Research on Alleviating Gastrointestinal Inflammation by Adjusting Intestinal Circadian Rhythm through Feeding Time

Background Information

Impaired expression of intestinal circadian rhythm genes has been observed in biopsies from patients with inflammatory bowel disease (IBD). Disruption of circadian rhythms, such as that occurring in shift workers, has been shown to be associated with an increased risk of gastrointestinal diseases, including IBD. Specifically in the intestine, the circadian clock in epithelial cells is thought to balance gastrointestinal homeostasis by regulating the microbiome. However, the role of intestinal circadian rhythms in IBD has not been fully elucidated.

Recent studies suggest that time-restricted feeding can improve metabolic health and inflammation, and influence the gut microbiota. Therefore, the research team hypothesized that adjusting intestinal circadian rhythms through feeding time could potentially influence the development and progression of IBD.

Paper Source

This research was conducted by researchers from the Technical University of Munich and the University of Surrey, including Yunhui Niu, Marjolein Heddes, Baraa Altaha, et al., and was published in the online version of the journal “Cellular & Molecular Immunology” on June 25, 2024.

Research Process

Research Design and Methods

1. Selection and Validation of Animal Models: The research team selected IL-10 gene-deficient mice (IL-10-/-) as an IBD-related mouse model, indicating problems in circadian behavior and gastrointestinal immune homeostasis. The mice’s behavioral performance under light-dark cycle (LD) and constant darkness (DD) conditions showed a slight decrease in total activity compared to wild-type controls, but no significant changes.

2. Molecular Biology Verification: The experiment simultaneously detected circadian rhythm genes and inflammation-related genes in colonic epithelial cells of wild-type and IL-10 gene-deficient mice. Results showed that in wild-type mice, circadian rhythm genes exhibited strong diurnal rhythms in colonic cells, while in IL-10 deficient mice, this rhythm was completely lost, and the expression of inflammation-related genes (such as TNF, IFNγ, etc.) was significantly enhanced.

3. Restriction of Feeding Time: To explore the effects of time-restricted feeding (RF), the research team restricted the feeding time of experimental mice to the night when they were awake (ZT13-ZT17), gradually reducing the feeding time from an initial 8 hours to 4 hours over 4 weeks. During this period, food intake and nighttime activity levels were measured, with similar food intake and activity levels observed in both groups of mice.

Data and Results

1. Recovery of Circadian Rhythm Genes: The experiment showed that nighttime restricted feeding significantly improved the rhythmic expression of circadian rhythm genes in colonic tissues of IL-10 deficient mice, reaching levels similar to those of the control group.

2. Changes in Gastrointestinal Inflammation Markers: Through feeding time adjustment, the levels of inflammatory markers (such as TNF and IFNγ) in IL-10 deficient mice were significantly reduced, the number of CD4+ T cells and colonic density in colonic epithelial tissues improved, and the inflammation score in colonic cross-sections was greatly reduced.

3. Restoration of Microbiome Rhythm: The study also examined the composition and rhythm of the gut microbiota. Results showed that the microbiota rhythm in IL-10 deficient mice was completely lost, but was restored after nighttime restricted feeding.

4. Immune Cell Migration: Immune cell quantification and transcriptome sequencing results indicated that restricted feeding significantly restored the circadian distribution of CD4+ T cells in the colonic lamina propria while reducing the total number of CD4+ T cells.

Conclusions and Significance

The research results suggest that the loss of intestinal circadian rhythms may be a key factor in the development of IBD. Through nighttime restricted feeding, intestinal circadian rhythms can be restored, thereby improving inflammatory responses and colonic health, significantly increasing the survival rate of IL-10 deficient mice. In contrast, this improvement effect of feeding time adjustment did not exist for mice lacking the intestinal circadian rhythm gene BMAL1, demonstrating the importance of intestinal circadian rhythms in determining the benefits of time-restricted feeding.

Research Highlights

1. Direct Evidence: For the first time, direct evidence was provided that intestinal circadian rhythm dysfunction causes host immune imbalance and promotes the development and progression of IBD-like colitis.
2. New Strategy: Restoring intestinal circadian rhythms through time-restricted feeding provides a new strategy for improving IBD symptoms and may be used to develop circadian rhythm-based treatments for IBD in the future.
3. Microbiome Research: The study revealed the role of gut microbiome rhythms in IBD development, further reinforcing the importance of intestinal circadian rhythms for gastrointestinal health.

Future Directions for Research

Although the research results strongly support the importance of intestinal circadian rhythms in IBD and the potential benefits of time-restricted feeding, further long-term experiments are still essential. Future research could consider: 1. Long-term RF Experiments: Evaluate the sustained improvement effects of long-term RF on IBD. 2. Exploration of Mechanisms: Delve deeper into the specific mechanisms of how RF influences IBD through intestinal circadian rhythm genes and related signaling pathways.

Summary

This study provides strong scientific evidence and new insights for alleviating and preventing gastrointestinal inflammatory diseases by adjusting intestinal circadian rhythms through feeding time, and offers potential intervention strategies for future treatment of IBD and other related metabolic diseases.