Investigating the onset of necrotizing enterocolitis using a unique study cohort of very low birthweight infants
Bioinformatics and Theoretical Biology
Parasitology and Biology of Tropical Infectious Disease Pathogens
Final Report Abstract
Necrotizing enterocolitis (NEC) is one of the most severe disorders in pediatric gastroenterology and a major reason for morbidity and mortality in preterm infants. NEC presents suddenly, predominantly in the first two months of life, and treatment and case fatality rates have not changed in decades. In recent years, massively next-generation sequencing of fecal specimens from prospective cohort studies have suggested associations of particular taxa with the risk of NEC development. These signatures, however, proved to have limited predictive value for early detection of NEC and its pathophysiology remains incompletely understood. Here, we leveraged a unique multicenter, prospective cohort of 972 very low birthweight infants to characterize the pre-onset microbiota composition (shotgun metagenomics) and activity (transcriptomics) as well as infant gut inflammatory processes (multiplex immunoprofiling). We extracted, processed and sequenced a total of 2119 pre-NEC stool metagenomes from 138 infants (46 cases/92 controls). We further developed a high-throughput, multiplexed protocol for RNA extraction, DNA and rRNA depletion, and RNAseq library preparation to profile 2119 metatranscriptomes corresponding to the profiled metagenomes. To characterize the pre-NEC intestinal inflammatory processes, we generated 567 stool immunoprofiles on the Luminex platform utilizing a customized extraction protocol. Initial results indicate that early- (pre 40 days of life) and late-onset (post 40 days of life) NEC may have distinct pathophysiologies. We discovered divergent microbiome trajectories in early- and late-onset NEC cases. From a microbial standpoint, early-onset NEC cases are indistinguishable from age-matched matched controls and do not significantly differ from controls in taxonomic composition or diversity. Late-onset NEC cases, however, have a clear microbial signature characterized by significantly lower alpha diversity, higher abundance of Enterobacteriaceae, and lower abundance of Bifidobacteriaceae, and Veillonellaceae. Preliminary analysis of our RNA-seq dataset suggests a similar pattern of transcriptomic divergence between cases and controls. This suggests that NEC may have fundamentally different etiologies at different points in early neonatal development. Data integration is ongoing.
Publications
- Comparative genomics of antibiotic-resistant uropathogens implicates three routes for recurrence of urinary tract infections. mBio Aug 2019, 10 (4) e01977-19
Thänert R, Reske KA, Hink T, Wallace MA, Wang B, Schwartz DJ, Seiler S, Cass C, Burnham CAD, Dubberke ER, Kwon JH, Dantas G
(See online at https://doi.org/10.1128/mBio.01977-19) - In vitro activity of meropenem/piperacillin/tazobactam triple combination therapy against clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus pseudintermedius and vancomycin-resistant Enterococcus spp, IJAA Jan 2020 55 (2) 105864
Yoneda A. & Thänert R., Burnham CAD, Dantas G
(See online at https://doi.org/10.1016/j.ijantimicag.2019.105864)
