked by these intestinal antibiotics can migrate to the liver and contribute to alcoholic liver disease.
Bernd Schnabl, associate professor of gastroenterology at the UCSD School of Medicine, explained to the UCSD Guardian how a previously understood correlation between high alcohol consumption and excessive intestinal bacteria growth encouraged further exploration of gut microbiota.
“We knew for a long time that patients with heavy drinking and alcoholic liver disease show intestinal bacterial overgrowth and dysbiosis,” Schnabl told the UCSD Guardian. “From preclinical studies we also knew that the gut microbiome is important … Why changes in the intestinal microbiome occur was not known.”
The human body naturally maintains consistent microbial concentrations in the intestine. Alcohol, however, prevents intestinal cells from producing the antimicrobials responsible for this regulation, allowing bacteria inherent to the gut to relocate to the liver.
By examining the effects of chronic alcohol consumption on mice, Schnabl and his team of researchers concluded that decreased intestinal levels of the antibiotic proteins REG3G and REG3B promote alcoholic liver disease.
“We used genetically engineered REG3G and REG3B deficient mice and subjected them to chronic ethanol feeding,” Schnabl said. “Deficiency in REG3 lectins mimics a suppression induced by heavy drinking.”
Schnabl added that his team also created a transgenic mouse that overexpressed REG3G in the intestine to determine whether or not “boosting” the intestinal defence would prevent alcoholic liver disease.
Their research, supported by the National Institute on Alcohol Abuse and Alcoholism, concluded that increasing levels of REG3 lectins reduced bacterial migration to the liver and prevented alcoholic liver disease. Mice genetically engineered to be deficient in REG3 lectins developed alcoholic liver disease that was more severe than mice with normal levels of the antibiotic proteins.
Intestinal microbiota can occur in the lumen, the interior of the gastrointestinal tract, or adhere to the mucosal lining surrounding the lumen. The researchers discovered, however, that only mucosa-associated bacteria accumulate in the absence of REG3 lectins.
Schnabl elaborated on how this study confirmed a link between increased levels of adherent microbiota in the absence of REG3 lectins and the development of alcoholic liver disease.
“Alcohol is known to damage the liver directly,” Schnabl said. “We now provide evidence that suppression of intestinal defence mechanisms leads to increased alcoholic liver disease by a mechanism that involves failure to control the adherent microbiota in the intestine. This is a completely new mechanistic link in the gut-liver axis and the first evidence linking intestinal antimicrobial molecules to extraintestinal disease.”
Fluctuating REG3 levels had similar effects on the adherent microbiota of humans. Schnabl expanded on how steps taken to control REG3 expression might contribute to future treatments of alcoholic liver disease.
“Our studies suggest that boosting the intestinal defence might help in the treatment of alcoholic liver disease,” said Schnabl. “We have some evidence that prebiotics increase the intestinal expression of REG3 lectins. Future research will have an important direction: Can we identify other molecules or strategies to increase REG3 expression, which could be used as therapeutic approach in patients with alcoholic liver disease.”