Author: Stacy Kish
Your gut is like a large apartment complex. It is home to a diverse collection of microbiota, from bacteria to fungi to Archaea to bacteriophages. This last collection of critters—viruses that infect bacteria—are often the most abundant members of the microbial community. New research is showing that bacteriophages have the potential to shape the communities that live within the gut and ultimately your health—for better or worse.
Many studies are now exploring ways to manipulate bacteriophage to treat disease in lieu of antibiotics. Researchers at University of Utah Health have discovered that these approaches may not be appropriate to treat all conditions. June Round, PhD, associate professor in pathology at U of U Health, is leading a team of scientists to explore the link between bacteriophages and autoimmune diseases, like inflammatory bowel disease (IBD). Their findings were published online in the February issue of journal Cell Host & Microbe.
“It was serendipitous,” said Round. “We started this project to see if we could use bacteriophages to get rid of a bad bacteria in mice while keeping the good bacteria, but we found the induction of immunity by the bacteriophage can worsen autoimmune disease.”
Previous research revealed that the gut microbiota of IBD patients are different than healthy individuals.
“There was evidence that patients with inflammatory bowel disease have an increased abundance of bacteriophages in the intestines,” said Lasha Gogokhia, MD, postdoctoral associate in medicine at Weill Cornell Medical College and first author on the paper. “It was unknown whether [these bacteriophage are] the cause or consequence of the heightened inflammation in the intestines.”
Round led a team of researchers to explore the possible connection between this autoimmune disease and the proliferation of bacteriophages in the gut. The team treated germ-free mice with several types of bacteriophage (Lactobacillus, Escherichia, and Bacteroides) to evaluate the immune response. They found that the bacteriophages increased the production of interferon-gamma, the cytokine that enhances the inflammatory response. As the concentration of bacteriophage increased, the mice experienced worsening in IBD symptoms.
“To be honest, I was surprised by these results,” Round said. “When we introduced bacteriophages to the gut of a mouse, which mimics levels found in a [normal] gut [community], the immune response was potent enough to make the disease worse.”
Round believes these results offer a cautionary approach for use of bacteriophage in future therapies. “I still believe that bacteriophage therapy could be useful,” Round said. “For diseases with an inflammatory component, we need to step back and think about mechanisms that are happening, as we could manipulate these pathways in conjunction with phage therapy.”
The design of the study is somewhat artificial. The mice in the study were not colonized with the specific bacterial host for which the bacteria target. This would not be the case in people. The result of killing inflammatory bacteria with bacteriophages may outweigh the inflammation caused by the phages themselves.
Future work will be necessary to shed light on the complex interactions between bacteriophages and the microbiotic environment to identify the most effective way to manipulate bacteriophages for future therapies.
“I was most excited to find the therapeutic implications of these findings,” Gogokhia said. “Specific anti-phage antibodies may be characteristic to the disease flare ups, which may be an excellent candidate for disease marker discovery. This could have tremendous implications in future IBD diagnostics and management.”
This work has been highlighted in Nature Microbiology, Science Translational Medicine and Biocentury.
Round and Gogokhia were joined in this project by Kate Buhrke, Rickesha Bell, Brenden Hoffman, D. Garrett Brown, Christin Hanke-Gogokhia, Arevik Ghazaryan, John Valentine, Ryan O’Connell, W. Zac Stephens, and Sherwood Casjens at U of U Health; Ellen Scherl, Carl Crawford, Vinita Jacob, and Randy Longman at Weill Cornell Medicine; Nadim Ajami and Matthew Wong at Baylor College of Medicine; and Nathan Porter and Eric Martens at University of Michigan Medical School. The work, titled Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis, was supported by the National Institutes of Health, the National Heart, Lung, and Blood Institute, the SHINE program, and the National Institute of General Medical Sciences.