2) Gut microbial rhythms and pathogen defence
In mice, gut microbial oscillations increase host resistance to gut pathogens such as Salmonella during the active phase by triggering the release of AMPs into the gut 13. Reducing the abundance of mucosal commensal SFB increases host susceptibility to Salmonella infection and also removes circadian rhythms in susceptibility 13, demonstrating that the rhythmic activity of gut mucosal commensals is a key mechanism governing microbiome-mediated pathogen defence. Testing for associations between the abundance and rhythmicity in mucosal commensals and infection status may therefore be a more effective method of uncovering the link between the gut microbiota and pathogen susceptibility than focusing on overall gut microbial diversity. Arhythmic gut microbial communities have been linked to disease in humans 34, and therefore it might be expected that individuals with disrupted or dampened gut microbiota rhythms are more susceptible to infection (Fig. 3).
Circadian rhythms in animal susceptibility and pathogen reproduction and transmission are well documented 18,72, with hosts and parasites having coevolved defensive and offensive rhythms, respectively. Yet the role of the gut microbiota in mediating infection outcomes is unclear and many questions remain. Do gut microbial rhythms protect the host against a broad range of pathogens, or are they only effective for specific gut pathogens? Microbial rhythms control the release of AMPs, which are effective against a wide range of pathogens including bacteria, fungi and viruses 73. Thus, it is likely that microbial rhythms protect the host against a broad range of pathogenic agents entering the gut. However, the gut is not the only entry point of pathogens and it remains unknown whether microbial rhythms also play a role in pathogen defence more generally.
Even less explored is the connection between gut microbial oscillations and adaptive immunity, which is an essential pillar of resistance again recurring parasitic challenges in jawed vertebrates74. Gut microbiome disruption impairs antibody responses in mice 75, and gut microbial metabolites influence the expression of the mammalian circadian clock genePer2 7,76, which is responsible for mounting both innate and adaptive responses to infection 77. Investigating which components of the gut microbiota affect the expression of clock genes and in which ecological contexts may identify the mechanisms by which the microbiota shape pathogen defence.