MSGID: 1:317/3 63dc8df5   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Study provides an explanation and potential solution for severe graft-   
   versus-host disease    
      
     Date:   
         February 2, 2023   
     Source:   
         Baylor College of Medicine   
     Summary:   
         Researchers found that alterations in the gut microbiome that   
         are linked to graft-versus-host disease severity are connected   
         to an increase in oxygen levels in the intestine that follows   
         immune-mediated intestinal damage. Pharmacologically reducing   
         intestinal oxygen levels alleviated the microbial imbalance and   
         reduced the severity of the condition in animal models.   
      
      
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   FULL STORY   
   ==========================================================================   
   The severity of immune-mediated intestinal diseases such as   
   graft-versus-host disease (GVHD) or inflammatory bowel diseases 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 at 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 connected to an increase in oxygen levels in the intestine that   
   follows immune-mediated intestinal damage. Pharmacologically reducing   
   intestinal oxygen levels alleviated the microbial imbalance and reduced   
   the severity of the intestinal disease.   
      
   "There is a lot of data showing that microbes change in many diseases,   
   but we do not understand how that happens," said leading author Dr. Pavan   
   Reddy, professor 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 a potential   
   solution for the imbalance in the gut microbiome that exacerbates GVHD and   
   possibly other inflammatory intestinal conditions."  GVHD is a potentially   
   life-threatening complication of bone marrow transplantation. "It is   
   the complication that can prevent us from using this therapy that has   
   proven to be effective to treat many blood cancers and inherited blood   
   diseases," Reddy said. "The idea is to understand what makes GVHD worse so   
   we can effectively control it. The study also is relevant to more common   
   inflammatory bowel diseases, including Crohn's disease and ulcerative   
   colitis."  Reddy and his colleagues discovered that the damage immune   
   cells cause to intestinal cells prevents these cells from fully using   
   oxygen to conduct their normal functions. Consequently, all the oxygen   
   that is not being used by intestinal cells oozes into the intestine,   
   changing the environment for the resident microbes.   
      
   "Most of the 'good microbes' we have in the intestine grow in oxygen-poor   
   environments -- oxygen is toxic to them. They are called anaerobic   
   (without oxygen) bacteria," Reddy said. "When oxygen levels in the   
   intestine increase, these microbes tend to disappear, and oxygen-loving   
   microbes tend to grow. An increase in oxygen level provides an explanation   
   for the microbiome changes in the context of these inflammatory diseases."   
   The findings suggested that restoring the normal environment by reducing   
   the oxygen level in the intestine could help reestablish the balance of   
   the microbial community and lead to attenuation of GVHD.   
      
   "Indeed, we discovered that reducing the intestinal oxygen level   
   actually made a difference in the progression of GVHD in the animal   
   models," Reddy said. "We found that a commonly used drug to reduce   
   iron overload, an iron chelator, mitigated 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, pulling it out and removing it from the body. "We discovered   
   that iron chelators also can act as oxygen sinks," Reddy said. "In our   
   animal models, iron chelators removed iron from the intestine and that   
   facilitated the restoration of an oxygen-poor environment that gave   
   anaerobic bacteria an opportunity to bloom. Importantly, this reduced   
   the severity of GVHD."  The researchers' next steps include conducting   
   studies to determine whether iron chelation can help control the severity   
   of GVHD in patients who have received a bone marrow transplant.   
      
   Another advantage of iron chelation would be that it may reduce or   
   avoid the use of immune suppressor medications that are usually used to   
   control GVHD.   
      
   Suppressing the immune system may control GVHD, but also favors   
   infections, which can be life-threatening. "If iron chelation   
   helps control the condition in patients, it would be a novel   
   non-immunosuppressive approach to treat GVHD with seemingly little side   
   effects," Reddy said.   
      
   Other contributors to this work include Keisuke Seike, Anders Kiledal,   
   Hideaki Fujiwara, Israel Henig, Marina Burgos da Silva, Marcel   
   R.M. 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 the US National Institutes of Health   
   grants P01HL149633, HL152605, CA217156, R01CA148828, 4 R01CA245546   
   and R01DK095201.   
      
   Further support was provided by National Cancer Institute 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.   
      
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   ==========================================================================   
   Story Source: Materials provided by Baylor_College_of_Medicine. Note:   
   Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig,   
      Marina   
         Burgos da Silva, Marcel R.M. 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,   
         Gregory Dick, Pavan Reddy. Ambient oxygen levels regulate   
         intestinal dysbiosis and GVHD severity after allogeneic stem cell   
         transplantation. Immunity, 2023; DOI: 10.1016/j.immuni.2023.01.007   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/02/230202112651.htm   
      
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