Current and future microbiome-based therapies in inflammatory bowel disease.

PURPOSE OF REVIEW: The role of the microbiome and dysbiosis is increasingly recognized in the pathogenesis of inflammatory bowel disease (IBD). Intestinal microbiota transplant (IMT), previously termed fecal microbiota transplant has demonstrated efficacy in restoring a healthy microbiome and promoting gut health in recurrent Clostridioides difficile infection. Several randomized trials (RCTs) highlighted IMT's potential in treating ulcerative colitis, while smaller studies reported on its application in managing Crohn's disease and pouchitis. RECENT FINDINGS: This review delves into the current understanding of dysbiosis in IBD, highlighting the distinctions in the microbiota of patients with IBD compared to healthy controls. It explores the mechanisms by which IMT can restore a healthy microbiome and provides a focused analysis of recent RCTs using IMT for inducing and maintaining remission in IBD. Lastly, we discuss the current knowledge gaps that limit its widespread use. SUMMARY: The body of evidence supporting the use of IMT in IBD is growing. The lack of a standardized protocol impedes its application beyond clinical trials. Further research is needed to identify patient profile and disease phenotypes that benefit from IMT, to delineate key donor characteristics, optimize the delivery route, dosage, and frequency.

Activated intestinal muscle cells promote preadipocyte migration: a novel mechanism for creeping fat formation in Crohn's disease.

OBJECTIVE: Creeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn's disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems. DESIGN: Tissues from normal, UC, non-strictured and strictured Crohn's disease intestinal specimens were obtained. The muscularis propria matrisome was determined via proteomics. Mesenteric fat explants, primary human preadipocytes and adipocytes were used in multiple ex vivo and in vitro cell migration systems on muscularis propria muscle cell derived or native extracellular matrix. Functional experiments included integrin characterisation via flow cytometry and their inhibition with specific blocking antibodies and chemicals. RESULTS: Crohn's disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by transforming growth factor-ß1. The muscle cell-derived matrix triggered migration of preadipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5ß1 on the preadipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularised intestinal tissue extracellular matrix. CONCLUSION: Crohn's disease creeping fat appears to result from the migration of preadipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation.

Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn's Disease: A Systematic Review.

BACKGROUND & AIMS: Stenosis is a common complication of Crohn's disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD. METHODS: We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system. RESULTS: We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed. CONCLUSIONS: In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.

Efficacy of Endoscopic Dilation of Gastroduodenal Crohn's Disease Strictures: A Systematic Review and Meta-Analysis of Individual Patient Data.

BACKGROUND & AIMS: Little is known about the effects of endoscopic balloon dilation (EBD) for strictures of the upper gastrointestinal (UGI) tract in patients with Crohn's disease (CD). We performed a pooled analysis of the efficacy and safety of EBD for UGI CD-associated strictures. METHODS: We searched Embase, Medline, and the Cochrane library, as well as bibliographies of relevant articles, for cohort studies of adults with CD and strictures of the stomach or duodenum (up to the ligament of Treitz) who underwent EBD through December 2016. We obtained data from 7 international referral centers on 94 patients who underwent 141 EBDs. We performed a patient-level meta-analysis of data from published and unpublished cohort studies to determine mechanical and clinical success. We performed a time-to-event analysis to assess symptom recurrence and need for redilation or surgery. The patients analyzed had strictures of the duodenum (n = 107), stomach (n = 30), or spanning both (n = 4). RESULTS: The rate of technical success for EBD was 100%, with 87% short-term clinical efficacy; major complications arose from 2.9% of all procedures. During a median follow-up period of 23.1 months, 70.5% of patients had a recurrence of symptoms, 59.6% required redilation, and 30.8% required surgical intervention. Patients whose disease was located in the small bowel had a higher risk for symptom recurrence (hazard ratio [HR], 2.1; P = .003). Asian race (HR, 2.8; P < .001) and location of disease in the small bowel (HR, 1.9; P = .004) increased the need for redilation. Prestenotic dilation was a risk factor for needing surgery earlier (HR, 1.9; P = .001). CONCLUSIONS: In a meta-analysis, we found EBD for CD-associated strictures of the UGI to be an effective alternative to surgery, with a high rate of short-term technical and clinical success, moderate long-term efficacy, and an acceptable rate of complications.

Tests for Serum Transglutaminase and Endomysial Antibodies Do Not Detect Most Patients With Celiac Disease and Persistent Villous Atrophy on Gluten-free Diets: a Meta-analysis.

BACKGROUND & AIMS: Tests to measure serum endomysial antibodies (EMA) and antibodies to tissue transglutaminase (tTG) were developed to screen for celiac disease in patients consuming gluten. However, they are commonly used to monitor patients on a gluten-free diet (GFD). We conducted a meta-analysis to assess the sensitivity and specificity of tTG IgA and EMA IgA assays in identifying patients with celiac disease who have persistent villous atrophy despite a GFD. METHODS: We searched PUBMED, EMBASE, BIOSIS, SCOPUS, clinicaltrials.gov, Science Citation Index, and Cochrane Library databases through November 2016. Inclusion criteria were studies of subjects with biopsy-confirmed celiac disease, follow-up biopsies, and measurement of serum antibodies on a GFD, biopsy performed on subjects regardless of symptoms, or antibody test results. Our analysis excluded subjects with refractory celiac disease, undergoing gluten challenge, or consuming a prescribed oats-containing GFD. Tests were considered to have positive or negative findings based on manufacturer cut-off values. Villous atrophy was defined as a Marsh 3 lesion or villous height:crypt depth ratio below 3.0. We constructed forest plots to determine the sensitivity and specificity of detection for individual studies. For the meta-analysis, a bivariate random effects model was used to jointly model sensitivity and specificity. RESULTS: Our search identified 5408 unique citations. Following review of abstracts, 442 articles were reviewed in detail. Only 26 studies (6 of tTG assays, 15 of EMA assays, and 5 of tTG and EMA assays) met our inclusion criteria. The most common reason studies were excluded from our analysis was inability to cross-tabulate histologic and serologic findings. The serum assays identified patients with persistent villous atrophy with high levels of specificity: 0.83 for the tTG IgA assay (95% CI, 0.79-0.87) and 0.91 for the EMA IgA assay (95% CI, 0.87-0.94). However, they detected villous atrophy with low levels of sensitivity: 0.50 for the tTG IgA assay (95% CI, 0.41-0.60) and 0.45 for the EMA IgA assay (95% CI, 0.34-0.57). The tests had similar levels of performance in pediatric and adult patients. CONCLUSIONS: In a meta-analysis of patients with biopsy-confirmed celiac disease undergoing follow-up biopsy on a GFD, we found that tests for serum tTG IgA and EMA IgA levels had low sensitivity (below 50%) in detection of persistent villous atrophy. We need more-accurate non-invasive markers of mucosal damage in children and adults with celiac disease who are following a GFD.

Cognitive Impairment and Insomnia in Celiac Disease: A Systematic Review and Meta-Analysis.

Emerging evidence suggests a broader spectrum of celiac disease (CeD) system involvement, including neurological manifestations. We aimed to conduct a systematic review and meta-analysis of the available evidence from studies assessing the association of cognitive impairment and insomnia with CeD. A total of 259 participants with CeD were included in the studies investigating insomnia and 179 were included in studies investigating cognitive impairment. The overall pooled odds ratio for insomnia in patients with CeD was 1.83 (95% confidence interval, 1.38 to 2.42; I2=0.00%). The present study provides valuable insights into the available evidence from studies investigating cognitive impairment in patients with CeD and our systematic review and metaanalysis revealed a significant association between CeD and insomnia.

Prevalence of celiac disease in systemic lupus erythematosus, sjogren syndrome and systemic sclerosis: A systematic review and meta-analysis.

BACKGROUND: Celiac disease (CeD) is an immune-mediated disorder affecting the small bowel, associated with genetic factors and increasing global prevalence. AIM: This study explores the association between CeD, Systemic Lupus Erythematosus (SLE), primary Sjogren syndrome (pSS), and Systemic Sclerosis (SSc). METHODS: A systematic review and meta-analysis were conducted following PRISMA guidelines. Searches across multiple databases yielded 2728 articles, with 15 studies selected. Data extraction included study characteristics, prevalence of CeD and CeD antibodies in SLE, pSS, and SSc. Quality assessment utilized the Newcastle-Ottawa Scale. RESULTS: The meta-analysis revealed a pooled prevalence of biopsy-proven CeD in SLE, pSS, and SSc of approximately 3%. Seroprevalence of any CeD antibody in SLE, pSS, and SSc ranged from 3% to 10%. Notably, pSS exhibited the highest prevalence at 5.59%. High heterogeneity was observed in seroprevalence across autoimmune conditions. Quality assessment indicated robust methodological quality in the selected studies. CONCLUSION: This study highlights a significantly higher prevalence of CeD, especially pSS, compared to the general population. The findings underscore the importance of recognizing elevated CeD antibodies in patients with SLE, pSS and SSc emphasizing the need for early detection and comprehensive care for gastrointestinal symptoms in these conditions.

Pancreatic enzyme supplementation versus placebo for improvement of gastrointestinal symptoms in non-responsive celiac disease: A cross-over randomized controlled trial.

Background: Pancreatic Exocrine Insufficiency (PEI) is a possible cause of recurrent/persistent symptoms in celiac disease. Although pancreatic enzyme supplementation may be used to treat non-responsive celiac disease (NRCD) in clinical practice, clinical outcomes are variable and there is limited and low quality evidence to support this practice. The aim of this study was to assess the efficacy of pancreatic enzyme supplements (PES) for improvement of gastrointestinal symptoms in NRCD. Methods: Prospective, randomized, placebo-controlled, double-blind, cross-over trial in adults with NRCD examining Celiac Disease-Gastrointestinal Symptom Rating Scale (CeD-GSRS) scores on PES (pancrelipase co-administered with omeprazole) versus placebo (omeprazole only) during a 10-day treatment period. The study was registered under the clinical trials registry (https://clinicaltrials.gov/ number, NCT02475369) on 18 Jun 2015. Results: Twelve participants (nine female) were included in the per-protocol analysis; one participant had low fecal elastase-1. Pancrelipase was not associated with significant change in CeD-GSRS compared to placebo (-0.03 versus -0.26; P = 0.366). There was a significant decrease in mean values of total CeD-GSRS scores (3.58 versus 2.90, P = 0.004), abdominal pain (2.92 versus 2.42, P = 0.009), and diarrhea sub-scores (3.44 versus 2.92, P = 0.037) during the run-in period with omeprazole. Conclusion: In this prospective, cross-over randomized, placebo-controlled study, PES did not improve symptoms in patients with NRCD. It is unclear whether this is a trial effect or related to administration of omeprazole.

Association between tree pollen counts and asthma ED visits in a high-density urban center.

BACKGROUND: Asthma exacerbation patterns are cyclic in nature and often correlate with air particle concentrations. OBJECTIVE: To examine the relationship between asthma-related emergency department (ED) visits and outdoor air quality for pediatric and adult patients in a high asthma prevalence area, the New York City borough of the Bronx. METHODS: Numbers of daily asthma-related adult and pediatric ED visits during one complete year (1999) were obtained from the seven major Bronx hospitals. Daily values of nitrogen oxides (NO(x)), ozone (O(3)), sulfur dioxide (SO(2)), and pollen counts were acquired. RESULTS: Asthma-related ED visit numbers were highest in December-January and lowest in July. There were three distinct peaks of increased asthma ED visits: winter (December-January), spring (late April-May), and fall (October). The spring peak was the most striking and coincided with high tree pollen counts (tree pollen: r = 0.90, p = .03). We observed a positive correlation between asthma ED visits in the winter and SO(2) and NO(x) levels. Winter peaks of SO(2) and NO(x) in early December appeared to precede the winter asthma peak. CONCLUSIONS: The spring asthma peak is closely associated with increased tree pollen counts, and the asthma increase at this time is likely due to allergic reactions to pollen. No significant associations could be established with the fall peak. The winter peak correlates with elevated SO(2) and NO(x) levels.

Comparison of volatile organic compound profiles in exhaled breath versus plasma headspace in different diseases.

Breath analysis is the study of volatile organic compounds (VOC's) in exhaled breath. This analysis provides information on the body's condition. In this study we investigated the relationship between 22 VOC's detected in exhaled breath and plasma headspace using a selected ion flow tube mass spectrometer (SYFT-MS). We compared pairs of exhaled breath and plasma samples from patients with pulmonary hypertension inflammatory bowel disease (IBD), and IBD patients after J-pouch surgery (pouch group). Half of the measured VOC's from exhaled breath were significantly associated with the VOC's from plasma headspace. Interestingly, six breath VOC's (trimethyl amine (FDR p = 0.02), hydrogen sulfide (FDR p = 7.64 × 10-30), ethanol (FDR p = 1.56 × 10-4), dimethyl sulfide (FDR p = 5.70 × 10-19), benzene (FDR p = 8.40 × 10-27), and acetaldehyde (FDR p = 4.27 × 10-17)) and two plasma headspace VOC's (1-Octene (FDR p = 0.02) and 2-propanol (FDR p = 2.47 × 10-9)) were able to differentiate between the three groups. Breath and plasma headspace share a similar signature with significant association in half of the measured VOCs. The disease discriminatory capacity of breath and plasma headspace appear to be different. Therefore, using the VOC's print from both breath and plasma headspace may better help diagnose patients.

Selective deletion of MyD88 signaling in α-SMA positive cells ameliorates experimental intestinal fibrosis via post-transcriptional regulation.

Intestinal fibrosis leading to strictures remains a significant clinical problem in inflammatory bowel diseases (IBD). The role of bacterial components in activating intestinal mesenchymal cells and driving fibrogenesis is largely unexplored. Tamoxifen-inducible α-SMA promoter Cre mice crossed with floxed MyD88 mice were subjected to chronic dextran sodium sulfate colitis. MyD88 was deleted prior to or after induction of colitis. Human intestinal myofibroblasts (HIMF) were exposed to various bacterial components and assessed for fibronectin (FN) and collagen I (Col1) production. RNA sequencing was performed. Post-transcriptional regulation was assessed by polysome profiling assay. Selective deletion of MyD88 in α-SMA-positive cells prior to, but not after induction of, experimental colitis decreased the degree of intestinal fibrosis. HIMF selectively responded to flagellin with enhanced FN or Col1 protein production in a MyD88-dependent manner. RNA sequencing suggested minimal transcriptional changes induced by flagellin in HIMF. Polysome profiling revealed higher proportions of FN and Col1 mRNA in the actively translated fractions of flagellin exposed HIMF, which was mediated by eIF2 alpha and 4EBP1. In conclusion, selectivity of flagellin-induced ECM secretion in HIMF is post-transcriptionally regulated. The results may represent a novel and targetable link between the gut microbiota and intestinal fibrogenesis.

Systematic review with meta-analysis: efficacy of balloon-assisted enteroscopy for dilation of small bowel Crohn's disease strictures.

BACKGROUND: Evidence for endoscopic balloon dilation of small intestinal strictures in Crohn's disease (CD) using balloon-assisted enteroscopy is scarce. AIM: To evaluate endoscopic balloon dilation for the treatment of small intestinal CD strictures using balloon-assisted enteroscopy. METHODS: Citations in Embase, MEDLINE, and Cochrane were systematically reviewed. In a meta-analysis of 18 studies with 463 patients and 1189 endoscopic balloon dilations, technical success was defined as the ability to dilate a stricture. Individual data were also obtained on 218 patients to identify outcome-relevant risk factors. RESULTS: In the pooled per-study analysis, technical success rate of endoscopic balloon dilation was 94.9%, resulting in short-term clinical efficacy in 82.3% of patients. Major complications occurred in 5.3% of patients. During follow-up, 48.3% of patients reported symptom recurrence, 38.8% were re-dilated and 27.4% proceeded to surgery. On the per-patient-based multivariable analysis, that patients with disease activity in the small intestine had lower short-term clinical efficacy (odds ratio 0.32; 95% confidence interval 0.14-0.73, P = 0.007). Patients with concomitant active disease in the small and/or large intestine had an increased risk to proceed toward surgery (hazard ratio 1.85; 95% confidence interval 1.09-3.13, P = 0.02 and hazard ratio 1.77; 95% confidence interval 1.34-2.34, P < 0.001). CONCLUSIONS: Balloon-assisted enteroscopy for dilatation of CD-associated small intestinal strictures has high short-term technical and clinical efficacy and low complication rates. However, up to two-thirds of patients need re-dilation or surgery.

Pathogenesis of fibrostenosing Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory disease, which could affect any part of the gastrointestinal tract. A severe complication of CD is fibrosis-associated strictures, which can cause bowel obstruction. Unfortunately, there is no specific antifibrotic therapy available. More than 80% of the patients with CD will have to undergo at least 1 surgery in their life and recurrence of strictures after surgery is common. Investigations on the mechanism of fibrostenosing CD have revealed that fibrosis is mainly driven by expansion of mesenchymal cells including fibroblasts, myofibroblasts, and smooth muscle cells. Being exposed to a pro-fibrotic milieu, these cells increase the secretion of extracellular matrix, as well as crosslinking enzymes, which drive tissue stiffness and remodeling. Fibrogenesis can become independent of inflammation in later stages of disease, which offers unique therapeutic potential. Exciting new evidence suggests smooth muscle cell hyperplasia as a strong contributor to luminal narrowing in fibrostenotic CD. Approval of new drugs in other fibrotic diseases, such as idiopathic pulmonary fibrosis, as well as new targets associated with fibrosis found in CD, such as cadherins or specific integrins, shed light on the development of novel antifibrotic approaches in CD.

The Mesenteric Fat and Intestinal Muscle Interface: Creeping Fat Influencing Stricture Formation in Crohn's Disease.

Adipose tissue is present in close proximity to various organs in the human body. One prominent example is fat contained in the mesentery that is contiguous with all abdominal digestive organs including the intestine. Despite the fact that mesenteric fat-wrapping around the inflamed gut (so called "creeping fat") was described as a characteristic feature of Crohn's disease (CD) in the early 1930s, the functional implications of creeping fat have received only recent attention. As a potent producer of fatty acids, cytokines, growth factors, and adipokines, creeping fat plays an important role in regulation of immunity and inflammation. Increasing evidence points to a link between creeping fat and intestinal inflammation in CD, where histopathologic evaluation shows a significant association between creeping fat and connective tissue changes in the bowel wall, such as muscular hypertrophy, fibrosis, and stricture formation. In addition, emerging mechanistic data indicate a link between creeping fat, muscularis propria hyperplasia, and stricturing disease. Information on fat-mesenchymal interactions in other organs could provide clues to fill the fundamental knowledge gap on the role of distinct components of creeping fat in intestinal fibrosis and stricture formation. Future studies will provide important new information that in turn could lead to novel therapeutic agents aimed at prevention or treatment of CD-associated fibrosis and stricture formation.

Meta-analysis comparing the efficacy and adverse events of biologics and thiopurines for Crohn's Disease after surgery for ulcerative colitis.

BACKGROUND: Long-term inflammatory complications of IPAA include Crohn's Disease (CD) or "CD-like" (CDL) condition. We performed a meta-analysis to evaluate the efficacy of anti-tumor necrosis factor (anti-TNF) with or without immunomodulator (IM) therapy in this group of patients. METHODS: Literature databases were searched from inception to October 4, 2017. Further searches using references from papers of interest were conducted and, abstracts from major GI conferences were searched. The primary endpoint was: complete clinical response in the two arms. RESULTS: Out of 9 identified studies 4 were included for quantitative analysis. 48% (84/175) were female and mean age was 30.7 years. There was no significant difference in complete clinical response rates, RR 0.58 (95%CI 0.13-2.54, p = 0.5) or partial clinical response rates of RR 0.98 (95%CI 0.52-1.83, p = 0.94). All patients achieved endoscopic and deep remission in the only study reporting these outcomes comparatively in the two arms. There was a trend towards higher risk of major [RR 3.89, (95%C 0.92-16.45 p = 0.09)], and minor adverse events [RR 3.07 (95%CI 0.7-13.52 p = 0.28)] when using anti-TNF therapy compared to anti-TNF with IM. CONCLUSION: We found no difference in outcomes with anti-TNF monotherapy compared to concurrent anti-TNF therapy with IM. Additional studies are needed to define the optimal therapy for CD after IPAA.

Efficacy, Safety, and Long-term Outcome of Serial Endoscopic Balloon Dilation for Upper Gastrointestinal Crohn's Disease-associated Strictures-A Cohort Study.

BACKGROUND: Gastric and duodenal Crohn's disease [CD]-associated strictures are rare. Evidence on endoscopic balloon dilation [EBD] of upper gastrointestinal [GI] CD strictures is limited, in particular in respect to serial dilations. METHODS: Prospective short- and long-term outcome data as well as complication rates on a cohort of upper GI CD-associated stricture dilations [stomach and duodenum] were collected from 1999 to 2015. Factors linked with clinical and technical success, long-term efficacy and complication rates were investigated. RESULTS: A total of 35 CD patients with symptomatic CD-associated upper GI strictures [20% gastric, 67% duodenal, 11% both; mean age at diagnosis 25 years; mean CD duration to stricture 79.9 months; median post-dilation follow-up 22.1 months] underwent a total of 96 pneumatic dilations [33 gastric and 63 duodenal]. The median maximal dilation diameter was 15 mm. Technical success was achieved in 93% and clinical success in 87%, with a complication rate of 4% per procedure. The mean time to re-dilation was 2.2 months and mean time to stricture-related surgery after first dilation was 2.8 months. There was no difference in short-term efficacy, safety, or long-term outcome between the first and any later dilation procedure in the same patient. CONCLUSIONS: Pneumatic dilation of upper GI CD-associated strictures has a high rate of short-term technical and clinical success, with moderate long-term efficacy and acceptable complication rates. Serial dilations do not change the efficacy and could be a feasible option to delay or prevent surgical intervention.

Current and novel therapeutic strategies in celiac disease.

INTRODUCTION: A gluten free diet (GFD) is the only available treatment for celiac disease (CD). However many patients fail to respond fully clinically or histologically. Several surveys highlight the psychosocial implications of adherence to a GFD. Hence, efforts are ongoing to develop therapeutic strategies beyond a GFD. AREAS COVERED: We conducted a search of PubMed and clinicaltrials.gov to extract articles on CD using keywords including 'celiac disease' and 'refractory celiac disease' (RCD) and focused on articles conducting pathophysiologic and therapeutic research in/ex-vivo models and human trials. We highlight novel therapeutics that manipulate these mechanisms including tight junction regulators, glutenases, gluten sequestrants and immunotherapy using vaccines, nanoparticles that may serve as adjuncts to a GFD or more ambitiously to allow for gluten consumption. We also highlight the role of anti-inflammatories, immunosuppressants and monoclonal antibodies in RCD. Expert commentary: Therapeutics including tight junction regulators, glutenases have the potential to be approved for non-responsive CD or as gluten adjuncts. We expect results of various phase 1/2 trials using AMG 714, BL 7010, IgY antibodies to be published. In the interim, off-label use of 5 amino-salicylates, budesonide, nucleoside analogues and newer biologics developed for other inflammatory diseases will be used in RCD.

Low testosterone in non-responsive coeliac disease: A case series, case-control study with comparisons to the National Health and Nutrition Examination Survey.

BACKGROUND: Adults with coeliac disease (CD) often report persistent fatigue, even when CD appears well controlled for unknown reasons. AIMS: To evaluate common indications for testosterone panel (TP) testing and prevalence of low testosterone (T) in CD. METHODS: In our case series, we determined common indications for checking TP in CD. Next, we conducted a case-control study to compare TP in CD vs. healthy controls (HC). We compared mean total T (TT), free T (FT) based on serologic, histologic disease activity. Finally, we assessed TT in tissue transglutaminase (tTG)+ vs. tTG- subjects and CD vs. HC obtained from the National Health and Nutrition Examination Survey (NHANES). RESULTS: 53 coeliac males had TP tested. Common indications included osteoporosis and fatigue. Low FT was observed in 7/13 men with osteoporosis and 5/6 with fatigue. In our case-control study (n=26 each), there was no difference in mean TT or FT between CD vs. HC, tTG+ vs tTG- or Marsh 0 vs. Marsh 3 groups. NHANES data showed no difference in mean TT between tTG+ vs tTG- (n=16 each) or CD vs. HC subjects (n=5 each). CONCLUSIONS: Low T occurs in CD patients at a similar rate as the general population. Common presentations of low T may mimic non-responsive CD symptoms.

A Distinct Colon-Derived Breath Metabolome is Associated with Inflammatory Bowel Disease, but not its Complications.

OBJECTIVES: The accuracy of available noninvasive biomarkers for diagnosis, stratification, and prediction of inflammatory bowel disease (IBD) courses is limited. We analyzed volatile organic compounds (VOCs) in the breath of IBD patients and controls for diagnosis and differentiation of IBD as well as their link with disease location, activity, and phenotype. METHODS: A prospective study of diagnostic testing was conducted, recruiting Crohn's disease (CD), ulcerative colitis (UC), other inflammatory gastrointestinal diseases (OGDs), and healthy controls (HCs), as well as subjects with ileal pouch anal anastomosis (IPAA). The breath VOC profile was analyzed using selective ion flow tube-mass spectrometry. RESULTS: One hundred and twenty-four subjects (n=24 CD, n=11 UC, n=6 OGD, n=53 HC, n=30 IPAA) were included. The breath metabolome was significantly different in patients with IBD, CD, or UC compared with OGD and HC (7 out of 22 VOCs), but not between CD and UC. No link between the level of VOCs with complications, disease location, and clinical or radiologic disease activity, as well as lab parameters or type of medication was found. Breath VOCs were markedly different in patients with IPAA compared with any other group (17 out of 22 VOCs) and the presence of pouch inflammation did not alter the VOC levels. CONCLUSIONS: A specific breath metabolome is associated with IBD and markedly changes in patients with IPAA. Analysis of a broader spectrum of VOCs can potentially aid in the development of breath prints to diagnose or differentiate inflammatory bowel disorders.