Alcohol harms the liver in two ways, by damaging the organ’s cells directly and by disrupting gut microbiota, which can scar the liver. Now researchers have figured out the mechanism behind the microbial imbalance due to drinking and could use the information to devise treatments for liver disease and a broad range of other medical conditions ranging from irritable bowel syndrome to autism.
“We’ve known for a very long time that patients with heavy drinking and alcohol use suffered an intestinal dysbiosis, where bacteria in the gut increase and they suffer from liver disease,” says University of California, San Diego, research gastroenterologist Bernd Schnabl, who had seen similar outcomes in mouse models. “If we give rodents nonabsorbable antibiotics, get rid of the flora, they essentially are protected from liver disease. We started asking, what is going on?”
That curiosity led Schnabl and his research team to focus on antimicrobial molecules REG3B and REG3G and the genes (Reg3b and Reg3g) that produce them. The genes are only expressed in the intestines; the pair of peptides the genes generate are only produced in the gut and have broad-spectrum activity against gram-negative and gram-positive organisms, respectively.
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Through a series of experiments, detailed in this week’s Cell Host & Microbe the researchers learned that administering alcohol downregulated the genes so that they produced significantly less of the antimicrobial molecules. Knockout mice lacking those genes developed more bacteria in their guts and more severe liver disease compared with normal wild-type mice.
CREDIT: UC San Diego Health
One surprise was that the microbes in the lumen, the center of the gut, were essentially the same in all of the animals, regardless of how much REG3 they produced. Only when the scientists looked closer at the mucosa, the slimy area next to the gut wall, did they see a difference. “The bacteria in the mucosa just proliferated dramatically in the absence of these molecules,” Schnabl says. The balance between microbes and immune defenses was upended and more bacteria were able to migrate through the gut wall into the body, eventually traveling through the bloodstream to the liver. T cells attacked the invaders and the resulting inflammation scarred the liver.
The team engineered another transgenic mouse, this time to overexpress the Reg3g gene. Bacteria did not stand a chance against the strengthened mucosal defenses and stayed contained within the gut, averting damage to the liver.
Schnabl and his colleagues completed the circle by looking at samples of human gut tissue taken during colonoscopies. Sure enough, heavy drinkers had more bacteria in their mucosa, just as was seen in the mouse model. That suggested the alcohol was suppressing production of the naturally protective peptides.
Schnabl says it may be possible to directly supplement the REG3 proteins, or possibly use prebiotics or probiotics to upregulate their production. Other researchers have shown that administering lipopolysaccharides can increase Reg3 gene expression, but those molecules can be harmful to an impaired liver so they probably could not be used to correct an alcohol-related deficiency. “We’ve shown for the first time a mechanism where alcohol impairs this intestinal defense strategy,” he says. “That leads to a failure of the body to control the bacteria microbiota; you get the bacterial translocation and you get liver disease.”
He believes the total amount of bacteria that translocates through the gut wall is the most important factor in causing disease. But it could be that specific types of bacteria also are important, a possibility he is currently investigating. “If you had told me five to 10 years ago, if you manipulated genes in the intestine, that could that affect the liver, I would have said are you crazy,” Schnabl says. But now we get this deeper understanding of this gut–liver axis; you manipulate such a specific thing in the intestine and you get an effect very far away from it.”
Much of the burgeoning new field of research involving the microbiome has been simply describing the organisms involved, says Sarkis Mazmanian, a microbiologist at the California Institute of Technology whose work includes associations of the microbiome with irritable bowel disease and autism, and who was not involved with the current study. “This study transcends that by isolating the mechanism of action [for causing disease] down to a particular set of factors, the registry proteins REG3B and REG3G.” He adds, “It nicely sets up future work to identify specific organisms that may be more causal to cirrhosis and think about treatment modalities that you can test in mice. Once you have a molecular handle on the process, then you can think about interventions in many different forms.” For example, Mazmanian notes, “one might “loosely look at Reg3 expression as a ‘biomarker’ for potential bacteria and bacterial products that may lead to cirrhosis, sepsis and hepatic encephalopathy. It may be diagnostic for predispositions for certain diseases.” Natural variations in the amount of REG3 a person produces may also affect how vulnerable that individual is to particular type of disease.
University of California, San Francisco, HIV researcher Peter Hunt, who was not involved with the study, agrees that the work “provides a compelling case that the REG3 pathway is a plausible mechanism” by which heavy alcohol use contributes to microbial translocation. Most people infected with HIV experience microbial translocation from a leaky gut, even when antiretroviral drugs completely suppress the virus. That appears to be because HIV kills off immune cells in the gut and some subsets of cells never recover. “The level of microbial translocation is even higher in heavy drinkers,” Hunt notes. “It is likely that the effect of the two is additive.” But, he cautions, it may be only part of the picture and not the complete explanation of what is taking place.
For Mazmanian, the study also drives home the limitation of many other studies in trying to understand the microbiome by simply looking at bacterial genes in feces. Disease often depends not on the presence or the total amount of an organism in the gut but rather on location, which in this case is the gut mucosa. That can only be determined by directly sampling the tissue, as Schnabl did. Location may be important in designing a therapeutic intervention. A product delivered to the middle of the gut may have little benefit; it may have to be packaged in a way to hone in on the mucosa. Potential treatments, however, are years if not decades away. Until then the best thing people can do is reduce alcohol consumption to lessen possible damage to the body.
“Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation.” Wang et al., Cell Host & Microbe 19, 1–13. http://dx.doi.org/10.1016/j.chom.2016.01.003