Homeostasis in Intestinal Epithelium Is Orchestrated by the Circadian Clock and Microbiota Cues Transduced by TLRs

Abstract

Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. Interactions between bacterial products (MAMPs) and Toll-like receptors (TLRs) are known to be mandatory for IEC homeostasis, but how TLRs may time homeostatic functions with circadian changes is unknown. Our functional and molecular dissections of the IEC circadian clock demonstrate that its integrity is required for microbiota-IEC dialog. In IEC, the antiphasic expression of the RORα activator and RevErbα repressor clock output regulators generates a circadian rhythmic TLR expression that converts the temporally arrhythmic microbiota signaling into circadian rhythmic JNK and IKKβ activities, which prevents RevErbα activation by PPARα that would disrupt the circadian clock. Moreover, through activation of AP1 and NF-κB, these activities, together with RORα and RevErbα, enable timing homeostatic functions of numerous genes with IEC circadian events. Interestingly, microbiota signaling deficiencies induce a prediabetic syndrome due to ileal corticosterone overproduction consequent to clock disruption.

Similarities and differences in the transcriptional control of expression of the mouse TSLP gene in skin epidermis and intestinal epithelium

“…Taken together with other recent reports (11,17,20,30), our present study provides an overall topological and functional map of the TSLP gene cis-acting regulatory elements, which are targeted by numerous signaling pathways to fine-tune the spatiotemporal regulation of TSLP expression, which is differentially exerted in two important epithelial tissues throughout life. ChIP, Nuclear Run-On, and 3C Assays.…”

“…4B). Note that, in IEC, where VD3 is synthesized (30), the DR3d DBS are constitutively functional (Fig. S1E).…”

“…Interestingly, we have shown that in IEC, the microbiota-elicited Toll-like receptor signaling is the major determinant of both the NF-κB and AP-1 activity, and also that a reduction of this signaling leads to a decrease in TSLP expression in IEC (30). Additionally, microbiota-derived signaling is known to regulate RA synthesis in the intestine (32), and we have recently found that a reduction in the microbiota signaling also reduces the expression of 25-(OH)D3 1-α-hydrodxylase (Cyp27B1, the rate-limiting enzyme in VD3 synthesis pathway) in IEC, thereby decreasing TSLP expression [by "inactivating" the DR3d DBS (30)]. Altogether, it appears that microbe-derived signaling in the "gut" is the major determinant of TSLP expression.…”

Microbiology: Create a global microbiome effort

“…Yet in the past two to three years, biologists have discovered that daily cycles in the motility of the gut -the production of digestive enzymes, gene expression in gut cells and so on -rely on the activities of gut microbiota. Compounds produced by microbes either cause changes in the gut directly or pass into the host's bloodstream and influence the central nervous system, possibly through neural, hormonal and immune pathways 5 .…”

The chemistry of negotiation: Rhythmic, glycan-driven acidification in a symbiotic conversation

“…Second, the nutritional and environmental changes that mark the developmental trajectory of an organism from its juvenile to adult form are accompanied by distinct shifts in both the composition and functions of the maturing host's microbiota (10,11). Finally, circadian rhythms coordinate much of the communication between a host and its microbiota, leading to the maintenance of physiological homeostasis (12)(13)(14). Taken together, these themes indicate that the terms of a protracted symbiotic negotiation are subject to a dynamic equilibrium that encompasses nutritional, immune, developmental, and circadian inputs.…”