Gut study reveals DNA changes in bacteria may alter how the body absorbs fat

Two-and-a-half thousand years ago, the Ancient Greeks were doing something right. They defeated the Persian empire, pioneered democracy, and created new forms of art. In the midst of all this success and innovation, one man dared to lead a revolution in how we understand, define, and treat disease — Hippocrates. Key to his philosophy was a credo that modern scientists are now coming back to: “All disease begins in the gut.”

Now known as the father of medicine, Hippocrates paved the way for a new form of thought supported by logic and observation. Two millennia later, scientists have found that the trillions of microorganisms living in your gut microbiome do play a hand in your immune system, mental health, and metabolism. This is a double-edged sword, however: The gut microbiome can do as much harm as good. This week, scientists discovered a new way the microbiome can interfere with a key aspect of gastrointestinal health: absorbing fat from our food.

What’s new — In the study, published this week in the journal Cell Host & Microbe, scientists looked at the genetic makeup of the myriad organisms within the gut microbiome. Their findings showed several structural variations that interfered with the intestine’s role in absorbing fat. Structural variations are differences in large regions of DNA across the genome.

Jingyuan Fu, an associate professor at the University of Groningen and senior study author, tells Inverse that the most surprising observation is that these variations appear to be very common.

Further, there appears to be some relationship between these variations, how well the intestines process fat, and a person’s dietary habits, the study suggests.

How they did it — The researchers studied the genetic material of 55 gut bacterial species found in the microbiomes of 1,437 Dutch people, specifically looking for any correlation between genetic variation in the bacteria and bile acid metabolism. Their study found about 8,282 structural variations in the genes of 55 species of bacteria across the study sample.

From there, the researchers found 809 associations between structural variants in gut bacteria and differences in bile acid metabolism — a marker of how well the intestine absorbs fat from the food that passes through it. Bile acids are involved in digesting fats and oils from the diet as well as reducing cholesterol levels.

The study also analyzed different lifestyle factors that could affect individuals’ microbiomes or bile acids, including their diet, drug use, and smoking habits.

Age, sex, and a person’s BMI could explain just 3 percent of the differences in bile acid concentration, but a person’s lifestyle choices could have a greater influence on structural variations in gut bacteria, and in turn, bile-acid metabolism.

The researchers observed that people who drink red wine had more structural variants in the DNA of specific bacteria, an association was also seen in people who reported drinking lots of soda. There was also an association between eating fish and the frequency of structural variants.

Fu says it is hard to pinpoint the exact effect of specific foods on the microbiome from this study, however.

“We don't [tend to] eat one single food, we eat a combination of things. For the dietary analysis we have conducted here, we need a further investigation to really prove exactly which food plays a role in the microbiome,” she explains.

Here’s the background — The relationship between the gut microbiome and bile acid metabolism is bidirectional. Past research has shown the gut microbiome’s genetic makeup can alter bile acid function, Fu says, but bile acids can also act on the microbiome.

Bile acids add selective pressure to the gut, Fu explains, controlling which bacteria can live in the microbiome. One way acids do this is to activate genes involved in the immune response to regulate bacterial overgrowth and reduce inflammation levels.

Why it matters — Hippocrates was the first to suggest that diseases come from natural causes, but he didn’t fully understand how to treat them. Understanding the complexity of the gut microbiome is essential for creating personalized medicine to treat gut-associated diseases, like metabolic conditions, Fu says. The current study shows that everyone’s microbiome may differ based on variations in the genetic makeup of gut bacteria — and these variations could alter how drugs or other treatment protocols work.

“Nowadays, people are talking about microbiome targeted approaches for diseases, prevention, and treatment. To really move forward with that direction, we first need to understand what [gut microbes] do,” she says.

Scientists are already tweaking the genes of bacteria to try to develop treatments for diseases, for example, engineering bacteria to invoke the immune system to kill tumor cells.

While the current study is a stepping stone for a future of personalized medicine, people can shape their future today by taking care of their gut microbiome. For example, you can help maintain a healthy microbiome by including more gut-friendly food like kimchi in your everyday diet.

What’s next — Fu and her team are doing several things to further understand the genetic landscape of the gut microbiome as a whole — structural variants are just part of that puzzle.

Another project in the works is looking at how the gut microbiome changes over time. Earlier this year, Fu and her team published an article showing that each person’s gut microbiome is specific to them and that it may become more diverse and stable over time. She wants to expand on those findings by observing changes in people’s microbiome composition from birth through development.

“The gut microbiome is an important player for personalized medicine. [But] if we want to use this information to predict disease development, then we also need to see how lifelong stable they are, including how frequently we should be sampling the microbiome,” Fu says.

Abstract: Bile acids (BAs) facilitate intestinal fat absorption and act as important signaling molecules in host-gut microbiota crosstalk. BA-metabolizing pathways in the microbial community have been identified, but it remains largely unknown how the highly variable genomes of gut bacteria interact with host BA metabolism. We characterized 8,282 structural variants (SVs) of 55 bacterial species in the gut microbiomes of 1,437 individuals from two cohorts and performed a systematic association study with 39 plasma BA parameters. Both variations in SV-based continuous genetic makeup and discrete clusters showed correlations with BA metabolism. Metagenome-wide association analysis identified 809 replicable associations between bacterial SVs and BAs and SV regulators that mediate the effects of lifestyle factors on BA metabolism. This is the largest microbial genetic association analysis to demonstrate the impact of bacterial SVs on human BA composition, and it highlights the potential of targeting gut microbiota to regulate BA metabolism through lifestyle intervention.