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Macrophage Immune-Competent Colon Assembloids for Functional Interrogation of Neuroinflammation-Induced Colonic Dysmotility

ABSTRACT: Functional gastrointestinal disorders (FGIDs) affect ∼40% of the global population and are frequently characterized by colonic dysmotility. Symptomatic manifestations of colonic dysmotility significantly reduce quality of life in inflammatory bowel disease (IBD), diabetes, and Gulf War Illness (GWI). Current in vitro models lack the integration of functional physiology with immune and neuronal complexity required to establish causal links between neuroinflammation and dysmotility. Here, an immune-competent bioengineered colon assembloid is introduced that integrates multiple cell types of the external colonic wall, along with functional readouts of motility. Within bioengineered colon assembloids, various inflammatory insults resulted in enteric neuroinflammation, cascading to changes in colonic motility. Key mechanisms of dysmotility following inflammatory insult within the bioengineered colon assembloids included impaired neuronal regeneration, and aberrant smooth muscle remodeling. The bioengineered colon assembloid model mimicked diverse aspects of enteric neuroinflammation. Ultimately, the platform offers a physiologically relevant avenue to interrogate neuroimmune crosstalk and dissect mechanisms of colonic dysmotility, paving the way to new therapeutic strategies to improve colonic motility.

ORGANISM(S): Mus musculus

PROVIDER: GSE316347 | GEO | 2026/01/13

REPOSITORIES: GEO

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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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Macrophage Immune-Competent Colon Assembloids for Functional Interrogation of Neuroinflammation-Induced Colonic Dysmotility

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