The metabolic crossfire hypothesis: glycolytic crosstalk between immune and epithelial cells in ulcerative colitis pathogenesis
- 1Department of Anorectal, the Second Affiliated Hospital of Hunan University of Chinese Medicine
- 2Graduate School of Hunan University of Chinese Medicine
Abstract
Ulcerative colitis (UC) is fundamentally driven by epithelial barrier dysfunction and aberrant immune activation. Metabolic reprogramming, particularly the shift toward aerobic glycolysis, actively contributes to UC pathogenesis rather than merely resulting from inflammation. This review proposes the metabolic crossfire hypothesis—an integrative framework, supported by accumulating preclinical evidence but not yet definitively validated in humans—in which infiltrating immune cells (e.g. M1 macrophages, Th17 cells, and neutrophils) and intestinal epithelial cells (IECs) reciprocally fuel each other’s pro-inflammatory and barrier-disrupting phenotypes through shared glycolytic pathways. First, this review outlines the core signaling hubs HIF-1α, NF-κB, and mTOR that have been implicated in driving immune cell glycolysis, and discusses their cell-type-specific manifestations. This review then examines the IEC switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and its impact on barrier integrity. Central to this review is the bidirectional nature of this metabolic crossfire: immune cells may attack IECs via lactate, ROS, and cytokines, whereas damaged IECs may retaliate by releasing metabolites, chemokines, and damage-associated molecular patterns (DAMPs), potentially forming a self-amplifying loop. Finally, we translate these mechanistic insights into therapeutic implications, underscoring the necessity of cell-type-specific targeting, human-relevant models, and biomarker-guided translation to guide future clinical trials.
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BibTeX
@article{wu2026metabolic,
title = {{The metabolic crossfire hypothesis: glycolytic crosstalk between immune and epithelial cells in ulcerative colitis pathogenesis}},
author = {Liyao Wu and Jinyin Xiao and Chunhua Liu and Keya Li and Zhenquan Wang},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1973121},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973121/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The metabolic crossfire hypothesis: glycolytic crosstalk between immune and epithelial cells in ulcerative colitis pathogenesis
AU - Liyao Wu
AU - Jinyin Xiao
AU - Chunhua Liu
AU - Keya Li
AU - Zhenquan Wang
PY - 2026
DA - 2026/11/02
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1973121
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973121/full
AB - Ulcerative colitis (UC) is fundamentally driven by epithelial barrier dysfunction and aberrant immune activation. Metabolic reprogramming, particularly the shift toward aerobic glycolysis, actively contributes to UC pathogenesis rather than merely resulting from inflammation. This review proposes the metabolic crossfire hypothesis—an integrative framework, supported by accumulating preclinical evidence but not yet definitively validated in humans—in which infiltrating immune cells (e.g. M1 macrophages, Th17 cells, and neutrophils) and intestinal epithelial cells (IECs) reciprocally fuel each other’s pro-inflammatory and barrier-disrupting phenotypes through shared glycolytic pathways. First, this review outlines the core signaling hubs HIF-1α, NF-κB, and mTOR that have been implicated in driving immune cell glycolysis, and discusses their cell-type-specific manifestations. This review then examines the IEC switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and its impact on barrier integrity. Central to this review is the bidirectional nature of this metabolic crossfire: immune cells may attack IECs via lactate, ROS, and cytokines, whereas damaged IECs may retaliate by releasing metabolites, chemokines, and damage-associated molecular patterns (DAMPs), potentially forming a self-amplifying loop. Finally, we translate these mechanistic insights into therapeutic implications, underscoring the necessity of cell-type-specific targeting, human-relevant models, and biomarker-guided translation to guide future clinical trials.
SN - 1664-3224
ER -