Hallmarks of gut microbial rhythms
Gut microbial oscillations have been identified in a wide range of species, including humans 34, meerkats 26, mice 13, cows 29,33, fish 31, and chickens 30,32 - even host-associated microbiota of zooplankton undergo diurnal cycles 53. The proportion of gut members that show oscillating behaviour varies between studies and species, with the proportion of common taxa being identified as oscillators ranging between ~35% (humans) and ~80% (meerkats) 12,26,34,54. In industrialized human societies, population-wide gut microbial oscillations identified from cross-sectional studies appear to be weak 34, and explain only a modest amount of variation in gut microbiota composition. In other species, diurnal rhythms of the gut microbiota are strong and dominate over individual identity effects 26,29,32,35, suggesting natural variation in the strength of microbial oscillations across species.
Nevertheless, there are some similarities in diurnal gut microbial dynamics across the mammalian species studied thus far. In laboratory mice, the absolute abundance of bacteria inhabiting the mucosal epithelial layer peaks in the middle of the active phase 11,13,40, with a 10-fold increase in bacterial numbers compared to the rest phase 11. This pattern is supported by increased number of bacteria in the gut more generally during the active phase 40. Similar findings were indicated for wild meerkats 26, with bacterial load increasing after dawn, although dynamics in the rest phase were not measured. In humans, the number of bacterial species in faecal samples peaks at midday, potentially indicating a similar pattern 34. Importantly, dissections of the mouse intestine show that faecal microbial rhythms reflect real changes to the composition of the intestinal microbiota 10,13, and are not simply a product of shedding patterns. Collectively, these findings suggest that at least some aspects of diurnal dynamics of gut microbes may be partly conserved across mammal species.
Members of Clostridiales undergo some of the strongest and most consistent oscillations in mammals 7,11,35,39,40 and this may also be true for birds 30,32. There is also growing evidence from mice that different types of gut microbes peak at different times of the day. Some bacteria, termed here mucosal commensals, colonise the mucosal gut lining, whilst others, termed here luminal bacteria, are mostly found in the gut lumen. Mucosal commensals are hypothesized to have co-evolved with the host and form a protective layer against other bacteria between the gut epithelium and the gut lumen. In mice, some mucosal commensals such as segmented filamentous bacteria (SFBs; order Clostridiales) peak at the start of the active phase and then commence to decline over the feeding period 11,13. In contrast, many luminal bacteria have low abundances at the start of the active period yet increase after feeding 11,13, presumably due to food availability driving population increases. However, the identification of oscillating taxa is biased by the fact that most studies apply relative rather than absolute abundances 40, which can generate misleading results, and by the difficulty of distinguishing between mucosal and luminal bacteria from metagenomic data. ­­­­
Molecular mechanisms underpinning circadian host-gut microbe interactions
How and why do gut microbiota oscillations mediate host immunity and metabolism, and what are regulatory mechanisms that entrain cycles? Food intake introduces both nutrients and food-borne pathogens into the gut, therefore the upregulation of both metabolism and components of innate immunity during feeding is crucial for gut function and pathogen defence during this period of acute pathogen exposure 46. Whilst this field of research is in its infancy, several recent experimental studies on murine models outline some of the mechanisms underpinning circadian host-gut microbe interactions. These mechanisms generally involve cyclical interactions between food intake, components of the immune system including antimicrobial peptides (AMPs) and the antibody secretory Immunoglobulin A (SIgA), and certain mucosal commensals (Fig. 2).