Circadian rhythms as a modulator of gut microbiota-tumor microenvironment crosstalk

Abstract

Circadian rhythms play a pivotal role in regulating diverse physiological functions, notably the composition and activity of gut microbiota. Accumulating evidence indicates that circadian rhythm disruption can induce dysbiosis of the gut microbiome, which in turn is implicated in influencing the tumor microenvironment (TME) and facilitating cancer progression. This review integrates and analyzes recent advances elucidating the complex interplay where circadian rhythms modulate gut microbiota, and how these circadian-driven microbial changes affect the TME. This review analyzes recent advances in elucidating the complex interplay among circadian rhythms, gut microbiota, and the TME. We examine how circadian disruption modifies the diversity and metabolic functions of gut microbiota, resulting in alterations of microbial metabolites, including but not limited to short-chain fatty acids and secondary bile acids. These metabolic alterations have the potential to modulate immune cell function, vascular remodeling, and tumor cell metabolism within the TME. We investigate the potential mechanisms through which gut microbial dysbiosis induced by circadian misalignment could promote an immunosuppressive TME and accelerate tumor growth. Additionally, we evaluate emerging therapeutic strategies that leverage the circadian-microbiome axis, encompassing chronotherapy, probiotic supplementation, and fecal microbiota transplantation. The integration of circadian biology, microbiology, and cancer immunology presents promising avenues for the development of novel diagnostic and therapeutic approaches. However, significant challenges persist in translating these findings into viable clinical applications. Further research is imperative to elucidate the molecular pathways interconnecting circadian rhythms, gut microbiota, and the TME, and to develop personalized chronobiological interventions for cancer prevention and treatment.

Keywords: Cancer; Circadian rhythm disruption; Gut microbiota dysbiosis; Probiotics; Tumor microenvironment.

Fig. 1

Effect of circadian rhythm disturbances on gut microbes. Perturbations in human circadian rhythms lead to significant alterations in the composition and diversity of gut microbiota. The abundance of potentially pathogenic bacteria increases while commensal bacteria decrease, resulting in dysbiosis of the intestinal microecosystem. Furthermore, the profile and concentrations of gut microbial metabolites, including bile acids, short-chain fatty acids, and amino acids, undergo significant changes, potentially disrupting intestinal homeostasis

Fig. 2

Influence of intestinal microbiota on tumor microenvironment. Dysbiosis of the gut microbiota compromises intestinal mucosal barrier function, primarily characterized by downregulation of tight junction proteins in intestinal epithelial cells, consequently increasing intestinal permeability. This enhanced permeability facilitates the translocation of potentially pathogenic bacteria into intestinal tissues, initiating inflammatory cascades that promote tumor proliferation and microvascular remodeling. Concurrently, increased lactate levels in the intestinal microenvironment contribute to tumor proliferation and induce the accumulation of tumor-associated macrophages and dendritic cells, further fostering a pro-tumorigenic microenvironment. Probiotic intervention has the potential to restore intestinal homeostasis, as evidenced by enhanced tight junctions between intestinal cells, increased goblet cell populations, and mucosal layer repair. In the tumor microenvironment, this intervention results in a reduction of regulatory T cells, attenuation of pro-inflammatory factors, augmentation of CD8 + T cell activity, and diminished presence of various myeloid-derived suppressor cell subtypes. These orchestrated changes synergistically modulate the microenvironment, culminating in the suppression of tumor growth

Fig. 3

Future perspective. Future research directions should explore modulating circadian rhythms to alter the composition and distribution of gut microbiota, potentially influencing the tumor microenvironment and facilitating control over tumor growth. Moreover, in-depth studies on the interactions between intratumoral microbiota and the host, as well as targeted interventions using microbial metabolites, show promise for the precise regulation of tumor growth. The integration of artificial intelligence technologies may enable more comprehensive analysis of tumor characteristics, thereby providing data support for the development of personalized treatment strategies. Incorporating circadian rhythm information could potentially aid in predicting tumor metastasis risk, thus providing a basis for developing more precise treatment strategies. Furthermore, integrating circadian rhythm research could potentially enhance the efficacy of immunotherapies by optimizing treatment timing and dosage, thereby improving the therapeutic effects targeting tumor-specific antigens. Exploring the regulatory effects of circadian rhythms on epigenetic networks could provide new insights into treatment strategies targeting tumor mutation sites. Through these studies, researchers anticipate achieving synergistic regulation among circadian rhythms, gut microbiota, and the tumor microenvironment, potentially offering new comprehensive strategies for cancer treatment