Gut microbiome communication with the bone marrow regulates intestinal inflammation.

Project Summary
Significance: There is an urgent need for novel approaches to treat or prevent Entamoeba histolytica as it is an
important cause of diarrhea in infants in low income countries. There is no vaccine and only a single class of
antiparasitics is effective for invasive amebiasis.
Hypothesis: This project will test the hypothesis that metabolic products of the gut microbiome are capable of
epigenetically altering the bone marrow to increase intestinal neutrophilic inflammation and provide antigen-
nonspecific protection during subsequent ameba infection.
Approach: This project will determine how the gut microbiome communicates with the bone marrow to regulate
intestinal inflammation to subsequent infection. Preliminary data suggest that epigenetic changes in the bone
marrow, caused by exposure to the intestinal bacteria Clostridium scindens, are sufficient to confer mucosal
protection from subsequent Entamoeba histolytica infection. This finding led to the hypothesis that gut
colonization with C. scindens increases a serum mediator (deoxycholate) that then acts on the marrow
(JMJD3) to help support granulocyte monocyte progenitor (GMP) expansion and a more robust gut neutrophil
response. Aim 1 will determine how C. scindens communicates from the gut to the marrow. Aim 2 and 3 will
determine how the bone marrow is epigenetically altered during C. scindens colonization and protects from
Entamoeba. Successful completion of these studies will identify how intestinal Clostridia communicate with the
marrow to induce epigenetic changes that induce antigen-nonspecific “trained innate immunity”. Additionally,
the impact of our approach extends beyond amebiasis and infectious diseases to basic mechanisms of
hematopoiesis and innate trained immunity. Successful completion of these studies will aid in development of
next generation treatments that leverage the microbiome and trained immunity to help in clearance of
pathogens or help modulate the severity of inflammation.
Innovation: This work will provide a greater understanding of fundamental processes underlying trained
immunity induced by the host microbiota. Novel concepts derived from this work will identify pathways
important in microbiota-mediated protection from infection that can be targeted by translational medicine.
The environment for this work is a research group and Division dedicated to the study of the pathogenesis of
infectious colitis, including amebiasis, for the past 25 years. Extensive expertise in Epigenetics, Bioinformatics,
and Clostridia biology is also included (see letters of support). Dr. Burgess, the project PI, is well cited in the
field of trained immunity and pioneered study of the microbiome in regulating susceptibility to amebic colitis.

Grant Number: 5R01AI146257-06
NIH Institute/Center: NIH
Principal Investigator: Stacey Burgess