Inflammation-induced epigenetic imprinting regulates intestinal stem cells

Area of Science:

• Gastroenterology
• Stem Cell Biology
• Immunology

Background:

• Intestinal stem cells (ISCs) are crucial for gut homeostasis and repair.
• The long-term effects of inflammation on ISC function and regenerative capacity remain unclear.

Purpose of the Study:

• To investigate how acute gastrointestinal graft-versus-host disease (GI GVHD) impacts Lgr5+ ISCs.
• To determine if inflammation-induced adaptations in ISCs leave persistent scars affecting regeneration.

Main Methods:

• Utilized single-cell transcriptomics, organoid cultures, metabolic assays, epigenomic profiling, and in vivo models.
• Examined Lgr5+ ISCs in clinically relevant models of acute GI GVHD.

Main Results:

• Inflammation induced metabolic changes in Lgr5+ ISCs, leading to succinate accumulation.
• Succinate accumulation epigenetically reprogrammed ISCs, reducing their differentiation and regeneration capacity ex vivo and in vivo.
• ISCs showed impaired regeneration even after inflammation resolution, indicating persistent maladaptive effects.

Conclusions:

• Inflammation leaves a persistent epigenetic imprint on ISCs.
• This imprint reduces ISC regenerative capacity and affects their ability to adapt to future challenges.
• Understanding these persistent effects is crucial for managing inflammatory conditions affecting the gut.