Cross-feeding of pathobionts by Bacteroides thetaiotaomicron as a possible mechanism for Necrotizing Enterocolitis

Ishita Shah, Dept. of Food Science and Technology, University of California, Davis, USA

Ishita M. Shah1, Steven A. Frese1,3, Gege Xu2, Carlito B. Lebrilla2, Juliana Maria Leite Nobrega De Moura Bell1, Daniela Barile1, and David A. Mills1
1. Department of Food Science and Technology, University of California, Davis;
2. Department of Chemistry, University of California, Davis;
3. Evolve Biosystems, Inc., Davis, CA

Infants born preterm and hospitalized in the NICU are at high risk of infections. A major threat is the development of an intestinal disease termed as Necrotizing Enterocolitis (NEC), which many times requires surgical intervention. With about 600,000 infant deaths occurring due to NEC globally, it clearly requires better therapeutics compared to current standard of care. NEC develops in infants harboring various pathobionts, often proteobacterial species, and clinical trials suggest intestinal dysbiosis precedes disease development. Here we show that microorganisms isolated from infants developing NEC showcase a complex cross-feeding mechanism, whereby, a clear donor-recipient relationship revolving around breastmilk sugar metabolism appears to play a pivotal role in the development of proteobacterial blooms, as predicted based on 16S rRNA marker gene sequencing, metagenomics, and mass spectrometry. Bacteroides thetaiotaomicron isolated from feces of infants that did develop disease, employs extracellular glycosyl hydroases to deconstruct human milk oligosaccharides leaving behind monomers like L-fucose in the extracellular milieu. L-fucose subsequently serves as the carbon source for pathogens like Escherichia coli and Klebsiella pneumoniae, isolated from infants who developed disease. We demonstrate the involvement of the fucose operon of E. coli in this “cross-feeding” mechanism using a chromosomal mutant, which gets rapidly out-competed by the wild-type when tested in medium supplemented with human milk oligosaccharides and conditioned by growth of B. thetaiotaomicron. These studies reveal the complex network of mechanisms by which human milk oligosaccharides are consumed in situ and identify a cross-feeding phenotype between Bacteroides species and the pathogens that cause NEC. Understanding this cross-feeding enables the rational design of probiotic treatments to eliminate cross-feeding and reduce enrichment of pathobionts associated with NEC.

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