Macrophages as orchestrators of gut-organ axis crosstalk: immunometabolic reprogramming and host-directed therapy in sepsis
4 affiliations
- 1Department of Intensive Care Medicine, the Second Affiliated Hospital of Zhejiang Chinese Medical University , , ,
- 2Department of Pharmacy, The Second Affiliated Hospital of Zhejiang Chinese Medical University , , ,
- 3Department of Clinical Laboratory, the Second Affiliated Hospital of Zhejiang Chinese Medical University , , ,
- 4Department of Endocrinology, Tongde Hospital of Zhejiang Province , ,
Abstract
Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection. Among the numerous contributory factors, the gut microbiota and its metabolites are increasingly recognized as potential modulators of systemic inflammation, acting through multiple gut-organ axes. Within this network, macrophages serve as central integrators that transduce microbial signals into organ-specific inflammatory or reparative outcomes. Disease evolution is critically determined by immune-metabolic reprogramming of macrophages. This reprogramming comprises tricarboxylic acid cycle truncation, lipid remodeling, mitochondrial dysfunction, and inflammasome activation. These processes are closely intertwined with NFκB, cGAS-STING, TLR/MyD88, and aryl hydrocarbon receptor signaling. Gut-derived metabolites, particularly short-chain fatty acids and indole derivatives, shape macrophage functions in distal organs. These mechanisms predominantly operate during the acute phase of sepsis, driving early organ injury. In contrast, sepsis survivors often enter a distinct chronic phase, characterized by persistent immune dysregulation. Trained immunity, through metabolic-epigenetic rewiring, may underlie this long-term dysfunction in survivors. Preclinical promise has been demonstrated by host-directed therapies that target macrophage metabolism. Nevertheless, major challenges impede clinical translation. These include inadequate preclinical models, the absence of validated real-time biomarkers for immune-metabolic phenotyping, and marked heterogeneity among patients. This review positions macrophages as actionable sentinels in gut-organ crosstalk during acute sepsis, and further explores their role in chronic sequelae, underscoring the need for biomarker-guided stratification and precision immune-metabolic editing to overcome barriers in both settings.
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BibTeX
@article{zeng2026macrophages,
title = {{Macrophages as orchestrators of gut-organ axis crosstalk: immunometabolic reprogramming and host-directed therapy in sepsis}},
author = {Wenqing Zeng and Ye Zhang and Liping Fan and Ying Xun and Zhaoqing Jiang and Feifei Dai},
journal = {Frontiers in cellular and infection microbiology},
year = {2026},
month = oct,
doi = {10.3389/fcimb.2026.1921762},
url = {https://europepmc.org/article/PMC/PMC13725824},
note = {CC BY},
}
RIS
TY - JOUR
TI - Macrophages as orchestrators of gut-organ axis crosstalk: immunometabolic reprogramming and host-directed therapy in sepsis
AU - Wenqing Zeng
AU - Ye Zhang
AU - Liping Fan
AU - Ying Xun
AU - Zhaoqing Jiang
AU - Feifei Dai
PY - 2026
DA - 2026/10/19
JO - Frontiers in cellular and infection microbiology
DO - 10.3389/fcimb.2026.1921762
UR - https://europepmc.org/article/PMC/PMC13725824
AB - Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection. Among the numerous contributory factors, the gut microbiota and its metabolites are increasingly recognized as potential modulators of systemic inflammation, acting through multiple gut-organ axes. Within this network, macrophages serve as central integrators that transduce microbial signals into organ-specific inflammatory or reparative outcomes. Disease evolution is critically determined by immune-metabolic reprogramming of macrophages. This reprogramming comprises tricarboxylic acid cycle truncation, lipid remodeling, mitochondrial dysfunction, and inflammasome activation. These processes are closely intertwined with NFκB, cGAS-STING, TLR/MyD88, and aryl hydrocarbon receptor signaling. Gut-derived metabolites, particularly short-chain fatty acids and indole derivatives, shape macrophage functions in distal organs. These mechanisms predominantly operate during the acute phase of sepsis, driving early organ injury. In contrast, sepsis survivors often enter a distinct chronic phase, characterized by persistent immune dysregulation. Trained immunity, through metabolic-epigenetic rewiring, may underlie this long-term dysfunction in survivors. Preclinical promise has been demonstrated by host-directed therapies that target macrophage metabolism. Nevertheless, major challenges impede clinical translation. These include inadequate preclinical models, the absence of validated real-time biomarkers for immune-metabolic phenotyping, and marked heterogeneity among patients. This review positions macrophages as actionable sentinels in gut-organ crosstalk during acute sepsis, and further explores their role in chronic sequelae, underscoring the need for biomarker-guided stratification and precision immune-metabolic editing to overcome barriers in both settings.
SN - 2235-2988
ER -