It's well-known now that humans have far more bacterial cells than human cells in their bodies. These bacteria are found on the skin, in the nose and ears, and most prominently in the gut.
For a long time, people thought of gut bacteria as separate entities – helpful for digestion but otherwise staying outside the body's protective barriers. However, research shows a significant interaction between the immune system and gut bacteria. At Johns Hopkins, researchers are studying how the composition of the gut microbiome changes with diseases, how the immune system engages with these bacteria, and how this interaction plays a role in illnesses.
“A huge proportion of your immune system is actually in your GI tract,” explains Dan Peterson, assistant professor of pathology at Johns Hopkins University School of Medicine. “The immune system is inside your body, and the bacteria are outside your body.” Yet, these two interact closely. For instance, certain cells in the gut lining constantly produce large quantities of antibodies, which are sent into the gut. Peterson and his team are exploring what kinds of antibodies are produced and how the body manages this delicate balance between itself and the gut bacteria.
Bacteria and Cancer in the Gut
Cynthia Sears, a professor of medicine at Johns Hopkins and a member of the Kimmel Cancer Center, examines how the microbiome influences colon cancer in both mice and humans. Colon cancer appears to arise from an interplay between the microbiome, the immune system, and the epithelial cells lining the colon.
Sears' lab focuses on enterotoxigenic Bacteroides fragilis (ETBF), a human colonic bacteria that produces three types of Bacteroides fragilis toxin (BFT), one of which – BFT2 – has a high carcinogenic potential and is common in humans. This toxin initiates a cascade of reactions in the colon's epithelial cells, causing inflammation and potentially cancer in some mice. Sears' team is working to identify the receptor in epithelial cells that interacts with this toxin, which could offer new insights into how cancer begins in the colon.
ETBF also triggers TH17 inflammation in the colon, a response generally useful for fighting bacteria and fungi. However, in some cases, this inflammation contributes to cancer development. Sears' group is investigating how TH17 inflammation impacts colon cells to promote cancer.
No single bacterial species has been definitively linked to colon cancer in humans. Instead, changes in the overall bacterial community of the gut may be key to understanding carcinogenesis. Advances in sequencing technology now allow researchers to explore the microbiome's role in colon cancer with greater precision. However, questions remain about whether bacteria initiate tumors or simply promote their growth.
From Lung to Belly
Graduate student Kathryn Winglee from the Johns Hopkins Center for Tuberculosis Research Laboratory studied the gut microbiome's role in tuberculosis (TB). She and her team hypothesized that the microbiome might provide a faster diagnostic method than the lengthy gold-standard TB test.
Winglee infected five mice with TB and collected stool samples monthly until the mice died, analyzing the genetic material in these samples. Her research revealed significant changes in the gut microbiome following infection. Initially, microbial diversity decreased, but over time, the microbiome became more diverse – albeit with new bacterial species replacing the original ones.
Although TB primarily affects the lungs, these changes were observed in the gut. Winglee and her colleagues suspect the immune system sends signals from the lungs to the gut, prompting the elimination of certain bacteria. The next step is identifying which aspects of the immune system drive these changes.
The Parts Bacteria Play
Dan Peterson studies gut-related diseases like inflammatory bowel disease (IBD) and colitis using mouse models. IBD likely stems from an abnormal immune response to gut bacteria, and the mice Peterson studies have a defect in the gut lining, which normally prevents bacteria from interacting with the host.
By sequencing the bacteria in diseased and healthy mice, Peterson’s team identifies which species are present in different states. They can then introduce specific bacteria to germ-free mice to observe their effects and determine whether any species provoke an immune response.
In a recent study, Peterson's team analyzed changes in gut bacteria in mice with colitis. One species, Lactobacilis johnsonii, became particularly abundant in the diseased mice, making up 30 percent of the gut bacteria in some cases. When researchers introduced L. johnsonii to germ-free mice, they found the bacteria might actually improve health, challenging assumptions about its role in colitis.
This highlights a major challenge in microbiome research: changes in bacterial populations don’t always correlate with disease in predictable ways. “Just because something goes up or goes down doesn’t mean it’s bad or good,” Peterson says.
The Human Microbiome Project has created extensive catalogs of microbiome data from individuals with various diseases. However, Peterson notes that interpreting all this data is the hardest part.
