While we mainly think of the immune system as a shield against harmful bacteria, immune cells also make antibodies against the trillions of helpful bacteria that live in our guts. These antibodies keep friendly bacteria from venturing out of the intestines. But scientists don’t know whether our immune cells mostly target each species individually, or whether they largely recognize many microbial varieties at once. The answer to that question has implications for treating intestinal diseases, since ideally, therapies would target pathogens while leaving beneficial species alone.
A study published today (July 8) in Science Immunology reports that mice make antibodies that are extremely specific to the particular bacterial species living in their guts. The repertoire of antibodies in mouse guts is like a fingerprint: unique and dependent on which bacterial strains have colonized their intestinal tracts. This specificity toward certain bacterial species could mean that future immune-based therapies might target pathogenic bacteria without negatively affecting the rest of our gut flora.
“It’s a beautiful paper. It’s what people have said all along,” says Charlotte Cunningham-Rundles, an immunologist at the Icahn School of Medicine at Mount Sinai who was not involved in the study. “When you make this [antibody] in your intestinal tract, it’s dictated by what’s in your gastrointestinal tract. In other words, personal to you.”
Previously, scientists knew that the body makes IgA antibodies—the most common type of antibody—that bind to gut bacteria, preventing them from attacking host tissues outside the gut. What was unknown is how specifically these antibodies target the trillions of bacteria in the gut.
To find out, researchers at the Icahn School of Medicine introduced one of eight species of bacteria into the intestines of germ-free mice. Typically, these germ-free mice produce very little IgA in their blood sera, stool, saliva, and other secretions. But after living with bacteria in their guts, they begin to produce heaps of IgAs.
After three weeks, the team collected serum and fecal IgAs from the mice. Then they tested how well the antibodies bound to other bacterial species. Mostly, the IgAs only bound to a single bacterial species, with only minor crossover with other species of the same genus. Some of these antibodies were even specific to just one strain of bacteria within a species.
“It looks like the immune system can distinguish between different species of bacteria, which is cool,” says Jeremiah Faith, a microbiologist at the Icahn School of Medicine at Mount Sinai and coauthor of the study. While human guts share some bacterial species in common, there are some that don’t overlap, so if these results apply to people, each of us have antibodies customized to our particular inhabitants. “It means that the immune system distinguishes me from you,” Faith says.
Next, the team sought to find out if mice with different species of bacteria in their intestines produced the same sort of bacterial species-specific antibodies. To do this, they introduced all eight of the bacterial species into the germ-free mice. Then, three weeks later, they used these mice’s B cells to produce hybridomas, combining a B cell and a myeloma in order to immortalize the B cell line. Hybridomas allow researchers to produce lots of monoclonal IgA antibodies in vitro.
The hybridomas produced 21 distinct IgAs, 19 of which targeted only one bacterial species (some were specific to just one strain). Only two of the IgAs bound all eight species of bacteria.
The researchers also found that they could deliver these hybridoma-produced antibodies to immune-deficient mice orally. Surprisingly, the antibodies survived the trip through the stomach and intestines and were found intact in fecal samples. The researchers say that this suggests a potential route for delivering therapeutic antibodies to target pathogenic bacteria.
Pathogenic bacteria can cause intestinal inflammation and alter the gut microenvironment, killing off the healthy bacteria. Bacterial infections are sometimes treated with antibiotics, which can also negatively affect commensal gut microbes. This study’s results indicate that one could potentially create an antibody that targets harmful bacteria for destruction while leaving the rest of the bacteria in the gut intact.
“It’s surprising . . . that the antibodies didn’t get absorbed like a steak,” says Cunningham-Rundles, and it’s unclear why they don’t. But that’s good news, she says, as it means you wouldn’t have to make the antibodies yourself; instead, maybe “you could just drink something.”
Chang Kim, an immunologist at the University of Michigan who did not work on the study, says that the therapeutic implications of this work are the “number one thing” that the researchers should explore next. He says that scientists could potentially make antibodies against pathogenic bacteria in the same manner as in the study, but could also replace gut antibodies in immune-deficient patients who suffer from dysbiosis, an imbalance in the gut microbial community caused by lack of antibody production, which affects up to 1 out of every 700 people in some geographic regions.