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Intraoperative intestinal ischemia-reperfusion injury aggravates postoperative delirium by remodeling gut microbiota

ABSTRACT: Postoperative delirium, is a notable and serious complication after surgery, commonly extending hospitalization by 2-3 days. In a cohort of 167 patients, elevated serum intestinal fatty acid binding protein (I-FABP) was identified as an independent risk factor for postoperative delirium. Complementary experiments conducted in murine models demonstrated that intestinal ischemia-reperfusion injury induced behaviors analogous to delirium, accompanied by disruption of the intestinal barrier and gut dysbiosis predominantly characterized by Enterobacteriaceae overgrowth. Fecal microbiota transplantation from healthy donors effectively restored the microbial homeostasis, improved cognitive performance, and preserved hippocampal synaptic integrity. Multiomics analyses further revealed that microbiome dysbiosis triggered intestinal expression of indoleamine-2,3-dioxygenase 1 (IDO1), leading to systemic accumulation of L-kynurenine. This accumulation activated microglia, leading to aberrant synaptic phagocytosis and consequent cognitive decline.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14186 | MetaboLights | 2026-03-30

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14186_LC-MS_negative_reverse-phase.txt	Txt
	a_MTBLS14186_LC-MS_positive_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14186_LC-MS_negative_reverse-phase_v2_maf.tsv	Tabular
	m_MTBLS14186_LC-MS_positive_reverse-phase_v2_maf.tsv	Tabular

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Project description:Background: Current studies provide compelling evidence that the enteric nervous system and neighboring resident macrophages in the muscularis externa modulate neuroimmune processes in the gut after abdominal surgery. While substantial knowledge exists about macrophage-enteric glia interactions, the fate of enteric neurons, which have an indispensable role in gut homeostasis and gastrointestinal motility, has not been thoroughly investigated during enteric neuroinflammation. Therefore, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. Methods: Neuroinflammation and postoperative ileus were induced in various transgenic mice by surgical manipulation of the small intestine. We studied enteric neurons and macrophage-specific transcriptomes using bulk RNA-Seq in neuron-specific RiboTag mice and sorted CX3CR1-GFP+ macrophages. To investigate their intercellular communication, we treated CX3CR1-GFP+ mice with CSFR1-antibody to deplete macrophages and subsequently induce POI through surgical trauma. These mice were examined for gastrointestinal motility, immune cell infiltration, and neuronal function. Ultimately, we validated the murine data in human gut samples collected early and late during abdominal surgery to understand the impact of surgical manipulation on patients' enteric nervous system function. Results: We detected strong neuronal activation in the early postsurgical phase, followed, after 24h, by transcriptional signatures of neuronal proliferation, neuronal death, and synaptic degradation. Neuron-specific transcriptome analysis confirmed these changes and verified the neuronal responses to the inflammatory environment. Simultaneously, our study revealed a neurodegenerative profile in macrophage-specific transcriptomes during POI. Depletion of macrophages before surgical manipulation led to decreased neuronal death, less synaptic decay, and improved GI motility, emphasizing the essential role of macrophages in neurodegeneration during intestinal neuroinflammation. In human jejunal muscularis externa samples, taken at early and late stages of pancreatectomies, we detected reactive and dying neurons with dysregulated gene expression of synaptic signaling and neurogenic processes. Conclusion: Surgical trauma and acute intestinal inflammation activate enteric neurons and induce neurodegeneration with severe synaptic decay, predominantly mediated by resident macrophages. Future studies should focus on neuroprotective mechanisms to dampen neurodegeneration and promote faster recovery from postoperative inflammation and motility disturbances.

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Intraoperative intestinal ischemia-reperfusion injury aggravates postoperative delirium by remodeling gut microbiota

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