Streptozotocin-induced hyperglycemia alters the cecal metabolome and exacerbates antibiotic-induced dysbiosis

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. [Display omitted] •The cecal metatranscriptome and metabolome are altered in hyperglycemic mice•The hyperglycemic microbiota has more simple sugars and shows higher respiratory activity•Hyperglycemia-related changes are associated with worsened antibiotic dysbiosis•Amoxicillin promotes Salmonella susceptibility in hyperglycemic mice Wurster et al. find that streptozotocin-induced hyperglycemia significantly changes the metabolome and transcriptional behavior of the cecal microbiome. These changes potentially exacerbate amoxicillin-induced dysbiosis and decrease colonization resistance against Salmonella enterica. Together these data suggest that modifications to host metabolism may perturb microbiome metabolism and potentiate antibiotic susceptibility.