Sleep is defined as a reversible behavioral state associated with unresponsiveness to the external environment and involves a complex orchestration of physiological processes for its initiation and maintenance [1]. The importance of sleep is elucidated through evidence supporting its active role in several different physiological functions necessary for survival, namely immune health [2], physical growth [3], metabolism [4], tissue repair [5], and the maintenance of cognitive performance [6,7]. Sleep also contributes to the maintenance of major biological processes; in particular, it can aid in the peripheral and neurologic clearance of metabolic end products, consolidation of long-term memories, learning through long-term potentiation, and restoration of biological systems [8-10].The onset of sleep is partly controlled by circadian factors as well as homeostatic factors (ie, sleep pressure), and the interplay between circadian and sleep pressure is often referred to as the two-process system of sleep regulation [11]. In addition, intrinsic and extrinsic variables influence sleep, including the environment, work schedules, food and drink consumption, and health behaviors.

Reduction in sleep duration or quality (ie, sleep fragmentation) is associated with sleep disorders such as insomnia and obstructive sleep apnea [12,13] and may result from occupational factors that alter sleep patterns or habits [14]. Reduced sleep duration or quality can also be a consequence of other chronic diseases such as congestive heart failure or chronic obstructive pulmonary disease [15,16]. The reduction in substantial sleep duration or sleep quality can further contribute to increased risk of human diseases and disorders, including cardiovascular disease [17], obesity [18], and diabetes [19]. More recently, the role of the glymphatic system in waste byproduct clearance and metabolite distribution within brain tissue has been uncovered [20]. As the glymphatic system is most active during slow wave sleep [8,21], the neurologic clearance of toxins and potentially harmful byproducts is also dependent on healthy sleep patterns [22]. The association of the proper function of the glymphatic system with the prevention of cerebral amyloid angiopathy and Alzheimer disease highlights the importance of the role that adequate sleep also plays in neurologic disease prevention [23]. Molecular clocks have evolved in most living organisms to synchronize vital physiologic activities with the external environment and rotation of the Earth’s axis around the sun. The superchiasmatic nucleus is responsible for the central maintenance of the rhythm of approximately 24-hour cycles (or the circadian rhythm), is located in the hypothalamus [24,25], and responds primarily to light and darkness cues [26]. Conversely, peripheral oscillators located in many organ systems respond to other cues such as food intake, exercise, and temperature [27,28].

In mammals including humans and rodents, the oscillatory central and peripheral rhythms synchronize important functions ranging from intracellular signaling to food metabolism and immune system activity [29]. These carefully orchestrated processes are disrupted when there is a misalignment between the activities of the central and peripheral oscillators and the external environment, which may happen when traveling across time zones, alternating sleep patterns related to occupational factors such as shift work, or when sleep is disrupted due to sleep pathology (ie, insomnia or obstructive sleep apnea) [30,31]. Although altered sleep quality and duration have been linked to chronic disease risk and mortality in numerous epidemiological studies and systematic reviews [32-34], current treatment options for inadequate sleep or sleep disorders are limited. Therefore, we are also including preclinical studies in this scoping review to understand the mechanisms associated with disrupted sleep that can be expanded on and confirmed in future translational clinical research. Continued research aimed at uncovering these mechanisms of healthy and pathologic sleep has the potential to elucidate specific biomarkers and signaling mechanisms that act as mediators between sleep impairment and broader physiological changes. An initiative toward understanding and mitigating the effects of chronic sleep loss is imperative to reducing the prevalence of comorbidities and the need for health care services and its accompanying costs that otherwise may not be needed in a time of limited health care delivery resources and access.

The gut microbiota, or the community of bacteria in the gastrointestinal system, has been shown to display diurnal fluctuations in composition and function, which are both coordinated with host feeding time, the anticipation of nutrient digestion, and energy metabolism [35]. The human gut microbiome is characterized by the bacteria that occupy the digestive tracts of humans in combination with their collective genetic information [36]. Gut microbiome bacteria perform vital physiological functions related to nutrient intake, such as the production of metabolites and synthesizing compounds that have the potential to influence human health and pathophysiology (ie, short-chain fatty acids and trimethylamine N-oxide) [37,38]. The bacteria of the gut microbiome communicate with the brain via metabolites, immune cells, and the vagus nerve [39]. This communication, or gut-brain axis signaling, is associated with the modulation of systemic and gastrointestinal motor, sensory, and secretory functions [40]. Different physiologic and pathophysiologic states have been found to shape the gut microbiome’s bacterial content, diversity, and activity. For example, changes in the bacterial composition of the gut microbiome have been associated with diet [41], stress [39], and the external environment [42]. Due to the fact that gut microbes are associated with health maintenance through their metabolic activity and gut-brain communication, a substantial increase or decrease in specific taxa may have functional and physiologic implications for the host [43].

Pathologic gut microbiome bacterial community alterations have been linked to similar disorders associated with inadequate sleep in preclinical and translational research models, including cardiovascular disease [44], obesity [45], diabetes mellitus [46], and hypertension [47]. Furthermore, established signaling mechanisms between the gut microbiome and brain through the gut-brain axis provide the mechanistic rationale that sleep and microbiome alterations may be linked [39]. Reduced sleep duration–associated gut microbiome changes have also been associated with putative inflammatory metabolite implications such as reduced short-chain fatty acid and increased secondary bile acid levels [47,48]. Recent studies modeling sleep fragmentation and deprivation in mice have shown significant changes in the diversity of and specific bacterial taxa [47,49,50], whereas other studies found no major effects on bacterial composition [51]. Studies examining the relationship between sleep and the gut microbiome have used various models of pathologic sleep, including circadian disruption [35], sleep fragmentation [47,52,53], and reduction in sleep quantity [54] and quality [49] (Table 1).

Despite the growing research on this topic, studies focused on sleep and microbiome associations include varying sleep intervention models and intervention durations. Furthermore, a wide range of global, taxonomic, and functional microbiome analysis techniques and a lack of reporting standardization across studies create challenges in comparing the global and specific gut microbiome community responses to healthy and disordered sleep. Although the associations between sleep and gut microbiome community changes have been established, it is unknown if altered sleep influences the microbiome, the microbiome influences sleep, or sleep and the microbiome mutually modulate each other and are altered by a disruption in either system. It is also unclear if the risk for health conditions with shared associations to sleep and microbiome changes are primarily driven by pathologic changes in one or both systems, and several studies on this topic are exploratory and observational. A concern that preclinical research results may not always be replicable in human studies necessitates our synthesis of both preclinical and translational studies to evaluate congruence and disagreement across sleep and microbiome associations. Therefore, a scoping review with rigorous data abstraction, charting, and outcome measure synthesis is essential to understand gut microbiome responses across various sleep conditions in preclinical and translational clinical research.

Our objective is to explore the influence of sleep and sleep pathology on the gut microbiome in preclinical and translational clinical studies to determine the extent sleep and gut microbiome–focused research has been undertaken, what sleep disorders have been studied, the methodologies used, and whether these studies are sufficient in characterizing the global and specific bacterial gut microbiome changes (and their byproducts) associated with healthy sleep and alterations in sleep physiology. Subresearch objectives with relevant examples are presented in Textbox 1, and the operational definitions used to formulate these research questions are listed in Table 1.

A scoping review of the currently published literature was chosen due to the variability of the microbiome and sleep measures reported to synthesize human and preclinical data on the associations between sleep and the gut microbiome. The PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews) and PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) guidelines will be used to guide the search strategy, study selection, and synthesis of results [72,73]. Briefly, PRISMA-ScR and PRISMA-P involve identifying research questions and objectives, identifying relevant studies through an electronic search strategy, study selection, and data charting and synthesis of results. The protocol for this scoping review is registered on Open Science Framework (69TBR).

Our research team met and developed relevant search terms to capture data sources covering the full scope of the intended aims, including the different iterations of sleep or sleep disruption, the gut microbiome, and human or rodent studies (for a full list of search terms and individual database search strategies, see Multimedia Appendix 1).

We worked closely with our institutional medical research librarian to develop and refine our search strategy and Medical Subject Headings terms and identify pertinent databases to be searched. The search strategy and methods were peer reviewed by a medical librarian independent of the scoping review team to improve validity and reproducibility. The databases listed previously will be used to identify the primary sources of evidence. Secondary searches will be performed within Web of Science using snowballing technique conducting backward and forward citation analysis of the reference lists as well as the cited studies of the included studies for additional relevant articles.

The following databases will be searched:

No limitations will be placed on year of publication. Gray literature sources will also be searched, such as medRxiv and bioRxiv preprint servers.