The microbiome interacts with the circadian clock and dietary composition to regulate metabolite cycling in the gut

Gut microbiomes play a key role in the maintenance of host metabolic homeostasis and health. An important aspect of metabolism is its circadian regulation, but how the microbiome regulates metabolite cycling under different conditions, including variations in dietary composition, remains undefined. In this study, we utilized high temporal resolution metabolite profiling of the Drosophila gut to investigate the role of the microbiome in metabolite cycling. We find that, in contrast to its effect on transcript cycling, the microbiome increases metabolite cycling in the gut. In the absence of a circadian clock, the microbiome has minimal effect on the number of metabolites cycling, but profoundly affects phase, suggesting that the clock stabilizes circadian phase in the face of microbial changes. Interestingly, the impact of the microbiome is also reduced in a timed feeding paradigm, and vice versa, suggesting that timed feeding and the microbiome have similar circadian effects. Finally, the microbiome increases metabolite cycling but does not alter phase in flies fed high protein diets, but suppresses metabolite cycling and changes cycling phase in flies fed high sugar diets. Enrichment analysis of cycling metabolites found that amino acid metabolism is particularly sensitive to changes in the microbiome, the circadian clock and timed feeding. Collectively, our observations highlight a key role of the microbiome in producing robust metabolite cycling, in conjunction with the circadian clock and dietary composition.

肠道微生物组（gut microbiome）在维持宿主代谢稳态与机体健康中发挥关键作用。代谢调控的重要内容之一为昼夜节律调控，但微生物组如何在包括膳食组成变异在内的不同条件下调控代谢物循环（metabolite cycling），迄今尚未阐明。本研究通过对果蝇（Drosophila）肠道开展高时间分辨率代谢物谱分析，探究了微生物组在代谢物循环中的作用。研究发现，与微生物组对转录循环的影响不同，其可增强肠道内的代谢物循环。在缺乏昼夜节律时钟（circadian clock）的情况下，微生物组对循环代谢物的数量影响极小，但会显著改变其循环相位；这表明，面对微生物组的变化，昼夜节律时钟可稳定代谢物的循环相位。有趣的是，在定时进食范式（timed feeding paradigm）中，微生物组的调控效应也会减弱，反之亦然，这提示定时进食与微生物组具有相似的昼夜节律调控效应。最终，在喂食高蛋白饮食（high protein diets）的果蝇中，微生物组可增强代谢物循环但不改变其相位；而在喂食高糖饮食（high sugar diets）的果蝇中，微生物组则会抑制代谢物循环并改变其循环相位。对循环代谢物的富集分析（enrichment analysis）显示，氨基酸代谢（amino acid metabolism）对微生物组、昼夜节律时钟及定时进食的变化尤为敏感。综上，本研究结果凸显了微生物组与昼夜节律时钟、膳食组成协同作用，以维持稳健代谢物循环的关键功能。