ESPE Yearbook of Paediatric Endocrinology

Cell Metab. 2025; 37(1): 138-153.e5. PMID: 39504963 doi: 10.1016/j.cmet.2024.10.003. https://pubmed.ncbi.nlm.nih.gov/39504963/

Brief summary: This in vitro and in vivo animal study provides compelling evidence that gut microbiota modulation of stress responsiveness exhibits diurnal rhythmicity.

Comment: Stress and circadian systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis to maintain responses to external stimuli. In addition to playing a central role in both stress and circadian signaling, the HPA axis is one of the key pathways through which the gut microbiota can shape brain function and behavior (1). The trillions of microorganisms that reside in the gut have co-evolved with their hosts, resulting in an intertwined relationship between the gut microbiota and host physiology (2). Stress-induced glucocorticoid release is modulated by the gut microbiota because germ-free (GF) mice display exaggerated glucocorticoid levels following stress that can be recovered upon colonization (3). In addition, the gut microbiome displays strong diurnal oscillations in composition and metabolic output that are important to maintain metabolic health (4-6), while microbial depletion leads to altered baseline levels of glucocorticoids at different times of the day (7). There is evidence that gut microbes regulate brain function, the stress response and circadian rhythms. However, the mechanisms how these signals are orchestrated remain unknown.

Conducted in germ-free mice with comprehensive bioinformatic analyses of transcriptomic and metabolomic data, this study shows that altering the gut microbiota disrupts diurnal oscillations in stress- and circadian-related pathways across key brain regions involved in both circadian regulation and the behavioral stress response. One of these regions, the suprachiasmatic nucleus, maintains glucocorticoid rhythms; the results show that gut microbiota-driven circadian disruption alters the diurnal pattern of circulating corticosterone.

These findings have significant implications. They reveal that diurnal rhythmicity is essential to how the gut microbiota regulates the stress response, providing the first clear evidence that the microbiota, circadian system, and stress axis operate in an integrated, time-dependent manner. Since glucocorticoids influence multiple physiological systems, including immunity and metabolism, the findings of this study deepen our understanding of microbe-host interactions. Given that many stress-related disorders involve disruptions in both circadian rhythms and gut microbiota and are exacerbated by modern lifestyle stressors, this work underscores the potential for microbiota-targeted interventions. Notably, the identification of Limosilactobacillusreuteri as a circadian-sensitive strain opens new avenues for developing time-specific treatments for stress-related conditions.

References: 1. Cryan JF, Dinan, TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour Nat. Rev. Neurosci. 2012; 13: 701-712.2. Gaulke CA, Arnold HK, Humphreys IR. Ecophylogenetics Clarifies the Evolutionary Association between Mammals and Their Gut Microbiota mBio. 2018; 9: e01348-18.3. Sudo N, Chida Y, Aiba Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 2004; 558:263-275.4. RiselyA, Wilhelm K, Clutton-Brock T. Diurnal oscillations in gut bacterial load and composition eclipse seasonal and lifetime dynamics in wild meerkats. Nat. Commun. 2021; 12: 6017.5. Thaiss CA, LevyM, Korem, T. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell. 2016; 167:1495-1510.e126. ZarrinparA, ChaixA, Yooseph S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 2014; 20:1006-1017.7. Mukherji A, KobiitaA, YeT. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell. 2013; 153:812-827.