Research News

Researchers at the Cleveland Clinic have discovered a new genus and species of bacterium, Tomasiella immunophila (T. immunophila) that plays a key role in degrading crucial immune components of the gut’s mucosal barrier.

Identifying the causative microorganism is the first step to potential new treatments for a variety of inflammatory and infectious diseases including IBD, Crohn’s and ulcerative colitis, associated with gut microbiome-mediated reductions in secretory immunoglobulin A (SIgA). The study, published in Science, was led by Thaddeus Stappenbeck, MD, PhD, chair of the Department of Inflammation & Immunity and Qiuhe Lu, PhD, research associate and the paper’s first author.

SIgA, an antibody that helps protect the mucosal surfaces, is produced and secreted to line these surfaces throughout the body, with the highest concentration found in the nose, lungs and gut. Within the gut, SIgA binds continuously to microbes, preventing them from reaching and interacting with host tissue. Decreased SIgA levels are associated with enhanced susceptibility to infection and excess inflammation in response to damage.

The Stappenbeck team had previously discovered that intestinal bacteria could reduce the levels of SIgA. Since hundreds of thousands of enzymes are continuously produced and secreted by gut microbes, SIgA would be expected to be degraded or destroyed in every host, however, the team unexpectedly found it is not. The next step was figuring out why. The team conducted a screening of gut bacteria in preclinical models with low levels of intestinal SIgA. The screening revealed a previously undefined bacterium, proposed as T. immunophila, which specifically degrades immunoglobulins.

Further study showed T. immunophila was difficult to isolate because it lacks the ability to produce a component of its own cell wall which is essential for its growth. The investigations also determined that colonization with T. immunophila reduced SIgA levels in the intestine, increased susceptibility to mucosal pathogens and caused delays in mucosal barrier damage.

The outcome of the study was unexpected: T. immunophila was discovered to be one of only two bacteria that cannot make their own cell walls. Instead, it scavenges cell wall components from other microbes to survive, making the microbe difficult to isolate and study.

“Dr. Lu showed remarkable insight and resilience during this project,” Dr. Stappenbeck says. “Initially we tried a computational approach, sequencing the identity of the microbes that degrade IgA. When this method was unsuccessful, Dr. Lu used his considerable skills in microbiology and took on the challenging task of uncovering a microbe that was difficult to isolate and handle. I admire Dr. Lu for his ability to not give up on this project and to come up with clever experimental systems to uncover this new microbe and discover its function.”

T. immunophila’s name is an homage to a pioneer in immunology. SIgA was discovered by Dr. Thomas Tomasi, who published his findings in a foundational paper in Science in 1963. Dr. Tomasi described SIgA as one of the predominant classes of immunoglobulins whose secretory fluids bathe mucous surfaces in the body.

“Drs. Stappenbeck and Lu's rigorous and elegant study provides a key insight and an exciting potential mechanism for why some people have low or absent levels of SIgA in their gut, yet retain normal levels of SIgA in their bloodstream,” says Michael Silverman, MD, PhD, a physician with the Division of Infectious Diseases at Children’s Hospital of Philadelphia, whose expertise includes immune system development and provided input on the research findings.

"This discovery is quite important, as SIgA in the intestine functions as a critical component of the barrier for the trillions of microbes that live in our intestines," he explains. “Recent studies argue that fecal SIgA tunes this barrier to allow a healthy level of interactions with our commensal microbes while avoiding overexposure from gut microbes that can lead to systemic inflammation and immune dysregulation. This study provides a new avenue to develop therapeutics to manipulate SIgA in the gut and improve health.“

“We know that there are a substantial number of patients that have this defect and are at risk for infection and inflammation in the intestine,” Dr. Lu says. “We surmised that a gut microbe that can degrade SIgA was the culprit. We believe that important therapeutic targets for a variety of inflammatory and infectious diseases in humans can be found through our work.”