The colon prevents gut bacteria from spreading to its surface by producing hydrogen peroxide and using it as a natural disinfectant, according to a mouse study that overturns an earlier theory for how bacteria are organized within the large intestine.
The findings, published in Cell Host & Microbe in December, identify a new defining force within the colonic environment, which may be useful to improve treatments of digestive disorders and related problems.
Most gut bacteria are located in the large intestine and aid in digestion, but they do not usually inhabit its mucous lining, which absorbs nutrients and is where they would cause inflammation by triggering immune responses. Previous research had suggested that the anaerobic bacteria were kept out by the fatally high oxygen levels found at the colon surface.
A team led by University of California at Davis researchers investigated whether a different force may be keeping the bacteria out. They studied the resources available in the colons of mice by tracking the infection of the bacterium Citrobacter rodentium, which attaches to the colon surface and causes lesions in mice.
“We were interested in what specific factors would provide an advantage, apart from them being right on the surface of epithelial cells,” said Andreas Bäumler, the paper’s lead author and a professor of medical microbiology and immunology at UC Davis.
Bäumler and his coauthors first exposed mice to C. rodentium and a mutated version of the pathogen that could not adhere to the colon. They detected the mutant in smaller numbers and observed that it was outcompeted by the original bacteria strain, suggesting that sticking close to the colon lining provides an early and crucial advantage to C. rodentium.
But previous research had shown that growth related to the bacteria’s oxygen-respiration enzyme isn’t correlated with the attaching mechanism until the lesions appear, so the pathogen’s early advantage on the colon lining seems to derive from elsewhere, according to the researchers.
“We thus entertained the idea that the spatial niche C. rodentium occupies provides access to a growth-limiting resource that is distinct from oxygen,” they wrote.
Another test revealed that C. rodentium is 20 times more prevalent when compared with a mutant that doesn’t produce cytochrome c peroxidase, an enzyme that reduces hydrogen peroxide into water and was found to be using the compound from the mouse liver for respiration. In other words, the bacteria was most infectious when it was “breathing” hydrogen peroxide present close to the colon surface.
Hydrogen peroxide is acting as a filter for bacteria on the colon surface, requiring them to use it for respiration like C. rodentium does or otherwise survive the disinfectant, Bäumler said. The mechanism could be holding off gut bacteria and restricting them to their habitat deeper in the large intestine.
The researchers searched for the hydrogen peroxide’s source and identified the enzyme NOX1, which is also present in humans. Defects in the gene that encodes NOX1 have been linked to conditions such as ulcerative colitis and very early onset inflammatory bowel disease. Bäumler said the medical associations are consistent with his team’s findings, because bacterial imbalances would be expected if a gene that determines the conditions in the colon were altered.
Understanding and fixing this “habitat filter” may lead to better treatments of inflammatory conditions in the gut, he said, as readjusting the conditions within the colonic environment could be more effective than simply killing the normally unwelcome microbes. The UC Davis professor is currently inspecting the relationships of the NOX1 enzyme, microbiota and inflammation changes in humans in the context of inflammatory bowel disease.
“In my opinion, these habitat filters are the treatment targets that you could use to rebalance the microbiota to remediate dysbiosis,” Bäumler said. “But in order to do that, you first have to identify the habitat filters, and then find ways of correcting the disease state by treating the host and correcting that habitat filter.”
The article, “Anaerobic Respiration of NOX1-Derived Hydrogen Peroxide Licenses Bacterial Growth at the Colonic Surface” was published Dec. 9 in Cell Host & Microbe. The authors of the study were Brittany Miller, Megan Liou, Lillian Zhang, Henry Nguyen, Eva-Magdalena Schorr, Connor Tiffany and Andreas Bäumler, University of California at Davis; Yael Litvak, University of California at Davis and Hebrew University of Jerusalem; Kyung Ku Jang, University of California at Davis and New York University; and Brian Butler, St. George’s University. The lead author was Andreas Bäumler.