Drug-induced Enteropathy Research Articles

Molecular Insights Into β-Glucuronidase Inhibition by Alhagi Graecorum Flavonoids: A Computational and Experimental Approach.

In this study, we aimed to investigate the inhibitory mechanisms of β-glucuronidase by flavonoids derived from Alhagi graecorum through both experimental and computational approaches. The activity of β-glucuronidase was assessed using an in vitro enzyme inhibition assay, where myricetin and chrysoeriol were identified as potent inhibitors based on their low IC50 values. Kinetic studies were conducted to determine the inhibition type, revealing that both compounds exhibit noncompetitive inhibition of β-glucuronidase-catalyzed hydrolysis of PNPG. Molecular docking was employed to explore the binding affinities of the flavonoids, showing that myricetin formed the highest number of polar interactions with the enzyme. Additionally, molecular dynamics (MD) simulations were performed to evaluate the stability of the enzyme-inhibitor complexes, demonstrating consistent trajectory behavior for both compounds, with significant energy stabilization. Interaction energy analyses highlighted the dominant role of electrostatic forces in myricetin's inhibition mechanism, while Van der Waals forces were more prominent for chrysoeriol. The MM/PBSA method was used to calculate the binding free energies, with myricetin and chrysoeriol exhibiting the lowest values. Potential energy landscape analysis further revealed that β-glucuronidase adopts a more closed conformation when bound to these inhibitors, limiting substrate access. These findings suggest that flavonoids from Alhagi graecorum hold promise for clinical applications, particularly in managing drug-induced enteropathy.

Gut microbiota biotransformation of drug glucuronides leading to gastrointestinal toxicity: Therapeutic potential of bacterial β-glucuronidase inhibition in mycophenolate-induced enteropathy

AimsDrug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity. Main methodsBy using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli-based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model. Key findingsWe observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions. SignificanceCollectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy.

A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy

Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor (LPAR2). In this study, we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury (enteropathy), another major complication of NSAID use. Wild-type (WT) and Lpar2 deficient (Lpar2−/−) mice were treated with a single, large dose (20 or 30 mg/kg, i.g.) of indomethacin (IND). The mice were euthanized at 6 or 24 h after IND treatment. We showed that IND-induced mucosal enteropathy and neutrophil recruitment occurred much earlier (at 6 h after IND treatment) in Lpar2−/− mice compared to WT mice, but the tissue levels of inflammatory mediators (IL-1β, TNF-α, inducible COX-2, CAMP) remained at much lower levels. Administration of a selective LPAR2 agonist DBIBB (1, 10 mg/kg, i.g., twice at 24 h and 30 min before IND treatment) dose-dependently reduced mucosal injury and neutrophil activation in enteropathy, but it also enhanced IND-induced elevation of several proinflammatory chemokines and cytokines. By assessing caspase-3 activation, we found significantly increased intestinal apoptosis in IND-treated Lpar2−/− mice, but it was attenuated after DBIBB administration, especially in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Finally, we showed that IND treatment reduced the plasma activity and expression of autotaxin (ATX), the main LPA-producing enzyme, and also reduced the intestinal expression of Lpar2 mRNA, which preceded the development of mucosal damage. We conclude that LPAR2 has a dual role in NSAID enteropathy, as it contributes to the maintenance of mucosal integrity after NSAID exposure, but also orchestrates the inflammatory responses associated with ulceration. Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy.

Drug-induced spruelike enteropathy

Drug-induced spruelike enteropathy

Pharmacological hypothesis: A recombinant probiotic for taming bacterial β-glucuronidase in drug-induced enteropathy.

Advances in pharmacomicrobiomics have shed light on the pathophysiology of drug‐induced enteropathy associated with the therapeutic use of certain non‐steroidal anti‐inflammatory drugs, anticancer chemotherapies and immunosuppressants. The toxicity pathway results from the post‐glucuronidation release and digestive accumulation of an aglycone generated in the context of intestinal dysbiosis characterized by the expansion of β‐glucuronidase‐expressing bacteria. The active aglycone could trigger direct or indirect inflammatory signaling on the gut epithelium. Therefore, taming bacterial β‐glucuronidase (GUS) activity is a druggable target for preventing drug‐induced enteropathy. In face of the limitations of antibiotic strategies that can worsen intestinal dysbiosis and impair immune functions, we hereby propose the use of a recombinant probiotic capable of mimicking repressive conditions of GUS through an inducible plasmid vector.

Drug-induced bowel complications and toxicities: imaging findings and pearls.

The use of diverse types of drugs can result in a variety of acute and chronic complications that affect almost any organ. The bowel is one of the organs impacted by the side effects of medications. Imaging frequently plays a crucial role in the detection and characterization of complications occurring in the bowel. They include pseudomembranous colitis or antibiotic-associated colitis; angioedema induced by angiotensin-converting enzyme inhibitors; nonsteroidal anti-inflammatory drug-induced enteropathy; cocaine toxicity; clozapine-induced hypomobility; and bowel toxicity induced by chemotherapeutic agents. It is imperative that radiologists are fully aware of these complications and toxicities as well as the relevant findings. In this way, proper treatment can be implemented immediately. The treatment will involve discontinuation of a drug or a change in regimen.

Identification of Escherichia coli β-glucuronidase inhibitors from Polygonum cuspidatum Siebold & Zucc.

Gut bacterial β-glucuronidase (GUS) can reactivate xenobiotics that exert enterohepatic circulation- triggered gastrointestinal tract toxicity. GUS inhibitors can alleviate drug-induced enteropathy and improve treatment outcomes. We evaluated the inhibitory effect of Polygonum cuspidatum Siebold & Zucc. and its major constituents against Escherichia coli GUS (EcGUS), and characterized the inhibitory mechanism of each of the components. Trans-resveratrol 4’-O-β-D-glucopyranoside (HZ-1) and (-)-epicatechin gallate (HZ-2) isolated from P. cuspidatum were identified as the key components and potent inhibitors. These two components displayed strong to moderate inhibitory effects on EcGUS, with Ki values of 9.95 and 1.95 μM, respectively. Results from molecular docking indicated that HZ-1 and HZ-2 could interact with the key residues Asp163, Ser360, Ile 363, Glu413, Glu504, and Lys 568 of EcGUS via hydrogen bonding. Our findings demonstrate the inhibitory effect of P. cuspidatum and its two components on EcGUS, which supported the further evaluation and development of P. cuspidatum and its two active components as novel candidates for alleviating drug-induced damage in the mammalian gut.

Inhibition of gut bacterial β-glucuronidase by chemical components from black tea: Inhibition interactions and molecular mechanism

Gut bacterial β -glucuronidase is regarded as an important molecular target for several therapeutic applications. Inhibitors of β -glucuronidase can effectively alleviate the drug-induced gastrointestinal tract toxicity. In this study, the ethanol extracts of black tea was found to display significant inhibitory activities against Escherichia coli β -glucuronidase (EcGUS), and seven polyphenols including catechins and theaflavins were identified as the key components responsible for the strong inhibitory potency of black tea towards EcGUS. Among these seven identified naturally occurring inhibitors, (−)-catechin gallate (CG), theaflavin-3-monogallate (TF-3-G), theaflavin-3′-monogallate (TF-3′-G) and theaflavin-3,3′-digallate (TFDG) were more potent inhibitors of EcGUS compared with (−)-epicatechin gallate (ECG), (−)-gallocatechin gallate (GCG), and (−)-epigallocatechin gallate (EGCG). Furthermore, molecular docking and molecular dynamics simulation results further indicated that TFDG could bind in the cavity of EcGUS and interacted with key residues Ser360, Glu413 and Ile560 of EcGUS through hydrogen bonds. Taken together, these data offer important information for efficient development of black tea and its catechins and theaflavins constituents for treating drug-induced enteropathy.

Review article: drug-induced small bowel injury.

Drug-induced gastrointestinal injury has been increasingly reported, but its exact incidence is not known. The small and large intestines represent the most affected sites of injury, accounting for 20%-40% of all gastrointestinal side effects. To provide an updated literature review detailing medications linked to the development of small bowel injury. We conducted a literature search on PubMed from its inception to May 1, 2021. We included English-language original studies, meta-analyses, systematic reviews, review articles and case reports. Drug-induced enteropathy can range from asymptomatic histological changes resulting in a subtle, self-limited disease to a chronic inflammatory condition mimicking inflammatory bowel disease, or bowel perforation. Endoscopy can demonstrate erythema, mucosal friability, oedema, erosions, ulcers or strictures in severe cases. Histology may include mucosal erosions and ulcerations, focal active enteritis, villous atrophy, epithelial apoptosis or necrotising enteritis. A well-established association has been found with the use of nonsteroidal anti-inflammatory drugs, immunosuppressants, chemotherapeutic agents, antibiotics, immunotherapies, etanercept and olmesartan. Possible associations have been reported with other biologic agents, medications used for glycemic control, antihypertensives, cholinesterase inhibitors, potassium and iron supplements, with conflicting data regarding contraceptives/hormonal therapy and isotretinoin. Physicians should be aware of the manifestations of drug-induced enteropathy as early recognition can lead to prompt discontinuation of the offending therapy and, therefore, a reduced risk of future complications.

Anorexia and Starvation Related Duodenal Villous Atrophy in an Adult Patient

Coeliac disease is the most well-known cause of villous atrophy in duodenal biopsies. Other well recognised causes of villous atrophy include infection with Giardia duodenalis and HIV, peptic duodenitis, drug-induced enteropathy, common variable immunodeficiency, Crohn’s disease, Whipple’s disease, small intestinal bacterial overgrowth, eosinophilic gastroenteritis, tropical or collagenous sprue and autoimmune enteropathy. While mucosal adaptation due to malnutrition, leading to villous atrophy, has been reported in paediatric populations in Africa and South America, in hibernating animals and animal models of experimental starvation, there is very little literature on adult human subjects. We report a case of a 76-year-old gentleman, presenting with chronic metabolic acidosis and anorexia who was found to have villous atrophy on duodenal biopsy, in the absence of any evidence of coeliac disease or other non-coeliac enteropathy. The nutritional state improved with correction of the underlying metabolic abnormality, and serial endoscopic assessment showed improvement in the villous atrophy. We discuss the relationship between malnutrition and villous atrophy, and suggest a potential workup for non-coeliac villous atrophy.

Amentoflavone from Selaginella tamariscina as a potent inhibitor of gut bacterial β-glucuronidase: Inhibition kinetics and molecular dynamics stimulation

Gut bacterial β-glucuronidase (GUS) plays a pivotal role in the metabolism and reactivation of a vast of glucuronide conjugates of both endogenous and xenobiotic compounds in the gastrointestinal tract of human, which has been implicated in certain drug-induced gastrointestinal tract (GI) toxicity in clinic. Inhibitors of gut microbial GUS exhibited great potentials in relieving the drug-induced GI toxicity. In this study, Selaginella tamariscina and its major biflavonoid amentoflavone (AMF) were evaluated for their inhibitory activity against Escherichia coli GUS. Two selective probe substrates for GUS (a specific fluorescent probe substrate for GUS, DDAOG and a classical drug substrate for GUS, SN38G) were used in parallel for charactering the inhibition behaviors. Both the extract of S. tamariscina and its major biflavonoid AMF displayed evident inhibitory effects on GUS, and the IC50 values of AMF against GUS mediated DDAOG and SN-38G hydrolysis were 0.62 and 0.49 μM, respectively. Inhibition kinetics studies indicated that AMF showed mixed type inhibition for GUS-mediated DDAOG hydrolysis, while displayed competitive type inhibition against GUS-mediated SN-38G hydrolysis, with the Ki values of 0.24 and 1.25 μM, respectively. Molecular docking studies and molecular dynamics stimulation results clarified the role of amino acid residues Leu361, Ile363, and Glu413 in the inhibition of AMF on GUS. These results provided some foundations for the potential clinical utility of S. tamariscina and its major biflavonoid AMF for treating drug-induced enteropathy.

CRYPTOGENIC MULTIFOCAL ULCEROUS STENOSING ENTERITIS (CMUSE): A 20-YEAR SINGLE CENTER CLINICAL AND RADIOLOGIC EXPERIENCE

Abstract Background Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare illness characterized by multiple strictures and shallow ulcers of the small bowel. Even though diagnostic criteria have been described, further ellucidation is needed on therapeutic interventions and potential discriminating factors between CMUSE and other more common causes of intestinal ulcerations, including Crohn’s disease. Aim The purpose of this article is to report the clinical, CT, and MR enterography characteristics of confirmed cases of CMUSE. Materials and Methods Retrospective review of electronic medical records identified 33 patients considered for a diagnosis CMUSE. Diagnosis was confirmed if all requirements of the previously published diagnostic criteria for CMUSE were met. Patients were excluded if they had less than one year follow-up or incomplete clinical data. Two GI radiologists reviewed all CT and MR enterography (CTE/MRE) exams in consensus of confirmed patients to characterize the cross sectional imaging features. Results CMUSE was confirmed in 9 patients (27%) and 24 patients (73%) had a confirmed alternative diagnosis. Crohn’s disease (CD) (30%, n=7) and drug-induced enteropathy (30%, n=7) were the most frequent alternative. Male gender (66.7% vs. 25%, p=0.04) and clinical manifestation of anemia at presentation were more commonly observed on CMUSE-confirmed cases (66.7% vs. 4.2%, p=0.005) when compared to patients with non-CMUSE diagnosis, in which abdominal pain was the most common presenting symptom (44.5% vs 87.5%, p=0.02). Multiple (100%) and circumferential (75%) ulcers with restricted mucosal involvement (55.6%) were major features at endoscopy and pathology. Most common treatments were corticosteroids (78%) or surgical resection (55.6%), with 33% receiving biologics. Disease recurrence after first treatment occurred in the majority (88.9%) after a median time of 6 months (Table 1). 9 CTE and 1 MRE of 8 confirmed cases images were analyzed (Table 2). Major imaging features included multiple (≥ 5; 88%; 7/8), short (< 2 cm; 100%; 8/8) circumferential (100%;8/8) strictures with moderate wall thickening (6–9 cm), and stratified hyper enhancement (100%; 8/8) located in the ileum (100%; 8/8). Median proximal small bowel dilation was 2.95 cm (2.5–4.1 cm). Less common findings included: mesenteric adenopathy (50%; 4/8), increased mesenteric edema/ascites (38%; 3/8), mesenteric vascularity (25%; 2/8), colon inflammation (13%; 1/8), and decreased small bowel fold pattern (13%; 1/8). No patients with confirmed CMUSE cases demonstrated penetrating disease (e.g., abscess, fistula). Conclusion CMUSE is rare cause of small bowel strictures with overlapping clinical and imaging features of more common etiologies such as Crohn’s Disease and NSAID enteropathy that need to be excluded through a multidisciplinary approach to confirm the diagnosis.

Mucoprotective drugs can prevent and treat nonsteroidal anti-inflammatory drug-induced small bowel enteropathy: a systematic review and meta-analysis of randomized controlled trials.

Background:Small bowel enteropathy (SBE) is a complication of nonsteroidal anti-inflammatory drug (NSAID) therapy occurring in 71% of NSAID users. We aimed to analyse the efficacy and safety of medications to prevent and treat NSAID-induced SBE in randomized controlled trials (RCTs).Methods:This review was registered on PROSPERO (CRD42021223371). We systematically searched four databases until 20 October for comparing mucoprotective (MP), antibiotic and probiotic treatments to placebo, proton-pump inhibitors (PPIs) or histamine-2 (H2) receptor antagonists in NSAID-associated small intestinal injuries. The main outcomes were mucosal integrity, mucosal breaks after treatment, mucosal injury improvement and complete healing of mucosal breaks. Meta-analytical calculations for weighted mean differences (WMDs) and odds ratios (ORs) were performed with the random-effects model and interpreted with 95% confidence intervals (CIs).Results:A total of 18 RCTs were included in the quantitative synthesis. MP medications administered preventively reduced the number of mucosal erosions (WMD = −1.24, CI: −2.15 to −0.34) and lead to a significantly lower chance of developing mucosal breaks after treatment (OR = 0.38, CI: 0.16–0.93). MP therapy was associated with a higher rate of complete healing of mucosal breaks (OR = 5.39, CI: 2.79–10.42). In the qualitative synthesis, there were tendencies for a lower increase in the mean number of mucosal breaks and reddened lesions with prophylactic and a higher decrease in mucosal breaks with therapeutic MP drug administration.Conclusion:MP treatment administered with NSAIDs can prevent and reduce small intestinal mucosal lesions.

S2793 Sprue-Like Enteropathy Secondary to Lisinopril Use

INTRODUCTION: Diarrhea is reported as a rare adverse effect of angiotensin-converting enzyme (ACE) inhibitors, but there are few reports of sprue-like enteropathy from its use. In contrast, this has been well described with the angiotensin II receptor blocker (ARB), olmesartan. We describe a case of drug-induced enteropathy secondary to lisinopril. CASE DESCRIPTION/METHODS: A 76-year-old man with hypertension and coronary artery disease presented with one year of diarrhea, abdominal discomfort and a 35-pound unintentional weight loss. His first EGD yielded duodenal biopsies with villous blunting and increased IELs. Tissue transglutaminase antibody (tTg, IgA) was 22 U/mL (negative is <20 U/mL), and the patient was advised to follow a gluten free diet. He did so for 9 months without symptom improvement and so returned to a gluten-rich diet. Despite a gluten-rich diet for 4 months, the patient’s repeat tTg, IgA and deamidated gliadin peptide (DGP) IgA and IgG were negative. In addition, he was negative for HLA-DQ2 and HLA-DQ8 genotypes, making celiac disease unlikely. All immunoglobulin levels were normal. Then on repeat EGD and colonoscopy, duodenal and terminal ileal biopsies showed villous blunting and dense infiltrate of IELs. Biopsies were negative for Congo red and periodic acid-Schiff diastase stains, sent to evaluate for amyloid and Whipple's disease. Video capsule endoscopy identified diffuse small bowel villous flattening, though no erosions, ulcerations or strictures were seen. Stool testing was negative for giardia and fecal calprotectin. Glucose hydrogen breath test was negative. The patient had a normal fasting gastrin level, and his ANA and anti-enterocyte antibody were negative. We then considered lisinopril-induced enteropathy, as the patient had been on lisinopril since symptom onset. After lisinopril was stopped, the patient's symptoms resolved within 3 months. He gained back weight and no longer had abdominal discomfort. Repeat endoscopy is planned, but was postponed during the COVID-19 pandemic. DISCUSSION: It is important to maintain a high degree of suspicion for drug-induced enteropathy. One study from Italy and Germany examined patients on olmesartan, ARBs and ACE inhibitors and found rare instances of ACE inhibitors leading to intestinal malabsorption (Malfertheiner et al. Pharmacoepidemiol Drug Saf. 2018, 581-586). Olmesartan is classically the medication associated with sprue-like enteropathy, and our case highlights that lisinopril should be considered as well.

Non-steroidal anti-inflammatory drug-induced enteropathy as a major risk factor for small bowel bleeding: a retrospective study

BackgroundSmall bowel (SB) bleeding accounts for 5% of all gastrointestinal (GI) bleeding cases and 80% of obscure GI bleeding cases. Although angioectasia is the common etiology of SB bleeding, nonsteroidal anti-inflammatory drug (NSAID)-induced SB lesions are also reported as a major cause in studies from Eastern countries. Herein, we assessed the frequency of occurrence of NSAID-induced SB lesions in Korean patients with obscure GI bleeding.MethodsWe retrospectively analyzed medical records of all consecutive patients aged ≥18 years who underwent capsule endoscopy from March 2018 to February 2019 at Ulsan University Hospital and Kosin University Gospel Hospital.ResultsOf the 83 subjects (all Korean; mean age ± standard deviation: 59 ± 18 years; age range: 18–84 years; men: n = 52; women: n = 31), 55 (66.2%) had stool with clear blood and 28 (33.8%) had normal stool with iron deficiency anemia. The detection rate of SB bleeding and lesions using capsule endoscopy was 72.3% (60 of 83 patients). A significantly higher frequency (40 of 51) of ulcerative/erosive lesions than other causes was observed in patients with inactive bleeding but visible SB lesions. As a result, NSAID-induced enteropathy accounted for 30.1% of 83 patients with obscure GI bleeding (25 of the all 60 SB bleeding cases).ConclusionsContrary to what is reported for patients in Western countries, this study in Korean patients showed an improved diagnostic yield of capsule endoscopy for obscure GI bleeding and that NSAID-induced enteropathy was the most common etiology of SB bleeding. Aggressive small intestine examination is required for patients with unexplained GI bleeding.

Diaphragm disease in emergency surgery.

Diaphragm disease of the small bowel has been described in the literature over the last three decades. The pathognomonic characteristic of multiple circumferential stenosis is noted on gross examination of the bowel. It is a severe form of non-steroidal anti-inflammatory drug-induced enteropathy, often presenting as acute small bowel obstruction. A systematic review was performed to identify risk factors and patient outcomes in histologically-proven diaphragm disease of the small intestine in patients undergoing emergency operation for small bowel obstruction. A comprehensive search was performed between January 1975 and March 2019 using relevant MeSH terms. Studies were chosen based on predefined inclusion criteria. Diaphragm disease of the small intestine was defined as macroscopically detected thin diaphragm-like mucosal folding inside the lumen of the bowel. The parameters assessed included patient characteristics, duration of use of non-steroidal anti-inflammatory drugs, type of emergency surgery performed, complications, recurrence, presentation and diagnosis of diaphragm disease. A total of 21 studies were analysed which included 17 case reports, one case series, and three retrospective comparative studies. Overall 29 patients with diaphragm disease of the small bowel were reported following emergency laparotomy for small bowel obstruction. Use of non-steroidal anti-inflammatory drugs was noted in all cases with an average duration of 3-5 years. All patients presented acutely with features of small bowel obstruction and had emergency laparotomy, except one who underwent laparoscopic resection. In the comparative studies patients were more likely to be female and to have been taking non-steroidal anti-inflammatory drugs for more than 7 years. This is a rare disease, difficult to diagnose and often confirmed by the intra-operative macroscopic appearance of circumferential stenosis of the bowel. Risk factors for developing small bowel diaphragm disease include long-term use of non-steroidal anti-inflammatory drugs, and female gender. Patients with this disease are at increased risk of developing acute small bowel obstruction, so early identification is important.

A181 ENDOSCOPIC BALLOON DILATION IS EFFECTIVE AND SAFE IN THE MANAGEMENT OF NSAID-INDUCED NON-ULCERATIVE GASTRIC OUTLET OBSTRUCTION

Abstract Background We describe an unusual case of NSAID-induced gastric outlet obstruction (GOO) in the absence of malignancy or ulcers. This was successfully managed conservatively with drug withdrawal and serial endoscopic balloon dilation (EBD). Aims Case Report Methods Case Report and Literature Review Results A 58-year-old woman with 20-year history of daily Ketorolac use for osteoarthritis presented with iron deficiency anemia (IDA) of 58 g/L and post-prandial emesis for 2 months. There was no overt GI bleeding. Gastroscopy revealed severe erosive esophagitis and GOO with no ulcers. After a negative CT imaging ruled out extrinsic malignant compression, GOO was managed with EBD. Examination of the duodenum post-EBD revealed complete atrophy and scalloping. Focused biopsies reveal chronic gastritis, complete villous atrophy in the duodenum; ruled out H. Pylori, celiac disease, amyloidosis and dysplasia. EUS negative for infiltrative disease or regional adenopathy. Vitamin B12, anti-TTG I IgA, HLA DQ2/8 were normal. These findings made drug-induced enteropathy the top contender. PPI therapy was initiated and NSAID discontinued. Five serial EBD were performed over 4 months to 18mm. A pureed diet was tolerated after 2 dilations. Follow-up at 3 months showed partial recovery of enteropathy and pyloric stenosis. No adverse events were seen. The severe esophagitis was likely an erosive process secondary to reflux from GOO. Her IDA is likely multifactorial: Severe enteropathy and GOO may have led to chronic malabsorption; occult GI bleeding from erosions or ulcers that have healed may further contribute. Ketorolac could explain the enteropathy. COX-1 inhibition leads to decreased gastric cytoprotection. In rat models, COX-2 inhibition has been suggested to delay gastric healing and dysregulated immune response to food antigens in the small bowel [4–6]. NSAID-induced GOO almost always occur in the context of peptic ulcer disease [1,2]. A similar case [3] found pyloric stenosis in a 75-year old woman with esophagitis and ulcer-induced pyloric stenosis. They postulate that post ulcerative healing led to benign pyloric stenosis and explained the absence of ulcers. Historically, surgical intervention and stent placement have played a major role in the management of benign mechanical GOO. EBD has replaced surgical intervention as first line therapy [7] showing promising results beyond 3 months post EBD[8], sparing patients from surgery related morbidity. An algorithm has been suggested by us [Img 1] for the management of benign GOO. Conclusions We present an unusual case of NSAID-induced mechanical GOO and enteropathy. This case highlights these entities as rare but serious complications of chronic NSAID use. Management of benign mechanical GOO should be individualized. Prudence with prescribing NSAIDs to at risk populations is recommended. Funding Agencies None

Duodenal Chemosensing of Short-Chain Fatty Acids: Implications for GI Diseases.

Short-chain fatty acids (SCFAs), the main bacterial fermentation products in the hindgut of hindgut fermenters, are also present in the foregut lumen. We discuss the impact of SCFAs in the duodenal defense mechanisms and in the gastrointestinal (GI) pathogenesis. Luminal SCFAs augment the duodenal mucosal defenses via release of serotonin (5-HT) and glucagon-like peptide-2 (GLP-2) from enteroendocrine cells. Released GLP-2 protects the small intestinal mucosa from nonsteroidal anti-inflammatory drug-induced enteropathy. SCFAs are also rapidly absorbed via SCFA transporters and interact with afferent and myenteric nerves. Excessive SCFA signals with 5-HT3 receptor overactivation may be implicated in the pathogenesis of irritable bowel syndrome symptoms. SCFA production exhibits diurnal rhythms with host physiological responses, suggesting that oral SCFA treatment may adjust the GI clocks. SCFAs are not only a source of energy but also signaling molecules for the local regulation of the GI tract and systemic regulation via release of gut hormones. Targeting SCFA signals may be a novel therapeutic for GI diseases and metabolic syndrome.

Olmesartan-Associated Enteropathy: An Unexpected Cause of Chronic Diarrhoea.

Olmesartan-associated enteropathy is a rare cause of severe enteropathy that should be considered in the differential diagnosis of patients with unexplained chronic diarrhoea. It may be difficult to recognise because of its clinical and histologic similarities to other clinical entities. The authors present the case of a 72-year-old woman with a 6-month clinical history of non-bloody diarrhoea and weight loss. Discontinuation of olmesartan resulted in clinical and histologic recovery, and therefore, physicians need to be aware of olmesartan-associated enteropathy in order to avoid unnecessary testing. Although rare, it is considered an emerging and underdiagnosed enteropathy.LEARNING POINTSOlmesartan-associated enteropathy is characterised by chronic diarrhoea (often severe) and weight loss that is unresponsive to a gluten-free diet.When a patient presents with unexplained chronic diarrhoea, a detailed medication review is needed. If duodenal biopsies reveal villous atrophy and coeliac disease is excluded, drug-induced enteropathy is likely.Clinical response and histologic improvement are expected after olmesartan is withdrawn.

Genetic analysis is helpful for the diagnosis of small bowel ulceration.

The widespread use of capsule endoscopy and balloon-assisted endoscopy has provided easy access for detailed mucosal assessment of the small intestine. However, the diagnosis of rare small bowel diseases, such as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), remains difficult because clinical and morphological features of these diseases are obscure even for gastroenterologists. In an issue of this journal in 2017, Hwang et al reviewed and summarized clinical and radiographic features of 20 patients with an established diagnosis of CMUSE. Recently, recessive mutations in the PLA2G4A and SLCO2A1 genes have been shown to cause small intestinal diseases. The small bowel ulcers in each disease mimic those in the other and furthermore those found in nonsteroidal anti-inflammatory drug-induced enteropathy. These recent and novel findings suggest that a clinical diagnosis exclusively based on the characteristics of small bowel lesions is possibly imprecise. Genetic analyses seem to be inevitable for the diagnosis of rare small bowel disorders such as CMUSE.