Gut Lactate Boosts Ruminococcus via Histone Lactylation to Mediate Time-Restricted Feeding Protection in Crohn's...

Area of Science:

• Gastroenterology and immunology
• Microbiome research
• Dietary interventions

Background:

• Crohn's disease (CD) involves impaired gut barrier function and reduced SCFA-producing bacteria like Ruminococcus.
• Time-restricted feeding (TRF) shows potential in restoring microbial balance and gut homeostasis.
• Mechanisms of TRF's protective effects in CD are not fully understood.

Purpose of the Study:

• To investigate the impact of TRF on Ruminococcus abundance in Crohn's disease.
• To elucidate the mechanisms by which TRF confers protection against CD.
• To evaluate TRF as a potential therapeutic strategy for CD.

Main Methods:

• Quantified Ruminococcus abundance in CD patients and controls.
• Assessed TRF regimens (12/12, 16/8, 20/4) using 16S rRNA sequencing.
• Evaluated TRF's protective effects in preclinical CD models via histopathology, RNA-seq, and epigenetic analyses.

Main Results:

• Reduced Ruminococcus abundance in CD patients correlated with disease activity.
• The 12/12 TRF regimen (TRF_12h) significantly increased Ruminococcus, stimulated mitochondrial β-oxidation, and lactate generation.
• TRF_12h protected against colitis and fibrosis by reducing inflammation and extracellular matrix deposition.
• TRF-mediated protection involved SCFA-dependent activation of HIF-1α signaling via a lactate-histone lactylation-SLC9A3 axis.

Conclusions:

• TRF enriches Ruminococcus via a lactate-histone lactylation-SLC9A3 pathway, reducing inflammation and fibrosis in CD.
• Ruminococcus-derived SCFA enhance epithelial mitochondrial function and HIF-1α signaling, strengthening barrier integrity.
• TRF presents a promising mechanistic basis for therapeutic dietary strategies in CD.