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The gut bacteria keep the intestinal molecular clock ticking

The gut homeostasis is orchestrated by the circadian clock of intestinal cells sent by the microbiota.

May 9, 2013


Since its inception, life on earth is orchestrated by the circadian cycle which corresponds to the alternation of day and night. In mammals, each cell has a molecular circadian clock that provides regular periods of 12 hours of activity and 12 hours of rest. In an article published in a recent issue of Cell (May 9th 2013), Pierre Chambon’s  team at the IGBMC demonstrates that in intestinal epithelium cells, the circadian clock mechanism requires the presence of non-pathogenic microorganisms (the microbiota, consisting mainly of bacteria) that live in a close symbiosis with their host.


A single layer of Intestinal Epithelial Cells (IEC) forms the physical barrier that separates the rest of the body from 100,000 billion of microorganisms. The intestinal microbiota is normally constituted mainly of non-pathogenic bacteria, known as commensals, living in harmony with their host. Numerous studies on germ-free mice have revealed that intestine colonization by bacteria is beneficial to the physiological balance (homeostasis) of the host. Indeed, bacteria control many processes of the intestinal epithelium (intestinal absorption, innate immunity, cell proliferation, metabolic activity, etc ...).

 

Over the past decade, studies have revealed the nature of the molecular dialogue underlying host-microbiota symbiosis, demonstrating that it requires the interaction of compounds from the microbiota and the "Toll -like receptors "(TLRs) located on the surface of IEC. How could then these interactions between TLRs and compounds derived from commensal bacteria can control numerous physiological functions at a molecular level? Many of these functions are orchestrated by the circadian clock and characterized by the alternation of two 12 hours phases, corresponding to the activity and rest periods. During each phase a set of genes responding to the specific needs of that phase is expressed. Taken altogether these observations led the IGBMC researchers to demonstrate that the expression of TLR genes is selectively triggered by an element of the circadian clock, the RORα gene, which is expressed early during the phase of activity.

 

Thus, through the rhythmic activation of RORα, the non-rythmic signals emitted by the microbiota are "converted" into rhythmic signals by TLRs, which selectively stimulate the expression of genes characteristic of the active phase. This is going on until the hand of the circadian clock has reached the resting phase. Then, another element of the clock, RervErbα, represses the synthesis of TLRs and allows the selective expression of genes which control homeostasis during the resting phase, as well as glucocorticoid synthesis by cells of the terminal portion of the small intestine, the ileum. (see Figure 1)

 

When microbiota is lacking, the microbiota-TLR-circadian clock "axis" is disrupted in the IEC. As a consequence, the expression of genes encoding proteins that constitute the machinery of the circadian clock and the expression of genes that normally exhibit a circadian expression profile is impaired. There is an increased expression of genes that are expressed during the resting phase at the cost of those expressed during the active phase. In addition, the overproduction of glucocorticoids by the ileum causes a pre-diabetic syndrome.

In conclusion, this study reveals as yet unknown molecular mechanisms underlying the extraordinary symbiosis between the microbiota and the intestinal epithelium. It demonstrates how signals from the microbiota bind to TLRs in order to control the circadian clock activity, which itself plays a crucial role in  intestinal physiology. Moreover, the work of  Pierre Chambon’s team illustrates strickingly how cell membrane receptors (here TLRs) may, in conjunction with the circadian clock, convert non-rhythmic signals into rhythmic  genes expression profiles. Finally, the discovery of a direct link between the intestinal microbiota, the circadian cycle and the physiological balance (homeostasis) of the intestinal epithelium opens new perspectives on the origin and pathogenesis of intestinal  and (or) systemic diseases which are linked to alterations of the microbiota and (or) the circadian cycle, especially among people working on night-shift.

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