Investigating the onset of necrotizing enterocolitis using a unique study cohort of very low birthweight infants

• Applicant: Dr. Robert Thänert
• Subject Area: Gastroenterology ; Bioinformatics and Theoretical Biology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402733540

Necrotizing enterocolitis (NEC) is a severe necroinflammatory injury of the intestine that is among the most common diseases in infants born with very low birthweights. Despite improving clinical care neither the incidence rate, nor the significant associated mortality of 20 to 30%, declined during the last decades. It is hypothesized that the unpredictable onset of NEC is influenced by intestinal immaturity and bacterial dysbiosis. A comprehensive understanding of the genesis and relative contribution of these processes to NEC pathophysiology has, however, been hindered by the lack of suitable infant specimens obtained prior to the onset of the disease. The proposed project overcomes these limitations by utilizing a unique, pre-existing collection of samples that precede and coincide with NEC onset. This collection consists of repeated fecal samples from 972 infants, who were enrolled in a three-site, prospective cohort study, of which 46 developed NEC. To shed light on the underlying mechanisms of the bacterial dysbiosis observed in prior studies and to explore a possible association of specific bacterial signatures with NEC risk, the functional and phylogenetic composition of the intestinal microbiome in cases and controls will be defined using shotgun metagenomic sequencing. Bacteria identified to be over-represented in cases or controls will be analyzed via whole genome sequencing, to investigate whether genetic alterations contribute to NEC onset and whether potential protective effects of specific taxa over-represented only in control cases are genetically determined. Based on the genetic information acquired from these bacteria of interest, a targeted sequence capture approach will be established, to assess their transcriptional profile as a determinant of NEC development. Metatranscriptomic assessments of the whole intestinal microbiome and investigation of the infant gut’s transcriptional profiles will elucidate their respective roles and the temporal dynamics before and during NEC onset. The data generated by all technologies will be used to develop a reliable risk measurement for NEC development in preterm infants and construct a predictive model of NEC onset. Moreover, the implementation of reduced models, using data generated with subsets of the applied technologies, will allow clinicians to adapt the range of variables measured to the local technology availability and enable cost/benefit considerations. By leveraging a unique pre-NEC sample collection, the proposed project will allow to identify processes that increase the risk for NEC development in low birthweight infants and could reveal novel approaches for disease prevention. A more comprehensive understanding of disease progression will, moreover, significantly improve treatment efficacy.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Gautam Dantas