The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis

Abstract

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.

Consequences of collagen induced inflammatory arthritis on circadian regulation of the gut microbiome

“…We did not see any significant difference in the diversity of this community, instead genus specific dampening of daily oscillations in abundance. Heddes and colleagues recently revealed a critical role for the IEC clock in driving 24 h rhythms in a significant proportion of the microbiota and its metabolic outputs 22 . Here, the temporal re‐organization of the microbiota occurs in the presence of a robust gut clock, thus we do not see this as a consequence of intestinal clock dampening.…”

“…13,16 We have identified rhythmic secretion of immunoglobulin A (IgA) as an important mechanism driving oscillations in the abundance of a number of commensal bacteria 21 and more recently a critical role for the intestinal epithelial cell (IEC) clock in driving the rhythmic microbiome has been demonstrated. 22 The circadian clock regulates a huge range of physiological processes via temporal control of cellular function. The nature of this regulation is cell, tissue and organ dependent, with 43% of all protein coding genes showing circadian rhythms in transcription somewhere in the body.…”

“…Mechanisms driving daily oscillations in the microbiome are not fully understood, but these rhythms are clearly influenced by dietary composition 14 and host behavioral rhythmicity, including timing of food intake, 13,14 also by the host circadian clock acting through neural and humoral outputs 13,16 . We have identified rhythmic secretion of immunoglobulin A (IgA) as an important mechanism driving oscillations in the abundance of a number of commensal bacteria 21 and more recently a critical role for the intestinal epithelial cell (IEC) clock in driving the rhythmic microbiome has been demonstrated 22 …”

Melatonin–Microbiome Two-Sided Interaction in Dysbiosis-Associated Conditions

“…On the other hand, if the food consumption timing is regulated in CLOCK-mutant mice, the microbial periodicity is restored [ 101 ]. Furthermore, the disruption of the host circadian clock by BMAL1 deletion alters fecal microbial composition [ 99 , 102 , 103 ]. Dysfunctional circadian rhythms can both cause and exacerbate inflammation in IBDs [ 100 ].…”

Time of Sample Collection Critical for Microbiome Replicability

“…One underexplored factor is that the microbiome is dynamic, and exhibits diurnal oscillations [8][9][10] . Disruption of microbiome diurnal dynamics [11][12][13][14][15] are associated with metabolic syndrome spectrum diseases (e.g.…”