We describe herein a case of severe relapsed pyoderma gangrenosum (PG) concomitantly with severe pouchitis treated by tacrolimus. A 25-year-old woman had undergone proctocolectomy with construction of ileo-anal pouch surgery for refractory ulcerative colitis (UC). She first developed PG with refractory pouchitis, and infliximab (IFX) was administered to induce remission due to resistance to glucocorticoid therapy. After achieving remission, IFX was stopped. Five years later, severe skin ulcers concomitantly with severe pouchitis recurred and treatment with 30 mg oral prednisolone (PSL) combined with topical tacrolimus showed partial improvement. When PSL was tapered to 15 mg, the skin ulcers and diarrhea aggravated. Endoscopy revealed multiple ulcers in the ileal pouch. Treatment with oral tacrolimus was initiated for severe pouchitis and refractory PG. Forty days later, all skin ulcers became scars and multiple ulcers in the ileal pouch were also improved. Our case suggests that oral tacrolimus treatment could be a valuable treatment option for UC patients with refractory PG and pouchitis.

<b><i>Background/Aims:</i></b> Behçet’s disease (BD) with intestinal lesions and Crohn’s disease (CD) share clinical features. However, no report has compared the 2 diseases with regard to lesions of the upper gastrointestinal tract (UGT). We aimed to evaluate endoscopic and histologic findings of UGT in CD and BD. <b><i>Methods:</i></b> We retrospectively assessed the endoscopic records and biopsy samples of 84 <i>Helicobacter pylori</i>-negative patients (50 CD, 34 BD). In duodenal samples, MUC5AC immunohistochemical analysis was performed to identify gastric foveolar metaplasia. <b><i>Results:</i></b> In endoscopic findings, bamboo joint-like appearance (17/50 CD, 0/34 BD) and erosions (14/50 CD, 2/34 BD) were significantly more frequent in CD gastric lesions (<i>p</i> &#x3c; 0.001, and <i>p</i> = 0.012). In histologic findings of stomach, focal neutrophil infiltration in lamina propria (15/48 CD, 1/34 BD) was significantly more frequent in CD (<i>p</i> &#x3c; 0.001). In that of duodenum, wide gastric foveolar metaplasia (19/49 CD, 1/34 BD) was significantly more frequent in CD duodenal lesions (<i>p</i> = 0.013). The mean maximum width of the gastric foveolar metaplasia was 114.0 ± 10.6 and 29.5 ± 4.5 μm for CD and BD respectively (<i>p</i> = 0.003). <b><i>Conclusions:</i></b> In <i>H. pylori</i>-negative patients, gastric focal neutrophil infiltration and wide duodenal gastric foveolar metaplasia were important for distinguishing CD from BD.

Background/Aim: Transforming growth factor β (TGFβ) signaling plays a key role in modulating intestinal epithelial cell (IEC) homeostasis. The present study aimed to investigate the direct effect of tacrolimus on TGFβ signaling in IECs. Materials and Methods: The protective effects of tacrolimus, with or without anti-TGFβ antibody, in dextran sulfate sodium (DSS)-induced colitis were evaluated. Results: Tacrolimus ameliorated IEC apoptosis-mediated mucosal destruction despite anti-TGFβ treatment. TGFβ receptor type II (TGFβ-RII), phosphor-SMAD family members 2/3, and phosphor-extracellular signal-regulated kinase (ERK) expression in IECs was enhanced in tacrolimus-treated mice, and these positive effects were maintained despite anti-TGFβ treatment. Moreover, tacrolimus induced TGFβ-RII up-regulation through ERK activation. Conclusion: Our data indicate that tacrolimus directly activated TGFβ-SMAD signaling via the ERK pathway in IECs, thereby providing protection against apoptosis-mediated intestinal epithelial injury. Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis (UC), are refractory chronic diseases with repeated relapse and remission cycles, which are mediated by multiple immunological dysfunctions (1). Transforming growth factor β (TGFβ) is a multifunctional cytokine that regulates cellular processes, including differentiation, proliferation, apoptosis, and extracellular matrix production, depending on the tissue and signal intensity (2). Deregulation of the TGFβ signaling pathway is one of the known immunological dysfunctions in IBDs. Loss of TGFβ signaling is involved in colitis development in experimental models and IBD pathogenesis in humans (3, 4).A report showed that selective loss of TGFβ signaling resulted in intestinal inflammation (5). Moreover, we reported that loss of TGFβ signaling increased apoptosis of epithelial cells (6) and cyclosporine, a calcineurin inhibitor, ameliorated dextran sulfate sodium (DSS)-induced colitis in mice by upregulating TGFβ expression in colonic tissue and activating TGFβ signaling in intestinal epithelial cells (IECs) (7). TGFβ signaling in IECs plays a key role in maintaining the gut's barrier function via regulation of epithelial cell apoptosis (8).TGFβ signaling in IECs is regulated by various signaling proteins such as protein kinase C, phospholipase C, protein phosphatase 1, RAS, several mitogen-activated protein kinase (MAPK) superfamily members, and mothers against decapentaplegic (SMAD) superfamily members (9). Each signaling cascade is known to intersect intricately with others and the intersections have not been fully elucidated. Identification of signaling pathways involved in intestinal epithelial injury will contribute to the discovery of new therapeutic approaches for preventing epithelial destruction.Like other calcineurin inhibitors, tacrolimus is a potent immunomodulator that blocks T-cell activation (10).

Background and aims A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would be exerted through relationships between intestinal epithelial cells (IECs) and the host microbiota. The present study was designed to elucidate the effects of cyclosporine on monocarboxylate transporter 1 (MCT1) regulation and butyrate uptake by IECs. Methods Colitis was induced in C57BL6 mice via the administration of 4% dextran sulfate sodium in drinking water, following which body weights, colon lengths, and histological scores were evaluated. To examine the role of butyrate in the protective effects of cyclosporine, MCT1 inhibitor and an antibiotic cocktail was administered and tributyrin (TB; a prodrug of butyrate) was supplemented; MCT1 protein expression and acetylated histone 3 (AcH3) signals in IECs, as well as the MCT1-membrane fraction of Caco-2 cells, were evaluated. To explore butyrate uptake, as s butyrate derivatives, 3-bromopyruvic acid (3-BrPA) and 1-pyrenebutyric acid were used. Results Treatment with cyclosporine inhibited body weight loss and colon length shortening. However, treatment with MCT1 inhibitor and the antibiotic cocktail negated the efficacy of cyclosporine, whereas TB supplementation restored its protective effect. Furthermore, cyclosporine upregulated MCT1 expression in the membrane and the AcH3 signal in IECs, while also inducing higher anti-inflammatory cytokine production compared to that in the vehicle-treated mice. The transcription level of MCT1 mRNA in IECs and Caco-2 cells did not increase with cyclosporine treatment; however, cyclosporine treatment increased membrane MCT1 expression in these cells and uptake of butyrate derivative. Conclusion Cyclosporine treatment modulates butyrate uptake via the post-transcriptional upregulation of membrane MCT1 levels in IECs.

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