Within the human body a considerable community of microorganisms, known as the human microbiota, exists in a mutualistic relationship with their host [1]. The largest concentration of these microbiota inhabits the human gastrointestinal tract (‘gut microbiota’), responsible for dietary and xenobiotic compound metabolism [2]. A microbiota-gut-brain axis has been proposed as a means of bidirectional communication between the brain and the gut microbiota, with implications for many psychiatric and neurological disorders [3]. One of the fields that have recently attracted more attention is that of circadian physiology due to its  strong overlap with diseases related to the gut microbiome [4]. Although the exact pathways by which the gut microbiota and the biological master clock might communicate remain currently largely unknown, this interaction might have great potential for treatment in neurological conditions.

The circadian system

The biological master clock is located in the hypothalamic suprachiasmatic nuclei (SCN) and regulates many of the 24h patterns occurring in the human body and many of its physiological processes [5]. The clock follows an approximately 24 h feedback loop of transcription and translation, relying on exogenous indicators of time, called zeitgebers, mainly consisting of (day)light (the primary zeitgeber), but also on food intake, temperature, and infective parameters to keep the circadian clock synchronised with its exogenous environment [6]. The output of the clock is largely mediated through melatonin, which’ production is regulated through the SCN’s main projection onto the pineal gland [6].

The gut microbiome and the master clock

The close interaction between the master clock and gut microbiota has been known for over 30 years and many gut microbiota show oscillatory or diurnal behaviour, recently reviewed by Teichman et al. [7]. Also in other rodent studies, dysregulation of the host circadian rhythm seemed to significantly affect microbial oscillations, including studies in clock gene knockout models, studies looking at timing or restriction of food availability, and altered entrainment of the light-dark phase [7]. Further evidence comes from rodents treated with antibiotics, where antibiotic-treated mice exhibited an alteration of peripheral and gut clocks, and microbiome-free mice have significantly different mRNA expression of liver circadian clock genes [7, 8]. Moreover, mice treated with antibiotics ablating their gut microbiota had significantly altered gut and peripheral circadian rhythmicity [7, 9].

Although the probably bidirectional pathway between the masterclock and the gut (Figure 1) has not been extensively explored, several important clues indicate its existence. For example, gut microbiota seem to be increasingly recognised as not only under the control of the SCN, but perhaps even acting as a zeitgeber. An interesting study in this respect was recently conducted by Brooks et al. [10]. The authors showed that, in rodents, environmental light cycles entrain circadian feeding behaviours in animals and that intestinal microbiota generated diurnal rhythms in innate immunity synchronised with feeding rhythms to anticipate exogenous microbial exposure [10]. Moreover, it has been shown that disruption of normal circadian timing and feeding rhythms can lead to increased intestinal permeability and thereby altering gut microbiota composition [11, 12].

Figure 1. The bidirectional interaction between the biological masterclock, located within the suprachiasmatic nuclei, and the gut microbiome.

Implications of the masterclock-gut bidirectional pathway and neurological disease: the example of Parkinson’s disease

In healthy subjects, but also in patients with Parkinson’s disease (PD), several smaller-scale studies have shown that motor performance fluctuates throughout the day, with a rise in activity after awakening, stable patterns during the morning and early afternoon, and worsening later during the day [13-18]. An example in PD is the study by van Hilten and colleagues who observed that in mildly to moderately affected patients diurnal patterns of motor activity were present, with greatest motor activity in the morning [16]. Also, other PD features appear to fluctuate according to time of the day, including gait patterns [17] and some non-motor symptoms [19, 20].

Not only motor symptoms appear to have a diurnal patterns, but several studies have also reported that other symptoms, including non-motor symptoms, such as autonomic function [21-23] and sleep–wake cycles [24], show diurnal fluctuation in people with PD [19, 20], suggesting a circadian influence on the expression of non-motor features of PD. Interestingly, acute psychological distress (anxiety) [25], excessive daytime sleepiness [26] and visual performance [27] have been shown to worsen as the day progresses in people with PD, consistent with motor pattern diurnal fluctuations [28]. This suggest that the intrinsic 24h master clock orchestrates both motor and non-motor fluctuations throughout the day. The recognition of physiological diurnal patterns holds importance for the use of dopaminergic medication in PD, as dopaminergic neurotransmission directly influences the biological master clock. In rodent studies it has been shown that the administration of Haloperidol, a dopamine receptor antagonist, increases the expression of mPer1, one the crucial clock genes in the SCN [29]. This effect might account for some of the observations that have been made in people with PD with regards to the disappearance of a diurnal pattern in activity counts in the advanced stage of the disease, whereas people with PD in Hoehn and Yahr stages 1 and 2 display a diurnal activity pattern similar to healthy controls [16]. Similar daytime patterns in tapping speed were also observed by Bonuccelli and colleagues, although this pattern was only present in patients with stable and advanced disease stages, but not in de novo patients [30]. In the latter study, the authors showed that the diurnal pattern might be explained by changes in levodopa pharmacodynamics despite stable repeated medication administration [30]. This is also supported by findings in advanced PD patients, where the clinical effects of intrajejunal levodopa infusion diminish in the afternoon despite stable continuous infusion rates of Levodopa [31].

Improving circadian rhythmicity through the gut microbiome

Improving disruptive circadian patterns has already been shown to improve a variety  of symptoms in neurodegenerative conditions. Examples are bright light therapy and melatonin administration, which both function as a zeitgeber for the masterclock, the latter due to autofeedback. The evidence so far shows that such circadian interventions can e.g. improve sleep and mood in people with PD, as well as cognitive function in people with Alzheimer’s disease [32-39]. In addition to these approaches using more classical zeitgebers, also chrononutrition, utilising dietary components or adjustments of meal timing, has been proposed as a treatment for circadian misalignment [40], with a range of substances, such as caffeine, harmine, tea phenols, and proanthocyanids being able to induce phase shifts in the hypothalamus [41-44]. Whether or not probiotics, which have recently gained more prominence in the treatment of neurodegenerative conditions, would be able to improve circadian rhythmicity and its associated problems, remains unknown but given the effect of the microbiota on the masterclock such an approach might prove feasible in the future.

Take home messages

  • 1. Increasing evidence is showing the link between the gut and the circadian masterclock.
  • 2. Dysregulation of circadian timing is linked to many symptoms, including worsening of motor symptoms and sleep in people with neurodegenerative conditions.
  • 3. Timing and contents of food intake may influence the circadian masterclock.
  • 4. In the future, the gut and its microbiome might prove to be a new therapeutic target for circadian dysfunction.

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