Inflammatory bowel disease (IBD) is an umbrella term that describes many disorders that involve chronic inflammation of the digestive tract, including ulcerative colitis and Crohn's disease. These conditions are tied to certain alternations in the gut flora.
The digestive tract is colonized by billions of bacteria and other microorganisms that play pivotal and beneficial roles. However, if these organisms are improperly controlled, as in dysbiosis, it can lead to a wide array of chronic inflammatory diseases.
In patients with these conditions, they have reduced bacterial diversity in the gut microbiota, with high levels of bacteria that produce a protein called flagellin, which can facilitate microbiota encroachment into the mucosa and activate pro-inflammatory gene expression.
In the intestinal tract, there is a sterile layer of mucous that covers the wall. The wall acts as a bacteria-resistance barrier between the body and the internal digestive tract, hence, providing protection from inflammation. The body has its own way of protecting against flagellin since studies in the past have shown that certain antibodies are found in the mucous layer.
Now, a new study, published in the journal Nature Communications, reports that targeted immunization against flagellin, the protein that forms the appendage that enables bacterial mobility, can provide benefit in altering the intestinal flora, reducing the bacteria’s ability to trigger inflammation, which can protect the body against chronic inflammatory diseases.
The researchers had previously found that one common feature of the gut flora linked to inflammation is an increased level of flagellin expression by certain bacterial species. This can lead the bacteria to penetrate the intestinal mucosa and alter homeostasis.
Gut bacteria, gut flora, microbiome 3D illustration. Image Credit: Anatomy Insider / Shutterstock
Vaccinating against chronic inflammatory diseases
Pioneered by researchers at the Institute for Biomedical Sciences and the Neuroscience Institute at Georgia State University, the study suggests that targeting flagellin can potentially pave the way to vaccinate against inflammatory diseases of the gastrointestinal tract, such as inflammatory bowel diseases, metabolic syndrome, and obesity.
“The administration of flagellin, and perhaps other bacterial antigens, has the potential to vaccinate against an array of diseases associated with, and driven by gut inflammation," Dr. Benoit Chassaing, assistant professor in the Neuroscience Institute and the Institute for Biomedical Sciences at Georgia State and senior study author, said.
"This work is a proof of concept and demonstrates that targeted training of the immune system can protect against an array of chronic inflammatory diseases. Yet, significant work is now needed to test other antigens, other immunization routes, and additional inflammatory models, as well as the human relevance of these findings,” he added.
To arrive at their findings and to test their hypothesis, the researchers immunized mice with flagellin to induce an adaptive immune response so the body can produce antibodies. The mice vaccinated also showed altered intestinal flora, which was associated with a lower inflammatory state.
Also, a detailed analysis of the intestines and microbiota showed not just decreased levels of bacterial that strongly express flagellin, but also being absent in the intestinal mucosa, compared to the unvaccinated group. Flagellin has also been tied to inducing common disorders such as obesity and diabetes, the team tried the vaccine on mice consuming a high-fat diet. They found that the vaccinated mice were protected from obesity while the unvaccinated group developed obesity.
“Thus, administration of flagellin, and perhaps other pathobiont antigens, may confer some protection against chronic inflammatory diseases,” the researchers wrote on the paper.
The researchers are planning to develop ingestible flagellin-filled nanoparticles to further conduct the study and to develop new ways to introduce the vaccine. Further experiments and analyses are on the way, with plans of testing the vaccine on animals with chronic inflammatory diseases or metabolic disorders.
Tran, H.Q., Ley, R.E., Gewirtz, A.T. et al. Flagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases. Nat Commun 10, 5650 (2019) doi:10.1038/s41467-019-13538-y, https://www.nature.com/articles/s41467-019-13538-y