Scientists finally discover the enzyme that turns urine yellow

Every animal needs to urinate to get rid of liquid waste in its body. Although a healthy person’s urine has a distinctly yellow color, scientists have been unclear for centuries as to what actually gives urine this hue. Now a team from the University of Maryland and the National Institutes of Health believe they have solved this mystery by identifying the microbial enzyme that turns our urine yellow. The findings are detailed in a study published Jan. 3 in the journal Natural Microbiology.

[Related: Renaissance-era doctors used to taste their patients’ pee.]

According to study co-author and microbiologist Brantley Hall of the University of Maryland, the team drew on decades of research going back to the 1960s and a difficult laboratory experiment lasting three and a half years to discover that the enzyme in the microbiome of intestine called bilirubin reductase, which is responsible for the color of urine.

“The gut microbiome is just full of amazing chemicals. It’s so important to human physiology, all these molecules that the gut microbes make,” says Hall PopSci. “When we understand more about the microbial chemistry in our gut, we’ll understand the important stuff.” But the first step to all of this is to understand the enzymes responsible. If you don’t know what’s going on, you can’t really even begin the research.

Solving a microbial mystery

Scientists previously knew that the yellow color came from how the body gets rid of old blood cells. Red blood cells usually reach the end of their life cycle after about 120 days and are broken down in the liver. A byproduct of this process called bilirubin is a bright orange substance that is secreted by the liver and into the intestines. Bacteria living in the gut then convert the bilirubin into a colorless substance called urobilinogen. Urobilinogen is finally broken down into the yellow pigment molecule called urobilin, which plays a role in coloration. What scientists didn’t know was the bacterial enzyme responsible.

The identification of this enzyme has long been a microbial mystery for two main reasons. According to Brantley, the first challenge is that cultivating anaerobic microbes has historically been very difficult and expensive in the laboratory.

“The microbes that perform this function cannot live with atmospheric oxygen. They die in minutes or seconds,” says Hall. “And they definitely never grow up.”

Brantley and team were able to use the scientific advances made in the last 15 years to cultivate these microbes that survive and thrive without oxygen.

The second challenge is the lack of genomic sequences of gut microbiomes. Recent improvements in genetic sequencing mean there are more sequences for the team to study to see how the microbes in the gut work.

“In our case, we identified microbes that reduce bilirubin and microbes that do not. And then we did a comparative genomic analysis between the two and identified candidate genes,” says Hall.

In the gut microbiome

In the study, the team compared the genomes of the exact types of human gut bacteria that convert bilirubin to urobilinogen with the types of gut bacteria that cannot. This helped them identify the specific gene that codes for bilirubin reductase. Then they used E. coli (E. coli) to test whether this enzyme can convert bilirubin to urobilinogen in him as well as in other gut bacteria.

After searching for this gene in all known bacterial species, the team found that the enzyme is predominantly produced by a species belonging to a large group of bacteria that dominate the gut microbiome called Firmicutes. After genetically screening the gut microbiomes of over 1,000 adults to find the pee-staining gene, they found that 99.9 percent of people have gut bacteria that carry the bilirubin reductase gene.

[Related: Bees make more friends when they’re full of healthy gut bacteria.]

“I think the biggest surprise to me is how prevalent this feature is in older people,” says Hall. “Basically, everyone’s urine is yellow and everyone’s poop is brown, so we knew there had to be microbes that did that. There aren’t really that many microbes that do, and they essentially predominate in every person.

Potential medical applications

The study also looked to see if this gene was present in adults with inflammatory bowel disease (IBD) and babies with jaundice. Only about 68 percent of those with IBD had the gene, and about 40 percent of babies under three months old who were at increased risk of jaundice. Although more research is needed, identifying what enzymes and genes could help develop better treatments for IBD, jaundice and even gallstones.

“People are so excited about gut health, and I just love talking to people about gut health,” says Hall. “Everyone either has or knows someone who has gut issues, and I just think there’s a huge opportunity to really modulate the gut microbiome and health in a positive way.”

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