CCL2 subnetwork structure in IBD patients. (A) Hypoxia and inflamed enteric neuron subnetworks from CD ileum constructed in the following BNs: control ileum, CD ileum, control colon, CD colon, and UC colon. FET was used to test enrichment with P < 0.05 as the cutoff. (B)CCL2 subnetworks comprised of the CCL2 node that is extended out to include all directly connected nodes within three path lengths in the IBD (CD Ileum, CD colon, and UC colon) and control (normal control colon) BNs. Present in normal control colon: ELF4, IRF4, SLAMF1, SLAMF7, and IFNG-AS1 (genes involved in Th17 immune responses) (Cao et al., 2023); DAB2IP, GPR15, and ELMSANI (regulators of neuronal differentiation) (Chang et al., 2013; Takeo et al., 2016; Mondal et al., 2020); and MARK2 and TOMIL2 (involved in neurodegeneration) (Matenia and Mandelkow, 2009; Ou et al., 2021); or SEMA4B (axon guidance proteins) (Jian et al., 2014). Present in inflamed CD ileum: IFGB5 (promotes neuronal apoptosis) (Guo et al., 2024), ZEB2 (promotes proliferation and differentiation of enteric neural precursor cells) (Feng et al., 2024), FIBIN (a neurogrowth factor highly expressed in the brain) (Lakner et al., 2011), PDK2 (a key component for inflammatory pain pathogenesis) (Jha et al., 2015), MLKL (involved in ischemia-induced neuronal necroptosis-driven microglia/macrophage polarization) (Yang et al., 2018), and PDGFRA (a marker for enteric neuron–associated fibroblast-like cells) (Kurahashi et al., 2011). Present in inflamed CD colon: NRP1 (encodes neuropilin-1 and controls enteric neuron connectivity) (Gonzales et al., 2020), NR2F1 (involved in neuronal differentiation and upregulated in aganglionic regions of Hirschsprung’s disease) (Gomez Ramos et al., 2024; He et al., 2023), SAMSN1 (regulates neural stem cell proliferation and promotes hypoxia-induced neuronal injury) (Wang et al., 2023), ENTPD2 (expressed by enteric glia and regulates enteric neuron numbers and phenotype) (Grubišić et al., 2019), and SGTB (promotes neuronal differentiation and neurite outgrowth and is associated with neuronal apoptosis after neuroinflammation) (Vuong et al., 2019; Cao et al., 2013). Present in inflamed UC colon: DCN (extracellular matrix protein protecting from traumatic brain injury) (Oshima et al., 2024), SRGN (amplifies microglia-mediated neuroinflammation and exacerbates ischemic brain injury) (Qian et al., 2024), HTRA1 (regulates neuronal differentiation, promotes HIF1α signaling, and is associated with Alzheimer’s disease) (Qian et al., 2024), KIRREL (involved in synaptogenesis, axon branching, and angiogenesis) (Baltar et al., 2024; Wang et al., 2024), MCAM (involved in angiogenesis) (Jiang et al., 2012), and PRKAR2B (inhibits postsynaptic function of neurons) (Weise et al., 2019).