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.