Streptozotocin-induced hyperglycemia alters the cecal metabolome and exacerbates antibiotic-induced dysbiosis
Jenna I. Wurster,
Rachel L. Peterson,
Claire E. Brown,
Swathi Penumutchu,
Douglas V. Guzior,
Kerri Neugebauer,
William H. Sano,
Manu M. Sebastian,
Robert A. Quinn,
Peter Belenky
Affiliations
Jenna I. Wurster
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02906, USA
Rachel L. Peterson
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02906, USA
Claire E. Brown
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02906, USA
Swathi Penumutchu
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02906, USA
Douglas V. Guzior
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
Kerri Neugebauer
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
William H. Sano
Department of Biology, University of Washington, Seattle, WA 98195, USA
Manu M. Sebastian
Department of Epigenetics and Molecular Carcinogenesis, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
Robert A. Quinn
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
Peter Belenky
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02906, USA; Corresponding author
Summary: It is well established in the microbiome field that antibiotic (ATB) use and metabolic disease both impact the structure and function of the gut microbiome. But how host and microbial metabolism interacts with ATB susceptibility to affect the resulting dysbiosis remains poorly understood. In a streptozotocin-induced model of hyperglycemia (HG), we use a combined metagenomic, metatranscriptomic, and metabolomic approach to profile changes in microbiome taxonomic composition, transcriptional activity, and metabolite abundance both pre- and post-ATB challenge. We find that HG impacts both microbiome structure and metabolism, ultimately increasing susceptibility to amoxicillin. HG exacerbates drug-induced dysbiosis and increases both phosphotransferase system activity and energy catabolism compared to controls. Finally, HG and ATB co-treatment increases pathogen susceptibility and reduces survival in a Salmonella enterica infection model. Our data demonstrate that induced HG is sufficient to modify the cecal metabolite pool, worsen the severity of ATB dysbiosis, and decrease colonization resistance.
