“Losing Track of Time” — How Gut Bacteria’s Daily Routine Impacts Our Health

Mario Corrado, Hons. BSc Microbiology and Immunology
Contributor

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Image courtesy of: https://www.helpscout.net/blog/sleep-habits/

        
​          I’m at the kitchen table. There’s a clock on the wall directly behind me. I’m not looking at it, but I can hear the incessant ticking — tick, tock, tick, tock. It’s nighttime, and I’m beginning to feel the gentle touch of sleep come over me: heavy eyelids, slow breathing, lack of focus… It’s odd really, that despite never turning around to look at the clock on my kitchen wall, my body acts as if it has been keeping track of time all along. 

            Because it has.

The Circadian Rhythm
          During my last year of undergraduate studies at McGill University, I was asked to give a short presentation on a cool topic in science to my fellow Honours Microbiology class. The assignment’s only guideline was to select a topic unrelated to our field of study. Driven by an uncanny fascination with the many mysteries surrounding the human brain, my presentation focused on the circadian rhythm, a built-in 24-hour cycle that instructs our body on when to sleep, rise and eat — among an endless list of other critical physiological processes that coalesce to ensure optimal body function. The devastating effects of disrupting our circadian rhythm have been well documented in the literature and range from lung pathologies (1), mood dysregulation (reviewed in (2)), impaired immune system function (3), liver impairment (4,5), and, strikingly enough, possibly breast cancer (6), Parkinson’s Disease (7) and Alzheimer’s Disease (8).

           I was surprised to learn that although the circadian rhythm plays a big part in dictating our daily routine, it was not actively researched until the late 1950s. Since then, we’ve made great leaps in our understanding of the “Biological Clock”. While there are many environmental cues (called “Zeitgebers”, a German word meaning “time-givers”) that influence the circadian rhythm, the best studied one is light. When light enters your eye, it excites light-sensitive cells named “retinal ganglion cells”. These cells will convert light into electrical signals that are delivered to a highly specialized region of the brain known as the “suprachiasmatic nucleus” (or SCN for short). 

           Think of the SCN as the “Master Clock”; once stimulated, it sends signals throughout the body to regulate a plethora of biological processes including sleep and feeding patterns, alertness, core body temperature, brain wave activity, hormone production, regulation of glucose and insulin levels, urine production and cell regeneration. For example, in the absence of light (9), the SCN will stimulate the pineal gland to produce melatonin (10), a hormone that causes drowsiness and lowers body temperature — which is exactly the physiological effect we would want near bedtime, in the absence of light (melatonin is also the chemical found in Nighttime Gravol to make us drowsy). In contrast, during the first hour after waking up, the SCN — now exposed to light — will instead stimulate the adrenal gland to produce cortisol, a notorious stress-related hormone that will increase alertness by increasing blood glucose levels and hence increasing our energy supply (11) (Want to learn more? More thorough and easy-to-read reviews on the circadian rhythm can be found here and here, and a great video can be found here).

The Circadian Rhythm of the Gut Microbiome
      I didn't know it at the time, but my presentation of the circadian rhythm as a topic outside of Microbiology was inadvertently misleading my peers; it ironically turns out that the circadian rhythm is deeply intertwined with our gut bacteria.

          In 2016, Dr. Eran Elinav was intrigued by the previous finding that metabolic chemicals influence the circadian clock (12). Since gut bacteria were already known to produce a large array of chemicals that influence human physiology, Elinav began to investigate the impact of gut bacteria on the circadian clock. Elinav and his research team in Israel ultimately reached three major conclusions, which were published in 2016 (13).

        First, Elinav’s team studied the bacteria that are found closest to the intestinal lining (that is, the bacteria that are actually attached to our intestines), since these are the bacteria that most strongly influence our physiology. They were able to show that these bacteria follow a sort of routine throughout the course of the day that they termed “diurnal oscillations”.  In other words, the bacteria will start their day at one location in the intestine, and, like clockwork, will move gradually during the day before returning to their original location roughly 24 hours later. Why does this matter? First of all, it’s pretty convincing evidence that our gut bacteria abide by their own circadian clock, which is fascinating in its own regard. But more importantly, what this means for us is that during the course of the day, the cells of our intestinal epithelium are exposed to different numbers and different species of bacteria, and are therefore exposed to the different chemicals that the different bacteria will produce. 

          Next, Elinav asked if the circadian patterns of the gut microbiome are influenced by the circadian rhythm of the host. To answer this question, researchers studied specialized mice (called Per1/2-/- mice) that lack a functional circadian clock (The Per1 gene is expressed mainly in the SCN and helps generate the circadian rhythm. Like the batteries of the clock, our circadian clock stops ticking in the absence of Per1, as is the case with the Per1/2-/- mice). Interestingly, they showed that the gut bacteria of Per1/2-/- mice lost their rhythm, which strongly suggests that the bacteria’s circadian rhythm depends on our own. Elinav went further, and showed that just by controlling the feeding times of these mice, he was able to restore some of the “diurnal oscillations”, implying that feeding time is a major contributing factor to maintaining the circadian clock of gut bacteria.

          Elinav then asked the opposite question — he wanted to see what would happen to our circadian rhythm if we disrupted that of the gut bacteria. To this end, antibiotics were used to kill most of the gut bacteria. They found that disrupting the bacterial clock did not alter our circadian clock, which means that while the bacterial clock depends on the host circadian rhythm, the reverse is not true. Instead, they identified compensatory mechanisms that are initiated in mice to counter the loss of gut bacteria.

           Finally, Elinav wanted to see if the circadian clock of the bacteria had any effects on host physiology beyond the gut, and discovered that the liver was heavily influenced by the diurnal oscillations of the gut microbiota. Elinav found that the daily routine of gut bacteria influences how well the liver can function to detoxify drugs. For example, it was found that in a normal mouse (with an intact gut microbiota), the liver’s ability to metabolize the drug APAP (also known as acetaminophen, which is the active ingredient in Tylenol) increases gradually during the course of the day. However, Per1/2-/- mice, mice treated with antibiotics, and “germ-free” mice (mice that are specially handled to be completely free of bacteria) do not benefit from this gradual increase in liver function throughout the day. (these results help to explain the findings in (4) and (5) that correlate an abnormal circadian rhythm with liver pathology). 

          In practical terms, this study teaches us that the circadian rhythm of our gut bacteria influences our liver’s ability to break down drugs, and that disrupting this bacterial clock would hamper our liver’s detoxification ability — and that can be extremely dangerous, say, if you are consuming alcohol (a drug that must be detoxified by the liver) and taking antibiotics or following a poor diet that weakens your gut microbiota.


Further Reading

1.  Sundar, I. K., H. Yao, M. T. Sellix, and I. Rahman. 2015. Circadian molecular clock in lung pathophysiology. Am. J. Physiol. Lung Cell Mol. Physiol. 309: L1056-1075., H. Yao, M. T. Sellix, and I. Rahman. 2015. Circadian molecular clock in lung  pathophysiology. Am. J. Physiol. Lung Cell Mol. Physiol. 309: L1056-1075.
2. Kim, J., S. Jang, H. K. Choe, S. Chung, G. H. Son, and K. Kim. 2017. Implications of Circadian Rhythm in Dopamine and Mood Regulation. Mol. Cells 40: 450-456.
3. Labrecque, N., and N. Cermakian. 2015. Circadian Clocks in the Immune System. J. Biol. Rhythms 30: 277-290.
4.  Udoh, U. S., J. A. Valcin, K. L. Gamble, and S. M. Bailey. 2015. The Molecular Circadian  Clock and Alcohol-Induced Liver Injury. Biomolecules 5: 2504-2537.
5. Reinke, H., and G. Asher. 2016. Circadian Clock Control of Liver Metabolic Functions.         Gastroenterology 150: 574-580.
6. Blakeman, V., J. L. Williams, Q. J. Meng, and C. H. Streuli. 2016. Circadian clocks and         breast cancer. Breast Cancer Res. 18: 89.
7. Wulff, K., S. Gatti, J. G. Wettstein, and R. G. Foster. 2010. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat. Rev. Neurosci. 11:  589-599.
8. Saeed, Y., and S. M. Abbott. 2017. Circadian Disruption Associated with Alzheimer's Disease. Curr. Neurol. Neurosci. Rep. 17: 29.
9. Bellastella, A., A. De Bellis, G. Bellastella, and K. Esposito. 2014. Opposite influence of  light and blindness on pituitary-gonadal function. Front. Endocrinol. (Lausanne)             4: 205.
10. Benarroch, E. E. 2008. Suprachiasmatic nucleus and melatonin: reciprocal interactions and clinical correlations. Neurology 71: 594-598.
11.  Hucklebridge, F. H., A. Clow, T. Abeyguneratne, P. Huezo-Diaz, and P. Evans. 1999.  The awakening cortisol response and blood glucose levels. Life Sci. 64: 931-937.
12.  Nakahata, Y., M. Kaluzova, B. Grimaldi, S. Sahar, J. Hirayama, D. Chen, L. P. Guarente, and P. Sassone-Corsi. 2008. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:         329-340.
13. Thaiss, C. A., M. Levy, T. Korem, L. Dohnalova, H. Shapiro, D. A. Jaitin, E. David, D. R. Winter, M. Gury-BenAri, E. Tatirovsky, T. Tuganbaev, S. Federici, N. Zmora, D. Zeevi, M. Dori-Bachash, M. Pevsner-Fischer, E. Kartvelishvily, A. Brandis, A. Harmelin, O. Shibolet, Z. Halpern, K. Honda, I. Amit, E. Segal, and E. Elinav. 2016. Microbiota Diurnal     Rhythmicity Programs Host Transcriptome Oscillations. Cell 167: 1495-1510.e1412.