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2726 Depletion of Lachnospiraceae Marks the Development of Antibiotic-Associated Neutropenia in Pediatric Patients

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Acquired: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research, Adverse Events
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Josaura Fernandez Sanchez, MD1,2, Arushana Maknojia3*, Enrico Moiso, PhD4*, Nusrat Shaikh5*, Hope Hendricks, MD6*, Hannah Yan, BA, PhD7*, Ritu Banerjee, MD, PhD8*, Jeremy Schraw, PhD2,9*, Megan Baldridge, MD, PhD10* and Katherine Y. King, MD, PhD11

1Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
2Texas Children’s Cancer and Hematology Centers, Houston, TX
3Immunology and Microbiology Program, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX
4Koch Institute for Integrative Cancer research at MIT, Cambridge, MA
5Pediatrics Research Resources Office, Baylor College of Medicine, Houston, TX
6Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN
7Immunology Program, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX
8Vanderbilt University Medical Center, Nashville, TN
9Center for Epidemiology and Population Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX
10Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO
11Pediatric Infectious Diseases, Baylor College of Medicine, Houston, TX

Prolonged antibiotic administration has been associated with peripheral cytopenias in up to 10-15% of patients. Of these, neutropenia is particularly notable because of the associated risk of severe bacterial infections. Yet, the mechanisms underlying antibiotic-associated neutropenia remain poorly understood. Recent studies in murine models demonstrate that antibiotics suppress hematopoiesis by depletion of the intestinal microbiota, with concomitant suppression of basal Type I interferon (IFN) and STAT1 signaling. Oral administration of the microbial metabolites that induce Type I IFN restores normal hematopoiesis in antibiotic-treated mice. These findings support a paradigm in which products of the intestinal microbiota enter the bloodstream and travel to the bone marrow where they promote production of growth cytokines that support normal hematopoiesis.

To identify microbiota and microbiota-derived metabolites altered in patients with antibiotic-associated neutropenia, we enrolled pediatric patients receiving antibiotic therapy for a planned duration of fourteen days or more in a multicenter-IRB approved study. We analyzed pre- and post-treatment stool samples from 51 subjects by 16S rRNA sequencing and untargeted metabolomics profiling.

Neutropenia occurred in 13% of prospectively enrolled subjects. In total, 10 neutropenic patients were included in the study, with 29 control patients selected by frequency matching for age, race, and ethnicity. Length of intravenous antibiotic treatment, total length of antibiotic treatment, length of stay and admission to the intensive care unit were correlated with the development of neutropenia, whereas type of antibiotic or type of infection were not.

Based on 16S rRNA sequencing, alpha diversity was significantly decreased in the stool of patients with neutropenia but not in controls (p= 0.027 vs p= 0.059). Analysis of taxa abundance showed significant depletion of Lachnospiraceae in patients with neutropenia (p=0.043), while no significant difference was identified in controls. Lachnospiraceae are a main producer of short chain fatty acids and have been linked to hematopoietic stem cell transplant outcomes.

Partial least square-discriminant analysis (sPLS-DA) showed that the metabolomes of neutropenic and control stools were similar at baseline. However, 17 metabolites were differentially abundant after antibiotic treatment in the neutropenic group but not in the control group including citrulline, tyrosine, and N-acetylglucosamine/N-acetylgalactosamine. Future work will assess whether these compounds can rescue antibiotic-associated neutropenia in the animal model.

This is the first clinical study linking changes in the intestinal microbiota with antibiotic associated neutropenia. An improved understanding of the molecular mechanisms by which the microbiome sustains normal hematopoiesis will lead to ways to prevent and treat antibiotic-associated bone marrow suppression.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH