Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet

BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.

Digesting gluten with oral endopeptidases to improve the management of celiac disease

In our editorial,we want to comment on the article by Stefanolo et al titled“Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet”.Celiac disease is an immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals.Although avoiding gluten can permit patients to live symptom-free,ongoing voluntary or involuntary exposure to gluten is common and associated with persistent villous atrophy in small bowel mucosa.As villous atrophy predisposes patients to life threatening complications,such as osteoporotic fractures or malignancies,therapeutic adjuncts to gluten-free diet become important to improve patients’quality of life and,if these adjuncts can be shown to improve villous atrophy,avoid complications.Oral administration of enzyme preparations,such as endopeptidases that digest gluten and mitigate its antigenicity to trigger inflam-mation,is one clinical strategy under investigation.The article is about the utility of one endopeptidase isolated from Aspergillus niger.We critique findings of this clinical trial and also summarize endopeptidase-based as well as other strategies and how they can complement gluten-free diet in the management of celiac disease.

Advances in understanding and managing celiac disease:Pathophysiology and treatment strategies

In this editorial,we comment on an article published in the recent issue of the World Journal of Gastroenterology.Celiac disease(CeD)is a disease occurring in genetically susceptible individuals,which is mainly characterized by gluten intolerance in the small intestine and clinical symptoms such as abdominal pain,diarrhea,and malnutrition.Therefore,patients often need a lifelong gluten-free diet,which greatly affects the quality of life and expenses of patients.The gold standard for diagnosis is intestinal mucosal biopsy,combined with serological and genetic tests.At present,the lack of safe,effective,and satisfactory drugs for CeD is mainly due to the complexity of its pathogenesis,and it is difficult to find a perfect target to solve the multi-level needs of patients.In this editorial,we mainly review the pathological mechanism of CeD and describe the current experimental and improved drugs for various pathological aspects.

Aspergillus niger prolyl endopeptidase in celiac disease

We comment here on the article by Stefanolo et al entitled“Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet”,published in the World Journal of Gastroenterology.Celiac disease is a well-recognized systemic autoimmune disorder.In genetically susceptible people,the most evident damage is located in the small intestine,and is caused and worsened by the ingestion of gluten.For that reason,celiac patients adopt a gluten-free diet(GFD),but it has some limitations,and it does not prevent re-exposure to gluten.Research aims to develop adjuvant therapies,and one of the most studied alternatives is supplementation with Aspergillus niger prolyl endopeptidase protease(AN-PEP),which is able to degrade gluten in the stomach,reducing its concentration in the small intestine.The study found a high adherence to the GFD,but did not address AN-PEP as a gluten immunogenic peptide reducer,as it was only tested in patients following a GFD and not in gluten-exposing conditions.This study opens up new research perspectives in this area and shows that further study is needed to clarify the points that are still in doubt.

Beyond the gluten-free diet:Innovations in celiac disease therapeutics

Celiac disease(CD)is an autoimmune disorder exacerbated by the ingestion of gluten in genetically susceptible individuals,leading to intestinal inflammation and damage.This chronic disease affects approximately 1%of the world’s po-pulation and is a growing health challenge due to its increasing prevalence.The development of CD is a complex interaction between genetic predispositions and environmental factors,especially gluten,culminating in a dysregulated immune response.The only effective treatment at present is a strict,lifelong gluten-free diet.However,adherence to this diet is challenging and often incomplete,so research into alternative therapies has intensified.Recent advances in under-standing the molecular and immunological aspects of CD have spearheaded the development of novel pharmacologic strategies that should provide more effec-tive and manageable treatment options.This review examines the latest inno-vations in CD therapies.The focus is on drugs in advanced clinical phases and targeting specific signaling pathways critical to the disease pathogenesis.We dis-cuss both quantitative strategies such as enzymatic degradation of gluten,and qualitative approaches including immunomodulation and induction of gluten tolerance.Innovative treatments currently under investigation include transglu-taminase inhibitors,which prevent the modification of gluten peptides,and nano-particle-based therapies to recalibrate the immune response.These new therapies not only promise to improve patient outcomes but are also expected to improve quality of life by reducing the burden of dietary restrictions.The integration of these new therapies could revolutionize the treatment of CD and shift the para-digm from strict dietary restrictions to a more flexible and patient-friendly thera-peutic approach.This review provides a comprehensive overview of the future prospects of CD treatment and emphasizes the importance of continued research and multidisciplinary collab-oration to integrate these advances into standard clinical practice.

Prevalence of malignant neoplasms in celiac disease patients-a nationwide United States population-based study

BACKGROUND Celiac disease(CeD)is an autoimmune disorder triggered by the immune response to gluten in genetically predisposed individuals.Recent research has unveiled a heightened risk of developing specific malignant neoplasms(MN)and various malignancies,including gastrointestinal,lymphomas,skin,and others,in individuals with CeD.AIM To investigate the prevalence of MN in hospitalized CeD patients in the United States.METHODS Using data from the National Inpatient Sample spanning two decades,from January 2000 to December 2019,we identified 529842 CeD patients,of which 78128(14.75%)had MN.Propensity score matching,based on age,sex,race,and calendar year,was employed to compare CeD patients with the general non-CeD population at a 1:1 ratio.RESULTS Positive associations were observed for several malignancies,including small intestine,lymphoma,nonmelanoma skin,liver,melanoma skin,pancreas myelodysplastic syndrome,biliary,stomach,and other neuroendocrine tumors(excluding small and large intestine malignant carcinoid),leukemia,uterus,and testis.Conversely,CeD patients exhibited a reduced risk of respiratory and secondary malignancies.Moreover,certain malignancies showed null associations with CeD,including head and neck,nervous system,esophagus,colorectal,anus,breast,malignant carcinoids,bone and connective tissues,myeloma,cervix,and ovary cancers.CONCLUSION Our study is unique in highlighting the detailed results of positive,negative,or null associations between different hematologic and solid malignancies and CeD.Furthermore,it offers insights into evolving trends in CeD hospital outcomes,shedding light on advancements in its management over the past two decades.These findings contribute valuable information to the understanding of CeD’s impact on health and healthcare utilization.

Simultaneous Compression of the Celiac Trunk, Superior Mesenteric Artery, and Renal Arteries by the Median Arcuate Ligament: About One Case

Median arcuate ligament syndrome (MALS), is a rare abdominal vascular compression syndrome caused by the compression of the proximal celiac trunk by the median arcuate ligament. According to many authors, a low insertion of the diaphragmatic crura or an abnormally high origin of the celiac trunk from the aorta can cause compression of the celiac artery. Usually, patients with MALS are asymptomatic. Computed tomography (CT) angiography of the abdomen is the main imaging modality to confirm the diagnosis. The coexistence of celiac trunk and superior mesenteric artery compression by the median arcuate ligament is rarely described in the literature. To our knowledge, until now, a simultaneous combination of three abdominal vascular compressions by the median arcuate ligament has never been described. From this case, we report a simultaneous compression of the celiac trunk, superior mesenteric artery, and renal arteries by the median arcuate ligament.

An Anatomical and Radiological Study of Origins of the Arteries Forming the Celiac Trunk: Clinical and Embryological Implications

The blood supply to the most of abdominal organs is provided by the branches of CT. The SMA supply caecum, ascends colon, all of the small bowels except the upper part of duodenum. Knowledge of variable anatomy of celiac axis and SMA may be useful in planning and executing radiological interventions such as celiacography and chemoembolization of hepatic and pancreatic tumors. In this study, the uncommon or low percentage cases of CT and SMA are presented in the light of clinical and embryological information. The celiac axises of a total of 30 adult corpses were examined. Dissections of abdominal region were performed in detail according to Cunningham’s manual. Angiographic images of 100 consecutive adult patients who underwent celiac MDCT angiography were evaluated. During autopsies, an incomplete celiac trunk or bifurcation of celiac trunk associated with the hepatomesenteric and gastrosplenic trunks (0.7%) and a celiacomesenteric trunk associated with high origin superior mesenteric artery and gastrosplenic trunk were detected (0.7%). During MDCT angiography, a case of total absence of celiac trunk associated with a hepatosplenomesenteric trunk (0.7%) and also a case of total absence of celiac trunk alone were observed (0.7%). The persistence or unusual development of ventral splanchnic arteries (VSAs) or ventral longitudinal anastomosis may result in variations or the unusual trunks related to celiac axis and SMA. The anomalous trunks of the CT may be result of either the persistence of some parts of the VSAs or ventral longitudinal anastomose that normally disappear or disappearance of parts that normally persist. The prevalence of unusual trunks of celiac axis and SMA in this study is quite low in literature. These abnormal vessels pose problems for surgeons and radiologists. Such vascular anomalies may cause clinical complications following surgical and radiological procedures such as resection of tumor of the pancreatic head, lymphadenectomy, coeliacography, aortic replacement with reimplantation of the trunk and coembolization of pancreatic and liver tumors.

Celiac disease screening in patients with cryptogenic cirrhosis

We write a letter to the editor commenting the article“Who to screen and how to screen for celiac disease”.We discuss the present literature on cirrhosis and celiac disease(CD)and recommend screening and treating CD in individuals with cryptogenic cirrhosis.

Gut microbiota predicts the diagnosis of celiac disease in Saudi children

BACKGROUND Celiac disease(CeD)is a multisystem immune-mediated multifactorial condition strongly associated with the intestinal microbiota.AIM To evaluate the predictive power of the gut microbiota in the diagnosis of CeD and to search for important taxa that may help to distinguish CeD patients from controls.METHODS Microbial DNA from bacteria,viruses,and fungi,was isolated from mucosal and fecal samples of 40 children with CeD and 39 controls.All samples were sequenced using the HiSeq platform,the data were analyzed,and abundance and diversities were assessed.For this analysis,the predictive power of the microbiota was evaluated by calculating the area under the curve(AUC)using data for the entire microbiome.The Kruskal-Wallis test was used to evaluate the significance of the difference between AUCs.The Boruta logarithm,a wrapper built around the random forest classification algorithm,was used to identify important bacterial biomarkers for CeD.RESULTS In fecal samples,AUCs for bacterial,viral,and fungal microbiota were 52%,58%,and 67.7%respectively,suggesting weak performance in predicting CeD.However,the combination of fecal bacteria and viruses showed a higher AUC of 81.8%,indicating stronger predictive power in the diagnosis of CeD.In mucosal samples,AUCs for bacterial,viral,and fungal microbiota were 81.2%,58.6%,and 35%,respectively,indicating that mucosal bacteria alone had the highest predictive power.Two bacteria,Bacteroides intestinalis and Burkholderiales bacterium 1-1-47,in fecal samples and one virus,Human_endogenous_retrovirus_K,in mucosal samples are predicted to be“important”biomarkers,differentiating celiac from nonceliac disease groups.Bacteroides intestinalis is known to degrade complex arabinoxylans and xylan which have a protective role in the intestinal mucosa.Similarly,several Burkholderiales species have been reported to produce peptidases that hydrolyze gluten peptides,with the potential to reduce the gluten content of food.Finally,a role for Human_endogenous_retrovirus_K in immune-mediated disease such as CeD has been reported.CONCLUSION The excellent predictive power of the combination of the fecal bacterial and viral microbiota with mucosal bacteria alone indicates a potential role in the diagnosis of difficult cases of CeD.Bacteroides intestinalis and Burkholderiales bacterium 1-1-47,which were found to be deficient in CeD,have a potential protective role in the development of prophylactic modalities.Further studies on the role of the microbiota in general and Human_endogenous_retrovirus_K in particular are needed.

Risk of pancreatic cancer in individuals with celiac disease in the United States:A population-based matched cohort study

BACKGROUND Celiac disease(CD)has been associated with gastrointestinal malignancies.However,the magnitude of the risk of pancreatic cancer(PC)associated with CD is much less clear,and risks have not been estimated from large populations.AIM To assess the risk of PC in CD patients.METHODS We conducted a population-based,multicenter,propensity score-matched cohort study with consecutive patients diagnosed with CD using the TriNeTx research network platform.We examined the incidence of PC in patients with CD compared with a matched cohort of patients without CD(non-CD,controls).Each patient in the main group(CD)was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.The incidence of PC was estimated using a Cox proportional hazards model with a hazard ratio(HR)and 95%confidence interval(CI).RESULTS A total of 389980 patients were included in this study.Among them,155877 patients had a diagnosis of CD,and the remaining 234103 individuals without CD were considered a control cohort.The mean duration of follow-up for patients in the CD and control cohorts was 5.8±1.8 and 5.9±1.1 years,respectively.During the follow-up,309 patients with CD developed PC,whereas 240 patients developed PC in the control group(HR=1.29;95%CI:1.09-1.53).In the secondary analyses in the first year after diagnosis of CD,patients with CD were at a significant increase in risk for PC;151 patients with CD had an incidence of PC compared with 96 incidences of PC among the patients in the non-CD control group(HR=1.56;95%CI:1.20-2.01)and sensitivity analysis showed similar magnitude to the one generated in the primary and secondary analysis.CONCLUSION Patients with CD are at increased risk of PC.Risk elevation persists beyond the first year after diagnosis to reference individuals without CD from the general population.

Efficacy of probiotics supplementation in amelioration of celiac disease symptoms and enhancement of immune system

Patients with celiac disease(CD)have a mucosal layer that is unable to regulate the gut microbiota,leaving the host vulnerable to dangerous infections and antigens.When compared to healthy people,this dysbiosis is marked by a decrease in intra-and intergeneric biodiversity,which demonstrates an imbalance between helpful bacteria and possibly harmful or proinflammatory species.The early gut microbiota is influenced by the genotype of newborns with the HLADQ2 haplotypes,and this may modify how gluten is handled in the intestinal lumen,polarize innate or adaptive immune responses,and result in glutensensitive enteropathy.The outcome of gluten digestion can vary depending on the composition of the intestinal gut bacteria and the partial conversion of gluten into peptides larger than ten amino acids in the small intestines,which can be immunogenic.In the small intestine,114 different bacterial strains belonging to 32 different species have 27 of them exhibiting peptidolytic activity.Thus,the individual risk of developing a gluten-related illness is further influenced by microbial composition and gluten degrading capacity.The conclusion that lactobacilli and Bifidobacterium spp.may be used as a probiotic supplement in CD patients is based on their shared possession of the most extensive peptidolytic and proteolytic activity thought to be engaged in the breakdown of gluten among all potential bacterial genera present in the gut microbiota.In children with CD autoimmunity,daily oral dose of Lactobacillus.plantarum HEAL9 and Lactobacillus.paracasei 8700:2 was found to modify the peripheral immune response.Bifidobacterium.breve strains have demonstrated a beneficial effect on reducing pro-inflammatory cytokine TNF-production in CD children on gluten-free diets.

Endoscopic ultrasonography guided celiac plexus neurolysis and celiac plexus block in the management of pain due to pancreatic cancer and chronic pancreatitis

Pain is a common symptom of pancreatic disease and is frequently difficult to manage. Pain relief provided by narcotics is often suboptimal and is associated with significant side effects. An alternative approach to pain management in pancreatic disease is the use of celiac plexus block (CPB) or neurolysis (CPN). Originally performed by anesthesiologists and radiologists via a posterior approach,recent advances in endoscopic ultrasonography (EUS) have made this technique an attractive alternative. EUS guided celiac plexus block/ neurolysis is simple to perform and avoids serious complications such as paraplegia or pneumothorax that are associated with the posterior approach. EUS guided CPN should be considered first line therapy in patients with pain due to pancreatic cancer. It provides superior pain control compared to traditional management with narcotics. A trend for improved survival in pancreatic cancer patients treated with CPN has been reported,but larger studies are needed to confirm this finding. At this time,the use of EUS guided CPB cannot be recommended as routine therapy for pain in chronic pancreatitis since only one-half of the patients experience pain reduction and the beneficial effect tends to be short lived. EUS guided CPB and CPN should be used as part of a multidisciplinary team approach for pain management.

Capsule endoscopy in celiac disease

Video capsule endoscopy is an attractive and patient- friendly tool that provides high quality images of the small bowel. Obscure gastrointestinal bleeding is the primary and most evaluated indication to capsule endoscopy;however,indications are expanding and a small number of preliminary reports have been presented concerning the role of video capsule endoscopy in the diagnosis of celiac disease. The purpose of this review is to update the current knowledge and to hypothesize on future perspectives of the use of video capsule endoscopy in patients with celiac disease.

Celiac disease:Management of persistent symptoms in patients on a gluten-free diet

AIM:To investigate all patients referred to our center with non-responsive celiac disease (NRCD),to establish a cause for their continued symptoms.METHODS:We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period.These individuals were investigated to establish the eitiology of their continued symptoms.The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement.They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion.A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible.Colonoscopy,lactulose hydrogen breath testing,pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted.Their clinical progress was followed over a minimum of 2 years.RESULTS:One hundred and twelve consecutive patients were referred with NRCD.Twelve were found not to have celiac disease (CD).Of the remaining 100 patients,45% were not adequately adhering to a strict gluten-free diet,with 24 (53%) found to be inadvertently ingesting gluten,and 21 (47%) admitting noncompliance.Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%.Refractory CD was diagnosed in 9%.Three of these were diagnosed with intestinal lymphoma.After 2 years,78 patients remained well,eight had continuing symptoms,and four had died.CONCLUSION:In individuals with NRCD,a remediable cause can be found in 90%:with continued gluten ingestion as the leading cause.We propose an algorithm for investigation.

Phenol-based endoscopic ultrasound-guided celiac plexus neurolysis for East Asian alcohol-intolerant upper gastrointestinal cancer patients:A pilot study

AIM: To investigate the effectiveness of phenol for the relief of cancer pain by endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN).

Endoscopic ultrasound-guided celiac plexus neurolysis using a reverse phase polymer

AIM:To assess the feasibility of endoscopic ultrasound(EUS)guided celiac plexus neurolysis(CPN) using a poloxamer. METHODS:In this prospective evaluation,six Yorkshire pigs underwent EUS-guided CPN.Three received an injection of 10 mL of 0.25%Lidocaine plus methylene blue(group 1) and three received an injection of 10 mL of 0.25%Lidocaine plus blue colored poloxamer(PS137-25)(group 2) .Necropsy was performed immediately after the animals were sacrificed.The abdominal and pelvic cavities were examined for the presence of methylene blue and the blue colored poloxamer.RESULTS:EUS-guided CPN was successfully performed in all 6 pigs without immediate complication.Methylene blue was identified throughout the peritoneal and retroperitoneal cavity in group 1.The blue colored poloxamer was found in the retroperitoneal cavity immediately adjacent to the aorta,in the exact location of the celiac plexus in group 2.CONCLUSION:EUS-guided CPN using a reverse phase polymer in a non-survival porcine model was technically feasible.The presence of a poloxamer gel at the site of the celiac plexus at necropsy indicates a precise delivery of the neurolytic agent.

Refractory celiac disease and sprue-like intestinal disease

Celiac disease is a gluten-dependent small intestinal mucosal disorder that causes malabsorption, often with diarrhea and weight loss. Diagnosis is based on detection of typical biopsy changes in the proximal small bowel, followed by evidence for an unequivocal response to a gluten-free diet. Refractoriness in celiac disease may be due to poor diet compliance, sometimes intentional, or consumption of ubiquitious sources of gluten. Alternatively, the original diagnosis may not be correct (eg., duodenal Crohn's disease), or a second cause for symptoms may be present (eg., collagenous colitis, functional bowel disorder). In some with recurrent symptoms, a complication may be present (eg., collagenous sprue, small bowel carcinoma, lymphoma). In some, a response to a gluten-free diet can not be unequivocally defined, and more precise historical terms have been used including "sprue-like intestinal disease" or "unclassified sprue". Although a "wastebasket diagnosis", these likely represent a heterogeneous group, and some, but not all, may develop lymphoma. Precise definition will be critical in the future as an array of new treatments, including biological agents, may emerge.

Adult celiac disease in the elderly

There is an increased awareness that celiac disease may occur in the elderly although presentations with either diarrhea, weight loss or both may be less common causing delays in diagnosis for prolonged periods. Higher detection rates also seem evident owing to active case screening, largely through serodiagnostic measures. In some elderly patients who are genetically predisposed, it has been hypothesized that celiac disease might be precipitated late in life by an antigen, possibly from an infectious agent. As a result, peptide mimicry or other poorly-defined mechanisms may precipitate an autoimmune gluten-dependent clinical state. Although diarrhea and weight loss occur, only isolated iron deficiency anemia may be present at the time of initial diagnosis. In addition, the risk of other autoimmune disorders, particularly autoimmune thyroiditis, and bone disease, are increased. Osteopenia may also be associated with an increased risk of fractures. Finally, elderly celiacs have an increased risk of malignant intestinal disease, especially lymphoma.

Non-celiac gluten sensitivity:Time for sifting the grain

In the last few years, a new nomenclature has been proposed for the disease induced by the ingestion of gluten, a protein present in wheat, rice, barley and oats. Besides celiac disease and wheat allergy, the most studied forms of gluten-related disorders characterized by an evident immune mechanism(autoimmune in celiac disease and Ig E-mediated in wheat allergy), a new entity has been included, apparently not driven by an aberrant immune response: the non-celiac gluten sensitivity(NCGS). NCGS is characterized by a heterogeneous clinical picture with intestinal and extraintestinal symptoms arising after gluten ingestion and rapidly improving after its withdrawal from the diet. The pathogenesis of NCGS is largely unknown, but a mixture of factors such as the stimulation of the innate immune system, the direct cytotoxic effects of gluten, and probably the synergy with other wheat molecules, are clues for the complicated puzzle. In addition, the diagnostic procedures still remain problematic due to the absence of efficient diagnostic markers; thus, diagnosis is based upon the symptomatic response to a gluten-free diet and the recurrence of symptoms after gluten reintroduction with the possibility of an important involvement of a placebo effect. The temporary withdrawal of gluten seems a reasonable therapy, but the timing of gluten reintroduction and the correct patient management approach are have not yet been determined.