My current research focuses on the influence of the microbiome on clinical outcomes in the pediatric oncology, hematology, and bone marrow transplant populations.
The gastrointestinal tract is the predicted reservoir for most bloodstream infections (BSIs) after hematopoietic stem cell transplantation (HSCT). Whole-genome sequencing and comparative genomics have the potential to improve our understanding of the dynamics of gut colonization that precede BSI in HSCT recipients.Within a prospective cohort study of children (<18 years) undergoing HSCT, 9 subjects met criteria for mucosal barrier injury BSI. We performed whole-genome sequencing of the blood culture isolate and weekly fecal samples preceding the BSI to compare the genetic similarity of BSI isolates to fecal strains. We evaluated temporal associations between antibiotic exposures and the abundances of BSI strains in the gut microbiota and correlated detection of antibiotic resistance genes with the phenotypic antibiotic resistance of these strains.Median age was 2.6 years, and 78% were male. BSIs were caused by Escherichia coli (n=5), Enterococcus faecium (n=2), Enterobacter cloacae (n=1), and Rothia mucilaginosa (n=1). In the 6 BSI episodes with evaluable comparative genomics, the fecal strains were identical to the blood culture isolate (>99.99% genetic similarity). Gut domination by these strains preceded only 4 of 7 E. coli or E. faecium BSIs by a median (range) of 17 (6-21) days. Increasing abundances of the resulting BSI strains in the gut microbiota were frequently associated with specific antibiotic exposures. E. cloacae and R. mucilaginosa were not highly abundant in fecal samples preceding BSIs caused by these species. The detection of antibiotic resistance genes for beta-lactam antibiotics and vancomycin predicted phenotypic resistance in BSI strains.Bacterial strains causing mucosal barrier injury BSI in pediatric HSCT recipients were observed in the gut microbiota prior to BSI onset, and changes in the abundances of these strains within the gut preceded most BSI episodes. However, frequent sampling of the gut microbiota and sampling of other ecological niches is likely to be necessary to effectively predict BSI in HSCT recipients.
View details for DOI 10.1016/j.bbmt.2019.07.019
View details for PubMedID 31326608
Growing evidence suggests that human microbiota likely influence diverse processes including hematopoiesis, chemotherapy metabolism, and efficacy, as well as overall survival in patients with hematologic malignancies and other cancers. Both host genetic susceptibility and host-microbiota interactions may impact cancer risk and response to treatment; however, microbiota have the potential to be uniquely modifiable and accessible targets for treatment. Here, we focus on strategies to modify microbiota composition and function in patients with cancer. First, we evaluate the use of fecal microbiota transplant to restore microbial equilibrium following perturbation by antibiotics and chemotherapy, and as a treatment of complications of hematopoietic stem cell transplantation (HSCT), such as graft-versus-host disease and colonization with multidrug-resistant organisms. We then address the potential use of both probiotics and dietary prebiotic compounds in targeted modulation of the microbiota intended to improve outcomes in hematologic diseases. With each type of therapy, we highlight the role that abnormal, or dysbiotic, microbiota play in disease, treatment efficacy, and toxicity and evaluate their potential promise as emerging strategies for microbiota manipulation in patients with hematologic malignancies and in those undergoing HSCT.
View details for DOI 10.1182/bloodadvances.2019000365
View details for PubMedID 31714965
BACKGROUND: Infections and graft-versus-host disease have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients.METHODS: We conducted a retrospective cohort study of children (<18 years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared two-year all-cause and cause-specific mortality during three time periods based on year of transplantation (1995-2001, 2002-2007, 2008-2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period.RESULTS: During the 20-year study period, 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995-2001 to 30% in 2008-2014 (P=0.0002). White patient race and non-malignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which graft-versus-host disease (18% vs 11%; P=0.06) or graft failure (9% vs 3%; P=0.01) were contributory than white children. Comparing 2008-2014 to 1995-2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex [hazard ratio (HR): 0.09; 95% confidence interval (CI): 0.01-0.76]. With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequent infectious causes of death in children after UCBT.CONCLUSIONS: Advances in clinical practice over the past 20 years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis.
View details for PubMedID 30481599
View details for DOI 10.1016/j.chom.2018.08.014
Repulsive guidance molecule c (RGMc; gene symbol: Hfe2) plays a critical role in iron metabolism. Inactivating mutations cause juvenile hemochromatosis, a severe iron overload disorder. Understanding mechanisms controlling RGMc biosynthesis has been hampered by minimal information about the RGMc gene. Here we define the structure, examine the evolution, and establish mechanisms of regulation of the mouse RGMc gene. RGMc is a 4-exon gene that undergoes alternative RNA splicing to yield 3 mRNAs with 5' different untranslated regions. Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. We identify 3 critical promoter elements responsible for transcriptional activation in skeletal muscle, comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, our results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.
View details for DOI 10.1016/j.ygeno.2010.09.001
View details for PubMedID 20858542
RGMs (repulsive guidance molecules) comprise a recently discovered family of GPI (glycosylphosphatidylinositol)-linked cell-membrane-associated proteins found in most vertebrate species. The three proteins, RGMa, RGMb and RGMc, products of distinct single-copy genes that arose early in vertebrate evolution, are approximately 40-50% identical to each other in primary amino acid sequence, and share similarities in predicted protein domains and overall structure, as inferred by ab initio molecular modelling; yet the respective proteins appear to undergo distinct biosynthetic and processing steps, whose regulation has not been characterized to date. Each RGM also displays a discrete tissue-specific pattern of gene and protein expression, and each is proposed to have unique biological functions, ranging from axonal guidance during development (RGMa) to regulation of systemic iron metabolism (RGMc). All three RGM proteins appear capable of binding selected BMPs (bone morphogenetic proteins), and interactions with BMPs mediate at least some of the biological effects of RGMc on iron metabolism, but to date no role for BMPs has been defined in the actions of RGMa or RGMb. RGMa and RGMc have been shown to bind to the transmembrane protein neogenin, which acts as a critical receptor to mediate the biological effects of RGMa on repulsive axonal guidance and on neuronal survival, but its role in the actions of RGMc remains to be elucidated. Similarly, the full spectrum of biological functions of the three RGMs has not been completely characterized yet, and will remain an active topic of ongoing investigation.
View details for DOI 10.1042/BJ20090978
View details for PubMedID 19698085