Resynchronized rhythmic oscillations of gut microbiota drive time-restricted feeding induced nonalcoholic steatohepatitis alleviation

ABSTRACT

With the drive of the endogenous circadian clock and external cues such as feeding behavior, the microbial community generates rhythmic oscillations in composition and function. Microbial oscillations are crucial in orchestrating host metabolic homeostasis during the predictable 24-hour diurnal cycle. A time-restricted feeding (TRF) regimen is a promising dietary strategy to optimize energy utilization, alleviate metabolic syndrome and reinforce microbial cyclical fluctuations. However, the causative relationship between reinforced microbial rhythmicity and TRF-induced metabolic improvement remains elusive. In this study, we corroborated that the TRF regimen notably alleviated obesity and nonalcoholic steatohepatitis (NASH) with reinstated rhythmicity of genera such as Lactobacillus, Mucispirillum, Acetatifactor, and Lachnoclostridium. The reshaped microbial oscillations correlate with cyclical fluctuations in intestinal amino acids. Furthermore, fecal microbiota transplantation (FMT) indicated that only the TRF feeding phase-derived microbiota, but not the TRF fasting phase-derived microbiota, could protect mice from NASH and reinstate microbial rhythmicity, confirming that the microbiota improved NASH in a time-of-day-specific manner. The unique role of the TRF-feeding phase-derived microbiota was accompanied by regulation of the serotonergic synapse pathway and rejuvenation of the microbial production of indole derivatives. Our results revealed the discrepant characteristics between the feeding and fasting phases and the time-of-day-specific configuration of microbiota functionality in the TRF regimen.

KEYWORDS:

• time-restricted feeding
• circadian rhythm
• nonalcoholic steatohepatitis
• gut microbiota
• tryptophan metabolism

Acknowledgments

The authors acknowledge Ran Zheng at the Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University for technical assistance.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The 16S rRNA gene sequencing data are available at NCBI’s Sequence Read

Archive (SRA) database under the BioProject accession code PRJNA923159 at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA923159 and PRJNA951532 at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA951532. The raw data of RNA sequencing are available at SRA database under the BioProject accession code PRJNA923592 at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA923592.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2221450

Additional information

Funding

This work was supported by the National Key Research and Development Program of China (2021YFC2301800)