Small Intestinal Ulcers Research Articles

FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats.

Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enteropathy in humans and experimental animals, a cause of considerable morbidity. Unlike foregut NSAID-associated mucosal lesions, most treatments for this condition are of little efficacy. We propose that the endogenously released intestinotrophic hormone glucagon-like peptide-2 (GLP-2) prevents the development of NSAID-induced enteropathy. Since the short-chain fatty acid receptor FFA3 is expressed on enteroendocrine L cells and on enteric nerves in the gastrointestinal tract, we further hypothesized that activation of FFA3 on L cells protects the mucosa from injury via GLP-2 release with enhanced duodenal HCO3- secretion. We thus investigated the effects of synthetic selective FFA3 agonists with consequent GLP-2 release on NSAID-induced enteropathy. We measured duodenal HCO3- secretion in isoflurane-anesthetized rats in a duodenal loop perfused with the selective FFA3 agonists MQC or AR420626 (AR) while measuring released GLP-2 in the portal vein (PV). Intestinal injury was produced by indomethacin (IND, 10mg/kg, sc) with or without MQC (1-10mg/kg, ig) or AR (0.01-0.1mg/kg, ig or ip) treatment. Luminal perfusion with MQC or AR (0.1-10µM) dose-dependently augmented duodenal HCO3- secretion accompanied by increased GLP-2 concentrations in the PV. The effect of FFA3 agonists was inhibited by co-perfusion of the selective FFA3 antagonist CF3-MQC (30µM). AR-induced augmented HCO3- secretion was reduced by iv injection of the GLP-2 receptor antagonist GLP-2(3-33) (3nmol/kg), or by pretreatment with the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTRinh-172 (1mg/kg, ip). IND-induced small intestinal ulcers were dose-dependently inhibited by intragastric administration of MQC or AR. GLP-2(3-33) (1mg/kg, ip) or CF3-MQC (1mg/kg, ig) reversed AR-associated reduction in IND-induced enteropathy. In contrast, ip injection of AR had no effect on enteropathy. These results suggest that luminal FFA3 activation enhances mucosal defenses and prevents NSAID-induced enteropathy via the GLP-2 pathway. The selective FFA3 agonist may be a potential therapeutic candidate for NSAID-induced enteropathy.

Chronic Enteropathy Associated With SLCO2A1 Gene [CEAS]-Characterisation of an Enteric Disorder to be Considered in the Differential Diagnosis of Crohn's Disease.

Small intestinal ulcers include mucosal damage caused by drugs, particularly nonsteroidal anti-inflammatory drugs [NSAIDs], infectious diseases, and idiopathic inflammatory bowel disease. Previously, a group of Japanese investigators reported an unusual and uncommon type of enteritis and referred to the condition as chronic nonspecific multiple ulcers of the small intestine [CNSU]. CNSU is characterised by chronic blood and protein loss through persistent small intestinal ulcers. Recently, four candidate mutations in the solute carrier organic anion transporter family, member 2A1 [SLCO2A1] gene, encoding a prostaglandin transporter, were identified by whole-exome sequencing in patients with CNSU. However, because the name 'CNSU' was somewhat ambiguous, the more appropriate nomenclature of 'chronic enteropathy associated with the SLCO2A1 gene' [CEAS] has been suggested. CEAS ulcers are characterised by multiple, circular or eccentric oblique, shallow lesions with discrete margins. The most frequently affected site of CEAS is the ileum, in contrast to 'cryptogenic multifocal ulcerous stenosing enteritis [CMUSE]', for which the most frequent site is the jejunum. Impaired prostaglandin utilisation is thought to cause the small intestinal mucosal damage observed in CEAS, CMUSE, and NSAID-induced enteropathy. This review article focuses on endoscopic and clinical features of genetically diagnosed CEAS, accumulated in a nationwide survey, and illustrates the observations in the format of an atlas.

Short article: Small intestinal mucosal injury in patients taking chemotherapeutic agents for solid cancers.

Chemotherapy for cancer is a systemic treatment often associated with side effects than can be debilitating and, in some cases, life-threatening. Few data are available on intestinal enterotoxicity. Wireless video capsule endoscopy (VCE) is a noninvasive method of imaging the small intestine. This study presents the results of VCE in patients with solid tumors undergoing antineoplastic regimens with agents, notably for toxicity for the gastrointestinal mucosa (i.e. carboplatin, cyclophosphamide, 5-fluorouracil, methotrexate, and cisplatin). The capsule endoscopy procedure was performed 4-13 days after the end of the antineoplastic course. Each patient received a polyethylene-glycol solution (1000 mg×2 in 2 l of water) for bowel preparation and fasted for 10 h before ingestion of the capsule. Videos were evaluated by one operator, supervised by a second operator, and conclusions were drawn by an expert reader. Twenty (age range: 38-77 years) patients were evaluated. The cecum was reached in 70% before exhaustion of the battery. The video capsule showed small widespread intestinal ulcerations in 25% and erosions in only one patient. The villus architecture appeared normal in all. VCE detected metastases in one patient with a melanoma. Few patients had more than one lesion. All capsules were passed in the stool. Our results suggest that chemotherapy in patients with solid cancers is associated with minimal visual small bowel injury. Factors other than damage of the intestinal mucosa causing loss of epithelium are likely involved in gastrointestinal toxicity and related symptoms.

Pediatric-onset Chronic Nonspecific Multiple Ulcers of Small Intestine: A Nationwide Survey and Genetic Study in Japan.

We performed a Japanese nationwide survey of pediatric-onset chronic nonspecific multiple ulcers of the small intestine between January 2000 and July 2013 in 176 institutions of pediatric surgery or pediatric gastroenterology and clarified the clinical features associated with genetic abnormalities in the Solute Carrier Organic Anion Transporter Family, Member 2A1 (SLCO2A1) gene. A total of 4 cases (3 girls and 1 boy) were diagnosed in this series, which had to be differentiated from Crohn disease, Behçet disease, tuberculosis, or drug-induced enteropathy. Clinical symptoms appeared in infants and accurate diagnosis required several years. Medical therapies for inflammatory bowel disease were administered in all patients; however, 2 of the 4 patients had mutation in the SLCO2A1 gene which are responsible for primary hypertrophic osteoarthopathy, and underwent strictureplasty or ileal resection after long-term follow-up. Pediatric gastroenterologists should include this new entity in the differential diagnosis of small intestinal ulcers and inflammatory bowel disease.

Clinical features of ten cases of cryptogenic multifocal ulcerous stenosing enteritis

Objective To investigate the clinical features of cryptogenic multifocal ulcerous stenosing enteritis(CMUSE), and to improve the diagnosis of this rare disease. Methods From 2010 to 2015, clinical data of 10 patients with CMUSE were retrospectively analyzed, including clinical features, laboratory examination, imaging examination, appearance under endoscopy, pathologic characteristics, location of lesions, treatment and prognosis. Results Among the 10 patients with CMUSE (male six, female four), the mean age was (35.1±14.8) years. The predominant clinical manifestation was melena (eight cases), abdominal pain (eight cases) and anemia (nine cases). The results of laboratory examination showed normal in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Among seven patients, hypersensitive C reactive protein (hsCRP) of two patients increased. Imaging examination showed intestinal stricture and appearance under endoscopic examination was intestinal ulcers and stenosis. Pathologic finding was superficial ulcers at mucosal and submucosal layers. Lesions mostly involved small intestine, and one case involving ileocecal valves and rectum. Among the 10 patients, seven patients received combination of surgical resection and prednisone treatment, and three patients were only administrated with medications. After treatment, seven patients remained remission and three patients relapsed after remission. Immunosuppressors and enteral nutrition was effective in two of them and glucocorticoid resistance happened in one patient. Conclusions The diagnosis of CMUSE should be considered in patients with unexplained recurrent bowel obstruction, melena, anemia and concomitant intestinal ulcer and stricture. Endoscopy plays an important role in the diagnosis. Glucocorticoid is effective but easy to relapse. Immunomodulators and enteral nutrition may be considered as second-line therapy. Key words: Cryptogenic multifocal ulcerous stenosing enteritis; Small intestinal ulcer; Intestinal stenosis; Gastrointestinal hemorrhage; Anemia

P215 Clinical features of chronic enteropathy associated with SLCO2A1 gene (CEAS)

Background: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare hereditary disease caused by mutations in SLCO2A1 gene, encoding a prostaglandin transporter. CEAS resembles Crohn's disease (CD) in presenting multiple small intestinal ulcers. However, because immunosuppressive therapies such as corticosteroid and anti-tumor necrosis factor-alpha antibody therapies are ineffective for CEAS in contrast to CD, recognition and precise diagnosis of CEAS are critical to avoid unnecessary therapies. Methods: Forty-one Japanese patients (10 male and 31 female) were diagnosed with CEAS by clinical findings and genetic analysis during a period of 2012 to 2016 and they were enrolled in this study. To identify the clinical features of CEAS, we reviewed the clinical information for the patients. In addition, because SLCO2A1 gene has also been reported as a causative gene of primary hypertrophic osteoarthropathy (PHO; OMIM 614441), we investigated whether CEAS patients had clinical manifestations of PHO. Results: We found recessive SLCO2A1 mutations located at 11 sites. Among the identified SLCO2A1 mutations, a splice-site mutation of intron 7 (c.940+1G>A) was the most frequent, and 17 of the 41 patients were homozygous for this mutation (41%). Median age at onset was 17 (1 to 69) and parental consanguinity was present in 12 patients (29%). Anemia and abdominal pain were present in 40 (98%) and 16 (39%) patients, respectively. On the other hand, there were little inflammatory findings in blood tests (median CRP 0.16mg/dl). During the course of the disease, 27 patients (66%) had undergone one or more surgeries such as partial resection of the small intestine. The most frequently involved gastrointestinal site was ileum (98%), but there was no patient with ulcerations in the terminal ileum. The stomach and duodenum were affected in 11 (27%) and 18 (44%) patients, respectively. Although no patients had clinical manifestations of PHO that required treatment, mild digital clubbing or periostosis was present in 12 patients (29%). Moreover, 4 male patients fulfilled the major clinical criteria for PHO, having digital clubbing, periostosis, and pachydermia. Conclusions: Although CEAS mimics CD, some clinical features of CEAS are different from those of CD, such as low inflammatory findings, terminal ileum-sparing ulcerations and extraintestinal manifestations. Genetic analysis should be considered if CEAS is clinically suspected.

内視鏡的拡張術が有効であった非特異性多発性小腸潰瘍症の1例

内視鏡的拡張術が有効であった非特異性多発性小腸潰瘍症の1例

Down-regulation of hepatic CYP3A1 expression in a rat model of indomethacin-induced small intestinal ulcers.

The liver and the small intestine are closely related in the processes of drug absorption, metabolism and excretion via the enterohepatic circulation. Small intestinal ulcers are a serious adverse effect commonly occurring in patients taking nonsteroidal anti-inflammatory drugs. However, the influence of small intestinal ulcers on drug metabolism has not been established. This study examined the expressional changes of cytochrome P450 (CYP) in the liver using an indomethacin-induced small intestinal ulcer rat model and in cultured cells. After the administration of indomethacin to rats, ulcers were observed in the small intestine and expression of CYP3A1, the major isoform of hepatic CYP, was significantly down-regulated in the liver, accompanied by increased expression of inducible nitric oxide synthase, tumor necrosis factor α, interleukin (IL)-1β and IL-6, in the small intestine and the liver. The indomethacin-induced small intestinal ulceration, the increase in inflammatory mediators in the small intestine and the liver, and the down-regulation of CYP3A1 expression in the liver were inhibited by co-administration of ampicillin, an antibacterial agent. In the human hepatic HepG2 cell line, IL-1β, IL-6 and NOC-18, an NO donor, caused down-regulation of CYP3A4, the major isoform of human CYP3A. Thus, this study suggests that after indomethacin treatment small intestinal ulcers cause the down-regulation of CYP3A1 in the rat liver through an increase in ulcer-derived inflammatory mediators. Copyright © 2016 John Wiley & Sons, Ltd.

Polyarteritis Nodosa Presenting as Small Intestinal Ulceration and Perforation

Polyarteritis Nodosa Presenting as Small Intestinal Ulceration and Perforation

An Unusual Cause of Small Intestinal Ulcers

An Unusual Cause of Small Intestinal Ulcers

Pharmaceutical Control of the Microbiome

The intestinal microbiota encode millions of genes that represent unique pharmaceutical targets for human diseases from neurological disorders to drug toxicity. We are focused on the role the intestinal microbiota play in reactivating compounds that have been inactivated through glucuronidation in the liver and tagged for excretion. In particular, the chemotherapy drug CPT‐11 (irinotecan) is inactivated by UGTs in the liver and then reactivated by bacterial glucuronidases in the large intestine resulting in dose‐limiting diarrhea. CPT‐11 is part of the FOLFIRI and FOLFIRINOX regimens essential in the treatment of colon and pancreas cancers, respectively. We characterized the structure and function of three glucuronidase enzymes from different bacteria and showed that a key bacterial loop allows for selective inhibition of these enzymes versus human enzyme orthologue. We developed using chemical biology novel inhibitors that potently and non‐lethally inhibit bacterial glucuronidases and alleviate CPT‐11‐induced GI toxicity in mouse models. We also examined the toxicity caused by the nonsteroidal anti‐inflammatory drugs (NSAIDs) diclofenac, ketoprofen, and indomethacin. These drugs has been hypothesized to be reactivated by bacterial glucuronidases, resulting in the longitudinal small intestinal ulcers that cause 40% of NSAID‐associated hospitalizations. We found our inhibitors are also effective against this type of drug toxicity and alleviated intestinal ulcers in mouse models. Thus, we have established that the microbiome contains targets for non‐lethal pharmacological intervention to address acute problems of human health.

Linagliptin, a dipeptidylpeptidase 4 inhibitor, ameliorates indomethacin‐induced enteropathy via GLP‐2 pathway

Glucagon‐like peptide‐2 (GLP‐2) is an intestinotrophic hormone secreted from enteroendocrine L cells. We have reported that dipeptidylpeptidase 4 (DPP4) inhibition prevents formation and promotes healing of indomethacin (IND)‐induced small intestinal ulcers in rats via GLP‐2 release and GLP‐2 receptor activation. We thus further examined the effect of the clinical DPP4 inhibitor linagliptin (LNG) on IND‐induced enteropathy.Small intestinal ulcers were induced by IND treatment (10 mg/kg, sc) in rats. LNG (0.1 – 5 mg/kg) was given once before IND for prevention, and for healing, once daily for 2 days starting 1 day after IND treatment.LNG treatment dose‐dependently reduced ulcer scores, accompanied by an increase of portal venous GLP‐2 concentrations. LNG promoted ulcer healing of IND‐induced intestinal ulcers. LNG‐induced healing was reversed by a GLP‐2 receptor antagonist. Ulcer healing was further accelerated by co‐treatment with L‐alanine plus inosinate, an umami taste receptor agonist. Compared to LNG, the DPP4 inhibitor NVP‐728, metabolized in the kidney, had a little effect on the enteropathy, suggesting that a long‐acting, entero‐hepatically circulated DPP4 inhibitor may be more efficacious in the prevention of intestinal mucosal damage.These results confirm our previous study that DPP4 inhibition prevents ulceration and promotes ulcer healing of NSAID‐induced enteropathy, enhanced by the luminal umami taste receptor activation, suggesting that GLP‐2 release enhanced by DPP4 inhibition and nutrient receptor activation is useful for the treatment of NSAID‐induced enteropathy.Supported by Boehringer Ingelheim, VA Merit Review, NIH R01 DK54221

Pharmaceutical Control of the Microbiome

The intestinal microbiota encode millions of genes that represent unique pharmaceutical targets for human diseases from neurological disorders to drug toxicity. We are interested in the role intestinal microbiota play in reactivating compounds that have been inactivated through glucuronidation. In particular, the chemotherapy drug CPT‐11 is inactivated by UGTs in the liver and then reactivated by bacterial Β‐glucuronidases in the large intestine resulting in dose‐limiting diarrhea. We characterized the structure and function of three Β‐glucuronidase enzymes from different bacteria and showed that a key bacterial loop allows for selective inhibition of these enzymes versus the human enzyme orthologue. We have developed, using chemical biology, novel inhibitors that potently and non‐lethally inhibit bacterial Β‐glucuronidases and stop drug toxicity of CPT‐11 in mouse models. We also examined the toxicity caused by the nonsteroidal anti‐inflammatory drugs (NSAIDs) diclofenac, ketoprofen, and indomethacin. These drugs were also hypothesized to be reactivated by bacterial Β‐glucuronidases, resulting in the acute longitudinal small intestinal ulcers that causer 40% of NSAID‐associated deaths. We found our inhibitors are also effective against this type of drug toxicity and alleviated the intestinal ulcers seen in mouse models. Thus, we have established that the microbiome contains targets for non‐lethal pharmacology to address acute problems of human health.Funding from NIH CA98468 and NSF Graduate Research Fellowship

Clinicopathologic features of chronic nonspecific multiple ulcers of the small intestine.

Chronic nonspecific multiple ulcers of the small intestine is a rare but distinct clinical condition, characterized by multiple small intestinal ulcers of nonspecific histology and chronic, persistent gastrointestinal bleeding without nonsteroidal anti-inflammatory drug use. However, because of the term "nonspecific" in its nomenclature, some gastroenterologists have misinterpreted the disease as the condition with small intestinal ulcers caused by undetermined etiologies without considering clinical features. Such misinterpretation has led to the heterogeneity of clinicopathologic features of the disease, as well as to ambiguity regarding a possible genetic contribution. It thus seems necessary to recognize the clinical entity of the disease precisely to avoid misinterpretation. In this review, we describe the clinicopathologic features, differential diagnosis, and the possibility of a genetic contribution to the disease.

Clinical Characteristics and Treatment Outcomes of Cryptogenic Multifocal Ulcerous Stenosing Enteritis in Korea.

Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare disease that is characterized by multiple, recurring small intestinal ulcers with stenosis of unknown causes. The aim of this study was to investigate the clinical characteristics and the treatment outcomes of patients with CMUSE in Korea. We performed a multicenter study to retrospectively analyze clinical data from 20 patients who suffered from CMUSE between 1984 and 2012. Their clinical characteristics and long-term disease courses were investigated. The most common initial symptom of CMUSE was abdominal pain (14/20, 70 %). Small bowel series (13/20, 65 %), double-balloon enteroscopy (12/20, 60 %), CT enterography (12/20, 60 %), and capsule endoscopy (10/20, 50 %) were used to diagnose CMUSE. The strictures of the patients were located in the jejunum (5/20, 25 %), ileum (7/20, 35 %), and both jejunum and ileum (6/20, 30 %). The number of patients in a state of remission, persistent disease, and relapse at the end of follow-up were 13/20 (65 %), 2/20 (10 %), and 5/20 (25 %), respectively. The median relapse-free survival was of 67.1 months. Seventy-five percent relapse-free survivals for female and male patients were 93 and 9 months, respectively (P = 0.031). CMUSE is difficult to diagnose and is an easily relapsing disease. Female patients might have a better prognosis than male patients in terms of the relapse-free time.

Combined treatment with dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin and elemental diets reduced indomethacin-induced intestinal injury in rats via the increase of mucosal glucagon-like peptide-2 concentration.

The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Treatment with an exogenous GLP-2 analogue increases intestinal villous mass and prevents intestinal injury. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP4), DPP4 inhibition may be an effective treatment for intestinal ulcers. We measured mRNA expression and DPP enzymatic activity in intestinal segments. Mucosal DPP activity and GLP concentrations were measured after administration of the DPP4 inhibitor sitagliptin (STG). Small intestinal ulcers were induced by indomethacin (IM) injection. STG was given before IM treatment, or orally administered after IM treatment with or without an elemental diet (ED). DPP4 mRNA expression and enzymatic activity were high in the jejunum and ileum. STG dose-dependently suppressed ileal mucosal enzyme activity. Treatment with STG prior to IM reduced small intestinal ulcer scores. Combined treatment with STG and ED accelerated intestinal ulcer healing, accompanied by increased mucosal GLP-2 concentrations. The reduction of ulcers by ED and STG was reversed by co-administration of the GLP-2 receptor antagonist. DPP4 inhibition combined with luminal nutrients, which up-regulate mucosal concentrations of GLP-2, may be an effective therapy for the treatment of small intestinal ulcers.

腸閉塞をきたした単純性小腸潰瘍に腹腔鏡補助下小腸切除術を施行した１例

腸閉塞をきたした単純性小腸潰瘍に腹腔鏡補助下小腸切除術を施行した１例

大量血便を来した小腸潰瘍に対し緊急大腸内視鏡で止血し得た1例

大量血便を来した小腸潰瘍に対し緊急大腸内視鏡で止血し得た1例

A Case of Hemorrhagic Small Intestinal Ulcers Developing after HepatectomyTreated by Transarterial Embolization

A Case of Hemorrhagic Small Intestinal Ulcers Developing after HepatectomyTreated by Transarterial Embolization

Lipolysis meets inflammation: arachidonic acid mobilization from fat

Lipolysis meets inflammation: arachidonic acid mobilization from fat