Gut Microbes Influence Eating Habits and Cholesterol, Two Studies Find

• Two recent studies have outlined additional functions of our gut microbes. 

• First, specific gut bacteria can modify both behavior and eating habits, as found in a study with worms, which may be due to an increase in the brain chemical tyramine made by the bacteria. 

• The second study found that certain microbes can lower cholesterol; people with higher enzymatic activity in their microbiome of the gene IsmA (Intestinal Steroid Metabolism A) had lower cholesterol because IsmA breaks down cholesterol into coprostanol, thus increasing cholesterol's metabolism and excretion in the stool.  

This article was posted on EurekAlert.org, based on a study published in Nature in June 2020: 

Gut bacteria are tiny but may play an outsized role not only in the host animal's digestive health, but in their overall well-being. According to a new study in Nature, specific gut bacteria in the worm may modify the animal's behavior, directing its dining decisions. The research was funded in part by the National Institutes of Health.

"We keep finding surprising roles for gut bacteria that go beyond the stomach," said Robert Riddle, Ph.D., program director at the NIH's National Institute of Neurological Disorders and Stroke (NINDS), which supported the study. "Here, the gut bacteria are influencing how the animal senses its environment and causing it to move toward an external source of the same bacteria. The gut bacteria are literally making their species tastier to the animal."

Researchers at Brandeis University, Waltham, Massachusetts, led by Michael O'Donnell, Ph.D., postdoctoral fellow and first author of the paper, and Piali Sengupta, Ph.D., professor of biology and senior author of the study, were interested in seeing whether it was possible for gut bacteria to control a host animal's behavior. The group investigated the effects of gut bacteria on how worms, called C. elegans, sniff out and choose their next meal.

Bacteria are the worms' primary food. In this study, the researchers measured how worms fed different strains of bacteria reacted to octanol, a large alcohol molecule secreted by some bacteria, which worms normally avoid when it is present at high concentrations.

Dr. O'Donnell and his colleagues discovered that worms grown on Providencia alcalifaciens (JUb39) were less likely to avoid octanol compared to animals grown on other bacteria. Curiously, they found that live JUb39 bacteria were present in the gut of the worms that moved toward octanol, suggesting that the behavior may be determined in part by a substance produced by these bacteria.

Next, the researchers wanted to know how the bacteria exerted control over the worms.

"We were able to connect the dots, all the way from microbe to behavior, and determine the entire pathway that could be involved in this process," said Dr. O'Donnell.

The brain chemical tyramine may play an important role in this response. In the worms, tyramine is transformed into the chemical octopamine, which targets a receptor on sensory neurons that controls avoidance behavior. The results of this study suggested that tyramine produced by bacteria increased levels of octopamine, which made the worms more tolerant of octanol by suppressing the avoidance of octanol that is driven by these neurons.

Using other behavioral tests, the researchers found that genetically engineering worms so that they did not produce tyramine did not affect suppression of octanol avoidance when the worms were grown on JUb39. This suggests that tyramine made by the bacteria may be able to compensate for the endogenous tyramine missing in those animals.

Additional experiments indicated that worms grown on JUb39 preferred eating that type of bacteria over other bacterial food sources. Tyramine produced by the bacteria was also found to be required for this decision.

"In this way, the bacteria can take control over the host animal's sensory decision-making process, which affects their responses to odors and may influence food choices" said Dr. Sengupta.

Future studies will identify additional brain chemicals produced by bacteria that may be involved in changing other worm behaviors. In addition, it is unknown whether specific combinations of bacterial strains present in the gut will result in different responses to environmental cues. Although worms and mammals share many of the same genes and biochemical processes, it is not known whether similar pathways and outcomes exist in higher order animals.

The second article was published on Harvard Department of Chemisty and Biology News, based on a study published in Cell Host & Microbe in June 2020: 

In the darkest parts of the world where light fails to block out the unfathomable bounty of the stars, look up. There are still fewer specks illuminating the universe than there are bacteria in the world, hidden from sight, a whole universe inside just one human gut.

Many species are known, like E. coli, but many more, sometimes referred to as "microbial dark matter," remain elusive. "We know it's there," said Doug Kenny, a Ph.D. candidate in the Graduate School of Arts and Sciences, "because of how it affects things around it." Kenny is co-first author on a new study in Cell Host and Microbe that illuminates a bit of that microbial dark matter: a species of gut bacteria that can affect cholesterol levels in humans.

"The metabolism of cholesterol by these microbes may play an important role in reducing both intestinal and blood serum cholesterol concentrations, directly impacting human health," said Emily Balskus, professor of chemistry and chemical biology at Harvard University and co-senior author with Ramnik Xavier, , core member at the Broad, co-director of the Center for informatics and therapeutics at MIT and investigator at Massachusetts General Hospital. The newly discovered bacteria could one day help people manage their cholesterol levels through diet, probiotics, or novel treatments based on individual microbiomes.

According to the Centers for Disease Control and Prevention (CDC), in 2016, over 12 percent of adults in the United States age 20 and older had high cholesterol levels, a risk factor for the country's number one cause of death: heart disease. Only half of that group take medications like statins to manage their cholesterol levels; while such drugs are a valuable tool, they don't work for all patients and, though rare, can have concerning side effects.

"We're not looking for the silver bullet to solve cardiovascular disease," Kenny said, "but there's this other organ, the microbiome, another system at play that could be regulating cholesterol levels that we haven't thought about yet."

Since the late 1800s, scientists knew that something was happening to cholesterol in the gut. Over decades, work inched closer to an answer. One study even found evidence of cholesterol-consuming bacteria living in a hog sewage lagoon. But those microbes preferred to live in hogs, not humans.

Prior studies are like a case file of clues (one 1977 lab even isolated the telltale microbe but the samples were lost). One huge clue is coprostanol, the byproduct of cholesterol metabolism in the gut. "Because the hog sewage lagoon microbe also formed coprostanol," said Balskus, "we decided to identify the genes responsible for this activity, hoping we might find similar genes in the human gut."

Meanwhile, Damian Plichta, a computational scientist at the Broad Institute and co-first author with Kenny, searched for clues in human data sets. Hundreds of species of bacteria, viruses and fungi that live in the human gut have yet to be isolated and described, he said. But so-called metagenomics can help researchers bypass a step: Instead of locating a species of bacteria first and then figuring out what it can do, they can analyze the wealth of genetic material found in human microbiomes to determine what capabilities those genes encode.

Plichta cross-referenced massive microbiome genome data with human stool samples to find which genes corresponded with high levels of coprostanol. "From this massive amount of correlations," he said, "we zoomed in on a few potentially interesting genes that we could then follow up on." Meanwhile, after Balskus and Kenny sequenced the entire genome of the cholesterol-consuming hog bacterium, they mined the data and discovered similar genes: A signal that they were getting closer.

Then Kenny narrowed their search further. In the lab, he inserted each potential gene into bacteria and tested which made enzymes to break down cholesterol into coprostanol. Eventually, he found the best candidate, which the team named the Intestinal Steroid Metabolism A (IsmA) gene.

"We could now correlate the presence or absence of potential bacteria that have these enzymes with blood cholesterol levels collected from the same individuals," said Xavier. Using human microbiome data sets from China, Netherlands and the United States, they discovered that people who carry the IsmA gene in their microbiome had 55 to 75 percent less cholesterol in their stool than those without.

"Those who have this enzyme activity basically have lower cholesterol," Xavier said.

The discovery, Xavier said, could lead to new therapeutics--like a "biotic cocktail" or direct enzyme delivery to the gut--to help people manage their blood cholesterol levels. But there's a lot of work to do first: The team may have identified the crucial enzyme, but they still need to isolate the microbe responsible. They need to prove not just correlation but causation--that the microbe and its enzyme are directly responsible for lowering cholesterol in humans. And, they need to analyze what effect coprostanol, the reaction byproduct, has on human health.

"It doesn't mean that we're going to have answers tomorrow, but we have an outline of how to go about it," Xavier said.