Gut microbes modulate (p)ppGpp during a time-restricted feeding regimen

Abstract

ABSTRACT Mammals exhibit daily fasting and feeding patterns that produce a fluctuating environment in the gut. By colonizing germfree mice with Bacteroides thetaiotaomicron and examining gene expression through a time-restricted feeding cycle, we demonstrate that this prominent gut commensal exhibits gene expression patterns characteristic of a stringent response and increases ppGpp levels during the host-fasting phase of the feeding regimen. Mutants unable to produce (p)ppGpp fail to produce this transcriptional response, exhibit unrestrained chromosomal replication, and cannot maintain population size during the host-fasting phase. Additionally, B. thetaiotaomicron requires (p)ppGpp to utilize host glycans both in vitro and in vivo , and mutants unable to produce (p)ppGpp display deficiencies in mucus layer colonization during the host-fasting phase. Complete gut microbial communities from mice and humans also increase ppGpp levels in this manner, demonstrating that this response appears to be general across species and conserved across mammalian gut communities. Together, these results identify an intracellular signal that allows gut microbes to coordinate their physiology with a time-restricted feeding regimen of their host. IMPORTANCE Mammals do not eat continuously, instead concentrating their feeding to a restricted portion of the day. This behavior presents the mammalian gut microbiota with a fluctuating environment with consequences for host-microbiome interaction, infection risk, immune response, drug metabolism, and other aspects of health. We demonstrate that in mice, gut microbes elevate levels of an intracellular signaling molecule, (p)ppGpp, during the fasting phase of a time-restricted feeding regimen. Disabling this response in a representative human gut commensal species significantly reduces colonization during this host-fasting phase. This response appears to be general across species and conserved across mammalian gut communities, highlighting a pathway that allows healthy gut microbiomes to maintain stability in an unstable environment.