Disturbed rhythmicity of intestinal hydrogen peroxide alters gut microbial oscillations in BMAL1-deficient monkeys.

Circadian oscillation of gut microbiota exerts significant influence on host physiology, but the host factors that sustain microbial oscillations are rarely reported. We compared the gut microbiome and metabolome of wild-type and BMAL1-deficient cynomolgus monkeys during a diurnal cycle by performing 16S rRNA sequencing and untargeted fecal metabolomics and uncovered the influence of intestinal H2O2 on microbial compositions. Ablation of BMAL1 induced expansion of Bacteroidota at midnight and altered microbial oscillations. Some important fecal metabolites changed significantly, and we investigated their correlations with microbes. Further analyses revealed that disturbed rhythmicity of NOX1-derived intestinal H2O2 was responsible for the altered microbial oscillations in BMAL1-deficient monkeys. Mechanistic studies showed that BMAL1 transactivated NOX1 via binding to the E1-E2 site in its promoter. Notably, BMAL1-dependent activation of NOX1 was conserved in cynomolgus monkeys and humans. Our study demonstrates the importance of intestine clock-controlled H2O2 rhythmicity on the rhythmic oscillation of gut microbiota.

Yang Y ，Yu P ，Lu Y ，Gao C ，Sun Q ... -  《Cell Reports》

Characterizing the rhythmic oscillations of gut bacterial and fungal communities and their rhythmic interactions in male cynomolgus monkeys.

Yang Y ，Yu M ，Lu Y ，Gao C ，Sun R ，Zhang W ，Nie Y ，Bian X ，Liu Z ，Sun Q ... -  《Microbiology Spectrum》

Clock-Bmal1 mediates MMP9 induction in acrolein-promoted atherosclerosis associated with gut microbiota regulation.

Circadian rhythm is believed to play important roles in atherosclerosis. The gut microbiota is found to be closely related to atherogenesis, and shows compositional and functional circadian oscillation. However, it's still unclarified whether circadian clock and intestinal microbiota are involved in the progression of atherosclerosis induced by environmental pollutant acrolein. Herein, patients with atherosclerosis showed higher MMP9, a promising biomarker for atherosclerosis, and lower Bmal1 and Clock expression in the plasma. Interestingly, acrolein exposure contributed to the increased MMP9, decreased Clock and Bmal1, and activated MAPK pathways in human umbilical vein endothelial cells (HUVECs). We found that knockdown of Clock or Bmal1 lead to upregulation of MMP9 in HUVECs, and that Clock and Bmal1 expression was elevated while MAPK pathways were blocked. Atherosclerotic apolipoproteinE-deficient mice consumed a high-fat diet were used and treated with acrolein (3 mg/kg/day) in the drinking water for 12 weeks. Upregulation of MMP9, and downregulation of Clock and Bmal1 were also observed in plasma of the mice. Besides, acrolein feeding altered gut microbiota composition at a phylum level especially for an increased Firmicutes and a decreased Bacteroidetes. Additionally, gut microbiota showed correlation with atherosclerotic plaque, MMP9 and Bmal1 levels. Therefore, our findings indicated that acrolein increased the expression of MMP9 through MAPK regulating circadian clock, which was associated with gut microbiota regulation in atherosclerosis. Circadian rhythms and gut microbiota might be promising targets in the prevention of cardiovascular disease caused by environmental pollutants.

Wu X ，Chen L ，Zeb F ，Li C ，Jiang P ，Chen A ，Xu C ，Haq IU ，Feng Q ... -  《-》

The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis.

Diurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the host's circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for microbiota composition and function, which is required to balance the host's gastrointestinal homeostasis.

Heddes M ，Altaha B ，Niu Y ，Reitmeier S ，Kleigrewe K ，Haller D ，Kiessling S ... -  《Nature Communications》

Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock.

Liang X ，Bushman FD ，FitzGerald GA 《-》