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Background/Aims: The hepatitis C virus nonstructural 3/4A protease has been shown to cleave protein tyrosine phosphatase nonreceptor type 2 (PTPN2, also known as T cell protein tyrosine phosphatase), thereby inducing a shift from a Th1 toward a nonantiviral Th2 immunity. Ribavirin therapy reverses these effects and supports direct-acting antiviral (DAA) therapy as an immunomodulatory compound and ultimately improves the response to DAA therapy. Here we aimed to assess whether intrahepatic levels of PTPN2 might be used as a clinical prognostic marker for the response to DAA therapy. Methods: Liver biopsies from hepatitis C virus-infected patients with and without cirrhosis were immunohistochemically stained for PTPN2 and scored for staining intensity as well as percentage of hepatocytes positive for nuclear PTPN2 localization. PTPN2 scores were correlated to sustained virologic response after DAA therapy, viral load, serum levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase (GGT), and the Model for End-Stage Liver Disease (MELD) score at the time of liver biopsy. Results: We did not detect a difference in intrahepatic PTPN2 levels between responders with cirrhosis, responders without cirrhosis, and nonresponders to DAA therapy. There was no correlation between intrahepatic PTPN2 levels and viral load or clinical markers such as liver transaminases, GGT, or the MELD score. Conclusion: Intrahepatic PTPN2 levels assessed via IHC staining do not represent a clinical prognostic marker for the response to DAA therapy.

Background and Aims: Local extracellular acidification is associated with several conditions, such as ischemia, cancer, metabolic disease, respiratory diseases, and inflammatory bowel disease (IBD). Several recent studies reported a link between IBD and a family of pH-sensing G protein-coupled receptors. Our previous studies point to an essential role for OGR1 (GPR68) in the modulation of intestinal inflammation and fibrosis. In the current study, we evaluated the effects of a novel OGR1 inhibitor in murine models of colitis. Methods: The effects of a novel small-molecule OGR1 inhibitor were assessed in the acute and chronic dextran sulfate sodium (DSS) murine models of colitis. Macroscopic disease indicators of intestinal inflammation were evaluated, and epithelial damage and immune cell infiltration and proliferation were assessed by immunohistochemistry. Results: The OGR1 inhibitor ameliorated clinical parameters in acute and chronic DSS-induced colitis. In mice treated with the OGR1 inhibitor, endoscopy showed no thickening and normal vascularity, while fibrin was not detected. Histopathological findings revealed a decrease in severity of colonic inflammation in the OGR1 inhibitor group when compared to vehicle-DSS controls. In OGR1 inhibitor-treated mice, staining for the macrophage marker F4/80 and cellular proliferation marker Ki-67 revealed a reduction of infiltrating macrophages and slightly enhanced cell proliferation, respectively. This was accompanied by a reduction in pro-inflammatory cytokines, TNF and IL-6, and the fibrosis marker TGF-β1. Conclusion: This is the first report providing evidence that a pharmacological inhibition of OGR1 has a therapeutic effect in murine colitis models. Our data suggest that targeting proton-sensing OGR1 using specific small-molecule inhibitors may be a novel therapeutic approach for the treatment of IBD.

Background/Aims: Knockdown of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) exaggerates IFN-γ-induced intestinal barrier defects, but mice constitutively lacking PTPN2 in epithelial cells (PTPN2xVilCre mice) do not show changes in epithelial function or enhanced susceptibility to experimental colitis. Here, we investigated whether PTPN2 modulates the expression of related tyrosine phosphatases. Methods: PTPN2 knockdown in HT-29 cells was induced using siRNA constructs. Acute colitis in PTPN2xVilCre mice was induced by 2% dextran sulfate sodium (DSS) in drinking water for 7 days. Colitis-associated tumors were induced by injection of azoxymethane prior to treatment with DSS for 3 consecutive cycles. Results: In HT-29 cells, PTPN2 depletion resulted in enhanced mRNA expression of PTPN11 and PTPN23 and in parallel to upregulation of IL-18 mRNA upon treatment with TNF for 24 h. DSS treatment of PTPN2-deficient mice resulted in a strong induction of Ptpn23 mRNA in colon tissue in vivo. In the tumor model, Ptpn23 mRNA was again clearly upregulated in nontumor tissue from PTPN2-deficient mice; however, this was not observed in tumor tissue. Conclusions: Our experiments show that PTPN23 function might, at least partially, compensate lack of PTPN2 in epithelial cells. Upregulation of PTPN23 might therefore crucially contribute to the lack of a colitis phenotype in PTPN2-VilCre mice.

Background/Objectives: Protein tyrosine phosphatase nonreceptor type 23 (PTPN23) has recently been associated with several human epithelial cancers via regulation of growth factor signaling. Colorectal carcinoma (CRC) is a leading cause for cancer-related death worldwide and is associated with aberrant epidermal (EGF) and vascular endothelial growth factor signaling. Here, we investigated whether PTPN23 might play a role in CRC. Methods: Expression of PTPN23 was analyzed in CRC tissue by immunohistochemistry. PTPN23 was silenced in HT-29 cells to address the role of PTPN23 in EGF signaling, gene expression, and cell migration. Results: PTPN23 silencing in HT-29 and Caco-2 intestinal epithelial cancer cells significantly enhanced activation of pro-oncogenic signaling molecules and genes promoting epithelial-to-mesenchymal transition (EMT) upon EGF treatment, while genes encoding tight junction proteins were significantly reduced. Conclusions: Our data clearly indicate that loss of PTPN23 is associated with increased activation of pro-oncogenic signaling pathways and an enhanced ability of human intestinal cancer cells to undergo EMT. Taken together, these findings show that PTPN23 acts as a tumor suppressor gene in CRC.

Introduction: The pathophysiology of inflammatory bowel disease (IBD) is incompletely understood. Current concepts imply that environmental factors (EFs) trigger disease onset as well as flares in genetically susceptible individuals. Objective: The objective of this study is to analyze the association between IBD and various EFs, which may influence the pathogenesis of the disease. Methods: 2,294 patients from the Swiss IBD Cohort Study (SIBDCS) received a questionnaire regarding EF including mode of delivery, breastfeeding, animals in household, and place of residence. The control group comprised patients’ childhood friends, who grew up in a similar environment (“friends cohort”). Results: A total of 1,111 questionnaires were returned from SIBDCS patients (response rate: 48.4%). Breastfeeding for p = 0.006). IBD patients reported less pet animals in the household than the control group (p = 0.004). The presence of cats or dogs (OR: 0.688, p = 0.015) and pet rodents (OR: 0.598, p = 0.001) in the household before the age of 20 was inversely associated with the risk for UC/IC. Conclusion: The present study underlines the importance of EFs in the pathogenesis of IBD. Overall, the development of UC/IC seems to be more affected from environmental influences than from Crohn’s disease. Our results imply a protective effect of possessing pet animals in household and short breastfeeding regarding the onset of UC/IC.

An acute sigmoid volvulus is due to the torsion of the sigmoid colon around its mesenteric axis. It mainly occurs in elderly patients and represents an abdominal emergency requiring urgent treatment. A 53-year-old male patient with severe craniocerebral injury and traumatic subarachnoidal bleeding 3 weeks prior presented on the ward with distended abdomen without abdominal pain, muscular defense, or resistances. He featured large volume diarrhea within the last few hours without signs of bleeding. A plain abdominal X-ray demonstrated a coffee bean sign indicating a sigmoid volvulus. A consequent CT scan of the abdomen revealed a deep outlet obstruction with massively dilated, elongated and twisted loop of the sigmoid colon and no signs of perforation. We performed emergency colonoscopy under the assumption of an acute sigmoid volvulus. After careful insertion of the endoscope completely refraining from insufflation of air or CO2, endoscopic reposition of the sigma could be achieved and a colonic drainage was placed over an inserted guide wire up to the proximal transverse colon. No relapse occurred and a diagnostic colonoscopy after 4 weeks revealed no tumor or polyps. Our report describes a classic case of acute sigmoid volvulus and undermines the potential of colonoscopy as conservative primary treatment of choice.

Background: Long-term data of certolizumab pegol (CZP) in Crohn's disease (CD) from pivotal registry trials are limited. We therefore aimed to evaluate the long-term efficacy of CZP in clinical practice in Switzerland. Methods: In the First Approved Certolizumab Therapeutic Experience in Switzerland-III phase IV multicenter cohort, patients receiving CZP were prospectively included all over Switzerland in (non-) academic hospitals and private practice. Results: We included 104 CD patients (52 male; only 22.1% anti-tumor necrosis factor (TNF) naïve, CZP as third anti-TNF agent in 46.2%) with follow-up time between 6 weeks up to 5 years. During treatment with CZP, we observed a significant decrease of the Harvey Bradshaw Index from a median of 7 at baseline (interquartile range 4-11) to 4, 5, 4, 3, 3, and 2 at weeks 6, 26, 52, 78, 104, and 156, respectively. While anti-TNF naïve patients showed a significantly better response at the end of induction, during CZP maintenance therapy response was similar as compared to anti-TNF experienced patients as well as between patients with a short (0-5 years) vs. long duration of disease (>5 years). Conclusions: CZP is an effective long-term treatment option, including CD patients with long disease duration and prior treatment with 1 or 2 anti-TNF agents.

Hepatitis C is frequently accompanied by immune-related extrahepatic manifestations affecting the skin, kidneys, central and peripheral nervous system and exocrine glands. We present the case of a 40-year-old man with left-sided ptosis, exophthalmos and headache. MRI demonstrated left-sided orbital pseudotumor with lacrimal and retro-orbital contrast enhancement extending to the cavernous sinus and the vestibulocochlear nerve. Immunological tests of serum and cerebrospinal fluid identified hepatitis C virus (HCV) as a potential causative agent but did not indicate any additional infectious, malignant or immunological disorder. Hepatological evaluation revealed no signs of advanced liver disease. After initial spontaneous improvement, the patient subsequently developed vestibulocochlear failure with gait disorder, tinnitus and transient left-parietal sensory loss. Lacrimal biopsy demonstrated lymphocytic infiltrate, prompting steroid treatment. After initial improvement, steroids could not be tapered below 40 mg daily for several months due to recurrent symptoms. Twelve months after the initial presentation, the patient’s chronic HCV infection was successfully treated with sofosbuvir, simeprevir and ribavirin and he remains now free of symptoms without steroids. In patients with chronic hepatitis C, lymphocytic infiltrate of the salivary and lacrimal glands is a frequent phenomenon. However, the extent of the lymphocytic infiltrate beyond the lacrimal gland to the tip of the orbit, cavernous sinus and vestibulocochlear nerve as in our patient is highly unusual. For all symptomatic extrahepatic manifestations of hepatitis C infection, treatment of HCV as the underlying immune stimulus is recommended, and it helped to control the symptoms in our patient. In addition, long-term follow-up for recurrent lymphocyte infiltrate and development of lymphoma is warranted.

Background: Gastrointestinal and extraintestinal malignancies are long-term complications in patients with inflammatory bowel disease (IBD), likely as a result of chronic inflammation and the use of immunosuppressive medications used to control inflammation. Here, we assessed the frequency of malignancies in a large tertiary IBD centre at the University Hospital Zurich. Methods: We performed a retrospective analysis of data from 1,026 patients from our IBD clinic treated between 2007 and 2014. Results: Twenty two of the 1,026 patients developed 28 cases of malignancies, 14 patients were male and 8 patients female. The median latency between IBD diagnosis and first malignancy was 13 years (range 2-27 years). Most common malignancies were non-Hodgkin lymphoma, colorectal cancer (CRC), urothelial carcinoma, cholangiocellular carcinoma (CCC) and prostate cancer. The most common tumour type in Crohn's disease patients (13/22) was lymphoma (5 cases), in ulcerative colitis patients (9/22) CCC (2 cases) and CRC (2 cases). The observed incidence of lymphoma (32.5/100,000), bladder carcinoma (21.7/100,000) and CCC (10.8/100,000) was higher than expected and known from general population. All of the patients that developed a malignancy had received immunosuppressive therapy. Compared to a cohort of 927 IBD patients without malignancies there were no statistical differences regarding gender, antibodies targeting tumour necrosis factor and thiopurine use. Conclusion: Our data support the assumption that a long-standing disease course and immunosuppressive therapy increase the risk for developing malignancies in IBD patients.

Background: The TNF-α antagonist golimumab is approved for the treatment of ulcerative colitis but not for Crohn's disease (CD). We herein report a case series of 8 difficult-to-treat patients with severe and refractory CD receiving golimumab as an off-label rescue medication and fourth-line anti-TNF agent in our tertiary referral inflammatory bowel disease center. Methods: We performed a retrospective analysis of clinical, biochemical, and radiological as well as endoscopic parameters. The patients all suffered from severe refractory CD with ongoing symptoms. Moreover, all 8 patients had previously been treated with all 3 other TNF-α antagonists approved for CD in Switzerland (infliximab, adalimumab, and certolizumab pegol) without durable clinical response. Results: Three out of 8 patients showed a primary nonresponse. Among the 5 patients responding after induction, 1 patient showed a loss of response, and in 1 patient, treatment was terminated due to side effects. Three patients have a continuous clinical response under golimumab. We did not observe any severe adverse events during golimumab administration. Conclusions: A considerable fraction of this highly selected subgroup of difficult-to-treat CD patients responded to golimumab, indicating a promising potential for refractory CD patients, including those with multiple previous anti-TNF exposures.

Background: The probiotic bacterial strain Escherichia coli Nissle 1917 (EcN) is used for the treatment of ulcerative colitis (UC), diarrhea and constipation. Its beneficial effects in the treatment of UC have been demonstrated in several controlled clinical studies; however, the mechanism of action on the cellular level is still not completely clear. The intracellular pattern recognition receptor NLRP3 is expressed in intestinal epithelial cells (IEC), activates caspase-1 within the inflammasome complex and has been implicated to play a role in the etiology of inflammatory bowel diseases. Methods: Probiotic EcN and commensal E. coli K12 were applied to IEC in vitro. Inflammasome activation, interleukin (IL)-18 release and caspase-1 activation were determined by coimmunoprecipitation, Western blot and ELISA. Apoptosis was investigated by Western blot. Results: Incubation of Caco-2 cells with EcN resulted in lower inflammasome activation and subsequent secretion of mature IL-18 as compared to the commensal strain K12. Induction of apoptosis as determined by cleavage of caspase-3 and poly (ADP-ribose) polymerase were lower in EcN-stimulated cells. Autophagy was induced by both bacterial strains, but to a higher extent by K12. Conclusion: These findings indicate that genetically very similar E. coli strains differ markedly in their ability to activate the inflammasome.

Background/Aims: Anthocyanins are plant-derived dietary components that are highly abundant, for example, in bilberries. We have previously demonstrated that anthocyanins exert anti-inflammatory properties in mouse colitis models and ameliorate disease activity in ulcerative colitis patients. Here, we studied the molecular mechanisms through which anthocyanin-containing bilberry extract (BE) exerts anti-inflammatory effects in human monocytic THP-1 cells. Methods: THP-1 cells were pre-incubated with BE 20 min prior to TNF-a or IFN-γ (100 ng/ml each) stimulation. Signalling protein activation was studied by Western blotting, mRNA expression by quantitative PCR and cytokine secretion by ELISA. Results: IFN-γ-induced phosphorylation of STAT1 and STAT3 was significantly reduced by BE co-treatment. Consequently, levels of mRNA expression and/or cytokine secretion of MCP-1, IL-6, TNF-a, ICAM-1, and T-bet were lower with BE co-treatment. In contrast, BE enhanced TNF-a-mediated p65-NF-γB phosphorylation but reduced ERK1/2 phosphorylation. BE co-treatment further increased TNF-a-induced mRNA expression and secretion of NF-γB target genes, such as IL-6, IL-8, and MCP-1, while mRNA levels of ICAM-1 were reduced. Conclusions: BE co-treatment reduced IFN-γ-induced signal protein activation, pro-inflammatory gene expression, and cytokine secretion, whereas it enhanced TNF-a-induced responses. These findings suggest a distinct role for anthocyanins in modulating inflammatory responses that need to be further studied to fully understand anthocyanin-mediated effects.

Crohn's disease (CD) is characterized by a breakdown of the intestinal epithelial barrier function leading to an uncontrolled immune response to bacterial antigens. Available data demonstrate that appropriate response and early host defense against invading bacteria are crucial to maintain tolerance towards commensal bacteria. When the mechanisms of early removal of invading bacteria are disturbed, a loss of tolerance and a full-blown adaptive immune reaction, which is mounted against the usually harmless commensal flora, are induced. Dysfunction of autophagy caused by genetic variations within CD susceptibility genes, such as ATG16L1 and IRGM, results in defective handling of intracellular and invading bacteria and causes prolonged survival and defective clearance of those microbes. Dysfunction of ATG16L1 and IRGM has also been shown to cause aberrant Paneth cell function and uncontrolled secretion of proinflammatory cytokines finally resulting in increased susceptibility to bacterial infection and the onset of colitis. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as NOD2 (nucleotide oligomerization domain 2) or PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and the presence of the CD-associated variations within these genes results in similar effects. Taken together, more and more evidence suggests a close functional correlation between loss of tolerance and defective autophagy in CD patients. Therefore, most likely, the onset of CD is triggered by both a loss of tolerance as well as a dysfunction of autophagy, which finally results in the onset of chronic intestinal inflammation.

Background and Aims: Paradoxically, psoriasis or psoriasiform skin lesions induced or exacerbated by anti-TNF antibodies have been described. Here, we report a series of 13 novel cases featuring exacerbation or occurrence of psoriatic skin lesions induced by anti-TNF antibodies in patients with Crohn's disease (CD). Methods: We performed a systematic analysis of exacerbation or occurrence of psoriasis or psoriasiform skin lesions induced by anti-TNF antibodies in an inflammatory bowel disease patient cohort at the University Hospital Zurich. Results: We identified 13 CD patients who developed psoriasis or psoriasiform lesions while receiving anti-TNF therapy. 10 of the 13 patients were female with an average age of 26.9 years at diagnosis. 11 of the 13 patients had a complicated disease. The mean time of clinical latency between diagnosis and onset of psoriasis was about 9.4 years, and the time between the beginning of all biological infusions and the onset of psoriasis was about 7 months. 7 of the 13 patients received infliximab, 3 adalimumab, and 3 certolizumab pegol at onset of psoriasis. In most of the cases, anti-TNF therapy was changed or discontinued and skin lesions improved. Conclusion: Most of our described patients featured a complicated disease course of CD and had an improvement of the rash after changing the anti-TNF therapy.

A characteristic feature of active inflammatory bowel disease is the infiltration of innate and adaptive immune cells into the intestinal lamina propria. This complex mixture of a broad variety of cel

T-cells are the key players in the adaptive immune system. In the healthy individual, the components of the adaptive immune system cooperate with each other as well as with the innate immune system to

Up to 80% of Crohn's disease (CD) patients and 10% of ulcerative colitis (UC) patients will require at least one bowel surgery during their lifetime. Other surgeries that are not related to inflammatory bowel disease may also be necessary for these patients. It is well known that the preoperative administration of steroids is associated with increased numbers of perioperative complications, anastomosis leaks and postoperative infections. For classical immunosuppressants, such as azathioprine and 6-mercaptopurine, significantly lower risks of the above-mentioned complications have been demonstrated. Thus, the careful consideration of preoperative therapy is crucial for the short-term and long-term outcomes of surgery in inflammatory bowel disease patients. The association of preoperative anti-TNF antibody therapy with a higher rate of postoperative complications has been debated in the literature. Two recent meta-analyses of CD patients have suggested that this therapy results in a slightly higher rate of postoperative infection complications in these patients, but its effects on UC patients are still unclear. This overview summarizes the current literature on the use of preoperative anti-TNF treatment and consecutive potential complications in CD and UC patients.