Research Uncovers Bacterial Enzyme Responsible for Crohn's Disease Development
Research in several different medical fields—most notably including mental health and autoimmune disease—have begun to trace the roots of their problems back to an unlikely source. Mental health disorders like depression and anxiety, and autoimmune disorders like Crohn’s disease, have been found to be closely tied to a complex system of bacteria that live in the gastrointestinal tract.
In 2006, EMBO reports released an article titled, “The gut flora as a forgotten organ.” The publication’s abstract begins by saying that “the intestinal microflora is a positive health asset that crucially influences the normal structural and functional development of the mucosal immune system.” Those with Crohn’s disease have a compromised mucosal immune system response, an overactive immune system that attacks the internal, healthy body.
From birth onwards, the body keeps a complex system of living, active bacteria in careful balance within the gut. Each bacterium has a role to play in the body’s digestive process, so much so that the article claims that the gut flora has a “collective metabolic activity equal to a virtual organ within an organ.” The article is claiming that there is enough activity from these resident bacteria alone to equal the functional activity of another organ.
Researchers are now discovering that a specific bacterial enzyme in the gut flora may be responsible for the development of Crohn’s disease. With this knowledge comes the hope of treating it, targeting the single enzyme and removing it from the ecosystem. While this is easier said than done, it echoes the 2006 EMBO report’s theory that “manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy” in the treatment of inflammatory bowel diseases like Crohn’s disease.
Composition of the microbiome
Those with Crohn’s disease know that the problem is not a dietary or digestive issue, rather, the problems of digestion and bowel movements are symptoms of the immune system’s attacks on the gastrointestinal tract. Inextricably tied into this relationship between the gastrointestinal tract and the immune system is the gut microbiome. The “forgotten organ” has a major role to play in the progression and symptomatic responses of the disease, but scientists are not quite sure exactly what that role is yet.
They know that one of the underlying causes of Crohn’s disease and other similar conditions is dysbiosis: an imbalance of the gut microbiome. While not always the case, dysbiosis is thought to be caused by inflammation, antibiotics, or poor diet, all of which might be common in individuals with inflammatory bowel disease. Scientists believed that if the problem was an imbalance of the gut flora, that perhaps the composition of the gut flora could be altered.
The idea had even more implications than originally expected. Authors of a study published in Science Translational Medicine were able to identify a single bacterial enzyme that led directly to dysbiosis in Crohn’s disease patients. They eliminated a significant amount of all of the bacteria in the gut microbiome and re-introduced bacteria that was known to promote healthy digestion and immune system responses. The results were outstanding, suggesting an entirely new way of treating Crohn’s disease.
The ureas enzyme
The bacteria responsible for causing Crohn’s disease feeds on urea, a common waste product that can end up in the colon. Bacteria that feeds on urea are present in both human and mice gut flora, and these bacteria were the type specifically removed and not re-introduced in the study. They are called Proteobacteria, and they promote enzymes that turn urea in the colon into ammonia, which in turn is reabsorbed by the body and causes the imbalances in the gut flora that leads to Crohn’s disease.
Dr. Gary D. Wu, MD authored the study that was published in Science Translational Medicine, and said that ideally doctors might eventually be able to “‘engineer’ the composition of the microbiota in some way that lacks this particular one.” He and the other authors on the study went on to hypothesize that good bacteria would not behave in the same way as Proteobacteria in the gut, and might prevent Crohn’s disease from developing altogether.
The process by which the bad bacteria turns urea into ammonia is called nitrogen metabolism. Dr. Wu wrote that the study was significant in that it proved that one enzyme could be responsible for changing the entire composition of gut flora. Nitrogen metabolism produces fecal amino acids, which researchers have linked strongly to Crohn’s disease, dsybiosis, an overabundance of Proteobacteria, and other inflammatory bowel diseases.
The study was conducted on mice, in the hopes that the results would be significant enough to justify further trials in humans. In order to test the mice’s microbiomes for changes due to urease enzymes, scientists killed off the bacteria in the mice’s gastrointestinal tracts with antibiotics. They then introduced two separate colonies of E. coli, one with urease-negative enzymes and one with ureas-positive enzymes.
The mice with urease-negative enzymes did not develop dsybiosis, but the mice with urease-positive enzymes did. It was further tested and discovered that mice with Crohn’s disease experienced a worsening of symptoms following the introduction of urease-positive E. coli. With the data showing that everything hinged on urease-positive enzymes, the mice trials were wrapped up and the team moved on to human trials, which are currently being conducted.
Reengineering gut microbiomes
The first step in changing the composition of gut flora is reducing the bacteria population residing along the walls of the GI tract. In humans, this can be achieved with a combination of antibiotics and polyethylene glycol (PEG), a chemical ingredient common in laxatives, among other medicines. Once enough bacteria have been removed from the system, new bacteria can properly establish itself in place of the bad bacteria.
Engineering the proper microbiome in humans is more difficult than simply adding bacteria and waiting. Even after new bacteria is introduced, competition and the body’s natural defense mechanisms prevent a majority of the bacteria from becoming established and taking up residency. Finding the proper configuration of bacteria is challenging as well; every person’s body is unique to their gut flora, and making changes is often unpredictable.
Gut flora is meant to be diverse, with millions of different bacteria playing different roles. The composition of any given person’s gut flora at any given time is the result of a lifelong competition between these bacteria, beginning with bacteria received from the mother during breastfeeding. Scientists are still unable to understand all of the mechanisms by which gut flora is established, and by which it evolves, but research is focusing on gut flora as the future of treating inflammatory bowel disease.
Applications to biologics
Dr. Wu claims that the goal is to one day build a “technology platform to engineer a beneficial composition of the gut microbiota for the treatment of inflammatory bowel disease.” Currently, researchers are exploring the application of biologics, which are medicines targeting specific aspects of the immune response according to the genetic nuances of an individual person. This is considered by many to be the next step in medicine, a move away from one-size-fits-all prescriptions.
The gut flora has a role to play in even this. Many prescription drugs ingested orally will come to interact in some way with the gut flora, and a person’s gut microbiome composition can either assist or hinder the effects of these and other medications. This is especially true when working with biologics, which interface with the immune system in a similar way to the bacteria in the gut. As research continues to press on, it is apparent that the gut flora is key to making the next major breakthrough in medicine, and perhaps one day soon a cure will be made available through gut flora reengineering.
References
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1500832/
