Ethanol-Making Microbe Tied to Nonalcoholic Fatty Liver Disease

By November 11, 2022No Comments

As its name suggests, nonalcoholic fatty liver disease describes a liver condition in which fat builds up in the livers of people who drink little or no alcohol. It can affect young, healthy people with no other comorbidities, leaving scientists and doctors stumped as to why some livers gradually fail.

A study published in Nature Medicine last week (October 10) provides clues as to a potential cause: the bacteria dwelling in our guts.

As they digest food, these microbes secrete byproducts, many of which are helpful. But some bacteria produce ethanol as they break down sugars, and a previous study in humans and mice linked ethanol-producing bacteria—namely Klebsiella pneumoniae—and fatty liver disease. In some patients, it appears, the commensal relationship between bacteria and host goes sour. The new study goes further, providing a potential mechanism for how ethanol-producing bacteria in the gut can evade diagnostic testing, stealthily dumping ethanol into the gut and wreaking havoc on the liver.

See “Gut Microbe Linked to Nonalcoholic Fatty Liver Disease”

“This paper is a proof of concept. . . . It’s coming to complete the story that we didn’t have in the past,” says Juan Pablo Arab, a gastroenterologist at Western University in Ontario who was not involved in the study.

The new project began when Abraham Stijn Meijnikman, a gastroenterologist at the University of Amsterdam, and a team of researchers were studying how to improve outcomes for people undergoing bariatric surgery. Meijnikman was curious about how a person’s microbiota composition might help them recover, and he became interested in the association between nonalcoholic fatty liver disease and gut flora.

Meijnikman says that one of the first people to tie the gut to ethanol production in the gut was Hans Krebs, the Nobel Prize–winning physician of Krebs cycle fame. Back in 1970, Krebs gave rats parasol, a drug that inhibits an enzyme that breaks down alcohol, and noticed afterward that the amount of alcohol leaving the portal vein, which drains the blood from the gastrointestinal tract to the liver, was higher than the amount in the peripheral circulation. Though Krebs established that the portal vein typically has a higher ethanol concentration than the peripheral veins, the association between ethanol-producing microbes and liver disease didn’t come until later.

Meijnikman and a team of researchers at his university decided to compare the ethanol concentration of the blood entering and leaving the liver in patients with nonalcoholic fatty liver disease (NAFLD) who were undergoing bariatric surgery. The researchers measured the amount of ethanol in the peripheral blood of 146 patients with NAFLD, both while fasting and after a meal. They compared their findings with a cohort of 51 age-matched healthy patients. In a subset of 37 patients with NAFLD, the team also measured ethanol in blood sampled from the portal vein during surgery.

In some patients, it appears, the commensal relationship between bacteria and host goes sour.
In this smaller patient subset, the amount of ethanol in the portal vein was 187 millimoles higher on average compared to the peripheral blood in the group overall. This ethanol had then been cleaned out by the liver, leaving little trace of it for researchers to find in the peripheral blood.

The researchers also found a correlation between higher blood ethanol concentration in the peripheral blood and disease severity.

The next step, explains Meijnikman, was to get causal evidence of the bacteria’s role. In a subsequent experiment, the researchers infused 10 individuals with NAFLD and 10 overweight but otherwise healthy controls with selective alcohol dehydrogenase (ADH) inhibitors before a meal. ADH is the enzyme that the liver uses to break down alcohol, and, as the researchers expected, this intervention increased patients’ blood ethanol concentration 15-fold compared to patients that had not received ADH. “There was one patient who even appeared to be a little bit intoxicated,” says Meijnikman. This told the researchers that normally, the liver cleans ethanol-rich blood coming from the gut before it reaches the peripheral blood.

Next, the researchers went after the bacteria, looking to disrupt ethanol production in the gut. When the patients received a broad-spectrum antibiotic before they received an ADH inhibitor, the authors did not see a spike in ethanol after a meal, indicating that gut microbes likely were responsible for converting food into ethanol.

Lastly, the researchers sequenced the gut flora of the individuals from the first experiment and their healthy counterparts, searching for ethanol-producing bacteria. They found one likely candidate, Lactobacillaceae, a bacteria that produces lactic acid as well as ethanol, which was associated with NAFLD. Its presence correlated with high peripheral blood ethanol after a meal, indicating that it might be at least partly responsible for ethanol production. Meijnikman says, likely, Lactobacillacea isn’t the only bacterium associated with NAFLD—other bacteria may be the predominant ethanol producers in other individuals or populations. He explains that the previous study that associated Klebsiella with NAFLD was performed on a Chinese cohort, while the new study enrolled mostly white European participants, which may account for the disparate results.

Arab says it’s not clear whether the bacterium causes the disease or the disease causes a shift in gut flora in patients with NAFLD. “Which is first, the chicken or the egg?” he asks.

Meijnikman agrees it’s still unknown whether the gut microbiota is the initial cause of NAFLD, and says that this is an area for further study. He stresses that not all patients in the study had higher-than-average concentrations of ethanol in their portal veins after a meal, suggesting that microbes may only be to blame for disease progression in some patients. “We should not go with a ‘one-size-fits-all’ treatment,” he says.