Engineering The Stomach’s Gut Flora May Help Cure Crohn's Disease
Penn Medicine researchers have singled out a bacterial enzyme behind an imbalance in the gut microbiome. The new study, published online this week at Science Translational Medicine, suggests that wiping out a significant section of the bacteria in the intestine microbiome, and then re-introducing a specific type of "good" bacteria that lack this enzyme, called urease, may be an effective approach to better cure these diseases.
"Since it's a single enzyme that is involved in this process, it may be a targetable solution," stated the study's senior author, Gary D. Wu, MD, associate chief for study at the branch of Gastroenterology in the Perelman School of Medicine in the University of Pennsylvania. "The idea is that we could 'engineer' the composition of the microbiota in some manner that lacks this particular one."
An imbalance in the gut microbiome -- more "bad" bacteria than "great" -- is known as dysbiosis, which is caused by environmental stressors, such as intestinal inflammation, antibiotics, or dietary plan. Gut dysbiosis is believed to gas Crohn's disease and other diseases, but researchers are seeking to strike a much healthier equilibrium for patients not fully understand the mechanisms behind that relationship.
In a series of human and mouse research, the researchers discovered that a kind of "bad" bacteria known as Proteobacteria feeding on urea, a waste product which can wind up back in the colon, played an important role in the development of dysbiosis.
The "bad" bacteria that harbour the urease enzyme, convert urea into ammonia ), which is then reabsorbed by bacteria to make amino acids that are associated with dysbiosis in Crohn's disease. "Good" bacteria might not respond similarly, and thus may serve as a possible therapeutic strategy to engineer the microbiome into a healthier state and cure disease.
The study is significant is because it indicates that the flow of nitrogen to bacteria is an important process in the development of dysbiosis," Wu said. "It also proves using a single enzyme can reconfigure the whole composition of the gut microbiota."
The study was conducted by Wu and colleagues from Penn Medicine and Children's Hospital of Philadelphia (CHOP), under the PennCHOP Microbiome Program with funds from the Crohn's and Colitis Foundation.
To investigate the function of nitrogen metabolism in dysbiosis, the researchers performed a metabolomic analysis characterizing small molecules from faecal samples from 90 patients with Crohn's disease in the Pediatric Longitudinal Study of Elemental Diet and Stool Microbiota Composition (PLEASE) research and 26 healthy kids.
The results demonstrated that a result of nitrogen metabolism, faecal amino acids, were significantly associated in patients with Crohn's disease, dysbiosis, along with a wealth of Proteobacteria. That led the investigators to track nitrogen metabolism action in the mouse models to assist show mechanisms that might be targeted for treating disease.
The slate of the microbiome needed to be wiped clean before the microbiota may be engineered into a specific configuration, to show that bacterial nitrogen metabolism and leads to dysbiosis. Researchers previously demonstrated pretreating mice with antibiotics (vancomycin and neomycin) and polyethene glycol (PEG), an intestinal purging agent used by patients in prep for a colonoscopy, significantly decreased the bacterial load sufficient to create an opportunity for a recently introduced bacterial community to prove themselves.
Using this approach, in the present study, researchers revealed that inoculating mice using a single bacterial species transformed the intestine microbiome in a manner that was substantial, based on the existence of urease. Mice injected with urease-negative E. coli didn't result in dysbiosis, while mice with urease-positive E. coli did. The urease-positive E. coli additionally exacerbated colitis from the mice.
Very similar to mice, PEG successfully reduced load from 100,000-fold as well as treating five subjects with the same two antibiotics.
"Now that we're able to effectively reduce bacterial loading in people it could now be possible to engineer the microbiota to a different configuration like what we have attained in mice," Wu explained. "Although we're closer now, there's still more work to be carried out."
The Penn and CHOP team are conducting a therapeutic clinical research in patients with Crohn's disease using a strategy based on the information.
"The results of the study and the analysis of gathered biospecimens will be a significant first step in building a technology platform to engineer a valuable composition of the gut microbiota for the treatment of inflammatory bowel diseases," Wu said.
