The clinical usefulness of serum leucine-rich alpha-2 glycoprotein (LRG) levels as a surrogate marker of endoscopic activity including postoperative recurrence in patients with Crohn’s disease (CD) remains unclear, and LRG production in the small intestinal mucosa has not been explored. The present study investigated the usefulness of serum LRG to ascertain endoscopic activity, the secretion of LRG from the small intestinal mucosa, and the significance of LRG as a predictor of postoperative disease course. We included 364 patients who underwent transanal endoscopy at Osaka University Hospital. Serum LRG correlated highly with endoscopic severity (LRG, r = 0.65; CRP, r = 0.37) and reflected strictly moderate endoscopic activity better than serum CRP. Especially, serum LRG reflected mucosal healing even in patients whose inflammation was confined to the small intestine. In multivariate analyses, serum LRG was an independent factor influencing mucosal healing. LRG was more strongly expressed in the inflamed mucosa of the small intestine compared with that in uninflamed mucosa, and serum LRG was more strongly correlated with postoperative small intestinal recurrence severity than CRP (LRG, r = 0.62; CRP, r = 0.32). In conclusion, serum LRG is a useful surrogate marker of endoscopic CD severity and activity, with increased LRG expression in the small bowel predicting postoperative recurrence.

Abstract Background Close monitoring of disease activity is essential for the therapeutic management of inflammatory bowel disease. A minimally invasive and reliable serum biomarker is desirable, but its reliability and validity have not yet been fully evaluated. The purpose of this study (UMIN000043185) was to investigate the utility of leucine-rich α-2-glycoprotein (LRG) in the management of vedolizumab therapy in patients with ulcerative colitis (UC), and to identify mucosal signatures and surrogate biomarkers by using serum cytokine and mucosal transcriptome analysis. Methods Serum LRG, C-reactive protein (CRP), serum Mucosal Vascular Addressin Cell Adhesion Molecule 1(MadCAM1), serum vedolizumab levels, 19 serum cytokines, and fecal calprotectin (fCal) were measured over 54 weeks (week 0, 2, 6, 14, 30, and 54) (n=21). Clinical remission (Mayo score <= 2, all subscore < = 1) and mucosal healing (Mayo endoscopic subscore <= 1) at week 14 were compared between the clinical remission (CR) group (n=11) and non-clinical remission (non-CR) group (n=10), and between the mucosal healing (MH) group (n=14) and non-mucosal healing (non-MH) group (n=7). Differentially expressed gene (DEG) extraction was performed by stratifying data at week 0 and comparing two groups: CR (n=10) and non-CR (n=3), and complete MH (Mayo endoscopic subscore = 0) (n=8) and non-complete MH (n=6) at week 14. Results Serum LRG concentrations were significantly lower in CR group compared to the non-CR group at week 0 (19.0 vs. 29.0 ug/mL, p=0.027) and week 6 (13.4 vs. 19.6 ug/mL, p=0.034) and significantly lower in MH group compared to the non-MH group at week 6 (13.7 vs. 21.6 ug/mL, p=0.033). In contrast, there were no significant differences in serum CRP and fecal calprotectin levels at any time point for either CR or MH. Serum MCP-1 levels showed significant differences between CR and non-CR at week 0 (609.0 vs 403.4 pg/mL, p=0.0018), between MH and non-MH at week 0 (587.2 vs 358.9 pg/mL, p<0. 001), week 6 (606.9 vs 451.6 pg/mL, p=0.015). DEGs extracted from colon tissue included LRG1 and LRG-related cytokines, MCP-1, reflecting the effect of vedolizumab treatment. Conclusion Both serum LRG (lower in CR/ MH group) and serum MCP-1 (higher in CR/MH group) were suggested to be promising predictive biomarkers of vedolizumab treatment response in patients with UC. Further studies are needed to assess their reliability and validity as indicators of treatment effectiveness.

Introduction: Budesonide, with its high topical steroidal activity, effectively prevents strictures following esophageal endoscopic treatment. However, its effectiveness in preventing restenosis after endoscopic balloon dilation (EBD) in patients with Crohn’s disease (CD) remains unclear. We aimed to evaluate the safety and effectiveness of oral budesonide after EBD in patients with CD. Methods: We conducted a multicenter prospective study of patients with CD who underwent EBD at the University of Osaka and its affiliated hospitals between March 2018 and March 2023 (UMIN000031839, jRCT1051190043). Oral budesonide was administered for 4 weeks after EBD, and patients were followed up for 52 weeks. Safety and effectiveness within 12 and 52 weeks of the procedure were evaluated, with endoscopic evaluation of restenosis at week 52. The stenosis diameter and length were estimated endoscopically and radiographically, respectively. In the historical control study, consecutive patients with CD who underwent EBD between February 2016 and July 2018 were included. The incidence rates of obstructive symptoms and hospitalization at 52 weeks after EBD were retrospectively investigated from the medical records. Results: Overall, 15 patients were analyzed (male, 14 [93.3%]; median age, 44 years [37–49]; disease type, L1, 8 [53.3%]/L3, 7 [46.7%]; stenosis location, jejunum, 1 [6.7%]/ileum, 8 [53.3%]/ileocolonic, 6 [40.0%]; median stenosis diameter, 5 mm [5–6]). No serious complications were observed within 12 or 52 weeks. Twelve (80%) patients showed no symptoms of stenosis within 52 weeks. Of the 14 patients who underwent an endoscopy at week 52, re-EBD was not required in 3 patients (21.4%). The stenosis diameter at week 52 improved significantly compared to the pre-dilation measurements (p = 0.004). Furthermore, the 15 patients treated with budesonide had a significantly lower incidence rates of obstructive symptoms and hospitalization compared to the 19 historical control patients (p = 0.020 and 0.035, respectively). Conclusion: Budesonide administration after EBD can be safely performed in patients with CD and may be effective in preventing restenosis and avoiding hospitalization and intestinal surgery.

There is insufficient evidence comparing the outcomes of tacrolimus-based remission induction therapy with infliximab in refractory ulcerative colitis (UC) and evidence regarding optimal strategies after tacrolimus-based remission induction therapy. We conducted a multi-institutional retrospective study of patients with UC treated with tacrolimus or infliximab between January 2010 and March 2019. The proportion of clinical remission at week 8 and cumulative colectomy-free rate were examined using propensity score matching analysis. The predictors for colectomy after tacrolimus induction were also investigated. Ninety patients in the tacrolimus group and 151 in the infliximab group were enrolled. The proportion of patients in clinical remission at week 8 was 65.2% in the matched tacrolimus group and 37.3% in the matched infliximab group (P = 0.0016), and the long-term colectomy-free rate was lower in the matched tacrolimus group than in the matched infliximab group (P = 0.0003). After clinical remission with tacrolimus, a serum albumin level of ≤ 3.5 g/dL at week 8 was extracted as a factor predicting colectomy (area under the curve: 0.94). Tacrolimus showed a higher remission induction effect for UC compared to infliximab. However, a high rate of colectomy after transition to maintenance treatment was found to be a concern for tacrolimus therapy.

Serum leucine-rich alpha-2 glycoprotein (LRG) can monitor disease activities during biologics treatment in patients with inflammatory bowel disease (IBD). It is unclear whether the pretreatment serum LRG level can predict clinical effectiveness including serum trough levels of ustekinumab in patients with IBD. This multicenter prospective cohort study included 184 patients (Crohn's disease, 104; ulcerative colitis, 80) who received ustekinumab (n=119) or anti-tumor necrosis factor (n=65) between January 2019 and March 2023. Multivariate logistic regression analysis revealed serum LRG level at week 0 (0w-LRG, odds ratio 0.12, 95% confidence interval 0.02-0.68) as one of significant factors for clinical remission at week 8. We divided patients into the low- and the high-LRG groups by the median 0w-LRG (18.2 mu g/mL) and compared the effectiveness. In patients who received ustekinumab, the proportion of clinical remission at week 8 was significantly different between in the low- (76.9%) and in the high-LRG group (59.3%, P=0.038), and median serum trough level at week 8 was significantly different between in the low- (10.9 mu g/mL, interquartile range 6.7-13.4) and the high-LRG group (5.3 mu g/mL, interquartile range 2.4-8.3, P<0.001). The 0w-LRG can predict the effectiveness including serum trough levels of ustekinumab during induction treatment for patients with IBD.

Abstract Background Serum leucine-rich alpha-2 glycoprotein (LRG) is a biomarker reflecting endoscopic activity in patients with inflammatory bowel disease (IBD). However, it remains unclear whether serum LRG can predict the effectiveness of anti-cytokine biologics (biologics) in patients with IBD. This study aimed to evaluate whether serum LRG could predict the effectiveness and serum trough concentrations of biologics in patients with IBD. Methods This was a multicentre prospective cohort study including patients with IBD (including ulcerative colitis [UC] or Crohn’s disease [CD]) who received the biologics [ustekinumab (UST), anti-tumor necrosis factor (anti-TNF)] from January 2019 to March 2023 at 15 hospitals participating in the Osaka Gut Forum. The effectiveness of biologics was evaluated by clinical remission (CR) at week 8. We defined CR as a partial Mayo score of 2 or lower, with each subscore of 0 or 1 for UC and a CD activity index of < 150 for CD. Factors associated with CR at week 8 such as backgrounds, disease activities and concomitant medications at week 0 were analyzed by Cox proportional hazards model. For each biologic, we compared the effectiveness of biologics in the high LRG group with that in the low LRG group divided by the median serum LRG levels at week 0 (cut-off = 18.2 μg/mL). Results A total of 184 patients with IBD (UC, 80; CD, 104) were enrolled (UST/ anti-TNF, 119/ 65; biologic exposure, 31.5%; median disease duration, 6 years [Interquartile range (IQR) 1-14]). Median serum LRG levels at week 0 and serum C-reactive protein levels at week 0 were 18.2 μg/mL [IQR 12.5-28.1] and 0.19 mg/dL [IQR 0.03-0.77], respectively. At week 0, 63 (34.2%) and 64 (34.8%) patients concomitantly received corticosteroids and immunomodulators, respectively. In 184 patients with IBD, multivariate analysis revealed that serum LRG level at week 0 < 18.2 μg/mL was extracted as a significant factor for CR at week 8 (Odds ratio: OR 2.70, 95% confidence interval: CI 1.22-5.96). In patients who received UST, the proportion of CR at week 8 in the low-LRG group (76.9%) was significantly higher than that in the high-LRG group (59.3%, P = 0.038). In patients who received anti-TNF, however, the proportion of CR in the low-LRG group (84.6%) was not differ from that in the high-LRG group (82.1%, P = 0.781). Median serum trough concentrations of UST at week 8 in the low-LRG group (10.9 μg/mL, IQR 6.7-13.4) was significantly higher than that in the high-LRG group (5.3 μg/mL, IQR 2.4-8.3, P < 0.001). Conclusion Serum LRG could predict the effectiveness and serum trough concentrations of UST and be a biomarker for selecting biologics in patients with IBD.

BACKGROUND AND AIM:Colonoscopy is necessary for diagnosing and surveilling patients with ulcerative colitis, though it may cause disease flares. Colonoscopy with carbon dioxide (CO2) insufflation decreases abdominal discomfort; however, its effect on exacerbation incidence in ulcerative colitis remains unclear. Therefore, this study aimed to evaluate the colonoscopy effects using CO2 insufflation in patients with ulcerative colitis.METHODS:Overall, 96 remissive patients with ulcerative colitis (partial Mayo score ≤ 2) who underwent total colonoscopy between March 2015 and December 2019 at Osaka University Hospital were enrolled and blindly randomized to the CO2 (n = 45) and air (n = 51) insufflation group (UMIN-CTR, number: UMIN000018801). The post-procedural abdominal discomfort and the clinical relapse (partial Mayo score ≥ 3) rate within 8 weeks were evaluated.RESULTS:Baseline backgrounds did not differ between the groups. The mean abdominal fullness and pain scores were significantly lower in the CO2 group than in the Air group immediately (p = 0.0003, p = 0.0003) and 30 min (p < 0.0001, p < 0.0001) after colonoscopy. While the overall clinical relapse rate remained unchanged between the groups, the clinical relapse rate at 8 weeks after colonoscopy was significantly lower in the CO2 group than in the Air group in patients not in complete remission (Mayo endoscopic subscore ≥ 1, p = 0.049; or partial Mayo score ≥ 1, p = 0.022).CONCLUSIONS:CO2 insufflation can reduce abdominal discomfort in remissive patients with ulcerative colitis and decrease clinical relapse at 8 weeks after colonoscopy for those not in complete remission.

Background and aimEnvironmental factors are associated with onset and course of inflammatory bowel disease (IBD). Our previous study by about 1,100 IBD patients revealed half of the patients experienced seasonal exacerbation of disease. We investigated the seasonality of fecal microbiota composition of IBD patients. MethodsFecal samples were consecutively collected in each season from IBD outpatients and healthy controls between November 2015 and April 2019. Participants who were treated with full elemental diet or antibiotics within 6 months or had ostomates were excluded. Bacterial profiles were analyzed by 16S rRNA sequencing, and the changes between the diseases and seasons were compared. ResultsA total of 188 fecal samples were analyzed from 47 participants comprising 19 Crohn's disease (CD) patients, 20 ulcerative colitis (UC) patients, and 8 healthy controls (HC). In CD patients, the phylum Actinobacteria and TM7 were both significantly more abundant in autumn than in spring and winter, but not in UC patients and HC. Moreover, the genera Actinomyces, a member of Actinobacteria, and c_TM7-3;o_;f_;g_ (TM7-3), that of TM7, were significantly more abundant in autumn than in spring, and the abundance of Actinomyces was significantly correlated with that of TM7-3 throughout the year in CD patients, but not in UC patients and HC. CD patients with high abundance of TM7-3 in the autumn required significantly fewer therapeutic intervention than those without seasonal fluctuation. ConclusionsOral commensals Actinomyces and its symbiont TM7-3 were correlatively fluctuated in the feces of CD patients by season, which could affect the disease course.

Background and Aim Non-steroidal anti-inflammatory drugs (NSAIDs) induce intestinal enteropathy and the pathophysiology is related to immune-mediated mechanisms. We aimed to investigate the role of C-C chemokine receptor type 7 (CCR7) which regulates immune cell migration in NSAID-induced enteropathy. Methods Injury of the small intestine was evaluated 24 h after the subcutaneous injection of indomethacin in CCR7-deficient (Ccr7(-/-)) and wild-type (WT) mice. The cellular profile and cytokine production in intestinal cells were analyzed. Indomethacin-induced enteropathy was evaluated in mice adoptively transferred with CD103(+) dendritic cells (DCs) from Ccr7(-/-) or WT mice. Results Indomethacin induced more severe intestinal injury in Ccr7(-/-) mice than in WT mice. The major inflammatory cytokines were not increased and the proportion of regulatory T cells following indomethacin injection was not decreased in Ccr7(-/-) mice compared with WT mice. The expression of interleukin (IL)-22 binding protein (IL-22BP), which inhibits IL-22 activity, was significantly higher in CD103(+) DCs from Ccr7(-/-) mice than those from WT mice. Mice adoptively transferred with CD103(+) DCs isolated from Ccr7(-/-) mice exhibited more severe intestinal injury following indomethacin injection compared with those adoptively transferred with CD103(+) DCs of WT mice. Ccr7(-/-) mice injected with indomethacin showed a significant reduction in regenerating islet-derived 1 (Reg1) mRNA expression, which is regulated by IL-22, in intestinal epithelial cells. Conclusions C-C chemokine receptor type 7 deficiency exacerbated NSAID-induced enteropathy in association with an altered phenotype of CD103(+) DCs that produces IL-22BP. CCR7 contributes to protect the small intestine from NSAID-induced mucosal injury.

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25–0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26–0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly ( P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

Microbiota alteration and IFN-γ-producing CD4+ T cell overactivation are implicated in Crohn's disease (CD) pathogenesis. However, it remains unclear how dysbiosis enhances Th1 responses, leading to intestinal inflammation. Here, we identified key metabolites derived from dysbiotic microbiota that induce enhanced Th1 responses and exaggerate colitis in mouse models. Patients with CD showed elevated lysophosphatidylserine (LysoPS) concentration in their feces, accompanied by a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A. LysoPS induced metabolic reprogramming, thereby eliciting aberrant effector responses in both human and mouse IFN-γ-producing CD4+ T cells. Administration of LysoPS into two mouse colitis models promoted large intestinal inflammation. LysoPS-induced aggravation of colitis was impaired in mice lacking P2ry10 and P2ry10b, and their CD4+ T cells were hyporesponsive to LysoPS. Thus, our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota promote Th1-mediated intestinal pathology.

hospital and received treatment as scheduled.During this pandemic, 97.5% of the patients continued oral medication and injections as physicians indicated.Most of participants felt the need for a family doctor and primarily sought guidance, and information regarding SARS-COV-2 from television or internet news.35.6% of the patients were given information about prevention of SARS-COV-2 by their physicians.42.6% of the patients received an explanation about the continuation of medication from their physicians.Conclusion: Japanese IBD patients had moderate disease-related anxiety.The percentage of patients with a behavioral change was small.Based on the content of anxiety obtained in this study, we should continue to proactively inform patients about infectious diseases such as SARS-COV-2 and the accompanying accurate information related to IBD management, thereby relieving their anxiety. EP1276

We reconstructed 19,084 prokaryotic and 31,395 viral genomes from 787 Japanese gut metagenomes as Japanese metagenome-assembled genomes (JMAG) and Japanese Virus Database (JVD), which are large microbial genome datasets for a single population. Population-specific enrichment of the Bacillus subtilis and β-porphyranase among the JMAG could derive from the Japanese traditional food natto (fermented soybeans) and nori (laver), respectively. Dairy-related Enterococcus_B lactis and Streptococcus thermophilus were nominally associated with the East Asian-specific missense variant rs671:G>A in ALDH2, which was associated with dairy consumption. Of the species-level viral genome clusters in the JVD, 62.9% were novel. The β crAss-like phage composition was low among the Japanese but relatively high among African and Oceanian peoples. Evaluations of the association between crAss-like phages and diseases showed significant disease-specific associations. Our large catalog of virus-host pairs identified the positive correlation between the abundance of the viruses and their hosts.

Background The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. Methods This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, β-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. Results A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab ( P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30–0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab ( P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. Conclusion Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Table 2: Risk of Suicide attempts among patients with IBD compared to the general population without IBD, including UC and CD subgroups.* In the multivariable logistic regression model, adjusted for age groups (as per definition from the Centers for Disease Control and Prevention), sex, race, and medical history of psychiatric disorders (including substance abuse disorders.All were P<.001.