Research Overview by Dr. Katie Golden, MD: Ectopic Colonization of Oral Bacteria in the Intestine Drives TH1 Cell Induction and Inflammation

Prior studies have shown a correlation between intestinal colonization of oral bacteria and inflammatory bowel disease. It remains unclear, however, if there is a causal relationship between this aberrant bacterial growth and gut inflammation. In a recent publication in Science by Atarashi et al., researchers isolated a specific strain of bacteria from human saliva, and describe how it directly induces T cell activation, suggesting a mechanism for its contribution to disease progression.

There are many disease states, including Crohn’s and Ulcerative Colitis, in which researchers have found altered microbial flora of the gut. More specifically, they found increased levels of bacteria that are traditionally limited to the oral cavity. In this study, researchers transplanted saliva from two patients with Crohn’s Disease into the gastrointestinal tract of mice. When they examined the intestinal epithelial mucosa of the mice, they found an increased accumulation of CD4 cells (T cells). They then used a combination of genetic sequencing as well in vivo studies to isolate a specific strain of bacteria, Klebsiella pneumoniae, that was not only a predominant component of the gut microbiota in the diseased mice, but also appeared to have the most profound impact on T cell activation. This effect was most pronounced, interestingly, in the colon and cecum (and there was no increase in T cell populations in the oral mucosa.)

Using this information, the investigators then examined host factors that also contributed to disease progression in the setting of Klebsiella colonization. First, given this particular bacterial strain is known for its antibacterial resistance, they fed the bacteria to pathogen-free mice pre-treated with antibiotics. They found much higher intestinal colonization rates in pre-treated mice, in comparison to antibiotic-naive mice, suggesting that antibiotic exposure potentiates pathologic colonization. Second, they studied responses to Klebsiella exposure in knock-out mice who were genetically predisposed to colitis, and compared this to wild-type mice.  Not surprisingly, they found the knock-out mice to have significantly increased T cell activation as well as colonic inflammation after pathogen exposure.

These findings suggest a role for both genetic and environmental factors in contributing to pathologic gut colonization of Klebsiella, and in turn, inflammatory bowel disease progression.

Finally, researchers studied and described the mechanism through which this particular strain of Klebsiella induced T cell activation. They isolated colonic dendritic cells that recognize specific bacterial antigens and surface proteins, which then induced T cell activation via interleukin signaling. They also found upregulation of interferon-inducible genes, coinciding with increased T cell activation. In an additional and interesting stage of the study, researchers applied this newly-acquired knowledge to genetic databases from inflammatory bowel disease patients. They not only found a relative abundance of Klebsiella in this population, but also that the genes responsible for Klebsiella-mediated T cell activation were increased in these patients. These new findings highlight a potential therapeutic intervention by targeting Klebsiella colonization in patients with inflammatory bowel disease.