Multi-omics analysis reveals that sleep deprivation exacerbates intestinal barrier injury via the microbiota-dependent taurodeoxycholic acid/group 3 innate lymphoid/IL-22 axis

BACKGROUND: Clinical studies demonstrated a correlation between sleep dysfunction and intestinal diseases. However, the detailed interactions and underlying mechanisms linking sleep disruption to intestinal microenvironment remain poorly understood. METHODS: We employed the Curling Prevention by Water (CPW) paradigm to establish a mouse model of sleep deprivation (SD) for durations ranging from 0 to 96 h. The dynamic changes in the intestinal microenvironment were systematically profiled using multi-omics approaches, including metagenomic sequencing, untargeted metabolomics and RNA sequencing. The causal role of microbial dysbiosis and the underlying mechanisms were further investigated using germ-free mice, fecal microbiota transplantation (FMT), flow cytometry, and targeted intervention. RESULTS: The intestinal microenvironment was highly sensitive to SD. Distinct microbial communities and metabolite profiles were observed among brief SD (< 24 h of SD), prolonged SD (24-96 h of SD) and control. Brief SD triggered a self-regulatory response of the gut microbiota, characterized by an increase in certain beneficial bacteria (e.g., Parabacteroides goldsteinii). In contrast, prolonged SD shaped a pro-inflammatory microbial structure, characterized by reduced Akkermansia muciniphila and enriched Pseudomonadota. Multi-omics analysis revealed that SD significantly inhibited microbial bile acid metabolism, particularly taurodeoxycholic acid (TDCA), and impaired intestinal barrier function while suppressing the intestinal immune response to bacteria antigens. Mechanistically, SD exacerbated intestinal barrier damage by inhibiting the TDCA/group 3 innate lymphoid cells (ILC3)/IL-22 axis. Supplementation with TDCA effectively restored ILC3 function, IL-22 production, and barrier integrity in SD mice. Furthermore, FMT from patients with sleep dysfunction significantly disturbed intestinal microenvironment and increased serum cortisol by regulating gut microbiota and inhibiting TDCA/ILC3/IL-22 axis. CONCLUSION: This study dynamically delineates how SD disrupts intestinal homeostasis by reshaping the gut microbiota and suppressing the TDCA/ILC3/IL-22 axis. These findings provide novel mechanistic insights and identify potential therapeutic targets for sleep dysfunction-associated intestinal complications.