This was striking both for the initial loss of neurons (which are not replaced (Sanovic et al., 1999)) and for the fact that numbers remain stable thereafter, even though the severity of inflammation increased (Blennerhassett et al., 2017 Venkataramana et al., 2015). In animal models of Crohn's disease such as TNBS-induced colitis, inflammation caused the loss of a significant number of neurons in the affected region by the first 48 h in both rat and mouse models (Blennerhassett et al., 2017 Linden et al., 2005 Sanovic et al., 1999 Venkataramana et al., 2015), as well as damage to the axons of surviving neurons (Lourenssen et al., 2005). In Crohn's disease, a form of Inflammatory Bowel Disease (IBD) that causes severe transmural inflammation, there is enteric ganglionitis and neuropathy that contributes to impaired gut function, with evidence of axonal necrosis and neurodegeneration (De Giorgio et al., 2004 Dvorak and Silen, 1985 Villanacci et al., 2008). Inflammation can cause damage and even death of enteric neurons that will affect gut function. Diverse neuronal types are present within each ganglion, assisting in the notable neuroplasticity of the intestine that supports adaptation to local damage and even surgical removal of entire segments. This is achieved by neurons resident in ganglia that are distributed along the length of the GI tract. The enteric nervous system (ENS) controls the diverse functions of the intestine, which include contraction and relaxation of the smooth muscle that create patterned motility, as well as secretion and absorption by the mucosa. This may support novel strategies to address recurrent inflammation in IBD. Therefore, inflammation challenges enteric neurons via ischemia, while GDNF is neuroprotective, activating RET and HIF-1α to limit programmed cell death. However, combinations of inhibitors or the RIP1kinase inhibitor Nec-1 prevented neuronal death, evidence for RIPK1-dependent necroptosis. In DNP-treated co-cultures, neuron death was not inhibited by zVAD, necrosulfonamide or GSK872, and cleaved caspase-3 or − 8 were undetectable. This includes a key role for upregulation of HIF-1α, which was detected in neurons in colitis, since the inhibitor chetomin blocked rescue by GDNF or ischemic pre-conditioning in vitro. Thus, both basal and upregulated GDNF levels signal via RET for neuronal survival. Neuroprotection was lost with RET inhibition by vandetanib or GSK3179106, which also caused neuron loss in untreated controls. These caused the specific loss of 50% of neurons by 24 h that was blocked by GDNF both in vitro and in whole mounts. This was examined in a primary co-culture model of rat myenteric neurons and smooth muscle, where metabolic challenge was caused by dinitrophenol (DNP), O -methyl glucose (OMG) or hypoxia. Inflammation could involve ischemia and metabolic inhibition leading to neuronal damage, which might be countered by a protective action of GDNF. In the animal model of TNBS-induced colitis, an influx of immune cells causes early neuron death in the neuromuscular layers, followed by axonal outgrowth from surviving neurons associated with upregulation of the neurotrophin GDNF (glial cell line-derived neurotrophic factor). Intestinal inflammation challenges both function and structure of the enteric nervous system (ENS).