Figure 1) Summary of the circadian crosstalk between gut microbes, components of the host innate immune system, and pathogen susceptibility, based on findings from laboratory mice. GM = Gut microbiota.
During the active phase, when animals are awake and feeding, high densities of diverse gut microbes are tolerated because they generate crucial metabolites, which are absorbed into the bloodstream via a porous gut lining (Fig. 2a). Because metabolites are crossing the gut-blood barrier during feeding, the permeable gut lining is vulnerable to opportunistic bacterial attack. To lower infection risk, most non-commensal bacteria are kept away from the mucosal layer by allowing only specific mucosal commensals to adhere to the gut lining10,13. In mice, this function appears to be largely performed by commensal SFBs. SFBs, as well as mucosal commensalsBacteroidetes fragilis and Akkermansia muciniphila, are suggested to perform this role in humans 42.The physical interaction between mucosal commensals and host epithelial cells, in particular at the start of the active phase11,13, triggers the mass release of components of innate immunity, including AMPs 13, that protect the host against a broad range of pathogens during feeding13, and feed back to control gut microbial rhythms11. Mucosal commensals also trigger the release of major histocompatibility complex (class II)-mediated cytokines10, which, whilst part of the adaptive arm of the vertebrate immune system, act to modulate the innate immune response51. Innate immune protection does not last the entire active phase, but rather begins to drop in the second half of the active phase 10,13. The reason for this is unclear, although it may be due to the feeding bouts that typically occur at the start of the active phase in mice 52.
Maintaining a high level of immune control across a 24-hour period is energetically expensive, and inflammation caused by pro-inflammatory cytokines also damages tissue 53. Many aspects of innate immunity are therefore downregulated during the rest phase when the gut lining becomes less permeable, and the host is less likely to encounter pathogens (Fig. 2b). This downregulation is preceded by mucosal commensals such as SFB detaching from the mucosal layer, the mechanisms of which remain unclear, thereby reducing the number of cytokines and AMPs secreted into the gut. In the absence of nutrients from food, the gut bacterial population declines, and remaining bacteria migrate to the gut epithelium to feed on the mucosal layer, replacing the protective layer of commensals 11,13. Perhaps to protect the integrity of the epithelial layer from feeding bacteria, the intestinal mucosal layer thickens during the rest phase11.
The downregulation of pro-inflammatory components of innate immunity during the rest phase is likely responsible for the well-studied phenomenon whereby animals are more susceptible to infection and mortality when challenged at the end of the rest phase compared with the middle of the active phase 54. Nevertheless, animals are not altogether undefended during the rest phase. A key gut antibody, sIgA, is upregulated during sleep 55. Secretory IgA is the most abundant antibody produced by mammals and is present across all mammals and bird species 56,57. It acts as bridge between innate and adaptive immunity, being able to distinguish between gut commensals and non-commensals58. During the rest phase, upregulated sIgA neutralises non-commensals and their toxins that are otherwise tolerated during the active phase, thereby ensuring that any potential pathogens that were introduced and proliferated during the active phase are killed. Another function of sIgA is to bind to beneficial mucosal commensals and control their adhesion to the mucosal layer 58,59, and it is therefore a key agent in triggering the circadian cycles of the gut microbiota at the start to the active phase 55. A peak in sIgA just prior to the start of the active phase is likely involved in bringing mucosal commensals back to the epithelial layer to begin the circadian cycle anew, although the exact mechanisms are still unknown. Interestingly, sIgA secretion is controlled by food intake rather than the master clock, with food intake repressing sIgA levels 55 in order to increase tolerance to gut bacteria during the active phase.