Influence of Dietary Timing on Circadian Rhythms of Gut Microbiota and Rheumatoid Arthritis Inflammation

Background Introduction

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and progressive joint destruction, severely affecting the quality of life of patients. The inflammation and symptoms of RA patients often exhibit circadian rhythm fluctuations, such as worsened symptoms in the morning that gradually alleviate throughout the day. This rhythmicity is closely related to the complex interactions between the biological clock, hormonal fluctuations, and immune system activities. However, the specific regulatory mechanisms of RA inflammation rhythms remain poorly understood.

The core of the biological clock lies in the suprachiasmatic nucleus (SCN) which coordinates the body’s circadian rhythms by regulating environmental cues such as light, feeding, and activity. In this context, dietary rhythms (e.g., meal timing and fasting intervals) are believed to potentially have a profound impact on the inflammation rhythms of RA. Additionally, the gut microbiota also demonstrates circadian rhythm changes in alignment with the host’s biological clock, potentially modulating inflammatory states by altering the host’s immune response.

Recent studies have found that the gut microbiota of RA patients differs significantly from that of healthy individuals, with certain bacteria (e.g., Prevotella copri and Collinsella spp.) possibly driving the occurrence and development of RA through pro-inflammatory immune responses. Therefore, the potential link between microbiota rhythms and dietary patterns has become an important direction in studying RA inflammation rhythms.

Paper Source and Research Aim

This paper was completed by Fopei Ma and his team, with the main researchers from Nanfang Hospital of Southern Medical University and other institutions. The article was published in the journal “Cell Metabolism” (November 2024). The authors aim to explore how time-related diets induce circadian rhythms in gut microbiota and further regulate the inflammation rhythms in RA. The research focuses on the role of a specific gut bacterium, Parabacteroides distasonis, and reveals its molecular mechanism of inhibiting RA inflammation through releasing a soy isoflavone component, Glycitein (Gly), via β-glucosidase (β-GC).

Research Process and Methods

Experimental Process

1. Rhythmic Inflammation Study in Humans and Mouse Models

   • The authors collected blood samples at four time points (00:00, 06:00, 12:00, 18:00) in one day from 41 RA patients and 30 healthy controls to analyze the circadian fluctuations of inflammatory factors such as IL-6 and TNF-α.
   • Joint fluid samples from RA patients were compared between morning and evening, analyzing the proportions of neutrophils and macrophages.
   • Similar inflammation fluctuations were observed in collagen-induced arthritis (CIA) mice, and by adjusting light-dark cycles and feeding times, the impact of dietary rhythms on inflammation rhythms was further analyzed.

2. Relationship Between Gut Microbiota and Dietary Rhythms

   • In CIA mice, gut microbiota were eliminated through antibiotic treatment to observe the impact of dietary rhythms on inflammation fluctuations.
   • Fecal microbiota transplantation (FMT) experiments were conducted, transferring morning and evening fecal microbiota from RA patients into germ-free mice to verify the rhythmic effect of microbiota.

3. Circadian Changes in Gut Microbiota and Their Regulatory Mechanisms

   • 16S rRNA sequencing technology was used to analyze the diurnal changes in gut microbiota of mice and RA patients.
   • Focus was placed on the diurnal fluctuations of P. distasonis, investigating its β-GC activity and its ability to release Gly.

4. Molecular Mechanisms and Functional Verification

   • Through metabolomics analysis, the circadian fluctuations of Gly and its anti-inflammatory effects were identified.
   • In vitro and in vivo experiments confirmed the key role of P. distasonis in regulating RA inflammation by inhibiting β-GC activity.
   • The anti-inflammatory mechanism of Gly via the SIRT5-NF-κB axis was explored.

Experimental Innovations

1. Circadian Rhythm Analysis

   • The authors used continuous sampling and high-frequency time point analysis to precisely reveal the rhythmic changes of inflammatory factors, microbiota, and their metabolites.

2. Role of Novel Strains

   • The potential of P. distasonis as a probiotic in regulating inflammation was elucidated, and genetically modified strains expressing β-GC were developed to enhance its therapeutic effect.

Research Results

1. Regulation of RA Inflammation by Dietary Rhythms

   • The inflammation rhythms of RA patients and CIA mice are closely related to meal timing, with minor influence from light-dark cycles.
   • Reversing feeding times can reverse inflammation rhythms in mice, indicating that dietary rhythms are a key regulatory factor.

2. Mediating Role of Gut Microbiota

   • Elimination of gut microbiota completely abolished the effect of dietary rhythms on inflammation fluctuations.
   • FMT experiments showed that morning microbiota of RA patients were more pro-inflammatory than evening microbiota.

3. Core Role of P. distasonis

   • The key role of P. distasonis in dietary regulation of inflammation is realized through its β-GC activity releasing Gly. Circadian fluctuations in Gly concentration correlated negatively with inflammatory factor levels.

4. Molecular Mechanism of Gly

   • Gly reduces inflammation by inhibiting the NF-κB signaling pathway through the upregulation of SIRT5.

Conclusions and Significance

This study is the first to reveal the mechanism by which time-related diets regulate RA inflammation rhythms through the circadian rhythms of gut microbiota. The research demonstrates that the diurnal fluctuations of specific microbiota like P. distasonis release Gly through metabolic activity, alleviating inflammation via the SIRT5-NF-κB axis. This finding provides new insights into RA treatment, potentially allowing for precision therapies targeting the microbiota-inflammation axis through optimized meal timing, probiotic interventions, or drug design.

Research Highlights

• Innovation: This is the first study linking dietary rhythms, microbiota circadian fluctuations, and RA inflammation rhythms.
• Clinical Value: Proposes personalized treatment strategies based on gut microbiota and meal timing, with significant application potential.
• Mechanistic Depth: Detailed analysis of the molecular mechanism of P. distasonis releasing Gly through β-GC.

Research Limitations

• Limited clinical sample size, requiring larger-scale studies for validation.
• Did not extensively explore the potential impact of other dietary components on gut microbiota and RA inflammation.

Future Prospects

This study opens up a new direction for the application of dietary rhythms in chronic inflammatory diseases. Future research can further explore precision treatment schemes based on microbiota rhythms, such as the timed application of probiotics or the development of functional foods, aiming to achieve more effective intervention for RA patients.