Background: Current studies provide compelling evidence that the enteric nervous system (ENS), together with immune cells, modulate neuroimmune processes in the gut. Previous work revealed the essential role of resident macrophages (Macs) therein. However, the closely associated enteric neurons (EN), which have an indispensable role in gut homeostasis, including barrier function and gastrointestinal motility, have not been thoroughly investigated regarding their interplay with Macs during enteric neuroinflammation. Therefore, we investigated the impact of EN-Mac interactions on postoperative trauma and subsequent motility disturbances, e.g., postoperative ileus (POI).
Methods: Neuroinflammation and POI were induced in various transgenic mice by surgical manipulation of the small intestine. To investigate the transcriptome of EN and Macs during gut inflammation, we used a neuron-specific RiboTag mouse and FACS-sorted CX3CR1-GFP⁺ Macs for cell-specific RNA-Seq analyses. To look closely at EN-Mac communication during neuroinflammation, we applied a CSFR1-antibody treatment to CX3CR1-GFP⁺mice to deplete Macs and subsequently perform surgical trauma to induce POI. These mice were examined for gastrointestinal (GI)-motility, immune cell infiltration, and various neuronal characteristics. Ultimately, we validated the murine data in human gut samples collected early and late during abdominal surgery to understand surgical manipulation's impact on patients' ENS function.
Results: In POI mice, we detected strong neuronal activation in the initiation phase (3h) and induction of neuron proliferation and death coinciding with synaptic degradation at the peak of the disease (24h). The neuronal transcriptome confirmed these severe changes and verified EN's response to the inflammatory environment. Analysis of the Mac-specific transcriptome revealed a distinct neurodegenerative gene profile, pointing to a detrimental effect of the EN-Mac interaction during POI. Depletion of Macs before surgical manipulation led to decreased neuron death, less synaptic decay, and improved GI motility, emphasizing the essential role of Macs in neurodegeneration during intestinal neuroinflammation. Concurrently, we analyzed the impact of surgical trauma on EN in human patient samples. There, we detected reactive and dying neurons in ENS ganglia that displayed dysregulated gene patterns for neuronal functions, e.g., synaptic signaling and neurogenesis.
Conclusion: Surgical trauma and acute intestinal inflammation activate enteric neurons and induce neurodegeneration with severe synaptic decay, predominantly by involving the resident Mac population. Future studies should focus on neuroprotective mechanisms to dampen neurodegeneration and thus assist patients in surmounting functional complications, such as motility impairment, after surgery more rapidly.

Joachim Schmidt

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