Crohn's Intestine Research Articles

Pro-inflammatory NK-like T cells are expanded in the blood and inflamed intestine in Crohn’s disease

Altered intestinal immune homeostasis leads to chronic inflammation in Crohn’s disease (CD). To address disease- and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with CD and healthy donors’ PBMCs. Chronic intestinal inflammation enforced activation, exhaustion, and terminal differentiation of CD4+ and CD8+ T cells and a relative enrichment of CD4+ regulatory T (Treg) cells. Moreover, enigmatic rare Treg subsets appeared upon inflammation, e.g. CD4+FOXP3+HLA-DR+TIGIT– and CD4+FOXP3+CD56+, expressing pro-inflammatory IFN-γ upon in vitro stimulation. Some conventional T (Tcon) cells acquired NK-like features. In CD patients’ blood, not well studied CD16+CCR6+CD127+ T cells appeared, being CD4+ or CD8+, a phenotype inducible on healthy T cells by CD blood plasma. Upon CD16-mediated antibody binding, they could attain effector function. These findings suggest an uncommon pro-inflammatory innate-like differentiation of Treg and Tcon cells with acquisition of non-specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.

Relationship between adipose tissue and intestine in Crohn’s disease

Relationship between adipose tissue and intestine in Crohn’s disease

Costs of Healthcare for Children with Inflammatory Bowel Diseases (IBD) in Poland.

The last two decades have seen an increase in the incidence of inflammatory bowel disease (IBD) in many regions of the world, which has had a significant impact on both the social and economic burden of governments and healthcare systems. The aim of this study was to determine the level of hospitalization and outpatient treatment costs for children and adolescents with Crohn's disease and ulcerative colitis, depending on age, location, and activity of the disease. Methods were a retrospective analysis of the medical documentation of 240 children with IBD, hospitalized in the Gastroenterology Ward, Department of Pediatrics Medical University of Silesia (Katowice, Poland), along the three years follow up. The costs of treatment consisted of calculations of the supply of oral and intravenous drugs, calculations of the costs of laboratory tests, imaging, and consultations, as well as person-day costs. The most important results, determined with high costs of IBD treatment, are associated with younger age, high disease activity, localization in the small intestine in Crohn's disease (CD), and inflammatory changes in the entire colon in Ulcerative Colitis (UC). During the observation, it was noticed that the shortening of the hospitalization time did not significantly affect the total costs, which remained at a stable level.

Magnetic resonance enterocolonography for assessing inflammation activity in Crohn’s disease using the CDMI and MEGS indices

AIM: to determine the diagnostic efficiency of magnetic resonance enterocolonography using inflammation indices (CDMI, MEGS) in assessing activity of the inflammatory process in the colon and small intestine in Crohn's disease.PATIENTS AND METHODS: the study included 42 patients with Crohn's disease (age ranged from 19 to 47 years). All patients underwent magnetic resonance enterocolonography (MRE) with intravenous contrast and diffusion-weighted images. According to the results of MRE, were determined MR indices of inflammation activity in the small and large intestine - CDMI and MEGS. The MR inflammatory activity indices CDMI and MEGS were compared with the endoscopic inflammatory activity index SES-CD.RESULTS: the MR inflammation activity index CDMI did not show a statistically significant diagnostic efficiency (p>0.05). The MR inflammation activity index MEGS showed a statistically significant diagnostic efficiency (p<0.0001). According to the nomogram, the MR inflammation activity index MEGS demonstrated a high predictive ability to determine the true activity of the inflammatory process in the small and large intestine. Correlation demonstrated direct strong relationship between the quantitative values of the MEGS inflammation indices and the endoscopic inflammation index (SES-CD) (r=0.843, p<0.0001).CONCLUSION: magnetic resonance enterocolonography using the MEGS activity index has a high diagnostic efficiency in assessing the activity of the inflammatory process in the small and large intestine in Crohn's disease. The MR inflammation activity index CDMI did not show statistically significant diagnostic efficacy. The results of the study should be considered preliminary and require further study of the possibilities of these indices of inflammation activity in a larger sample of patients.

Risk factors and characteristics of gut microbiota and metabolites in inflammatory bowel diseases patients with urolithiasis

Objective: To identify the related factors and characteristics of gut microbiota and metabolites in inflammatory bowel disease (IBD) patients with urolithiasis. Methods: A total of 68 IBD patients with urolithiasis and 136 gender-and age-matched IBD patients without urolithiasis in the Department of Gastroenterology, Peking Union Medical College Hospital from January 2014 to December 2019 were recruited. The diagnosis of urolithiasis was confirmed by plain films, ultrasonography, abdominal computed tomography or intravenous urography. The clinical data of patients were collected, and the association between the clinical characteristics and urolithiasis was further analyzed. The fecal samples were collected from 10 patients with urolithiasis and 18 patients without urolithiasis, and the gut microbiota and metabolites composition were analyzed. Results: There were 49 male and 19 female IBD patients with urolithiasis, with a mean age of (36.0±12.4) years, and 98 male and 38 female patients without urolithiasis, with a mean age of (36.1±12.5) years. Univariate analysis revealed that the rate of ileostomy and the resection of small intestine in Crohn's disease (CD) patients with urolithiasis (n=34) was significantly higher than CD patients without urolithiasis (n=68) (26.5% vs 7.4%, P=0.019). And the erythrocyte sedimentation rate was also higher [26.5 (12.0, 40.8) vs 13.0 (7.2, 32.5) mm/1 h, P=0.022] in CD patients with urolithiasis. There were no significant differences in clinical characteristics and biochemical parameters between the ulcerative colitis (UC) patients with urolithiasis (n=34) and without urolithiasis (n=68) (all P>0.05). The multivariate logistic regression analysis indicated that ileostomy and the resection of small intestine were the independent related factors for urolithiasis in CD patients (OR=4.619, 95%CI: 1.178-18.111, P=0.028). There was no significant difference in α and β diversity between the two groups (all P>0.05). At the phylum level, there was no significant difference in the abundance of microbiota (all P>0.05). At the genus level, the abundance of Enterococcus (P=0.049), Eubacterium_eligens (P=0.036) was significantly decreased. At the species level, the abundance of Bacteroides_coprocola was increased in urolithiasis group (P=0.035), while the abundance of Blautia_caecimuris was significantly decreased (P=0.042). No significant difference was found in fecal metabolites between the two groups (all P>0.05). According to LDA effect size (Lefse) analysis, taxa including Sphingomonadales, Fenollaria, Bacteroides_coprocola contributed greatly to the difference between the two groups. Conclusions: Ileostomy and the resection of small intestine are related factors for urolithiasis in patients with CD. Gut microbiota may be involved in the occurrence of urolithiasis in patients with IBD.

Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo

Chronic inflammation of the human intestine in Crohn’s disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-Rβ or NFκB but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1β and TNFα, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNFα and IL-1β, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.

The microbiome can predict mucosal healing in small intestine in patients with Crohn's disease.

Mucosal healing is the main treatment goal for Crohn's disease. In this situation, some patients have difficulty with endoscopic evaluation of the entire small intestine. Crohn's disease is closely associated with the gut microbiota, but the relationship between the microbiome and disease activity in the small intestine remains unclear. We examined the association between the microbiome and endoscopic findings in the small intestine and determined whether the microbiome can predict mucosal healing. The patients with Crohn's disease who were scheduled for capsule or balloon-assisted endoscopy were included in this prospective study. Patients whose entire small intestine was evaluated were divided into two groups based on ulcerative findings. The microbiomes in the fecal samples were analyzed using 16S rRNA sequencing. The 38 enrolled patients were divided into the ulcer group (24) and mucosal healing group (14). The ulcer group exhibited lower α diversity. Six genera, namely Faecalibacterium (P = 0.008), Lachnospira (P = 0.009), Paraprevotella (P = 0.01), Dialister (P = 0.012), Streptococcus (P = 0.025), and Clostridium (P = 0.028) were enriched in the mucosal healing group. A predictive score for mucosal healing was defined using these six genera. The area under the curve was 0.795 and the sensitivity and specificity for predicting mucosal healing were 0.643 and 0.917, respectively. Fecal microbiome is corelated with disease activity in the entire small intestine in Crohn's disease patients. The predictive score proposed by microbiota characteristics was a potential biomarker for mucosal healing in the small intestine.

Prospects of Using Microbiota Correction Methods in the Treatment of Inflammatory Bowel Disease

Aim. The present article examines key methods of microbiota correction (antibiotic therapy; pro-, pre- and metabiotic therapy; faecal microbiota transplantation) used in treating inflammatory bowel disease, as well as compares the clinical trial results of these methods.Key findings. Inflammatory bowel disease (IBD) is an umbrella term used to describe a group of chronic diseases of unknown aetiology. In the past, bacteriological methods based on the isolation of a pure bacterial culture were used to determine the microbiota composition. However, such methods did not provide complete information on the microbiota composition. In recent years, preference has been given to more accurate and faster molecular genetic methods allowing a more detailed study of the key mechanisms by which microbiota affects the intestine in Crohn’s disease (CD) and ulcerative colitis (UC), as well as of the effect of microbial metabolites on their pathogenesis. The article provides an overview of main microbiota metabolites and their role in regulating the intestinal barrier function. One of the current issues consists in the development of personalised approaches to therapy and remission maintenance in IBD, including via methods for correcting the microbial composition: probiotic, prebiotic and metabiotic therapy, as well as faecal microbiota transplantation.Conclusion. The use of probiotics, prebiotics, and metabiotics can enhance the effectiveness of therapeutic regimens and significantly improve the quality of life of patients with chronic IBD. The use of antibiotics and faecal microbiota transplantation in treating IBD is the subject of extensive discussion and debate. The safety of these methods has not been confirmed so far; therefore, it is vital to continue studying their influence on the clinical condition of patients.

Usefulness of intestinal real-time virtual sonography in patients with inflammatory bowel disease.

Transabdominal ultrasonography (US) examination for the intestine is often difficult, and its precedence for intestinal examination depends on accessibility to experienced ultrasonographers. Real-time virtual sonography (RVS) assists examination of US as a fusion method by synchronizing US images with pre-captured computed tomography or magnetic resonance images. We aimed to evaluate the feasibility to use RVS for the examination of the intestine. The time to scan three parts of the intestine was compared between conventional US and RVS in seven participants without intestinal diseases. Whether RVS accurately synchronized US images with reference images of intestinal target lesions was judged in 20 patients with inflammatory bowel disease. Examination time to scan the ascending colon and the ileocecum using intestinal RVS was significantly shorter than that using conventional US alone (36.7 vs 50.0s [P=0.0313] and 35.4 vs 66.4s [P=0.0156], respectively) in participants without intestinal diseases. Well-synchronized US images of the intestinal lesions, such as stenosis, with reference computed tomography/magnetic resonance images were obtained by RVS in all the lesions in the fixed parts of the colon (ascending and descending colon), and images of nine lesions in 12 lesions (75%) were well synchronized in the unfixed part of the intestine in Crohn's disease patients. Real-time virtual sonography significantly reduced the examination time of intestinal US. Intestinal RVS can help the ultrasonographer to guide the US probe to detect and monitor intestinal lesions by synchronizing reference images, especially in inflammatory bowel disease patients (UMIN Clinical Trials Registry number: UMIN000011571).

Indian guidelines on imaging of the small intestine in Crohn's disease: A joint Indian Society of Gastroenterology and Indian Radiology and Imaging Association consensus statement.

The Indian Society of Gastroenterology (ISG) Task Force on Inflammatory Bowel Disease and the Indian Radiological and Imaging Association (IRIA) developed combined ISG-IRIA evidence-based best-practice guidelines for imaging of the small intestine in patients suspected to have or having Crohn's disease. The 29 consensus statements, developed through a modified Delphi process, are intended to serve as reference for teaching, clinical practice, and research.

T-cell Composition in Ileal and Colonic Creeping Fat - Separating Ileal from Colonic Crohn's Disease.

Creeping fat [CF] is a hyperplasia of adipose tissue adjacent to inflamed intestine in Crohn's disease [CD]. Data from genome-wide association studies [GWAS] distinguished Crohn's colitis from ileal CD and ulcerative colitis [UC]. This study analysed the T-cell compartments of ileal and colonic mesenteric fat and corresponding mucosa to provide cellular proof for the suggested GWAS classification. Samples were obtained from 34 CD or UC patients. Cells were analysed by immunohistochemistry and flow cytometry, and tissue cytokine release was assessed by cytometric bead array. Only ileal CF revealed the distinct adipocyte hyperplasia combined with dense T-cell infiltration and fibrosis; colonic fat from CD and UC patients lacked these findings. T-cell subpopulations differed between mesenteric fat in ileal CD, colonic CD and UC: ileal CF had nearly 10 times more T-cells than colonic fat. The proportions of regulatory and central memory T-cells were significantly higher in ileal CF compared with colonic fat in CD and UC. In all groups, the mucosal T-cell compartment was distinct from the mesenteric fat. Remarkably, correlation between disease activity and proportion of pro- and anti-inflammatory T-cell subpopulations was inverse, comparing ileal and colonic fat in CD. This first in-depth analysis of the T-cell compartment in ileal and colonic mesenteric adipose tissue in CD and UC identifies a unique T-cell niche in the ileal mesenteric fat tissue in CD. From a clinical point of view, our findings underscore the novel concept of colonic and ileal CD as distinct IBD entities.

Imaging of the small intestine in Crohn's disease: Joint position statement of the Indian Society of Gastroenterology and Indian Radiological and Imaging Association.

The Indian Society of Gastroenterology (ISG) Task Force on Inflammatory Bowel Disease and the Indian Radiological and Imaging Association (IRIA) developed combined ISG-IRIA evidence-based best-practice guidelines for imaging of the small intestine in patients with suspected or known Crohn's disease. These 29 position statements, developed through a modified Delphi process, are intended to serve as reference for teaching, clinical practice, and research.

Magnetic resonance enterography for the evaluation of the deep small intestine in Crohn's disease.

For the control of Crohn's disease (CD) a thorough assessment of the small intestine is essential; several modalities may be utilized, with cross-sectional imaging being important. Magnetic resonance (MR) enterography, i.e., MRE is recommended as a modality with the highest accuracy for CD lesions. MRE and MR enteroclysis are the two methods performed following distension of the small intestine. MRE has sensitivity and specificity comparable to computed tomography enterography (CTE); although images obtained using MRE are less clear compared with CTE, MRE does not expose the patient to radiation and is superior for soft-tissue contrast. Furthermore, it can assess not only static but also dynamic and functional imaging and reveals signs of CD, such as abscess, comb sign, fat edema, fistula, lymph node enhancement, less motility, mucosal lesions, stricture, and wall enhancement. Several indices of inflammatory changes and intestinal damage have been proposed for objective evaluation. Recently, diffusion-weighted imaging has been proposed, which does not need bowel preparation and contrast enhancement. Comprehension of the characteristics of MRE and other modalities is important for better management of CD.

Mo1578 Usefulness of Evaluating Small Intestinal Mucosa With Capsule Endoscopy in Clinically Inactive Crohn's Disease

In Japan, patency capsule (PC) was approved on July 2012. Using PC, Capsule Endoscopy (CE) enables non-invasive visualization of small intestine in Crohn's disease (CD). CD patients can be managed according to CE findings in addition to symptoms and laboratory findings. Aims: We aimed to examine the usefulness of evaluating small intestinal mucosa with CE in CD.

Su1245 Modifying and Validating Endoscopic and Magnetic Resonance Scoring Systems for the Deep Small Intestine in Crohn's Disease

Su1245 Modifying and Validating Endoscopic and Magnetic Resonance Scoring Systems for the Deep Small Intestine in Crohn's Disease

Reactive angioendotheliomatosis of the intestine in Crohn’s disease: A second case report with 10-year follow up

Reactive angioendotheliomatosis (RAE) is a rare cutaneous vascular disorder, usually associated with systemic diseases. RAE has previously been described only in the skin, with the single exception of one case involving the intestine in a patient with Crohn’s disease, associated with lower gastrointestinal bleeding. We report a second case of intestinal RAE, also associated with Crohn’s disease and bleeding, with 10-year follow up. A 48-year-old man with Crohn’s disease presented with fever and chills associated with an abscess-like lesion in the ileum. The patient underwent ileocecectomy. The specimen showed histologic features of Crohn’s disease. In addition, a florid vascular lesion was identified in the ileum, proximal to the area involved by Crohn’s enteritis. Histomorphology and immunophenotype of this vascular lesion was consistent with RAE. The lesion was intimately associated with mesenteric hematoma, suggestive of bleeding. No abscess was identified. Currently, 10years after surgery, the patient has persistent ileal Crohn’s enteritis, but otherwise remains healthy with no evidence of vascular disorder. Although rarely reported, intestinal RAE in Crohn’s disease may be under recognized. The co-existence of Crohn’s disease in our patient and prior case report suggests that immunologic factors underlie its pathogenesis. Pathologic recognition of the lesion and awareness of the existence of intestinal RAE in hemorrhagic forms of Crohn’s disease is warranted.

Granulomas obstruct lymphatics in all layers of the intestine in Crohn's disease.

After an earlier study defining immunolabeled lymphoid follicles, obstructed lymphatics, and granulomas of the diseased ilea of 24 Crohn's disease patients, we chose to trace the lymphatics of these cases and 10 additional by serial sectioning. Particular attention was given to establishing physical continuity between granuloma-obstructed lymphatics and lymphatics with 'lymphocytic thrombi'. Formalin-fixed paraffin-embedded tissue blocks from resected diseased ilea and proximal colons from 34 patients were reviewed. Patients were 13 men and 21 women, aged 14-60years. Duration of disease ranged from 1month to 10years. Immunohistochemistry employed D2-40 antibody to label lymphatics and anti-CD68 to label granulomas. Twenty-nine of the 34 (85%) resection tissues had lymphangectasia, in mucosa, submucosa, and subserosa. In 53% of the specimens, lymphatics of the various layers were obstructed by granulomas that filled the lumina. In 44%, 15/34, there were also distended lymphatics that were totally plugged with lymphocytes. In 10 of the 15, serial sections revealed continuity between the lymphocyte-plugged lymphatics and the endolymphatic granulomatous obstruction downstream. In 5 of the cases, D2-40 immunostaining revealed redundant lymphatic endothelium interwoven with the granuloma cells. Granulomas totally obstruct lymphatics in all layers of the intestine in Crohn's disease. Upstream of these obstructions, lymphatics are distended with lymphocytes. The degree and extent of this potentially irreversible 'lymphangitis nodosa' have undoubtedly confounded treatment regimens and clinical trials. There currently are no imaging methods to demonstrate the lymphangitis, nor treatments to resolve it.

Circulating fibrocytes and Crohn's disease

Despite advances in medical therapy, there remains no effective preventive or non-surgical therapeutic option for fibrostenotic Crohn's disease (CD). Symptomatic recurrences are common, necessitating reintervention. Intestinal fibroblasts mediate stricture formation, but their exact source is unclear. Recent evidence indicates that circulating fibrocytes drive fibrosis through differentiation into fibroblasts and the production of extracellular matrix proteins. The aim of this review is to describe current understanding of the pathophysiology underlying fibrosis in CD, the cellular and molecular biology of fibrocytes and their role in CD. The electronic literature (January 1972 to December 2012) on 'circulating fibrocytes' and 'Crohn's fibrosis' was reviewed. Circulating fibrocytes appear universally involved in organ fibrosis. A complex array of cytokines, chemokines and growth factors regulate fibrocyte biology, and these are associated with fibrogenesis in CD. The cytokines transforming growth factor β1, connective tissue growth factor and interleukin 13, overexpressed in the strictured Crohn's intestine, promote fibrocyte generation and/or differentiation. Levels of circulating fibrocytes are raised in conditions marked by exaggerated fibrosis. These and other observations prompt a characterization of fibrocyte activity in CD with a view to investigating a pathogenic role.

Ultrasound of selected pathologies of the small intestine.

Intestines, especially the small bowel, are rarely subject to US assessment due to the presence of gases and chyme. The aim of this paper was to analyze ultrasound images in selected pathologies of the small intestine in adults, including the aspects of differential diagnosis.Material and methodsIn 2001–2012, abdominal ultrasound examinations were conducted in 176 patients with the following small bowel diseases: Crohn's disease (n=35), small bowel obstruction (n=35), yersiniosis (n=28), infectious diarrhea (n=26), bacterial overgrowth syndrome (n=25), coeliac disease (n=15) and small bowel ischemia (n=12). During examinations patients were fasting and no other particular preparations were needed. Convex transducers of 3.5–6 MHz and linear ones of 7–12 MHz were used. The assessment of the small intestine in four abdominal quadrants constituted an integral element of the examination. The following features of the small bowel ultrasound presentation were subject to analysis: thickness and perfusion of the walls, presence of thickened folds in the jejunum, reduction of their number, presence of fluid and gas contents in the intestine, its peristaltic activity, jejunization of the ileum and enteroenteric intussusception. Furthermore, the size of the mesenteric lymph nodes and the width of the superior mesenteric artery were determined and the peritoneal cavity was evaluated in terms of the presence of free fluid.ResultsStatistically significant differences were obtained between the thickness of the small intestine in Crohn's disease or in ischemic conditions and the thickness in the remaining analyzed pathological entities. Small bowel obstruction was manifested by the presence of distended loops due to gas and fluid as well as by severe peristaltic contractions occurring periodically. In the course of ischemic disease, the intestinal walls were thickened without the signs of increased perfusion and in the majority of cases intestinal stenosis was observed. Fluid in the intestine was detected in all patients with coeliac disease, gas in 86.7% of patients, thickening of the folds in the jejunum in 86.7%, their reduction in 80%, increased (enhanced) peristalsis in 93.3% and jejunization in 40%. In 80% of coeliac disease cases, the intestine showed the features of hyperemia on color Doppler examination and in 53.3% of patients the dilated lumen of the superior mesenteric artery was detected. Enlarged mesenteric lymph nodes were visualized in 73.3% of the subjects, enteroenteric intussusception in 33.3% and free fluid in the peritoneal cavity in 60%.Conclusions Small bowel obstruction is manifested by the presence of evidently dilated intestinal loops filled with gas and fluid and periodical severe deepened peristalsis.Ischemic changes and Crohn's disease are characterized by the presence of fragmentarily thickened intestinal walls and intestinal stenosis. Moreover, in Crohn's disease, increased wall perfusion and mesenteric adenomegaly is encountered.Coeliac disease is manifested by: increased amount of fluid mainly in the jejunum, thickened and hyperemic jejunal walls, increased peristalsis;hypertrophied mucosal folds – often their number is reduced, jejunization and transient enteroenteric intussusception;ultrasound changes that require the differentiation with small intestinal bacterial overgrowth syndrome and, to a lesser degree, with infectious diarrhea.

Daikenchuto (TU-100) ameliorates colon microvascular dysfunction via endogenous adrenomedullin in Crohn’s disease rat model

Daikenchuto (TU-100), a traditional Japanese medicine, has been reported to up-regulate the adrenomedullin (ADM)/calcitonin gene-related peptide (CGRP) system, which is involved in intestinal vasodilatation. The microvascular dysfunction of the intestine in Crohn's disease (CD), due to down-regulation of the ADM/CGRP system, is etiologically related to the recurrence of CD. Therefore, we investigated the vasodilatory effect of TU-100 in a CD rat model. Colitis was induced by the rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. Laser Doppler blood flowmetry was used to measure colonic blood flow. ADM, CGRP, and their receptors in the ischemic colon were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme immunoassays. Additionally, we determined whether the intestinal epithelial cell line IEC-6 released ADM in response to TU-100. TU-100 increased blood flow in ischemic segments of the colon but not in hyperemic segments. Pretreatment with an antibody to ADM abolished the vasodilatory effect of TU-100. CGRP levels and βCGRP mRNA expression were decreased in the ischemic colon, while protein and mRNA levels of ADM were unchanged. Hydroxy α-sanshool, the main constituent of TU-100, was the most active component in improving blood flow. Additionally, both TU-100 and hydroxy α-sanshool enhanced the release of ADM from IEC-6 cells. In the ischemic colon, endogenous βCGRP, but not ADM, was decreased. Thus, it was concluded that TU-100 ameliorated microvascular dysfunction by the up-regulation of endogenous ADM in the CD rat model. TU-100 may be a possible therapeutic agent for gastrointestinal ischemia-related diseases including CD.