| Autor: |
Pavao A; Massachusetts Host-Microbiome Center, Dept. Pathology, Brigham and Women's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Zhang E; Dept. Pathology, and A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA., Monestier A; Laboratoire Pathogenèse des Bactéries Anaérobies, Institut Pasteur, UMR-CNRS 2001, Université de Paris, Institut Pasteur, Paris, France., Peltier J; Laboratoire Pathogenèse des Bactéries Anaérobies, Institut Pasteur, UMR-CNRS 2001, Université de Paris, Institut Pasteur, Paris, France.; Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette, France., Dupuy B; Laboratoire Pathogenèse des Bactéries Anaérobies, Institut Pasteur, UMR-CNRS 2001, Université de Paris, Institut Pasteur, Paris, France., Cheng L; Dept. Pathology, and A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA., Bry L; Massachusetts Host-Microbiome Center, Dept. Pathology, Brigham and Women's Hospital, Boston, MA, USA.; Clinical Microbiology Laboratory, Brigham and Women's Hospital, Boston, MA, USA. |
| Abstrakt: |
Stickland-fermenting Clostridia preferentially ferment amino acids to generate energy and anabolic substrates for growth. In gut ecosystems, these species prefer dual redox substrates, particularly mucin-abundant leucine. Here, we establish how theronine, a more prevalent, mucinabundant substrate, supports dual redox metabolism in the pathogen Clostridioides difficile . Realtime, High-Resolution Magic Angle Spinning NMR spectroscopy, with dynamic flux balance analyses, inferred dynamic recruitment of four distinct threonine fermentation pathways, including ones with intermediate accrual that supported changing cellular needs for energy, redox metabolism, nitrogen cycling, and growth. Model predictions with 13 C isotopomer analyses of [U- 13 C]threonine metabolites inferred threonine's reduction to butyrate through the reductive leucine pathway, a finding confirmed by deletion of the hadA 2-hydroxyisocaproate CoA transferase. In vivo metabolomic and metatranscriptomic analyses illustrate how threonine metabolism in C. difficile and the protective commensal Paraclostridium bifermentans impacts pathogen colonization and growth , expanding the range of dual-redox substrates that modulate host risks for disease. |
