Genetically Predicted Higher Levels of Caffeic Acid Are Protective Against Ulcerative Colitis: A Comprehensive Metabolome Analysis.

BACKGROUND: It is crucial to pinpoint the metabolites that cause Crohn's disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC. METHODS: As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance-weighted method, while stability of the findings was evaluated through sensitivity analyses. RESULTS: After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10-3; and OR, 0.64; P = 1.90 × 10-2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10-4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10-2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10-2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10-2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites. CONCLUSIONS: In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.

This metabolome-wide study using Japanese cohorts found that caffeic acid significantly reduces the risk of ulcerative colitis, while 3-hydroxybutyrate and 2-hydroxyvaleric acid increase it. Trans-glutaconic acid and tryptophan reduce the risk of Crohn's disease.

White spots around colorectal tumors are cancer-related findings and may aid endoscopic diagnosis: a prospective study in Japan.

Background/Aims: During endoscopy, white spots (WS) are sometimes observed around benign or malignant colorectal tumors; however, few reports have investigated WS, and their significance remains unknown. Therefore, we investigated the significance of WS from clinical and pathological viewpoints and evaluated its usefulness in endoscopic diagnosis. Methods: Clinical data of patients with lesions diagnosed as epithelial tumors from January 1, 2019, to December 31, 2020, were analyzed (n=3,869). We also performed a clinicopathological analysis of adenomas or carcinomas treated with endoscopic resection (n=759). Subsequently, detailed pathological observations of the WS were performed. Results: The positivity rates for WS were 9.3% (3,869 lesions including advanced cancer and non-adenoma/carcinoma) and 25% (759 lesions limited to adenoma and early carcinoma). Analysis of 759 lesions showed that the WS-positive lesion group had a higher proportion of cancer cases and larger tumor diameters than the WS-negative group. Multiple logistic analysis revealed the following three statistically significant risk factors for carcinogenesis: positive WS, flat lesions, and tumor diameter ≥5 mm. Pathological analysis revealed that WS were macrophages that phagocytosed fat and mucus and were white primarily because of fat. Conclusions: WS are cancer-related findings and can become a new criterion for endoscopic resection in the future.

Clinical practice and outcome of patients with elderly-onset ulcerative colitis: Insights from a nationwide claims database study in Japan.

Background and Aim: The number of older patients with ulcerative colitis is increasing; however, limited data exist regarding the differences between elderly- and non-elderly-onset ulcerative colitis. We aimed to compare the clinical practice and course of elderly-onset ulcerative colitis with those of non-elderly-onset ulcerative colitis. Methods: We selected older patients with ulcerative colitis and divided them into the elderly- and non-elderly-onset ulcerative colitis groups according to their age at onset. We compared the cumulative systemic steroid-free, molecular targeting drug-free, and surgery-free rates between the two groups. We performed a multivariate analysis to identify the clinical factors related to systemic steroid administration, the use of molecular targeting drugs, surgery, and death. Results: We collected data of 2669 and 277 elderly and non-elderly-onset ulcerative colitis patients, respectively. The cumulative systemic steroid-free rate of elderly-onset ulcerative colitis was significantly lower than that of non-elderly-onset ulcerative colitis. However, no difference was observed in the cumulative molecular targeting drugs and surgery-free rates between the two groups. Elderly-onset ulcerative colitis significantly increased the risk of systemic steroid administration and death but not the use of molecular targeting drugs and surgery. Conclusion: The disease severity of ulcerative colitis and clinical practice may not differ between the elderly- and non-elderly-onset groups. However, elderly-onset ulcerative colitis was associated with increased mortality risk. Thus, we need to pay attention to the patients' condition and appropriate timing of surgery for patients with elderly-onset ulcerative colitis.

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Prescribing in pregnant women with inflammatory bowel disease and its relationship to congenital malformations in Japan.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD) frequently affects younger patients and poses various challenges concerning pregnancy and childbirth. Maintaining good disease control throughout pregnancy is crucial, but expectant and pregnant patients may worry about the fetal impact of medications, leading to treatment discontinuation due to uncertainty about this issue. This study investigated the real-world drug-prescribing practices for pregnant patients with IBD in Japan and their potential connection to major congenital malformations (MCMs). METHODS: Overall, 277 female IBD patients who gave birth between 2010 and 2019 were selected from the JMDC claims database. The prescribing patterns of IBD medications and MCMs in the patients' offspring were analyzed. RESULTS: Among pregnant IBD patients, 74.4% received at least one medication from 90 days before pregnancy to 90 days after delivery. Trends in medication prescriptions during pregnancy in 2010-2019 revealed consistent use of oral 5-ASA, variable use of topical medications, a decrease in systemic steroids, and an increase in biologics. The prevalence of MCMs in children born to IBD-affected mothers did not differ significantly between those who did and did not receive IBD medications (8.6% vs 6.8%). Although circulatory system MCMs were slightly more common in the IBD medication group (4.9% vs 1.4%), this difference was not significant. Logistic regression analysis did not reveal an association between MCM risk and first-trimester use of IBD medications, including corticosteroids and biologics. CONCLUSIONS: This study provides insights into medication patterns in pregnant IBD patients and suggests no increased risk of MCMs associated with first-trimester IBD medication use.

Live-attenuated vaccination in patients with inflammatory bowel disease while continuing or after elective switch to vedolizumab.

Background/Aims: Vedolizumab (VDZ) is a gut-selective agent with a favorable safety profile. We aimed to assess the feasibility of elective switch from other advanced therapies to VDZ and subsequent live-attenuated vaccination while continuing VDZ in patients with inflammatory bowel diseases (IBD). Methods: We measured antibody titers specific for measles, rubella, mumps, and varicella viruses in IBD patients under immunosuppressive therapy. Those with negative titers and without vaccination history were judged unimmunized. Patients were administered vaccines while continuing VDZ or switched to VDZ if receiving other advanced therapies and then administered vaccines. Co-primary outcomes were the rate of maintaining disease severity after vaccination and the rate without vaccine-induced infection. Results: Among 107 unimmunized patients, 37 agreed to receive live-attenuated vaccines while continuing VDZ (17 patients) or after switching to VDZ (20 patients). In the 20 patients who electively switched to VDZ, disease severity was maintained except for 1 patient who developed intestinal infection. After 54 weeks, 18 patients (90%) continued to receive VDZ, excluding 2 patients who reverted to their originally administered biologics. In all 37 patients administered live-attenuated vaccines under VDZ treatment, disease severity was maintained after vaccination. Antibody titers became positive or equivocal in 34 patients (91.9%). There were no cases of vaccine-induced infection during a median observation period of 121 weeks. Conclusions: While live-attenuated vaccines are contraindicated under immunosuppressive therapy, they may be safely administered while receiving VDZ immunotherapy. Switching from other advanced therapies to VDZ and subsequently receiving live-attenuated vaccines may be a safe alternative in unimmunized patients.

N-Desmethylmajusculamide B, a lipopeptide isolated from the Okinawan cyanobacterium Okeania hirsuta.

A new lipopeptide, N-desmethylmajusculamide B (1), was isolated from the Okinawan cyanobacterium Okeania hirsuta along with 2 known compounds majusculamide A (2) and majusculamide B (3). The planar structure of (1) was elucidated by a detailed analysis of mass spectrometry and nuclear magnetic resonance spectra. The absolute configurations of the amino acid residues were determined using Marfey's analysis. The configuration of C-16 in the α-methyl-ß-keto-decanoyl moiety was determined unambiguously to be S by conducting a semisynthesis of N-desmethylmajusculamide B from 3. The cytotoxicity against mouse L1210 leukemia cells was evaluated for majusculamides (1-3).

Clinical Utilization of Generic Drugs and Biosimilars for Ulcerative Colitis Treatment: Insights from a Nationwide Database Study in Japan.

Introduction: Limited data exist regarding the prevalence and clinical practice involving generic drugs and biosimilars for treating ulcerative colitis (UC) in Japan. We aimed to clarify the clinical usage of these generic drugs and biosimilars for UC treatment in Japan using a nationwide database. Methods: We collected data from 30,675 UC cases, along with their prescriptions for both generic drugs or biosimilars and their original counterparts, using a medical claim database provided by DeSC Healthcare, Inc. We calculated the prescription and penetration rates of generic drugs and biosimilars and demonstrated the transition of these rates. Additionally, the cumulative retention rates between infliximab originator and biosimilar were compared using the Kaplan-Meier method. Results: The prescription rate of generic mesalazine increased from approximately 10% in 2015 to over 30% in 2021. Although the prescription rate of generic molecular targeting drugs (MTDs) also increased from approximately 0.15% in 2014 to 2.5% in 2021, the increment was lower than that of generic mesalazine. The penetration rates of generic 5-aminosalicylic acid and tacrolimus ranged from over 30% to approximately 50%. Infliximab biosimilar achieved an approximate 20% penetration rate, whereas adalimumab achieved <5%. The cumulative retention rates did not differ between infliximab originator and biosimilar. Conclusions: The penetration rates of generics and biosimilars for UC treatment are relatively low compared with those for treatment in other fields and the goal of the Ministry of Health, Labor, and Welfare. Several countermeasures are necessary for the widespread use of generics and biosimilars, ultimately contributing to cost-effective and sustainable healthcare delivery.

Okeanic acid-A, a trihydroxy fatty acid from the Okinawan cyanobacterium Okeania hirsuta.

Trihydroxy fatty acids are oxidative metabolites of polyunsaturated fatty acids isolated from plants, bacteria, fungi, and microalgae and have a variety of biological activities. In this study, a new trihydroxy fatty acid, okeanic acid-A (1), was isolated together with malyngic acid (2) and 15,16-dihydromalyngic acid (3) from the cyanobacterium Okeania hirsuta collected in Okinawa, Japan. The planar structure of 1 was elucidated by detailed analyses using high-resolution ESI-MS and 1D and 2D NMR spectroscopy. The absolute configurations of the hydroxy groups in 1 were determined unambiguously by chemical derivatisation and a modified Mosher's method. These cyanobacterial trihydroxy fatty acids (1-3) have identical configurations at their respective trihydroxy parts. Okeanic acid-A (1) showed mild growth-inhibitory activity against the marine diatom Nitzschia amabilis.

Acute Liver Injury and Bilateral Pulmonary Artery Thrombosis due to Hypereosinophilic Syndrome: A Case Report.

A 46-year-old Japanese man was referred to our hospital because of a marked increase in his eosinophil count (22,870/µL) and elevated liver enzyme levels. Computed tomography (CT) showed thrombi measuring approximately 8 cm in both femoral veins. A liver biopsy revealed eosinophilic infiltration, hepatocyte necrosis, fibrosis, and multiple thrombi. We suspected acute liver injury and deep vein thrombosis associated with hypereosinophilic syndrome and initiated steroids and heparin treatment. Four days after starting treatment, the patient experienced sudden chest pain and cardiopulmonary arrest. CT revealed bilateral pulmonary artery thrombosis, and despite administration of a tissue plasminogen activator, the patient died.

Effectiveness of Antibiotics for Uncomplicated Diverticulitis: A Retrospective Investigation Using a Nationwide Database in Japan.

INTRODUCTION: The efficacy of antibiotics for diverticulitis without abscess or peritonitis (uncomplicated diverticulitis) is controversial. We aimed to investigate the effectiveness of antibiotics for uncomplicated diverticulitis. METHODS: We collected admission data for patients with acute uncomplicated diverticulitis using a nationwide database. We divided eligible admissions into two groups according to antibiotic initiation within 2 days after admission (antibiotic group vs. nonantibiotic group). We conducted propensity score matching and compared the rates of surgery (intestinal resection and stoma creation), in-hospital death, and medical costs between the groups. We also performed multivariate analysis to identify the clinical factors that affect surgery. RESULTS: We enrolled 131,936 admissions; among these, we obtained 6,061 pairs after propensity score matching. Rates of both intestinal resection and stoma creation in the antibiotic group were lower than those in the nonantibiotic group (0.61 vs. 3.09%, p < 0.0001, and 0.08 vs. 0.26%, p = 0.027, respectively). Median costs in the antibiotic group were higher than those in the nonantibiotic group (315,820 JPY vs. 300,175 JPY, p < 0.0001, respectively). Multivariate analysis showed that non-initiation of antibiotics within 2 days after admission was a clinical factor that increased the risk of intestinal resection (odds ratio [OR] = 5.19, 95% confidence interval [CI]: 4.38-6.16, p < 0.0001) and stoma creation (OR = 2.68, 95% CI: 1.53-4.70, p = 0.0006). CONCLUSION: Our results indicated that antibiotics for uncomplicated diverticulitis expected to have moderate to severe disease activity may reduce the risk of intestinal resection and stoma creation. Further investigations are warranted.

Small bowel cancer in a patient with Crohn's disease diagnosed preoperatively by double-balloon enteroscopy.

A 53-year-old female patient, who had been treated for Crohn's disease for approximately 20 years, was admitted to our hospital with a chief complaint of persistent bloody stools. Colonoscopy, computed tomography, and magnetic resonance enterography revealed two stenoses of the ileum and multiple enlarged lymph nodes around the oral-side ileal stenosis. We accordingly performed transoral double-balloon enteroscopy and found ileal stenosis with an irregular mucosal surface. Based on pathological examination of the stenosis, adenocarcinoma of the small bowel was diagnosed for the oral-side stenosis. The stenosis on the anal side was benign. The two stenoses were resected simultaneously, and lymph node dissection was performed on the cancerous lesion. The diagnosis of the cancerous lesion was pStage IIIB, and immunohistochemical staining was positive for tumor protein 53. Patients with Crohn's disease are at a high risk of small bowel cancer, but no surveillance protocol has been established to date. We encountered a case of Crohn's disease in which radical surgery was possible, owing to preoperative pathological diagnosis, by using balloon-assisted enteroscopy. In this paper, we report a case that suggests the importance of performing balloon-assisted enteroscopy when small bowel stenosis is detected in patients with Crohn's disease.

A ring-like accretion structure in M87 connecting its black hole and jet.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation1,2. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of [Formula: see text] Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects, in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow.

A Case of Autoimmune Gastritis and Hepatitis with Enlarging Gastric Polyps after Reducing the Dose of Prednisolone.

Autoimmune gastritis is immune-mediated gastritis that destroys the oxyntic mucosa. Autoimmune hepatitis is an inflammatory liver disease caused by an autoimmune reaction. These diseases share similar pathogeneses as organ-specific autoimmune disorders; however, cases involving both diseases are quite rare and scarcely reported. Herein, we report a patient with concurrent autoimmune gastritis and hepatitis who developed enlargement of hyperplastic polyps and progression of gastric atrophy. The patient was a 79-year-old female referred to our hospital for the treatment of hyperplastic polyps detected on a follow-up upper gastrointestinal endoscopy. The patient's previous upper gastrointestinal endoscopy from 3 years prior revealed small hyperplastic polyps and no mucosal atrophy. However, the current upper gastrointestinal endoscopy revealed three 10-mm red polyps, severe mucosal atrophy in the corpus, and mild atrophy in the antral area. In addition, biopsy samples from the gastric body revealed decreased parietal cells and diffuse lymphocytic infiltration of the deep mucosa. Further, chromogranin A-positive endocrine cell micronests and enterochromaffin-like cell hyperplasia were detected. After confirming the diagnosis of autoimmune gastritis, endoscopic mucosal resection was performed for all the polyps, which were histopathologically diagnosed as hyperplastic polyps without malignancy. Therefore, clinicians should consider autoimmune gastritis for enlarged hyperplastic polyps and gastric atrophy progression.

Antihypertensive effects of abalone viscera fermented with Lactiplantibacillus pentosus SN001 via angiotensin-converting enzyme inhibition.

Abalone viscera, which accounts for more than 20% of body weight, is typically discarded. With increases in abalone aquaculture production, novel uses for abalone viscera are needed. Here, we evaluated the effects of abalone viscera fermented with Lactiplantibacillus pentosus SN001 on angiotensin-converting enzyme (ACE) activity and blood pressure elevation in spontaneously hypertensive rats. The fermented product significantly reduced systolic blood pressure compared with the control. There were no significant differences in blood glucose, triglyceride, total cholesterol, or high-density lipoprotein cholesterol levels; alanine aminotransferase activity; and aspartate aminotransferase activity between the fermented product and control groups. Uracil was isolated and identified from the fermented product. Uracil may be the active component. Overall, L. pentosus SN001-fermented abalone viscera showed sustained inhibitory effects on blood pressure elevation but did not alter blood components after long-term intake. These results provide insights into the safety of L. pentosus SN001-fermented abalone viscera as a food product.

Antihypertensive and Probiotic Effects of Hidakakombu (Saccharina angustata) Fermented by Lacticaseibacillus casei 001.

Hidakakombu (Saccharina angustata), commonly known as kelp, is an edible macroalgae mainly grown in the Hidaka region of Hokkaido. Hidakakombu is graded based on its shape and color. Low-grade Hidakakombu has low value and is distributed at a low price. It is desired to establish a method to add value to low-grade Hidakakombu. In this study, low-grade Hidakakombu was fermented by Lacticaseibacillus casei 001 to add value. Fermentation of Hidakaombu enhanced the inhibition of blood pressure elevation due to ACE inhibition. L. casei 001 in fermented Hidakakombu remained viable in simulated gastric and intestinal juices. The ACE inhibitory component in L. casei 001-fermented Hidakakombu was isolated from the fraction below 3 kDa using high-performance liquid chromatography. The purified amino acid was identified as D-Trp using nuclear magnetic resonance, mass spectroscopy, and optical rotation measurements. This is the first report on the ACE inhibitory activity of D-Trp in L. casei 001-fermented Hidakakombu. Hidakakombu fermented by L. casei 001 was shown to be a source of probiotics and functional components against hypertension. Therefore, fermentation by L. casei 001 was found to be an effective means of adding high value to low-grade Hidakombu.

Liquid Biopsy for Colorectal Adenoma: Is the Exosomal miRNA Derived From Organoid a Potential Diagnostic Biomarker?

INTRODUCTION: MicroRNAs (miRNAs) can serve as tumor biomarkers; however, their role in evaluating colorectal adenoma (CRA) is unclear. Recently, the organoid culture system enabled long-term expansion of human colon epithelium. This study aimed to examine the potential of exosomal miRNAs extracted from CRA organoids as biomarkers in the clinical liquid biopsy CRA test. METHODS: We established organoid cultures from normal colon and CRA using resected specimens. Exosomes were isolated from the conditioned medium organoids. MiRNAs were isolated from the exosomes, and their expression profiles were compared using microarray analysis. To identify miRNA candidates for liquid biopsy, we prospectively compared changes in their expression in serum and exosomes before and after endoscopic resection in 26 patients with CRA. RESULTS: Seven exosomal miRNAs were overexpressed in CRA organoids: miR-4323, miR-4284, miR-1268a, miR-1290, miR-6766-3p, miR-21-5p, and miR-1246. The expression levels of 4 exosomal miRNAs (miR-4323, miR-4284, miR-1290, and miR-1246) and 2 serum miRNAs (miR-1290 and miR-1246) were significantly lower in posttreatment sera. The combined expression of 4 exosomal miRNAs could identify both CRA and large-size (>12.6 cm2) CRA with respective areas under the curve of 0.698 (95% confidence interval [CI] = 0.536-0.823) and 0.834 (95% CI = 0.660-0.929). Combinations of 2-serum miRNA expression values could identify both CRA and large-size CRA with respective area under the curves of 0.691 (95% CI = 0.528-0.817) and 0.834 (95% CI = 0.628-0.938). DISCUSSION: We found that exosomal miRNAs derived from the CRA organoid culture could be potential diagnostic biomarkers for CRA.