UC patients with histological remission have a significant 52% RR reduction in clinical relapse/exacerbation compared with those with histological activity. Histological remission is also superior to endoscopic and clinical remission in predicting clinical outcomes. As ~30% of patients with endoscopic and clinical remission still have histological activity, addition of histological status as an end point in clinical trials or practice has the potential to improve clinical outcomes.

Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the digestive tract that is often debilitating. It affects patients’ quality of life and imposes a financial burden. Despite advances in treatment with medications such as biologics, a large proportion of patients do not respond to medical therapy or develop adverse events. Therefore, alternative treatment options such as electrical neuromodulation are currently being investigated. Electrical neuromodulation, also called bioelectronic medicine, is emerging as a potential new treatment for IBD. Over the past decade, advancements have been made in electrical neuromodulation. A number of electrical neuromodulation methods, such as vagus nerve stimulation, sacral nerve stimulation, and tibial nerve stimulation, have been tested to treat IBD. A series of animal and clinical trials have been performed to evaluate efficacy with promising results. Although the exact underlying mechanisms of action for electrical neuromodulation remain to be explored, this modality is promising. Further randomized controlled trials and basic experiments are needed to investigate efficacy and clarify intrinsic mechanisms.

BackgroundMatrix metalloproteinases (MMPs) are a family of enzymes that are typically released from intracellular stores to act on specific extracellular substrates. MMP expression and activity can be increased in a neuronal activity-dependent manner, and further increased in response to tissue injury. MMP substrates include cell adhesion molecules (CAMs) that are abundantly expressed in the brain and well positioned for membrane proximal cleavage. Importantly, CAM integrity is important to synaptic structure and axon-myelin interactions, and shed ectodomains may themselves influence cellular function.MethodsIn the present study, we have examined proteolysis of N-cadherin (N-cdh) by MMP-7, a family member that has been implicated in disorders including HIV dementia, multiple sclerosis, and major depression. With in vitro digest assays, we tested N-cdh cleavage by increasing concentrations of recombinant enzyme. We also tested MMP-7 for its potential to stimulate N-cdh shedding from cultured neural cells. Since select CAM ectodomains may interact with cell surface receptors that are expressed on microglial cells, we subsequently tested the N-cdh ectodomain for its ability to stimulate activation of this cell type as determined by nuclear translocation of NF-κB, Iba-1 expression, and TNF-α release.ResultsWe observed that soluble N-cdh increased Iba-1 levels in microglial lysates, and also increased microglial release of the cytokine TNF-α. Effects were associated with increased NF-κB immunoreactivity in microglial nuclei and diminished by an inhibitor of the toll-like receptor adaptor protein, MyD88.ConclusionsTogether, these in vitro results suggest that soluble N-cdh may represent a novel effector of microglial activation, and that disorders with increased MMP levels may stimulate a cycle in which the products of excess proteolysis further exacerbate microglial-mediated tissue injury. Additional in vivo studies are warranted to address this issue.

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