BOSTON — The human gut is integral to just about every part of the body, but especially our immune system when you consider that roughly 70 percent of it lies within the gut. In a surprising discovery, Harvard Medical researchers are demonstrating how gut microbes fuel our immune systems to heal muscle injuries.
T cells are a type of white blood cell that help protect the body from invasive germs and infection. Researchers found that gut bacteria powers specific cells called regulatory T cells (Tregs). The main function of these cells is to go around the body and respond to stressors found at injury sites in order to heal them.
“Our observations indicate that gut microbes drive the production of a class of regulatory T cells that are constantly exiting the gut and act as sentries that sense damage at distant sites in the body and then act as emissaries to repair that damage,” says study senior author Diane Mathis, professor of immunology in the Blavatnik Institute at Harvard Medical School, in a university release.
Study authors say Tregs are highly specialized cells that have unique roles to play in the body. In the gut, they play an active role in gut health maintenance. They help protect against food allergens, autoimmune diseases like colitis, and even colorectal cancer. It’s also well-understood that gut microbes are heavily implicated in gut immunity through Treg production, but there is minimal evidence about what Tregs do to tissues outside of the gut.
So, when the team found similarly-structured cells in the muscles, they were pretty surprised.
“I stumbled upon some cells that looked very similar, and had all the same features of Tregs that derive from the gut,” says study first author Bola Hanna, a research fellow in immunology at Harvard Medical School. “This caught our attention because we know these cells are produced in the gut and are shaped by the microbita.”
Fewer microbes leads to more scars after an injury
This prompted the team to answer the question of why these cells would be here, using animal models. To do this, researchers first had to make sure that the Tregs found within the muscle tissue were actually from the gut. The scientists analyzed the molecular structure and confirmed their identity. They then tagged the Tregs with light and followed them as they moved around the bodies of mice. They found that the cells left the gut lining and moved to other parts of the body. Finally, they examined the surface receptors of the Tregs for antigens, which is a barcode unique to the cells.
“The immune cells we had found in the muscle shared the same barcodes with the equivalent Treg cells in the gut,” Hanna reports.
While monitoring the healing process, the team found that genetically modified mice lacking these Tregs had slower muscle recovery than those who had them. They examined this more closely and found that these mice had more inflammation at the injury site. Even once they did heal, they had scarring or fibrosis. This indicates that the muscle didn’t heal well. To see if gut bacteria played a role in this, the team fed mice antibiotics to kill their beneficial gut bacteria. They found that these mice also had a difficult time with muscle repair. Once their gut flora was back to normal, they were able to heal better.
“It is well known that antibiotics can eradicate beneficial gut microbes as collateral damage of their main function, which is to kill harmful bacteria,” Mathis says. “Our results further underscore the importance of judicious antibiotic use, which is important for many reasons that go well beyond muscle recovery.”
These microbes also protect against organ damage
Finally, the team wanted to see if this relationship could be seen more generally as well. They looked for traces of gut Tregs in various organs such as the liver, kidneys, and spleen — all of which contain intestinal Tregs, but in smaller amounts. To conduct this experiment, the team induced fatty liver disease in a group of mice because the disease can result in liver scarring, cell death, and organ damage. The researchers discovered that mice with fatty livers have higher levels of colonic Tregs than those with healthy livers, implying that these cells can regulate inflammation in places besides the gut.
The researchers think that this area of research is worth exploring much more in-depth, as it could help pave the way for new treatments with different mechanisms that promote using healthy gut microbes — not just for protecting the gut itself, but for healing external injuries and fatty livers.
The findings are published in the journal Immunity.