Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

Long-term Risks of Recurrence After Hospital Discharge for Acute Lower Gastrointestinal Bleeding: A Large Nationwide Cohort Study.

BACKGROUND & AIMS: Currently, large, nationwide, long-term follow-up data on acute lower gastrointestinal bleeding (ALGIB) are scarce. We investigated long-term risks of recurrence after hospital discharge for ALGIB using a large multicenter dataset. METHODS: We retrospectively analyzed 5048 patients who were urgently hospitalized for ALGIB at 49 hospitals across Japan (CODE BLUE-J study). Risk factors for the long-term recurrence of ALGIB were analyzed by using competing risk analysis, treating death without rebleeding as a competing risk. RESULTS: Rebleeding occurred in 1304 patients (25.8%) during a mean follow-up period of 31 months. The cumulative incidences of rebleeding at 1 and 5 years were 15.1% and 25.1%, respectively. The mortality risk was significantly higher in patients with out-of-hospital rebleeding episodes than in those without (hazard ratio, 1.42). Of the 30 factors, multivariate analysis showed that shock index ≥1 (subdistribution hazard ratio [SHR], 1.25), blood transfusion (SHR, 1.26), in-hospital rebleeding (SHR, 1.26), colonic diverticular bleeding (SHR, 2.38), and thienopyridine use (SHR, 1.24) were significantly associated with increased rebleeding risk. Multivariate analysis of colonic diverticular bleeding patients showed that blood transfusion (SHR, 1.20), in-hospital rebleeding (SHR, 1.30), and thienopyridine use (SHR, 1.32) were significantly associated with increased rebleeding risk, whereas endoscopic hemostasis (SHR, 0.83) significantly decreased the risk. CONCLUSIONS: These large, nationwide follow-up data highlighted the importance of endoscopic diagnosis and treatment during hospitalization and the assessment of the need for ongoing thienopyridine use to reduce the risk of out-of-hospital rebleeding. This information also aids in the identification of patients at high risk of rebleeding.

Outcomes and recurrent bleeding risks of detachable snare and band ligation for colonic diverticular bleeding: a multicenter retrospective cohort study.

BACKGROUND AND AIMS: Ligation therapy, including endoscopic detachable snare ligation (EDSL) and endoscopic band ligation (EBL), has emerged as an endoscopic treatment for colonic diverticular bleeding (CDB); its comparative effectiveness and risk of recurrent bleeding remain unclear, however. Our goal was to compare the outcomes of EDSL and EBL in treating CDB and identify risk factors for recurrent bleeding after ligation therapy. METHODS: We reviewed data of 518 patients with CDB who underwent EDSL (n = 77) or EBL (n = 441) in a multicenter cohort study named the Colonic Diverticular Bleeding Leaders Update Evidence From Multicenter Japanese Study (CODE BLUE-J Study). Outcomes were compared by using propensity score matching. Logistic and Cox regression analyses were performed for recurrent bleeding risk, and a competing risk analysis was used to treat death without recurrent bleeding as a competing risk. RESULTS: No significant differences were found between the 2 groups in terms of initial hemostasis, 30-day recurrent bleeding, interventional radiology or surgery requirements, 30-day mortality, blood transfusion volume, length of hospital stay, and adverse events. Sigmoid colon involvement was an independent risk factor for 30-day recurrent bleeding (odds ratio, 1.87; 95% confidence interval, 1.02-3.40; P = .042). History of acute lower GI bleeding (ALGIB) was a significant long-term recurrent bleeding risk factor on Cox regression analysis. A performance status score of 3/4 and history of ALGIB were long-term recurrent bleeding factors on competing risk regression analysis. CONCLUSIONS: There were no significant differences in outcomes between EDSL and EBL for CDB. After ligation therapy, careful follow-up is required, especially in the treatment of sigmoid diverticular bleeding during admission. History of ALGIB and performance status at admission are important risk factors for long-term recurrent bleeding after discharge.

Timing of colonoscopy in acute lower GI bleeding: a multicenter retrospective cohort study.

BACKGROUND AND AIMS: We aimed to determine the optimal timing of colonoscopy and factors that benefit patients who undergo early colonoscopy for acute lower GI bleeding. METHODS: We identified 10,342 patients with acute hematochezia (CODE BLUE-J study) admitted to 49 hospitals in Japan. Of these, 6270 patients who underwent a colonoscopy within 120 hours were included in this study. The inverse probability of treatment weighting method was used to adjust for baseline characteristics among early (≤24 hours, n = 4133), elective (24-48 hours, n = 1137), and late (48-120 hours, n = 1000) colonoscopy. The average treatment effect was evaluated for outcomes. The primary outcome was 30-day rebleeding rate. RESULTS: The early group had a significantly higher rate of stigmata of recent hemorrhage (SRH) identification and a shorter length of stay than the elective and late groups. However, the 30-day rebleeding rate was significantly higher in the early group than in the elective and late groups. Interventional radiology (IVR) or surgery requirement and 30-day mortality did not significantly differ among groups. The interaction with heterogeneity of effects was observed between early and late colonoscopy and shock index (shock index <1, odds ratio [OR], 2.097; shock index ≥1, OR, 1.095; P for interaction = .038) and performance status (0-2, OR, 2.481; ≥3, OR, .458; P for interaction = .022) for 30-day rebleeding. Early colonoscopy had a significantly lower IVR or surgery requirement in the shock index ≥1 cohort (OR, .267; 95% confidence interval, .099-.721) compared with late colonoscopy. CONCLUSIONS: Early colonoscopy increased the rate of SRH identification and shortened the length of stay but involved an increased risk of rebleeding and did not improve mortality and IVR or surgery requirement. Early colonoscopy particularly benefited patients with a shock index ≥1 or performance status ≥3 at presentation.

Weekend Effect on Clinical Outcomes of Acute Lower Gastrointestinal Bleeding: A Large Multicenter Cohort Study in Japan.

INTRODUCTION: Weekend admissions showed increased mortality in several medical conditions. This study aimed to examine the weekend effect on acute lower gastrointestinal bleeding (ALGIB) and its mortality and other outcomes. METHODS: This retrospective cohort study (CODE BLUE-J Study) was conducted at 49 Japanese hospitals between January 2010 and December 2019. In total, 8,120 outpatients with acute hematochezia were enrolled and divided into weekend admissions and weekday admissions groups. Multiple imputation (MI) was used to handle missing values, followed by propensity score matching (PSM) to compare outcomes. The primary outcome was mortality; the secondary outcomes were rebleeding, length of stay (LOS), blood transfusion, thromboembolism, endoscopic treatment, the need for interventional radiology, and the need for surgery. Colonoscopy and computed tomography (CT) management were also evaluated. RESULTS: Before PSM, there was no significant difference in mortality (1.3% vs. 0.9%, p = 0.133) between weekend and weekday admissions. After PSM with MI, 1,976 cases were matched for each admission. Mortality was not significantly different for weekend admissions compared with weekday admissions (odds ratio [OR] 1.437, 95% confidence interval [CI] 0.785-2.630; p = 0.340). No significant difference was found with other secondary outcomes in weekend admissions except for blood transfusion (OR 1.239, 95% CI 1.084-1.417; p = 0.006). Weekend admission had a negative effect on early colonoscopy (OR 0.536, 95% CI 0.471-0.609; p < 0.001). Meanwhile, urgent CT remained significantly higher in weekend admissions (OR 1.466, 95% CI 1.295-1.660; p < 0.001). CONCLUSION: Weekend admissions decrease early colonoscopy and increase urgent CT but do not affect mortality or other outcomes except transfusion.

Continuous use of antithrombotic medications during peri-endoscopic submucosal dissection period for colorectal lesions: A propensity score matched study.

BACKGROUND AND AIM: The aim of this study was to elucidate the continuous use of antithrombotic medications during the peri-colorectal endoscopic submucosal dissection (ESD) period. METHODS: This study included 468 patients with colorectal epithelial neoplasms treated by ESD, consisting of 82 under antithrombotic medications and 386 patients without the medications. Among patients taking antithrombotic medications, antithrombotic agents were continued during the peri-ESD period. Clinical characteristics and adverse events were compared after propensity score matching. RESULTS: Before and after propensity score matching, post-colorectal ESD bleeding rate was higher in patients continuing antithrombotic medications (19.5% and 21.6%, respectively) than in those not taking antithrombotic medications (2.9% and 5.4%, respectively). In the Cox regression analysis, continuation of antithrombotic medications was associated with post-ESD bleeding risk (hazard ratio, 3.73; 95% confidence interval, 1.2-11.6; P < 0.05) compared with patients without antithrombotic therapy. All patients who experienced post-ESD bleeding were successfully treated by endoscopic hemostasis procedure or conservative therapy. CONCLUSIONS: Continuation of antithrombotic medications during the peri-colorectal ESD period increases the risk of bleeding. However, the continuation may be acceptable under careful monitoring for post-ESD bleeding.

Early feeding reduces length of hospital stay in patients with acute lower gastrointestinal bleeding: A large multicentre cohort study.

AIM: No studies have compared the clinical outcomes of early and delayed feeding in patients with acute lower gastrointestinal bleeding (ALGIB). This study aimed to evaluate the benefits and risks of early feeding in a nationwide cohort of patients with ALGIB in whom haemostasis was achieved. METHODS: We reviewed data for 5910 patients with ALGIB in whom haemostasis was achieved and feeding was resumed within 3 days after colonoscopy at 49 hospitals across Japan (CODE BLUE-J Study). Patients were divided into an early feeding group (≤1 day, n = 3324) and a delayed feeding group (2-3 days, n = 2586). Clinical outcomes were compared between the groups by propensity matching analysis of 1508 pairs. RESULTS: There was no significant difference between the early and delayed feeding groups in the rebleeding rate within 7 days after colonoscopy (9.4% vs. 8.0%; p = 0.196) or in the rebleeding rate within 30 days (11.4% vs. 11.5%; p = 0.909). There was also no significant between-group difference in the need for interventional radiology or surgery or in mortality. However, the median length of hospital stay after colonoscopy was significantly shorter in the early feeding group (5 vs. 7 days; p < 0.001). These results were unchanged when subgroups of presumptive and definitive colonic diverticular bleeding were compared. CONCLUSION: The findings of this nationwide study suggest that early feeding after haemostasis can shorten the hospital stay in patients with ALGIB without increasing the risk of rebleeding.

LONG-HOSP Score: A Novel Predictive Score for Length of Hospital Stay in Acute Lower Gastrointestinal Bleeding - A Multicenter Nationwide Study.

INTRODUCTION: Length of stay (LOS) in hospital affects cost, patient quality of life, and hospital management; however, existing gastrointestinal bleeding models applicable at hospital admission have not focused on LOS. We aimed to construct a predictive model for LOS in acute lower gastrointestinal bleeding (ALGIB). METHODS: We retrospectively analyzed the records of 8,547 patients emergently hospitalized for ALGIB at 49 hospitals (the CODE BLUE-J Study). A predictive model for prolonged hospital stay was developed using the baseline characteristics of 7,107 patients and externally validated in 1,440 patients. Furthermore, a multivariate analysis assessed the impact of additional variables during hospitalization on LOS. RESULTS: Focusing on baseline characteristics, a predictive model for prolonged hospital stay was developed, the LONG-HOSP score, which consisted of low body mass index, laboratory data, old age, nondrinker status, nonsteroidal anti-inflammatory drug use, facility with ≥800 beds, heart rate, oral antithrombotic agent use, symptoms, systolic blood pressure, performance status, and past medical history. The score showed relatively high performance in predicting prolonged hospital stay and high hospitalization costs (area under the curve: 0.70 and 0.73 for derivation, respectively, and 0.66 and 0.71 for external validation, respectively). Next, we focused on in-hospital management. Diagnosis of colitis or colorectal cancer, rebleeding, and the need for blood transfusion, interventional radiology, and surgery prolonged LOS, regardless of the LONG-HOSP score. By contrast, early colonoscopy and endoscopic treatment shortened LOS. CONCLUSIONS: At hospital admission for ALGIB, our novel predictive model stratified patients by their risk of prolonged hospital stay. During hospitalization, early colonoscopy and endoscopic treatment shortened LOS.

Treatment strategies for reducing early and late recurrence of colonic diverticular bleeding based on stigmata of recent hemorrhage: a large multicenter study.

BACKGROUND AND AIMS: Treatment strategies for colonic diverticular bleeding (CDB) based on stigmata of recent hemorrhage (SRH) remain unstandardized, and no large studies have evaluated their effectiveness. We sought to identify the best strategy among combinations of SRH identification and endoscopic treatment strategies. METHODS: We retrospectively analyzed 5823 CDB patients who underwent colonoscopy at 49 hospitals throughout Japan (CODE-BLUE J-Study). Three strategies were compared: find SRH (definitive CDB) and treat endoscopically, find SRH (definitive CDB) and treat conservatively, and without finding SRH (presumptive CDB) treat conservatively. In conducting pairwise comparisons of outcomes in these groups, we used propensity score-matching analysis to balance baseline characteristics between the groups being compared. RESULTS: Both early and late recurrent bleeding rates were significantly lower in patients with definitive CDB treated endoscopically than in those with presumptive CDB treated conservatively (<30 days, 19.6% vs 26.0% [P < .001]; <365 days, 33.7% vs 41.6% [P < .001], respectively). In patients with definitive CDB, the early recurrent bleeding rate was significantly lower in those treated endoscopically than in those treated conservatively (17.4% vs 26.7% [P = .038] for a single test of hypothesis; however, correction for multiple testing of data removed this significance). The late recurrent bleeding rate was also lower, but not significantly, in those treated endoscopically (32.0% vs 36.1%, P = .426). Definitive CDB treated endoscopically showed significantly lower early and late recurrent bleeding rates than when treated conservatively in cases of SRH with active bleeding, nonactive bleeding, and in the right-sided colon but not left-sided colon. CONCLUSIONS: Treating definitive CDB endoscopically was most effective in reducing recurrent bleeding over the short and long term, compared with not treating definitive CDB or presumptive CDB. Physicians should endeavor to find and treat SRH for suspected CDB.

The Compositional Structure of the Small Intestinal Microbial Community via Balloon-Assisted Enteroscopy.

INTRODUCTION: An association has been found between human-gut microbiota and various diseases (e.g., metabolic disease) by analyzing fecal or colonic microbiota. Despite the importance of the small intestinal microbiota, sampling difficulties prevent its full analysis. We investigated the composition and metagenomic functions of microbiota along the small intestine and compared them with the microbiota from feces and from other gastrointestinal (GI) sites. METHODS: Mucosal samples from the six GI sites (stomach, duodenum, distal jejunum, proximal ileum, terminal ileum, and rectum) were collected under balloon-assisted enteroscopy. Fecal samples were collected from all participants. The microbial structures and metagenomic functions of the small intestinal mucosal microbiota were compared with those from feces and other GI sites using 16S ribosomal RNA gene sequencing. RESULTS: We analyzed 133 samples from 29 participants. Microbial beta diversity analysis showed that the jejunum and ileum differed significantly from the lower GI tract and the feces (p < 0.001). Jejunal and duodenal microbiotas formed similar clusters. Wide clusters spanning the upper and lower GI tracts were observed with the ileal microbiota, which differed significantly from the jejunal microbiota (p < 0.001). Veillonella and Streptococcus were abundant in the jejunum but less so in the lower GI tract and feces. The metagenomic functions associated with nutrient metabolism differed significantly between the small intestine and the feces. CONCLUSIONS: The fact that the compositional structures of small intestinal microbiota differed from those of fecal and other GI microbiotas reveals that analyzing the small intestinal microbiota is necessary for association studies on metabolic diseases and gut microbiota.

[A case of chronic enteropathy associated with SLCO2A1 gene diagnosed by capsule endoscopy and successfully treated by ferric carboxymaltose].

Chronic non-specific multiple ulcers of the small intestine is a disease condition postulated in Japan. It is an uncommon gastrointestinal disease that causes chronic anemia and hypoalbuminemia by causing numerous ulcers without any histopathologically identifiable features. In recent years, it has been revealed that the mutations of SLCO2A1, which codes the prostaglandin transporter protein, are the cause of this disease;it is called the new name "chronic enteropathy associated with SLCO2A1 gene." The ileum, except the terminal ileum, is the most common place making it difficult to identify major lesions. Other than conservative treatments, such as nutrition therapy and iron supplements, no effective treatment has been identified so far. We present a case of chronic non-specific multiple ulcers of the small intestine diagnosed by capsule endoscopy and effectively treated by ferric carboxymaltose. A 48-year-old female had chronic iron deficiency anemia since around the age of 15. Because of severe anemia, the patient had upper and lower endoscopy at the age of 47 to find the source of the bleeding, but it was not detected. Except for the terminal ileum, the capsule endoscopy revealed ring-like ulcers, tape-like ulcers, and oblique ulcer scars in the ileum. Genetic analysis showed a homozygous mutation in intron 7, c.940+1G>A, indicating a definitive diagnosis of non-specific multiple ulcers of the small intestine. Anemia and anemia-related symptoms such as general malaise persisted despite continuous oral administration of iron drugs. Three intravenous injections of ferric carboxymaltose increased hemoglobin and enhanced the symptoms.

Identifying Bleeding Etiologies by Endoscopy Affected Outcomes in 10,342 Cases With Hematochezia: CODE BLUE-J Study.

INTRODUCTION: The bleeding source of hematochezia is unknown without performing colonoscopy. We sought to identify whether colonoscopy is a risk-stratifying tool to identify etiology and predict outcomes and whether presenting symptoms can differentiate the etiologies in patients with hematochezia. METHODS: This multicenter retrospective cohort study conducted at 49 hospitals across Japan analyzed 10,342 patients admitted for outpatient-onset acute hematochezia. RESULTS: Patients were mostly elderly population, and 29.5% had hemodynamic instability. Computed tomography was performed in 69.1% and colonoscopy in 87.7%. Diagnostic yield of colonoscopy reached 94.9%, most frequently diverticular bleeding. Thirty-day rebleeding rates were significantly higher with diverticulosis and small bowel bleeding than with other etiologies. In-hospital mortality was significantly higher with angioectasia, malignancy, rectal ulcer, and upper gastrointestinal bleeding. Colonoscopic treatment rates were significantly higher with diverticulosis, radiation colitis, angioectasia, rectal ulcer, and postendoscopy bleeding. More interventional radiology procedures were needed for diverticulosis and small bowel bleeding. Etiologies with favorable outcomes and low procedure rates were ischemic colitis and infectious colitis. Higher rates of painless hematochezia at presentation were significantly associated with multiple diseases, such as rectal ulcer, hemorrhoids, angioectasia, radiation colitis, and diverticulosis. The same was true in cases of hematochezia with diarrhea, fever, and hemodynamic instability. DISCUSSION: This nationwide data set of acute hematochezia highlights the importance of colonoscopy in accurately detecting bleeding etiologies that stratify patients at high or low risk of adverse outcomes and those who will likely require more procedures. Predicting different bleeding etiologies based on initial presentation would be challenging.

Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway.

BACKGROUND: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST. METHODS: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated. RESULTS: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action. CONCLUSION: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.

Adding Thiopurine After Loss of Response to Infliximab Versus Early Combination in Treating Crohn's Disease: A Retrospective Study.

BACKGROUND: Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX. METHODS: This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups. RESULTS: One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001). CONCLUSION: Considering the risk-benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD.

Mucosal dysbiosis in patients with gastrointestinal follicular lymphoma.

Because the pathogenesis of gastrointestinal follicular lymphoma (GI-FL) remains unclear, no standardized treatment strategy has been established. Of the gastrointestinal lymphomas, gastric mucosa-associated lymphoid tissue lymphomas are strongly associated with Helicobacter pylori; hence, the microbiota may be involved in GI-FL pathogenesis. However, the association between GI-FL and the microbiota remains uninvestigated. Therefore, we compared the mucosal microbiotas of GI-FL patients with those of controls to identify microbiota changes in GI-FL patients. Mucosal biopsy samples were obtained from the second portion of the duodenum from 20 GI-FL patients with duodenal lesions and 20 controls. Subsequent 16S rRNA gene sequencing was performed on these samples. QIIME pipeline and LEfSe software were used to analyze the microbiota. The GI-FL patients had significantly lower alpha diversity (P = .049) than did the controls, with significant differences in the microbial composition (P = .023) evaluated by the beta diversity metrics between the two groups. Comparing the taxonomic compositions indicated that the genera Sporomusa, Rothia, and Prevotella and the family Gemellaceae were significantly less abundant in the GI-FL patients than in the controls. GI-FL patients presented altered duodenal mucosal microbial compositions, suggesting that the microbiota might be involved in the GI-FL pathogenesis.

Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease.

BACKGROUND AND AIM: Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. METHODS: Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan-Meier method. Overall adverse events (AEs) during follow-up were also analyzed. RESULTS: Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non-responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow-up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. CONCLUSIONS: Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment.

Predictive Factors for Rebleeding after Negative Capsule Endoscopy among Patients with Overt Obscure Gastrointestinal Bleeding.

BACKGROUND: Although capsule endoscopy (CE) is useful to evaluate obscure gastrointestinal bleeding (OGIB), CE does not always identify the responsible lesions in patients with overt OGIB. OBJECTIVES: To identify factors predictive of rebleeding after negative CE in patients with overt OGIB. METHODS: We retrospectively analyzed the clinical data of 221 patients who underwent CE for overt OGIB. Among 120 patients with negative CE findings, clinical course of 112 patients after CE was followed-up. Clinical factors associated with rebleeding after negative CE and lesions responsible for rebleeding were investigated. RESULTS: Rebleeding was identified in 37 patients (33.0%) during follow-up after negative CE, and 36 patients (32.1%) developed rebleeding within 24 months after negative CE. Multivariate analyses showed that ongoing overt OGIB (OR 2.67; 95% CI 1.07-5.80; p = 0.036) and severe anemia at the initial CE examination (OR 2.54; 95% CI 1.33-4.96; p = 0.005) were independent factors -associated with rebleeding. Rebleeding source was detected in 13 patients. CONCLUSIONS: Rebleeding is not a rare condition among patients with overt OGIB after negative CE. Patients with ongoing overt OGIB or severe anemia at the initial CE examination seem to have a higher risk of rebleeding.

Comparison of the microbial community structure between inflamed and non-inflamed sites in patients with ulcerative colitis.

BACKGROUND AND AIM: The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC-related changes. We thus investigated paired mucosa-associated microbiota obtained from both inflamed and non-inflamed sites of UC patients and corresponding sites of non-inflammatory bowel disease (IBD) controls. METHODS: Mucosal biopsies of both inflamed and non-inflamed sites were obtained from 14 patients with active UC of the left-sided or proctitis type. Paired mucosal biopsies of the corresponding sites were obtained from 14 non-IBD controls. The microbial community structure was investigated using 16S ribosomal RNA gene sequences, followed by data analysis using qiime and LEfSe softwares. RESULTS: Microbial alpha diversity in both inflamed and non-inflamed sites was significantly lower in UC patients compared with non-IBD controls. There were more microbes of the genus Cloacibacterium and the Tissierellaceae family, and there were less microbes of the genus Neisseria at the inflamed site when compared with the non-inflamed site in UC patients. Decreased abundance of the genera Prevotella, Eubacterium, Neisseria, Leptotrichia, Bilophila, Desulfovibrio, and Butyricimonas was evident at the inflamed site of UC patients compared with the corresponding site of non-IBD controls. Among these taxa, the genera Prevotella and Butyricimonas were also less abundant at the non-inflamed site of UC patients compared with the corresponding site in non-IBD controls. CONCLUSIONS: Mucosal microbial dysbiosis occurs at both inflamed and non-inflamed sites in UC patients. The taxa showing altered abundance in UC patients might mediate colonic inflammation.

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn's disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of "chronic enteropathy associated with SLCO2A1 gene" (CEAS).

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population.

We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.