TRANSCRIPTIONAL RESPONSES OF GUT MICROBIOMES IN PREMATURE INFANTS RELATED TO HYPOXIA AND THE DEVELOPMENT OF NECROTIZING ENTEROCOLITIS SYMPTOMS

Yonatan Sher 1 Matthew R. Olm 1 Tali Raveh-Sadka 1 David Burstein 1 Christopher T. Brown 1 Michael J. Morowitz 2 Jillian F. Banfield 1
1Department of Environmental Science, Policy, and Management, University of California, Berkeley, Berkeley, California, USA
2School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Necrotizing enterocolitis (NEC) is a common and sometimes lethal disease of premature infants, and it is characterized by necrosis of gut tissue and presence of gas cysts in the bowel wall. It has been theorized that abnormally low vascular supply of oxygen to the intestine contributes to NEC pathogenesis by possibly affecting the conditions within the gut lumen and residing microbiome. To test the hypothesis that the transcriptional responses of gut microbiomes reflect oxygen conditions in the gastrointestinal tract, we performed paired metagenomic and metatranscriptomic analyses on fecal samples from four premature infants, two of which were later diagnosed with NEC. We sequenced samples from 4-6 time points within the first 10 to 40 days of life. Genomes were assembled and binned from metagenomic samples, and RNA reads were mapped to draft genomes. The expression ratio of cytochrome bd (higher oxygen affinity) to cytochrome c oxidase (lower oxygen affinity) was higher in NEC-diagnosed infants, indicating low oxygen availability. The expression ratio of nitric oxide (NO) detoxifying genes to their repressing genes (a ratio indicative of NO exposure) was lower in infants diagnosed with NEC, consistent with lower NO availability in NEC infants. As oxygen is needed for host NO synthase activity, this observation further indicates low oxygen availability in infants diagnosed with NEC.The expression ratio of H2 forming formate dehydrogenase to other fermentation genes was higher in NEC infants, consistent with high H2 concentrations found in the guts of NEC diagnosed infants. Overall, our results suggest that transcriptional activity in the gut microbiome of premature infants may be a predictor for later NEC diagnosis.









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