Clocking the Microbes: How Circadian Rhythms Shape Gut Health

The circadian clock system is a complex network of transcription factors that orchestrate rhythmic gene expression, aligning the body’s physiological processes with the geophysical time. It has been established that disruptions in circadian rhythms can lead to a range of health issues, including sleep and psychiatric disorders, ischemic disease, cardiovascular dysfunction, diabetes, cancer, and neurodegenerative diseases. However, much of previous research has been conducted using standard rodent models, which do not fully mimic human circadian rhythms. In a new study published in the peer-reviewed Cell Reports Journal by Dr. Yunpeng Yang, Dr. Peijun Yu, Dr. Yong Lu, Dr. Changshan Gao, and Dr. Qiang Sun from the Institute of Neuroscience at the Chinese Academy of Sciences, sought to bridge this gap by employing gene-edited cynomolgus monkeys with disrupted circadian rhythms, as their genetic, physiological, and behavioral traits are more akin to humans. They also discussed the disruption of circadian rhythms and its impact on the gut microbiota of cynomolgus monkeys, providing valuable insights into how these rhythms influence host health.

The research team examined the gut microbiota, a dynamic ecosystem residing in the gastrointestinal tract that intimately interacts with the host. Previous research has shown that the composition and function of gut microbiota exhibit rhythmic oscillations during the 24-hour light-dark cycle. These microbial oscillations can influence the host’s circadian epigenetic and transcriptional landscape, subsequently impacting physiology and disease susceptibility. However, most of this work has been carried out in rodents and humans, leaving a substantial knowledge gap concerning non-human primates. Emerging evidence suggests that the host genotype and host-derived resources play a significant role in shaping the gut microbiome. Genomic and microbiome-wide analyses have revealed the influence of host genetic variation on the gut microbiota composition. Moreover, factors like salivary amylase gene copy numbers, nutrient sensing in innate immune cells, and epithelial-derived H₂O₂ can influence the microbial communities within the gut. Nevertheless, the host factors governing the rhythmic oscillation of gut microbes remain largely unexplored. The authors investigated the rhythmic oscillations of the gut microbiome and metabolome in cynomolgus monkeys and showed that monkeys lacking the BMAL1 gene exhibited significant changes in their gut microbiota and luminal metabolites at midnight. Notably, the altered gut microbial oscillations were linked to disturbed rhythmicity of intestinal H₂O₂, which is primarily produced from intestinal NOX1 (NADPH oxidase). Importantly, the study identified that BMAL1 could activate the transcription of NOX1 by binding to a specific site in its promoter. This discovery was consistent not only in cynomolgus monkeys but also in humans, highlighting the evolutionary conservation of this mechanism.

The authors’ findings demonstrated the significance of intestinal clock-controlled H₂O₂ rhythmicity in shaping the rhythmic oscillation of gut microbiota. The gut microbial composition in BMAL1-deficient monkeys underwent significant oscillations, and the study revealed that these changes were induced by the expansion of Bacteroidota microorganisms, primarily Prevotella and Alloprevotella, at a specific time point (ZT18). They also investigated the fecal metabolome, identifying significant differences in fecal metabolites between wild-type and BMAL1-deficient monkeys at various time points. The rhythmic variations of metabolites were observed, and two key metabolites, ascorbic acid and GABA, were found to synchronize with the altered microbial oscillations in BMAL1-deficient monkeys. Reduced GABA levels at midnight could be associated with issues like sleeplessness and anxiety. It’s also noted that some specific microbial genera, such as Prevotella and Alloprevotella, are capable of degrading GABA, which may exacerbate this issue. Indeed, this correlation emphasizes the important connections between the gut microbiota and metabolites and their potential roles in host health. Furthermore, the study highlighted the crucial role of luminal H₂O₂ in modulating the gut microbial composition in cynomolgus monkeys. Luminal H₂O₂, primarily produced by intestinal NOX1, was shown to be a key factor in shaping the gut microbial composition. The deficiency of intestinal NOX1 resulted in significant gut microbial alternations in BMAL1-deficient monkeys, further underlining the critical relationship between H₂O₂ and gut microbiota. The work of Dr. Yang and his team significantly advances our knowledge of the relationships between circadian rhythms, the gut microbiome, and host health. The study’s comprehensive approach, combining genomics, metagenomics, and metabolomics, provides a valuable framework for future investigations into the circadian control of host-microbiome interactions.