Differences in Coronavirus disease - 19 vaccination related side effects in patients with ulcerative colitis and Crohn's disease in Japan.

BACKGROUND/PURPOSE OF THIS STUDY: It has been recommended that individuals with inflammatory bowel disease (IBD) be vaccinated against Coronavirus disease - 19 (COVID-19). Recently, we documented the incidence of side effects (SEs) after COVID-19 immunization among individuals with IBD in Japan. However, the study did not show differences between the types of IBD or the patients' clinical backgrounds. In this survey, we aimed at investigating whether the frequency of SEs differed among patients with IBD. METHODS: A cross-sectional survey was conducted among adult patients with IBD at Kobe University between March 2022 and September 2022. RESULTS: Total 195 patients, including 134 with ulcerative colitis (UC) and 61 with Crohn's disease (CD), completed the questionnaire and were included in the analysis. Of these, 92.3%, 91.3% and 44.1% received the initial, second and third dose of the COVID-19 vaccine, respectively. The frequency of local symptoms following the initial, second and third dose of the vaccine was comparable between patients with UC and CD (69.6% vs. 72.7%, 64.2% vs. 69.1% and 63.5% vs. 73.9%, respectively). Muscle pain after the initial and second doses of the COVID-19 vaccine was more common among patients treated with corticosteroids (58.1% vs. 37.6% and 60.0% vs. 31.8%, p < 0.05). Female sex, younger age and current or former smoking were associated with an increased incidence of fever or chills after the initial dose of the vaccine (p < 0.05). In contrast, corticosteroid use was identified as a factor associated with an increased incidence of muscle pain after the initial dose of vaccine (p < 0.05). CONCLUSION: The use of corticosteroids could increase the risk of muscle pain following COVID-19 vaccination. Additionally, factors such as female sex, younger age and current or former smoking can affect the incidence of fever or chills. This information should encourage patients with IBD to get vaccinated against COVID-19.

Disseminated Mycobacterium avium Complex Infection in a Patient Treated With Immunosuppressants.

Mycobacterium avium complex (MAC) is an important cause of opportunistic infections in immunosuppressed hosts, such as patients with HIV infection and solid organ transplant recipients. MAC disease usually presents in 4 distinct clinical categories: chronic pulmonary disease, disseminated disease, skin/soft-tissue infection, and superficial lymphadenitis. However, clinical reports on gastrointestinal (GI) MAC disease are rare, especially in patients without HIV infection or a history of organ transplantation. We describe a case of non-HIV-associated GI MAC disease in a patient with long-term mycophenolate mofetil use. In this case, MAC organisms in the GI tract and ascites were observed. Endoscopy revealed a unique colonic image with large, deep epithelial denudations. This suggests that apart from patients with HIV infection or transplant recipients, those treated with immunosuppressants can have disseminated MAC. Therefore, internal physicians need to monitor patients undergoing mycophenolate mofetil immunosuppressant therapy.

LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice.

BACKGROUND: Amino acid transporters play an important role in supplying nutrition to cells and are associated with cell proliferation. L-type amino acid transporter 1 (LAT1) is highly expressed in many types of cancers and promotes tumor growth; however, how LAT1 affects tumor development is not fully understood. METHODS: To investigate the role of LAT1 in intestinal tumorigenesis, mice carrying LAT1 floxed alleles that also expressed Cre recombinase from the promoter of gene encoding Villin were crossed to an ApcMin/+ background (LAT1fl/fl; vil-cre; ApcMin/+), which were subject to analysis; organoids derived from those mice were also analyzed. RESULTS: This study showed that LAT1 was constitutively expressed in normal crypt base cells, and its conditional deletion in the intestinal epithelium resulted in fewer Paneth cells. LAT1 deletion reduced tumor size and number in the small intestine of ApcMin/+ mice. Organoids derived from LAT1-deleted ApcMin/+ intestinal crypts displayed fewer spherical organoids with reduced Wnt/ß-catenin target gene expression, suggesting a low tumor-initiation capacity. Wnt3 expression was decreased in the absence of LAT1 in the intestinal epithelium, suggesting that loss of Paneth cells due to LAT1 deficiency reduced the risk of tumor initiation by decreasing Wnt3 production. CONCLUSIONS: LAT1 affects intestinal tumor development in a cell-extrinsic manner through reduced Wnt3 expression in Paneth cells. Our findings may partly explain how nutrient availability can affect the risk of tumor development in the intestines.

Side Effects of COVID-19 Vaccines in Patients with Inflammatory Bowel Disease in Japan.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are recommended to receive the coronavirus disease 2019 (COVID-19) vaccine. However, a recent survey showed that patients with IBD are more hesitant to receive the vaccine than the general population. Detailed information on the side effects of the COVID-19 vaccine is necessary to encourage vaccination among patients with IBD. AIM: To investigate the frequency of side effects following COVID-19 vaccination in patients with IBD in Japan. STUDY DESIGN: a cross-sectional survey was conducted using a questionnaire administered to adult patients with IBD in a tertiary medical facility. RESULTS: Among the participants who answered the questionnaire, 92.6%, 91.5%, and 41.5% of the participants had received their first, second, and third doses of the COVID-19 vaccine, respectively. Of the vaccinated participants, 88.3%, 86.3%, and 89.0% experienced side effects after receiving the first, second, and third doses of the vaccine, respectively. The incidences of fever, chills, and headaches were significantly higher among female participants than among male participants (p < 0.05). However, the frequencies of most side effects were comparable between the BNT162b2 mRNA and mRNA-1273 vaccines. CONCLUSION: The findings of our survey can help encourage patients with IBD to receive the COVID-19 vaccine.

Efficacy and predictor of anti-TNFα agents in patients with intestinal Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a recurrent multisystem inflammatory disease. Anti-tumor necrosis factor (TNF) α agents have been used to treat patients with intestinal BD with severe disease activity or those who are resistant to conventional treatments; however, the long-term efficacy of anti-TNFα agents in intestinal BD remains unclear. In the present study, we investigated the clinical outcomes and predictors of discontinuation of anti-TNFα agents in patients with intestinal BD. METHODS: We reviewed the medical records of patients with intestinal BD who received first-line anti-TNFα agents between January 2009 and June 2020. The primary outcome was the percentage of patients who continued anti-TNFα therapy for 48 weeks. Secondary outcomes included the percentage of patients who achieved marked improvement, complete remission, and mucosal healing, as well as predictors of discontinuation of anti-TNFα agents. RESULTS: A total of 29 patients were included in the study. Twenty-two (75.9%) patients continued anti-TNFα therapy for 48 weeks. The percentage of patients who achieved marked improvement, complete remission, and mucosal healing at week 48 was 48.3%, 37.9%, and 48.3%, respectively. At week 96, 11 (37.9%) patients achieved marked improvement, complete remission, and mucosal healing. A higher C-reactive protein level (CRP; ≥ 1 mg/dL) at baseline was a predictor of discontinuation of anti-TNFα agents. CONCLUSIONS: The 48-week continuation rate of anti-TNFα agents was 75.9% in bio-naïve patients with intestinal BD. However, a higher baseline CRP level (≥ 1 mg/dL) was associated with discontinuation of anti-TNFα agents.

A case of autoimmune enteropathy with CTLA4 haploinsufficiency.

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.

Effect of Daikenchuto On Spontaneous Intestinal Tumors in ApcMin/+ Mice.

Daikenchuto (TU-100) is herbal medicine which predominantly contains ginger, Japanese pepper, and ginseng. We investigated whether TU-100 can affect the composition of gut flora and intestinal tumor development using ApcMin/+ mice, a murine model of intestinal tumor. Bacterial 16S rRNA sequencing and short-chain fatty acid analysis were performed on faecal samples. Tumor number and size were analysed. Any change in gene expression of the tumor tissues was assessed by real-time PCR. Principal coordinate analysis (PCoA) showed that the faecal microbiota cluster of TU-100-fed mice was different from the microbiota of control mice. However, no significant difference was observed in the concentration of short-chain fatty acids, tumor number, and gene expression levels between the two groups. Our data showed that TU-100 can affect the intestinal environment; however, it does not contribute in tumor progression or inhibition in our setting.

Interleukin-33 overexpression reflects less aggressive tumour features in large-duct type cholangiocarcinomas.

AIMS: The aim of the present study was to elucidate the clinicopathological significance of interleukin (IL)-6 and IL-33 expression in intrahepatic cholangiocarcinomas (iCCAs) and perihilar cholangiocarcinomas (pCCAs). METHODS AND RESULTS: IL-6 and IL-33 mRNA expression levels were examined in iCCAs (n = 55) and pCCAs (n = 32) by the use of quantitative real-time polymerase chain reaction and a highly sensitive in-situ hybridisation protocol (RNAscope), and expression levels were correlated with clinicopathological features. According to a recently proposed classification scheme, iCCAs were separated into small-duct (n = 33) and large-duct (n = 22) types. IL-6 and IL-33 expression levels were higher in large-duct iCCAs and pCCAs than in small-duct iCCAs, and there was a positive correlation between the expression levels of these cytokines. Double in-situ hybridisation/immunostaining showed that IL-6 mRNA was expressed in actin-positive (myo)fibroblasts, whereas IL-33 mRNA was mainly produced by CD31-positive endothelial cells. With the average expression level as a cut-off point, cases were classified as IL-6high and IL-6low or IL-33high and IL-33low . In the combined cohort of large-duct iCCAs and pCCAs, IL-6high and IL-6low cholangiocarcinomas shared many features, whereas IL-33high cases had less aggressive characteristics than IL-33low cases, as shown by lower tumour marker concentrations, smaller tumour sizes, less common vascular invasion, lower pT stages, and higher lymphocyte/monocyte ratios in blood. KRAS mutations were slightly less common in IL-33high cases than in IL-33low cases (9% versus 29%; P = 0.061). The strong expression of IL-33 in tissue appeared to be an independent favourable prognostic factor. CONCLUSIONS: IL-33high cholangiocarcinomas may represent a unique, less aggressive carcinogenetic process of the large bile ducts.

Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria.

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Side effects including an increased risk of intestinal infections have been reported. It is assumed that PPIs can increase susceptibility to enteropathogens; however, the underlying mechanisms are unknown. Here in this study, we explored whether Lansoprazole (Laz), one of the PPIs, increases the susceptibility to enteropathogens, and further investigated the mechanism of it. METHODS: Mice were administered Laz intraperitoneally once daily and orally infected with Citrobacter rodentium (C. rodentium). The establishment of intestinal infection was assessed by histology and inflammatory cytokine expression levels measured by quantitative PCR. To test whether Laz changes the intestinal environment to influence the susceptibility, intestinal pH, microbiota, metabolites and immune cell distributions were evaluated via pH measurement, 16S rRNA gene sequencing, metabolome, and flow cytometry analyses after Laz administration. RESULTS: Colitis was induced with less C. rodentium in Laz-treated mice as compared with the controls. We found that increased numbers of C. rodentium could reach the cecum following Laz administration. Laz increased pH in the stomach but not in the intestines. It induced dysbiosis and changed the metabolite content of the small intestine. However, these changes did not lead to alterations of immune cell distribution. CONCLUSIONS: Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.

Short-Term and Long-Term Outcomes of Infliximab and Tacrolimus Treatment for Moderate to Severe Ulcerative Colitis: Retrospective Observational Study.

BACKGROUND/AIMS: While some studies have shown that IFX and TAC exhibit similar efficacy against UC in the short-term, it is unclear which drug produces better long-term outcomes. In this study, we compared the long-term efficacy of IFX and TAC in patients with moderate to severe UC. METHODS: This retrospective study was conducted from 2009 to 2017. It included patients with no history of IFX or TAC treatment. We analyzed the clinical response and remission rates at 12 and 52 weeks, and colectomy-free and relapse-free survival were evaluated until the end of the study. RESULTS: At 12 weeks, 94.4% and 77.8% of the patients in the IFX group (n = 18) had demonstrated clinical responses and clinical remission, respectively, whereas 72.7% of the patients in the TAC group (n = 11) exhibited clinical responses and clinical remission. The clinical response, clinical remission, and colectomy-free rates did not differ significantly between the groups. At 52 weeks, clinical responses and clinical remission had been achieved in 76.5% and 70.6% of the patients both in the IFX group, respectively. In the TAC group, clinical responses and clinical remission were achieved in 50.0% of patients. Relapse-free and colectomy-free survival were estimated significantly better in IFX group evaluated by Kaplan-Meier curves. CONCLUSION: This study indicates that IFX and TAC produce similar short-term outcomes in UC patients, but IFX produces better long-term outcomes than TAC especially with avoidance of colectomy. Our data suggest that IFX therapy may be prioritized over TAC for the treatment of moderate to severe UC.

IL-8 Expression in Granulocytic Epithelial Lesions of Idiopathic Duct-centric Pancreatitis (Type 2 Autoimmune Pancreatitis).

Type 2 autoimmune pancreatitis (type 2 AIP) develops in isolation or sometimes in association with ulcerative colitis. Its diagnosis requires the histologic confirmation of granulocytic epithelial lesions (GELs) with no diagnostic biomarker currently available. This study aimed to elucidate the tissue expression of cytokines and their diagnostic value in this condition. In quantitative polymerase chain reaction for multiple cytokines using tissue-derived mRNA, the expression level of interleukin (IL)-8 was markedly higher in type 2 AIP than in type 1 AIP (P<0.001). In immunostaining, IL-8 expression was detected in the ductal/ductular epithelium (11/13; 85%) and infiltrating neutrophils or lymphocytes (12/12; 100%) in type 2 AIP, but was almost entirely negative in type 1 AIP (n=13; both, P<0.001). Although obstructive pancreatitis adjacent to pancreatic cancers (peritumoral pancreatitis) exhibited IL-8 expression in the epithelium (3/12; 25%) and inflammatory cells (10/12; 83%), expression levels were significantly lower than those in type 2 AIP (P<0.001 and 0.020, respectively). The presence of either GELs or IL-8-positive epithelium discriminated type 2 AIP from type 1 AIP or obstructive pancreatitis with 92% sensitivity and 92% to 100% specificity. Furthermore, CD3/IL-8-coexpressing lymphocytes were almost restricted to type 2 AIP. Interestingly, a similar pattern of IL-8 expression was also observed in colonic biopsies of ulcerative colitis. In conclusion, the overexpression of IL-8 may underlie the development of GELs in type 2 AIP, and IL-8 immunostaining or IL-8/CD3 double staining may become an ancillary method for its diagnosis. The similar expression pattern of IL-8 in ulcerative colitis also suggests a pathogenetic link between the 2 conditions.