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The synchronized clocks of the host and microbiota

Circadian rhythms are ubiquitous, being found at the molecular, physiological and behavioural level, and are a fundamental feature of most living organisms. They increase energy efficiency by temporally separating incompatible metabolic processes, such as anabolism and catabolism. The study by Segers et al demonstrates that circadian rhythms are not limited to the host and that the gut microbiota mimics the host circadian rhythms reinforcing the efficiency of physiological systems, such as colonic motility. Circadian (Circa: approximately; dian day) rhythms are oscillations, with a periodicity of about 24 hours, that finely tune the function of almost all organ systems, including the gastrointestinal tract. The circadian clock in mammals consists of the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and the peripheral clocks located throughout the body. In very basic terms, rhythmicity at the level of the SCN has two roles: (a) integrating input from the retina via the optic nerve, and (b) communicating with peripheral clocks via endocrine and nerve signals. As a consequence of the direct input from the retina, the light‐dark cycle is a powerful driver (zeitgeber) of circadian rhythms. In most organisms, the working molecular mechanism for the circadian clock consists of an interlocked transcription‐translation feedback loop (TTFL). In mammals, the positive component of the TTFL consists of the transcriptional activators brain and muscle ARNT‐like protein 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK). After heterodimerization, the heterodimer initiates transcription by binding to specific elements, an E‐box motif, in the promoters of target genes, including Period (Per) and Cryptochrome (Cry) genes. As the protein levels of PER and CRY rise, they also form heterodimers which deactivate the CLOCK: BMAL1 dimer in the nucleus, thus inhibiting their own transcription. Finally, degradation of PER and CRY is required to initiate the new cycle. There are additional layers to the TTFL and the control of circadian rhythmicity with many reviews covering the subject; however, loss of either CLOCK or BMAL1 eliminates functionality of the TTFL with subsequent loss of circadian rhythms in physiology and behaviour. Peripheral clocks display circadian rhythmicity that is under the control of the SCN. However, they also respond to zeitgebers other than light such as food intake, temperature and activity. The gastrointestinal tract contains a powerful circadian clock which can be uncoupled from the master clock in the SCN by altering the nutrient composition or timing of food intake. The gastrointestinal tract plays an essential role in the supply of nutrients and energy and desynchronization of gastrointestinal clocks favours the development of metabolic disease and other gastrointestinal disorders. For example, the liver clock can be influenced by food/nutrient intake. Synchrony of circadian clocks to daily fluctuations in food intake is important to optimize energy efficiency. They achieve this by regulating metabolic processes that have opposing effects such as hepatic fatty acid synthesis and degradation. Disruption of circadian rhythmicity can have significant health implications and it has been shown that modelled shift work in mice results in hepatic lipid accumulation. Short chain fatty acids (SCFAs) derived from the microbiota, by the fermentation of fibre, can be a communication mechanism between the microbiota and the host. There are a number of recent publications indicating that the gut microbiota also exhibits diurnal rhythms with food intake as a strong zeitgeber. This influence of food intake may reflect nutrient availability for the bacteria. In addition, it is possible that these diurnal rhythms in the gut microbiota can be synchronized by the host circadian rhythms and it has been demonstrated that diurnal patterns in the level of faecal SCFAs are abolished by disruption of the host circadian clock. However, disruption of the host circadian clock is usually accompanied by changes in food intake. For example, knockout of clock genes, such as BMAL1, disrupts host circadian rhythms and diurnal patterns in food intake. Further, high‐fat diets weaken circadian physiology and behaviour and in high‐fat diet fed mice diurnal food intake patterns are dampened. Diurnal patterns in faecal SCFA levels can also be manipulated by diet. Therefore, it is extremely difficult to establish whether the host circadian clock is driving circadian rhythmicity in the gut microbiota or it is driven by food intake patterns. The study by Segers et al aimed to investigate whether the diurnal rhythm in SCFA production was in line with host colonic SCFA receptor expression and SCFA‐induced changes in mouse colonic smooth muscle contractility. They observed that the inhibitory effect of SCFAs on neural contractions in colonic muscle strips demonstrated a diurnal rhythm that oscillated in phase with faecal SCFA Received: 14 December 2018 | Revised: 15 December 2018 | Accepted: 18 December 2018 DOI: 10.1111/apha.13243