LAUSR

Inflammatory bowel diseases (IBD), including Crohn disease (CD) and ulcerative colitis (UC), are chronic diseases with no definite cure found to date. The etiology of IBD is complex, as many factors are associated with disease onset and/or progression, including environmental factors (e.g., geographical variation, smoking, antibiotics, diet, and microbes), genetics, and a dysfunctional gut barrier [1]. Multifactorial involvement renders it difficult to pinpoint a single causative agent and provide targeted treatment for IBD. As a result, current treatment paradigms focus on inducing remission and reducing the frequency of flares, mostly by suppressing the uncontrolled immune response; this of course introduces treatment risks, including infection and malignancy. The chronic inflammation associated with IBD centers around activation of nuclear factor kappa-light-chainenhancer of activated B cells (NF-κβ) and tumor necrosis factor-α (TNF-α); indeed, inhibition of TNF-α is an effective treatment for IBD. NF-κβ, an important contributor to innate immunity and altered gut homeostasis in IBD, activates NF-κβ, exacerbating inflammation [2]. TNF-α, which is downstream of NF-κβ, is an important regulator of gut barrier function associated with IBD in that it regulates intestinal epithelial cell shedding and is associated with gut barrier disruption [3]. Therefore, novel approaches to suppress or better regulate the NF-κβ/TNF-α pathways carry excellent potential to benefit IBD patients. The close association of TNF-α-induced protein 3, also known as A20, with NF-κβ, and TNF-α warrants further investigation to better define potential mechanisms for regulating inflammation in IBD. The A20 gene is induced by NF-κβ activation, whereas A20 protein negatively regulates NF-κβ signals. Indeed, A20 is involved in controlling inflammation in IBD through multiple mechanisms, such as maintaining the integrity of the gut barrier and controlling microbial influx from the gut lumen to the underlying tissue [4]. Conditional knockout of A20 in intestinal epithelial cells in mice increased apoptosis and influx of commensal bacteria after administration of TNF-α [5]. The gut barrier protective function of A20 is further elucidated by a study in which mice with A20 overexpression did not exhibit signs of increased intestinal paracellular permeability after lipopolysaccharide (LPS) administration [6]. Bacterial influx to the underlying tissue is frequently mediated through M cells; however, as paracellular permeability is a marker of facilitated bacterial entry from the lumen to submucosal lymphatic tissues, effects of A20 on the barrier might reflect facilitated transmucosal bacterial uptake. A recent study investigated potential reasons for failure of A20 to downregulate inflammation in pediatric CD. While A20 expression in ileal biopsies of pediatric CD patients was high, the protein level was low. The difference in levels of A20 expression and protein levels could be due to the low expression of ABIN-1, an A20 accessory protein, and instability of the A20 protein due to inhibition of post-translational phosphorylation, which in turn could be a result of low expression of IKKβ [7]. Nevertheless, the protective potential of A20 in IBD models has been poorly investigated to date. In this current study by Donghui Chen and colleagues, published in this issue of Digestive Diseases and Sciences [8], the authors explored the potential protective effect of A20 on intestinal paracellular permeability in a mouse * Eytan Wine [email protected]