Gut Microbiota: Closely Tied to the Regulation of Circadian Clock in the Development of Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is a global epidemic that imposes significant economic and social burdens. Despite extensive research, the pathogenesis of T2DM remains incompletely understood. Recent studies have increasingly focused on the role of circadian rhythm disruptions, caused by irregular sleep patterns and unhealthy diets, in the development of T2DM. However, the contribution of the endogenous circadian clock system to T2DM pathogenesis has not been fully explored. Emerging evidence suggests that the gut microbiota and the circadian clock interact to regulate host metabolism. This review examines the relationship between the gut microbiota, circadian clock, and T2DM, proposing that the gut microbiota plays a critical role in regulating the circadian clock during T2DM development. This insight opens new avenues for gut microbiota-directed therapies to mitigate circadian disruptions linked to T2DM.
Introduction
Diabetes mellitus, often referred to as the “disaster of the 21st century” by the World Health Organization, has become a major global health challenge. In 2019, the International Diabetes Federation reported approximately 463 million diabetes patients worldwide, with T2DM being the most prevalent form. T2DM arises from a combination of genetic and environmental factors, and its prevalence has surged due to lifestyle changes associated with industrialization and modernization. As such, understanding the pathogenesis of T2DM and developing effective interventions remain urgent priorities.
The circadian rhythm, which aligns with the day-night cycle and feeding-fasting cycles, is regulated by circadian clock elements. Disruptions in circadian rhythm, such as irregular work schedules and unhealthy eating patterns, have been linked to impaired glucose control, insulin resistance, and an increased risk of T2DM. However, the role of the endogenous circadian clock system in T2DM development is not yet fully understood. Recent research highlights the interaction between the gut microbiota and the circadian clock in regulating host metabolism. This review explores how the gut microbiota influences the circadian clock in the context of T2DM, offering potential therapeutic strategies.
The Circadian Clock
The circadian rhythm is an internal 24-hour cycle that helps organisms adapt to environmental changes. It is regulated by a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks found in various tissues, including the liver, pancreas, and intestines. The molecular circadian clock is maintained by clock genes, such as Clock, Bmal1, Per1, Per2, Cry1, and Cry2, which form a transcriptional-translational feedback loop (TTFL). This loop regulates thousands of rhythmic processes, including metabolism, and connects the circadian clock system to metabolic reactions.
Effects of Circadian Disruption on T2DM Development
Circadian disruptions, such as those caused by shift work, have been linked to an increased risk of T2DM. Shift workers, who often have irregular sleep and eating patterns, exhibit reduced glucose tolerance, insulin resistance, and a higher risk of obesity. Epidemiological studies have shown that shift workers, particularly those on rotating night shifts, have a significantly higher risk of developing T2DM. For example, a meta-analysis of 12 studies involving over 200,000 participants found that shift workers had a 9% higher risk of diabetes compared to non-shift workers.
Experimental models have provided further evidence of the link between circadian disruptions and T2DM. Mice with mutations in clock genes, such as Clock and Bmal1, exhibit metabolic abnormalities, including impaired glucose tolerance, hyperglycemia, and insulin resistance. These findings underscore the importance of the circadian clock in glucose metabolism and T2DM development.
Gut Microbiota and Its Oscillation Rhythm
The gut microbiota, a complex community of trillions of microorganisms in the intestinal tract, plays a crucial role in digestion, nutrient absorption, and immune function. It also influences host metabolism and energy homeostasis. Recent studies have shown that the gut microbiota exhibits diurnal fluctuations in composition and activity, which are influenced by host feeding patterns. Disruptions in circadian rhythm can alter the gut microbiota, leading to metabolic disorders such as obesity, insulin resistance, and T2DM.
Effects of Gut Microbiota on the Circadian Clock in T2DM
The gut microbiota and the circadian clock have a bidirectional relationship. Changes in feeding behavior, such as time-restricted feeding (TRF) or high-fat diets (HFD), can alter the expression of circadian genes in peripheral tissues, including the liver and intestines. For example, mice fed HFDs during their inactive phase (daytime) developed worse glucose tolerance and obesity compared to those fed during their active phase (nighttime). These changes were associated with altered expression of circadian clock genes in peripheral tissues.
The gut microbiota also influences the circadian clock through microbial metabolites, such as short-chain fatty acids (SCFAs). SCFAs, including butyrate, propionate, and acetate, are produced by gut bacteria during the fermentation of dietary fibers. They play a role in regulating insulin sensitivity, inflammation, and glucose metabolism. Studies have shown that SCFAs can modulate the expression of circadian genes, such as Bmal1 and Per2, in peripheral tissues. For instance, oral administration of SCFAs induced phase shifts in peripheral clocks in mice, highlighting their role in circadian regulation.
Metabolites as Mediators in Gut Microbiota-Circadian Clock Interaction
SCFAs are key mediators in the interaction between the gut microbiota and the circadian clock. They activate G protein-coupled receptors (GPRs), such as GPR43, which regulate insulin signaling, inflammation, and glucose metabolism. Activation of GPR43 by SCFAs can improve insulin sensitivity and reduce fat accumulation in adipose tissue, thereby mitigating metabolic disorders associated with T2DM. Additionally, SCFAs have anti-inflammatory effects and enhance intestinal barrier function, further supporting their role in metabolic health.
Conclusions and Future Directions
T2DM is a complex metabolic disorder influenced by genetic, environmental, and lifestyle factors. The role of circadian disruptions in T2DM development has gained increasing attention, particularly in the context of shift work and irregular eating patterns. The gut microbiota, through its interaction with the circadian clock, plays a critical role in regulating host metabolism and influencing T2DM pathogenesis. Microbial metabolites, such as SCFAs, are key mediators in this interaction, offering potential therapeutic targets for T2DM.
Future research should focus on elucidating the specific mechanisms by which the gut microbiota regulates the circadian clock in T2DM. This includes exploring the role of microbial metabolites, such as SCFAs, in circadian and metabolic regulation. Additionally, gut microbiota-directed therapies, such as probiotics and prebiotics, hold promise for mitigating circadian disruptions and improving metabolic health in individuals with T2DM. By understanding the intricate relationship between the gut microbiota, circadian clock, and T2DM, we can develop novel strategies to prevent and manage this debilitating disease.
doi.org/10.1097/CM9.0000000000000702
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