Society: AGA

The molecular circadian clock helps optimize host physiology to the environment by influencing the timing and coordination of metabolic processes. Host-microbe interactions also play an important role in determining metabolic responses to environmental challenges. The gut microbiome helps break down diet-derived nutrients indigestible by the host, thereby generating metabolites that influence host metabolism and immune function. Host-microbe interactions can be influenced by dietary quality and timing, as well as daily light/dark cycles that entrain circadian rhythms in the host. Together, the gut microbiome and the circadian clock play a coordinated role in determining host metabolism and response to environmental stimuli. In this session, you will learn about the bidirectional interactions between the circadian clock, gut microbiota, and host metabolic systems and their effects on energy homeostasis, obesity and immune dysfunction.

BACKGROUND: Diurnal rhythmicity in the gut is important for the maintenance of gut integrity, peripheral circadian rhythms, and host metabolic homeostasis. However, studies exploring these rhymicities have focused on host transcription and 16S compositional data. Metatranscriptomics is a method by which we can determine the RNA transcriptional expression of microbial communities. In this study, we characterize the normal diurnal fluctuation of the mice cecal metatranscriptome and metagenome as well as the effects of diet induced obesity (DIO) and time restricted feeding (TRF) feeding. We hypothesize that the metatranscriptome will be more dynamic compared to metagenomic and 16S compositional data in addition to being more disrupted by DIO, but corrected with TRF.
METHODS: We collected cecum samples from mice in three diet and feeding regimens: normal chow diet ad libitum (control), high-fat diet (HFD) ad libitum (DIO), and HFD with TRF, every four hours for 24 hours. Metatranscriptome and metagenomic sequencing was performed on the cecal content and the transcripts and genes quantified using Woltka2. We analyzed these genes and transcripts for circadian rhythmicity and differential expressions.
RESULTS: HFD, regardless of feeding condition, completely altered the functional landscape of the metatranscriptome as well its dynamics, suggesting that diet is the main driver of microbial functional change. In the normal chow control mice, cycling functions included translation and regulation of transcription, which were lost in the HFD conditions. TRF featured cyclical fluctuation in carbohydrate metabolic processes and proteolysis that did not exist in the DIO mice. More transcripts are differentially expressed between DIO and control mice than they are between TRF and control mice, suggesting eating patterns can potentially serve a functional restorative effect. A function of particular interest that showed microbe dependent diurnal differences was bile salt hydrolase (BSH). BSH is a microbial enzyme that deconjugates bile acids, and can maintain insulin sensitivity. Our metabolomics results suggest that differential BSH activity could explain the protective effects of TRF against obesity, NAFLD, and diabetes. Though a number of microbes have diurnal changes in BSH in the normal chow control mice, Dubosiella newyorkensis exhibited change in the TRF group, suggesting that the metabolic benefits of TRF may be conveyed by the action of few bacterial species.
CONCLUSIONS: The cecum metatranscriptome pool exhibits similar HFD changes in cycling as observed in its compositional counterpart with DIO being destructive to cyclical functional rhythms and TRF partially restoring effects on luminal dynamics. Diet is the main driver of differential expression changes in the metatranscriptome.

Rob Knight

Appearances