• Gut clock
• Microbe-host interaction
• Metabolic effects
• Microbes, circadian clock, and the brain

What is already known on this topic
The circadian rhythm is the body’s internal clock, which regulates an individual’s energy expenditure, appetite, and sleep. The gut microbiota composition is influenced by host circadian rhythms, and in turn, gut microbes are essential for the regulation of host circadian pathways. Changes in this microbe-host interaction affect disease risk and severity.

What this research adds
Researchers summarized current knowledge on the microbiota-gut-brain relationship, and how gut bacteria and circadian rhythms act together to influence health and disease.

Conclusion
More work is needed to investigate how gut bacteria and circadian rhythms modulate the risk and severity of certain diseases. What’s more, the molecular mechanisms underlying the relationship between circadian rhythms, the microbiota, and the brain remain unclear.

The circadian rhythm is the body’s internal clock, which regulates an individual’s energy expenditure, appetite, and sleep. The gut microbiota composition is influenced by host circadian rhythms, and in turn, gut microbes are essential for the regulation of host circadian pathways. Several studies have examined how changes in relationship between circadian rhythms, the microbiota, and the brain affect disease risk and severity, but the molecular mechanisms underlying this interaction remain unclear.

John Cryan at the University College Cork in Ireland and his colleagues reviewed current knowledge on the microbiota-gut-brain relationship, and how gut bacteria and circadian rhythms act together to influence health and disease. Their work is published in Cell Metabolism.

Gut clock

Many gut bacteria exhibit oscillatory behavior in response to the time of day and time of eating. For example, the bacterial load in mice peaks at 11 p.m. and reaches a trough at 7 a.m.; the peak is associated with a maximum in the Bacteriodetes population, whereas the trough corresponds with a maximum in the Firmicutes population. Bacteroidetes and Firmicutes represent more than 99% of the known gut microbiota.

Several studies have shown that germ-free and antibiotic-treated mice experience an alteration of their circadian clocks, and changes in the host’s circadian rhythm, including jet lag and shift work, can significantly affect microbial oscillations.

Both jet lag and shift work have been associated with an altered microbiota composition as well as with several metabolic, inflammatory, and stress-related diseases in people. Animals housed for 24 hours in either dark or light conditions lost all gut microbial diurnal rhythmicity when compared to mice housed under normal conditions, and they exhibited increased weight gain and glucose intolerance when fed a high-fat diet.

Microbiota-derived metabolites such as short-chain fatty acids (SCFAs) and bile acids can also alter circadian rhythms. Oral administration of SCFAs to antibiotic-treated mice changed the rhythms of two genes that play major role in the circadian clock. Microbiota-related bile acids can upregulate circadian rhythm genes in cells grown in a lab dish, and alter circadian clock gene expression in the mouse gut and liver.

Microbe-host interaction

The interplay between the host circadian clock and microbiota oscillations influences many physiological processes, including host metabolism, the regulation of the endocrine system, and immune system function.

The gut microbiota has been shown to regulate the expression of proteins that are linked to lipid absorption and obesity. And mice lacking a gene involved in the circadian clock had increased fat accumulation, increased glucose production, and increased blood levels of leptin—a hormone that helps to regulate energy balance by inhibiting hunger.

Hormones, which are secreted by the endocrine system, play a key role in circadian rhythmicity and influence the gut microbiota, which in turn affects the secretion of such hormones. Melatonin, for instance, is important for diurnal rhythms and can determine the circadian rhythms of some gut microbes. Hormones such as growth hormone, testosterone, and estradiol secretion are all altered in germ-free mice, and the levels of ghrelin, which controls appetite and thus the timing of food, are reduced in the presence of microbes such as Bifidobacterium and Lactobacillus, and increased in the presence of Bacteroides and Prevotella in rodents.

But the influence of the microbiota and circadian rhythms goes beyond the endocrine system. Gut microbes are involved in the development of several types of immune cells, and many immune molecules shown diurnal rhythmicity. Germ-free mice’s T cells, B cells, and neutrophils are less efficient than those of mice raised in normal conditions. What’s more, the immune system is less effective in response to infection in mice that lack microbes altogether.

Metabolic effects

Several studies suggest that metabolic disorders can arise from the interaction between diet and other environmental factors, including circadian rhythm disruption and changes in the composition of the gut microbiota. For example, gut microbes of people with cardiovascular disease, diabetes, and obesity are more likely to cause inflammation than the bacteria present in the microbiota of healthy individuals.

The lack of gut bacteria protects mice from the negative effects of a high-fat diet, and disrupting the circadian clock of rodents leads to metabolic conditions such as obesity and diabetes. Similarly, rodents that lack key circadian genes have decreased glucose tolerance and insulin secretion. People with diabetes also show differences in gut microbiota composition and altered oscillations of circadian clock genes compared to healthy individuals.

Finally, individuals with atherosclerosis show increased inflammation and higher levels of Enterobacteriaceae and Streptococcus bacteria than healthy people. And mouse models of cardiovascular disease recovered faster when raised on a regular 24-hour light-dark cycle compared to those on a disrupted circadian rhythm.

Microbes, circadian clock, and the brain

Alterations of circadian rhythms due to shift work or jet lag have all been associated with an increased prevalence or severity of depression, and individuals with depression or bipolar disorder exhibit significant differences in their microbiota compared to healthy people. Mouse models of schizophrenia show an altered circadian cycle in which melatonin is released earlier than normal.

However, little is known about how the interplay between the microbiota-gut-brain axis and circadian rhythms influences brain disorders. “More preclinical and clinical work needs to be done to examine how both systems may engage with one another to modulate psychiatric disorders, positively and negatively,” the researchers conclude.

Elderly people with dementia or Alzheimer’s disease (AD) exhibit increased confusion and agitation as the sun sets, and they have lower melatonin levels than healthy individuals. Also, AD patients have increased levels of pro-inflammatory Escherichia/Shigella bacteria and reduced levels of anti-inflammatory E. rectale compared to healthy people of the same age. Finally, the gut microbiota of people with Parkinson’s disease and those with sleep behavior disorder are very similar.

The connection between AD, circadian rhythms, and the microbiota-gut-brain axis calls for more research in this area, the researchers say. The team also cautions that so far, studies have mostly examined the effect of either circadian rhythms or gut microbes independently, but not together.

“More work needs to be done to examine not only how both the microbiota-gut-brain axis and circadian rhythms influence disease, but also how they interplay with one another in the context of disease,” the researchers say.