Study helps explain serious graft-versus-host disease and potential solution

The severity of immune-mediated bowel diseases such as graft versus host disease (GVHD) or inflammatory bowel disease is known to be associated with alterations in the gut microbiome, but what leads to such disruption in the microbial community has remained a mystery.

Researchers from Baylor College of Medicine, the University of Michigan, and collaborating institutions working with animal models of GVHD report today in the journal Immunity that alterations in the gut microbiome are linked to increased oxygen levels in the gut that follows immune-mediated gut damage. The pharmacological reduction of intestinal oxygen levels alleviates the microbial imbalance and reduces the severity of intestinal disease.

“There are lots of data showing that microbes change in many diseases, but we don’t understand how this happens,” the lead author said. Dr Pavan Reddyprofessor and director of Baylor’s Dan L Duncan Comprehensive Cancer Center, who was at the University of Michigan during the development of this project. “This study is one of the first to provide an explanation and potential solution to the gut microbiome imbalance that exacerbates GVHD and possibly other inflammatory bowel conditions.”

GVHD is a life-threatening complication of bone marrow transplantation. “This is the complication that may prevent us from using this therapy which has been shown to be effective in treating many blood cancers and inherited blood diseases,” Reddy said. “The idea is to understand what makes GVHD worse so that it can be effectively controlled. The study is also relevant to more common inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis.

Reddy and his colleagues found that immune cell damage to intestinal cells prevents these cells from fully utilizing oxygen to carry out their normal functions. Consequently, all the oxygen that is not used by the intestinal cells seeps into the intestine, changing the environment for the resident microbes.

“Most of the ‘good bugs’ we have in the gut thrive in low oxygen environments – oxygen is toxic to them. They are called anaerobic (without oxygen) bacteria,” Reddy said. “When oxygen levels in the gut increase, these microbes tend to die out and oxygen-loving microbes tend to thrive. An increase in oxygen level provides an explanation for changes in the microbiome in context of these inflammatory diseases.

The results suggest that restoring the normal environment by reducing the oxygen level in the gut might help restore the balance of the microbial community and lead to the alleviation of GVHD.

“Indeed, we found that reducing the level of intestinal oxygen actually made a difference in the progression of GVHD in animal models,” Reddy said. “We found that a drug commonly used to reduce iron overload, an iron chelator, alleviated the microbial imbalance and reduced the severity of GVHD.”

Iron chelators have been used for many years to treat conditions in which excess iron causes tissue damage, such as hemochromatosis. Iron chelators are compounds that bind to iron, drawing it out and removing it from the body. “We found that iron chelators can also act as oxygen sinks,” Reddy said. “In our animal models, iron chelators removed iron from the intestine, which facilitated the restoration of an oxygen-poor environment that allowed anaerobic bacteria to grow. Importantly, it reduced the severity of GVHD.

The researchers’ next steps include conducting studies to determine if iron chelation can help control the severity of GVHD in patients who have received bone marrow transplants.

Another advantage of iron chelation would be that it can reduce or avoid the use of immunosuppressive drugs which are usually used to control GVHD. Suppressing the immune system can control GVHD, but also promotes infections, which can be life-threatening. “If iron chelation helps control the disease in patients, it would be a novel, non-immunosuppressive approach to treating GVHD with apparently few side effects,” Reddy said.

Other contributors to this work include Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos da Silva, Marcel RM van den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li , Yaping Sun, Thomas M. Schmidt, Yatrik M. Shah, Robert R. Jenq, and Gregory Dick. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of Michigan, Okayama University Hospital, Rambam Health Care Campus-Israel, Memorial Sloan Kettering Cancer Center, Yale University School of Medicine, and MD Anderson Cancer Center.

This work was supported by grants P01HL149633, HL152605, CA217156, R01CA148828, 4 R01CA245546, and R01DK095201 from the US National Institutes of Health. Additional support was provided by award numbers R01-CA228358, R01-CA228308, P30 CA008748 MSK Cancer Center Support Grant/Core Grant and P01-CA023766; National Heart, Lung, Blood Institute award number R01-HL123340 and R01-8 HL147584; Tri-Institutional Stem Cell Initiative and NIH Grant CA46592.