OBJECTIVE: This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR). METHODS: Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway. RESULTS: Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon. CONCLUSION Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.
Rats ; Animals ; Crohn Disease/pathology* ; Moxibustion/methods* ; Toll-Like Receptor 4/metabolism* ; Rats, Sprague-Dawley ; Myeloid Differentiation Factor 88/metabolism* ; Colitis ; Inflammation ; Enterohepatic Circulation ; RNA, Messenger/metabolism*

Characterizing inflammation and fibrosis in Crohn's disease (CD) is necessary to guide clinical management, but distinguishing the two remains challenging. Novel ultrasound (US) techniques: contrast-enhanced US (CEUS) and shear wave elastography (SWE) offer great potential in evaluating disease activity in pediatric patients. Three patients ages 16 to 20 with known CD underwent CEUS and SWE to characterize bowel wall inflammation and fibrosis. Magnetic resonance enterography, endoscopy, or surgical pathology findings are also described when available. The patients' disease activity included acute inflammation, chronic inflammation with stricture formation, and a fibrotic surgical anastomosis without inflammation. CEUS was useful in determining the degree of inflammation, and SWE identified bowel wall fibrosis. Used together these techniques allow for better characterization of the degree of fibrosis and inflammation in bowel strictures. With further validation CEUS and SWE may allow for improved characterization of bowel strictures and disease flares in pediatric patients suffering from CD.
Adolescent ; Anastomosis, Surgical ; Constriction, Pathologic ; Contrast Media ; Crohn Disease ; Elasticity Imaging Techniques ; Endoscopy ; Fibrosis ; Humans ; Inflammation ; Inflammatory Bowel Diseases ; Pathology, Surgical ; Pediatrics ; Ultrasonography

BACKGROUND/AIMS: Classical M1 macrophage activation exhibits an inflammatory phenotype while alternative M2 macrophage activation exhibits an anti-inflammatory phenotype. We aimed to determine whether there are discriminant patterns of macrophage polarization in Crohn's disease (CD) and intestinal tuberculosis (iTB). METHODS: Colonic mucosal biopsies from 29 patients with iTB, 50 with CD, and 19 controls were examined. Dual colored immunohistochemistry was performed for iNOS/CD68 (an M1φ marker) and CD163/CD68 (an M2φ marker), and the ratio of M1φ to M2φ was assessed. To establish the innate nature of macrophage polarization, we analyzed the extent of mitochondrial depolarization, a key marker of inflammatory responses, in monocyte-derived macrophages obtained from CD and iTB patients, following interferon-γ treatment. RESULTS: M1φ polarization was more prominent in CD biopsies (P=0.002) than in iTB (P=0.2) and control biopsies. In granuloma-positive biopsies, including those in CD, M1φ predominance was significant (P=0.001). In iTB, the densities of M1φ did not differ between granuloma-positive and granuloma-negative biopsies (P=0.1). Interestingly, higher M1φ polarization in CD biopsies correlated with high inflammatory response exhibited by peripheral blood-derived monocytes from these patients. CONCLUSIONS: Proinflammatory M1φ polarization was more common in colonic mucosa of CD patients, especially in the presence of mucosal granulomas. Further characterization of the innate immune system could help in clarifying the pathology of iTB and CD.
Biopsy ; Colon ; Crohn Disease* ; Granuloma ; Humans ; Immune System ; Immunohistochemistry ; Macrophage Activation ; Macrophages* ; Monocytes ; Mucous Membrane ; Pathology ; Phenotype ; Tuberculosis*

BACKGROUND/AIMS: Gastric pathology and Helicobacter pylori (H. pylori) infection among Asian patients with Crohn's disease (CD) are still unclear. We evaluated gastric histologic features and frequency of H. pylori infection in Korean patients with CD. METHODS: Among 492 patients with CD receiving upper gastrointestinal (GI) endoscopic evaluation in 19 Korean hospitals, we evaluated the endoscopic findings and gastric histopathologic features of 47 patients for our study. Histopathologic classification was performed using gastric biopsy tissues, and H. pylori infection was determined using the rapid urease test and histology. RESULTS: There were 36 men (76.6%), and the median age of patients at the time of upper GI endoscopy was 23.8 years (range, 14.2-60.5). For CD phenotype, ileocolonic disease was observed in 38 patients (80.9%), and non-stricturing, non-penetrating disease in 31 patients (66.0%). Twenty-eight patients (59.6%) complained of upper GI symptoms. Erosive gastritis was the most common gross gastric feature (66.0%). Histopathologically, H. pylori-negative chronic active gastritis (38.3%) was the most frequent finding. H. pylori testing was positive in 11 patients (23.4%), and gastric noncaseating granulomata were detected in 4 patients (8.5%). Gastric noncaseating granuloma showed a statistically significant association with perianal abscess/fistula (P=0.0496). CONCLUSIONS: H. pylori-negative chronic active gastritis appears to be frequent among Korean patients with CD. The frequency of H. pylori infection was comparable with previous studies. An association with perianal complications suggests a prognostic value for gastric noncaseating granuloma in patients with CD.
Asian Continental Ancestry Group ; Biopsy ; Classification ; Crohn Disease* ; Endoscopy ; Gastritis ; Granuloma ; Helicobacter pylori ; Humans ; Korea* ; Male ; Pathology ; Phenotype ; Stomach ; Urease

Endoscopy plays a significant role in the diagnosis, management, and surveillance of colorectal cancer (CRC) and inflammatory bowel diseases (IBDs). Moreover, magnifying endoscopy and image-enhanced endoscopy has a crucial role in the clinical setting. Recently, a super-magnifying endoscope has been developed, and two devices, confocal laser endomicroscopy (CLE) and an endocytoscopy system (ECS), which allow in vivo microscopic inspection of the microstructural mucosal features of the gastrointestinal tract, are currently available. Studies on the use of ECS in CRC were reported by a Japanese group. Additionally, a few studies on the use of ECS in IBD have been reported. CLE has been shown to be reliable in assessing the activity of the disease in IBDs in both ulcerative colitis and Crohn's disease. Various published studies evaluated the use of CLE during colonoscopy to distinguish colorectal polyp pathology and neoplasia. However, these studies are heterogeneous, and further evidence is necessary to confirm the efficacy of CLE.
Asian Continental Ancestry Group ; Colitis, Ulcerative ; Colonoscopy ; Colorectal Neoplasms ; Crohn Disease ; Diagnosis ; Endoscopes ; Endoscopy* ; Gastrointestinal Tract ; Humans ; Inflammatory Bowel Diseases ; Pathology ; Polyps

BACKGROUND/AIMS: C-reactive protein (CRP) is a serologic activity marker in Crohn's disease (CD), but it may be less useful in evaluating CD activity in ileal CD patients. We aimed to investigate the usefulness of CRP as a disease activity marker in CD according to disease location. METHODS: Korean CD patients in a single hospital were evaluated. Factors associated with elevated CRP concentration at the time of diagnosis of CD and the association between the physician's prediction regarding upcoming surgery and the sites of the lesions directly related to surgery were analyzed. RESULTS: Of 435 CD patients, 25.7%, 6.9%, and 67.4% had ileal, colonic, and ileocolonic CD, respectively. Multivariate analysis revealed that an elevated erythrocyte sedimentation rate, reduced serum albumin, CD activity index (CDAI) >220, and ileocolonic/colonic location were associated with an elevated CRP level and that the CRP level was significantly correlated with the CDAI in all CD patients (gamma=0.466, p<0.01). However, the correlation coefficient was dependent on the location, with values of 0.395, 0.456, and 0.527 in patients with an ileal, ileocolonic, and colonic disease location, respectively. Surgery for ileal lesions was less predictable than surgery for ileocolonic or colonic lesions during follow-up. CONCLUSIONS: CRP is less useful as a disease activity marker in patients with ileal CD than those with ileocolonic or colonic CD.
Adolescent ; Adult ; Aged ; Biological Markers/blood ; Blood Sedimentation ; C-Reactive Protein/*analysis ; Child ; Colon/pathology ; Crohn Disease/blood/*diagnosis/pathology ; Female ; Humans ; Ileum/pathology ; Male ; Middle Aged ; Serum Albumin/analysis ; Severity of Illness Index ; Young Adult

Inflammatory bowel disease (IBD) is a chronic progressive idiopathic inflammatory disorder that involves the digestive tract from the mouth to the anus. Over the past decades, many therapeutic strategies have been developed to manage IBD, but therapeutic strategies based only on relief of clinical symptoms have not changed the natural history of this disease entity. This underlines the importance of understanding the natural history of IBD itself. When we look at the natural history of Crohn's disease (CD), it first begins with inflammation of the intestinal mucosa and this inflammatory reaction proceeds to stenosing or penetrating reaction if not adequately controlled. However, it takes a considerable amount of time before mucosal inflammation proceeds to stenosis of the intestinal lumen or penetration into the adjacent bowel. Therefore, it can be expected that if proper care is given during that period, progression of CD to such a complicated disease could be prevented. Even though the concept of mucosal healing was introduced in the early 1990s, no correlation could be observed between healing of mucosal lesions and relief of clinical symptoms. However, the introduction of biologic agents targeting tumor necrosis factor has changed the way to treat IBD that is refractory to standard medications and has allowed us to aim for a new therapeutic goal, 'deep remission'. Further advances in biologic agents have provided highly effective treatments for IBD, making deep remission a realistic goal. Whether IBD patients may benefit by experiencing a 'deep' remission beyond the control of clinical symptoms need to be evaluated in further investigation. Nevertheless, it can be anticipated that attaining deep remission might ultimately have an impact on important outcomes such as the need for surgery and the quality of life.
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Colitis, Ulcerative/drug therapy/metabolism/pathology ; Crohn Disease/drug therapy/metabolism/pathology ; Humans ; Inflammatory Bowel Diseases/drug therapy/metabolism/*pathology ; Intestinal Mucosa/metabolism/pathology ; Mesalamine/therapeutic use ; Tumor Necrosis Factor-alpha/immunology/metabolism

BACKGROUND/AIMS: Pediatric inflammatory bowel disease (IBD) has been increasing worldwide. The characteristics of pediatric-onset IBD have mainly been reported in Western countries. We investigated the clinical characteristics of pediatric IBD in Korea and compared these with the data from the 5-year European multicenter study of children with new-onset IBD (EUROKIDS registry). METHODS: Children who were diagnosed with IBD between July 1987 and January 2012 were investigated at five Korean university hospitals. Their clinical characteristics were retrospectively evaluated by medical record review. The results were compared with the EUROKIDS data. RESULTS: A total of 30 children with Crohn's disease (CD) and 33 children with ulcerative colitis (UC) were enrolled. In comparison with the EUROKIDS group, Korean pediatric IBD patients showed a male predominance (86.7% vs 59.2%, p=0.002 in CD; 75.8% vs 50%, p=0.003 in UC). Korean pediatric CD patients had a higher prevalence of terminal ileal disease (36.7% vs 16.3%, p=0.004) and perianal disease (33.3% vs 8.2%, p<0.001) than patients in the EUROKIDS group. Korean pediatric UC patients had a higher prevalence of proctitis than patients in the EUROKIDS group. CONCLUSIONS: Our results suggest that the characteristics of Korean pediatric IBD patients and European pediatric IBD patients may be different.
Adolescent ; Anus Diseases/complications/epidemiology/pathology ; Child ; Colitis, Ulcerative/complications/epidemiology/*pathology ; Crohn Disease/complications/epidemiology/*pathology ; Europe/epidemiology ; Female ; Humans ; Ileal Diseases/complications/epidemiology/pathology ; Male ; Prevalence ; Proctitis/epidemiology/etiology ; Registries ; Republic of Korea/epidemiology ; Retrospective Studies ; Sex Factors

A 66-year-old male with dyspepsia and weight loss was referred to our hospital for evaluation. On laboratory examination, anti-saccharomyces cerevisiae (ASCA)-IgA was positive and iron deficiency anemia was present. PET/CT and abdominal CT scan images showed multiple small bowel segmental wall thickening and inflammation. Capsule endoscopy images showed multiple small bowel ulcerative lesions with exudates. Based on laboratory test results and imaging studies, the patient was diagnosed with Crohn's disease and treated with prednisolone and 5-aminosalicylic acid (5-ASA). However, the patient underwent second operation due to small bowel perforation within 2 month after initiation of treatment. Pathology report of the resected specimen was compatible to primary small bowel diffuse large B cell lymphoma and pertinent treatment was given to the patient after recovery. Herein, we describe a case of primary small bowel diffuse large B cell lymphoma that was mistaken for Crohn's disease.
Aged ; Antibodies/blood ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Capsule Endoscopy ; Crohn Disease/diagnosis/drug therapy ; Diagnostic Errors ; Humans ; Immunoglobulin A/blood ; Intestinal Perforation/surgery ; Lymphoma, Large B-Cell, Diffuse/*diagnosis/drug therapy/pathology ; Male ; Mesalamine/therapeutic use ; Positron-Emission Tomography ; Saccharomyces cerevisiae/immunology ; Tomography, X-Ray Computed

Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.
Anticholesteremic Agents/therapeutic use ; Bile Acids and Salts/*physiology ; Crohn Disease/complications ; Diarrhea/*etiology/pathology/therapy ; Feces/chemistry ; Fibroblast Growth Factors/deficiency ; Gastrointestinal Microbiome ; Humans ; Irritable Bowel Syndrome/complications