title: Characterization of oral and gut microbiome temporal variability in hospitalized cancer patients.
abstract: Understanding longitudinal variability of the microbiome in ill patients is critical to moving microbiome-based measurements and therapeutics into clinical practice. However, the vast majority of data regarding microbiome stability are derived from healthy subjects. Herein, we sought to determine intra-patient temporal microbiota variability, the factors driving such variability, and its clinical impact in an extensive longitudinal cohort of hospitalized cancer patients during chemotherapy.
  
  
  
  The stool (n = 365) and oral (n = 483) samples of 59 patients with acute myeloid leukemia (AML) undergoing induction chemotherapy (IC) were sampled from initiation of chemotherapy until neutrophil recovery. Microbiome characterization was performed via analysis of 16S rRNA gene sequencing. Temporal variability was determined using coefficients of variation (CV) of the Shannon diversity index (SDI) and unweighted and weighted UniFrac distances per patient, per site. Measurements of intra-patient temporal variability and patient stability categories were analyzed for their correlations with genera abundances. Groups of patients were analyzed to determine if patients with adverse outcomes had significantly different levels of microbiome temporal variability. Potential clinical drivers of microbiome temporal instability were determined using multivariable regression analyses.
  
  
  
  Our cohort evidenced a high degree of intra-patient temporal instability of stool and oral microbial diversity based on SDI CV. We identified statistically significant differences in the relative abundance of multiple taxa amongst individuals with different levels of microbiota temporal stability. Increased intra-patient temporal variability of the oral SDI was correlated with increased risk of infection during IC (P = 0.02), and higher stool SDI CVs were correlated with increased risk of infection 90 days post-IC (P = 0.04). Total days on antibiotics was significantly associated with increased temporal variability of both oral microbial diversity (P = 0.03) and community structure (P = 0.002).
  
  
  
  These data quantify the longitudinal variability of the oral and gut microbiota in AML patients, show that increased variability was correlated with adverse clinical outcomes, and offer the possibility of using stabilizing taxa as a method of focused microbiome repletion. Furthermore, these results support the importance of longitudinal microbiome sampling and analyses, rather than one time measurements, in research and future clinical practice.
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Galloway-Peña
authors.affiliation: The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Smith
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Pranoti
authors.initials: P
authors.lastname: Sahasrabhojane
authors.affiliation: Department of Statistics, Rice University, Houston, TX, 77005, USA.
authors.forename: W Duncan
authors.initials: WD
authors.lastname: Wadsworth
authors.affiliation: Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Fellman
authors.affiliation: The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Ajami
authors.affiliation: Department of Stem Cell Transplantation, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Naval
authors.initials: N
authors.lastname: Daver
authors.affiliation: Department of Statistics, University of California, Irvine, CA, 92697, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Guindani
authors.affiliation: The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Petrosino
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, TX, 77030, USA. sshelburne@mdanderson.org.|Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, 77030, USA. sshelburne@mdanderson.org.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Shelburne
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001419:Bacteria / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D005243:Feces / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000382:microbiology*; D008297:Male; D008875:Middle Aged; D012336:RNA, Ribosomal, 16S; D012463:Saliva / Q000382:microbiology; D017422:Sequence Analysis, DNA
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D012336:RNA, Ribosomal, 16S
keywords: Antibiotics; Chemotherapy; Leukemia; Microbiome; Temporal variability