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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