Journal article
Species-specific enhancement of enterohemorrhagic E. coli pathogenesis mediated by microbiome metabolites.
- Tovaglieri A Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Sontheimer-Phelps A Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Geirnaert A Department of Health Sciences and Technology, ETH Zurich, 8092, Zurich, Switzerland.
- Prantil-Baun R Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Camacho DM Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Chou DB Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Jalili-Firoozinezhad S Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- de Wouters T Department of Health Sciences and Technology, ETH Zurich, 8092, Zurich, Switzerland.
- Kasendra M Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Super M Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Cartwright MJ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
- Richmond CA Division of Gastroenterology, Boston Children's Hospital, Boston, MA, 02115, USA.
- Breault DT Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
- Lacroix C Department of Health Sciences and Technology, ETH Zurich, 8092, Zurich, Switzerland.
- Ingber DE Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA. don.ingber@wyss.harvard.edu.
- 2019-03-21
Published in:
- Microbiome. - 2019
Animals
Bacteria
Benzoates
Caproates
Cells, Cultured
Enterohemorrhagic Escherichia coli
Escherichia coli Infections
Female
Gastrointestinal Microbiome
Heptanoic Acids
Humans
Intestines
Male
Mice
Microchip Analytical Procedures
Organ Culture Techniques
Species Specificity
English
BACKGROUND
Species-specific differences in tolerance to infection are exemplified by the high susceptibility of humans to enterohemorrhagic Escherichia coli (EHEC) infection, whereas mice are relatively resistant to this pathogen. This intrinsic species-specific difference in EHEC infection limits the translation of murine research to human. Furthermore, studying the mechanisms underlying this differential susceptibility is a difficult problem due to complex in vivo interactions between the host, pathogen, and disparate commensal microbial communities.
RESULTS
We utilize organ-on-a-chip (Organ Chip) microfluidic culture technology to model damage of the human colonic epithelium induced by EHEC infection, and show that epithelial injury is greater when exposed to metabolites derived from the human gut microbiome compared to mouse. Using a multi-omics approach, we discovered four human microbiome metabolites-4-methyl benzoic acid, 3,4-dimethylbenzoic acid, hexanoic acid, and heptanoic acid-that are sufficient to mediate this effect. The active human microbiome metabolites preferentially induce expression of flagellin, a bacterial protein associated with motility of EHEC and increased epithelial injury. Thus, the decreased tolerance to infection observed in humans versus other species may be due in part to the presence of compounds produced by the human intestinal microbiome that actively promote bacterial pathogenicity.
CONCLUSION
Organ-on-chip technology allowed the identification of specific human microbiome metabolites modulating EHEC pathogenesis. These identified metabolites are sufficient to increase susceptibility to EHEC in our human Colon Chip model and they contribute to species-specific tolerance. This work suggests that higher concentrations of these metabolites could be the reason for higher susceptibility to EHEC infection in certain human populations, such as children. Furthermore, this research lays the foundation for therapeutic-modulation of microbe products in order to prevent and treat human bacterial infection.
Species-specific differences in tolerance to infection are exemplified by the high susceptibility of humans to enterohemorrhagic Escherichia coli (EHEC) infection, whereas mice are relatively resistant to this pathogen. This intrinsic species-specific difference in EHEC infection limits the translation of murine research to human. Furthermore, studying the mechanisms underlying this differential susceptibility is a difficult problem due to complex in vivo interactions between the host, pathogen, and disparate commensal microbial communities.
RESULTS
We utilize organ-on-a-chip (Organ Chip) microfluidic culture technology to model damage of the human colonic epithelium induced by EHEC infection, and show that epithelial injury is greater when exposed to metabolites derived from the human gut microbiome compared to mouse. Using a multi-omics approach, we discovered four human microbiome metabolites-4-methyl benzoic acid, 3,4-dimethylbenzoic acid, hexanoic acid, and heptanoic acid-that are sufficient to mediate this effect. The active human microbiome metabolites preferentially induce expression of flagellin, a bacterial protein associated with motility of EHEC and increased epithelial injury. Thus, the decreased tolerance to infection observed in humans versus other species may be due in part to the presence of compounds produced by the human intestinal microbiome that actively promote bacterial pathogenicity.
CONCLUSION
Organ-on-chip technology allowed the identification of specific human microbiome metabolites modulating EHEC pathogenesis. These identified metabolites are sufficient to increase susceptibility to EHEC in our human Colon Chip model and they contribute to species-specific tolerance. This work suggests that higher concentrations of these metabolites could be the reason for higher susceptibility to EHEC infection in certain human populations, such as children. Furthermore, this research lays the foundation for therapeutic-modulation of microbe products in order to prevent and treat human bacterial infection.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s40168-019-0650-5
- PMID 30890187
- Persistent URL
- https://folia.unifr.ch/global/documents/288752
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