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Everywhere you go, you carry a population of microbes in your gastrointestinal tract that outnumber the human cells making up your body.

This microbiome has important connections to health in your gut, brain and immune system. Some resident bugs produce vitamins, antioxidants, nutrients and other helpful compounds. Even those whose direct effects seem neutral take up space that makes it harder for harmful microbes to move in.

There is still much to be understood about the gut microbiome, but its connections to health suggest the potential for curating this community to address disease. New discoveries from a research team at the California NanoSystems Institute at UCLA, or CNSI, offer a promising step in that direction.

The scientists investigated a known mechanism that changes genes in microbes, driven by what are called diversity-generating retroelements. DGRs carry collections of genes that function together to create random mutations in specific hotspots in bacterial genomes. Effectively, they accelerate evolution in their hosts, enabling microbes to change and adapt.

DGRs are more common in the gut microbiome than any other environment on Earth where they've been measured. However, their role in the gut has not been investigated until now.

In a study in the journal Science, the team explored bacteria commonly seen in the healthy digestive tract. They found that about one-quarter of those microbes' DGRs target genes vital for latching on to grow colonies in new surroundings. The researchers also demonstrated that DGRs travel well: They can transfer from one strain of bacterium to others nearby, and infants inherit DGRs from their mothers that seem to aid in starting up the gut microbiome.

"One of the real mysteries in the microbiome is exactly how bacteria colonize us," said senior author Jeff F. Miller, director of CNSI, holder of the Fred Kavli Chair in NanoSystems Science and a professor of microbiology, immunology and molecular genetics at UCLA. "It's a highly dynamic system intimately connected with human physiology, and this knowledge about DGRs could one day be applied for engineering beneficial microbiomes that promote good health."

Changes in the gut microbiome have been linked to inflammatory bowel disease, Crohn's disease, metabolic syndrome, colon cancer and—more distantly—conditions such as anxiety, depression and autism. An increase in disease-causing bacteria in children is associated with higher long-term risk for chronic autoimmune illness.

"The developing microbiome is connected to our developing immune system, and that primes us for the rest of our lives," said first and co-corresponding author Ben Macadangdang, a UCLA Health neonatologist and an assistant professor of pediatrics at the David Geffen School of Medicine at UCLA. "When the microbiome is disrupted, we see higher rates of chronic disease later in life. This presents a strong opportunity to engineer the infant gut microbiome to prevent these risks."

DGRs were first discovered in Miller's lab. In a single spot in the genome, which varies from case to case, DGRs replace the letter A from the four-letter alphabet that makes up DNA, adding a C, G or T in that spot.

Many DGRs target genes that determine the shape of binding proteins—that is, proteins that fit with other molecules like a pair of puzzle pieces. This type of binding is the fundamental mechanism by which cells interact with the world around them. Changes to binding proteins can expand their repertoire for interaction, so DGRs accelerate evolution in a way that expand microbes' capabilities.

This system can be compared to a more-familiar method through which biology remixes proteins: the production of new antibodies by the human immune system to expand the roster of invaders it can recognize. But by contrast, each immune cell that recombines antibodies does so only once, while DGRs can introduce mutations over and over in the same cell.

DGRs are also a far more powerful engine for broadening variety. If each unique antibody made by the immune system were a grain of sand, those grains would fill less than a quarter of 1% of the Empire State Building. By contrast, it would take 270 million Empire State Buildings to hold grains of sand equal to the unique variations of DGR-mutated proteins.

Miller and his colleagues examined the genome of bacteria frequently seen in the gut microbiome, from the genus Bacteroides. In this population, DGRs were plentiful, with an average of one per strain and some strains carrying up to five. They were also varied, with more than 1,100 unique DGRs identified.

The researchers focused on a subset of DGRs targeting genes for the hairlike appendages that protrude from Bacteroides, called pili. Pili act together like the fibers in Velcro, enabling the bacteria to anchor themselves to other microbes or onto surfaces. The DGRs worked primarily to diversify the proteins that help pili to adhere. This suggests DGRs have an important role in Bacteroides' adapting to new locations, including the unique environment of each person's gut microbiome.

"We think DGRs allow the bacteria to rapidly change what their pili can adhere to," Macadangdang said. "A bacterium may be optimized for one person's gut, but if it goes out and tries to colonize someone else, it encounters a very different environment. Finding something new to bind to gives the bacteria an advantage, and we think that's why we see so many DGRs within the microbiome."

The study also found that DGRs can hop from one strain of bacteria to another through a process called horizontal transfer. In that way, microbes seem to share their adaptive superpower within the larger community surrounding them.

To examine how DGRs affect the development of the newborn gut microbiome, the team analyzed microbiomes from mothers and their children over the first year of life. Certain DGRs were transferred from mother to infant. In offspring, the researchers pinpointed changes to DNA for Bacteriodes' pili proteins, indicating that DGRs altered the bugs to help set up shop in their new home. This finding suggests DGRs are one mechanism important for establishing the developing microbiome.

The researchers plan to dig deeper into DGRs and the gut microbiome with lab models and observational studies in humans. They believe that the insights in the current study may be a jumping-off point for future discoveries that improve human health, or even yield new methods for genetic engineering.

"We're at this really early stage," Miller said. "There are so many questions that this raises, we're just realizing how much we don't know about DGRs in the microbiome, or what exploiting them for applications could yield. I've never been more excited about what's going to come next."

Umesh Ahuja, a UCLA research associate, is co-corresponding author of the study. Other co-authors are Yanling Wang, Cora Woodward, Jessica Revilla, Bennett Shaw, Kayvan Sasaninia, Gillian Varnum and Sara Makanani, all of UCLA; and Chiara Berruto of Caltech.