bluuebunny/crossref_metadata_2025 huggingface dataset:
PROTON PUMP INHIBITORS (PPI) INDUCES COLONIC TIGHT JUNCTION BARRIER (TJ) DYSFUNCTION VIA AN UPREGULATION OF TJ PORE FORMING CALUDIN-2 PROTEIN
Authors: Nighot Meghali , Nighot Prashant , Ma Thomas
Published: January 2021

Background

Proton pump inhibitors (PPIs) are highly effective antagonists of gastric acid secretion and are widely used to treat a number of gastroesophageal disorders, including peptic ulcer disease, GERD, and Barrett’s esophagus. PPI-induced elevation in intra-gastric pH and subsequent alterations of gastrointestinal physiology are thought to cause undesired effects on the entire GI tract. Defective intestinal Tight Junction (TJ) barrier is an important pathogenic factor for intestinal inflammation. Claudin-2 is a pore forming TJ protein whose overexpression causes selective increase in TJ permeability to small molecules. Claudin-2 expression is known to be up-regulated in intestinal inflammation and inflammation-associated colon carcinogenesis. The effect of PPI on Intestinal TJ barrier is not known. Aim: The aim of the present study was to study the effect of PPI on Intestinal TJ permeability.

Methods

A cell culture model of filter grown human intestinal epithelial Caco-2 monolayers, was used to study intestinal epithelial TJ barrier function. The mouse colonic permeability was measured by Ussing chambers studies. Western blot (WB) and Immunofluorescence (IF) was used to study the protein expression of claudin-2 in Caco-2 cells and in mouse colon. Cell surface biotinylation was used to study intracellular trafficking of TJ proteins.

Results

PPIs, caused a concentration- and time-dependent decrease in transepithelial resistance (TER), and increase in urea flux in filter-grown Caco-2 cells. Further studies on intestinal TJ revealed that PPI caused a significant increase in pore forming TJ protein claudin-2 protein level (western blot), but not mRNA (RT-PCR) in Caco-2 monolayers. Claudin-2 was co-localized to its known intercellular trafficking vesicles, clathrin pits. PPI treatment caused an increase in expression and junctional localization of claudin-2 and a decrease in its cytoplasmic co-localization with clathrin. Similarly, pulse-chase assay showed that the claudin-2 half-life was increased by PPI. In cell surface biotinylation assay, the rate of claudin-2 endocytosis was significantly reduced by PPI. In ex-vivo, Ussing chamber studies, PPI administration for 45 days resulted in a significant decrease in murine colonic TER and increase in urea flux. Immunofluorescence and Western blot analysis showed that PPI also caused an increase in TJ protein claudin-2 expression in mice colonic mucosa.

Conclusion

Our results suggest that the PPIs induces colonic TJ permeability via increasing pore forming claudin-2 levels. PPIs affect intracellular trafficking to reduce claudin-2 degradation and increased its junctional localization.
CLONAL EPIGENETIC MOSAICISM: MECHANISM FOR CROHN’S DISEASE HETEROGENEITY
Authors: Gupta Saumya , Bortvin Andrew , Vinogradova Svetlana , Shivdasani Ramesh , Gimelbrant Alexander
Published: January 2021

Crohn’s disease is a chronic heterogenous disorder with patients showing complex phenotypes and highly variable response to therapies. GWAS studies have identified hundreds of genetic factors associated with the disease but the precise mechanism with which these genes cause variable phenotype in the disease are unknown. We observed an autosomal analog of X-chromosome inactivation causes clonally stable epigenetic mosaicism in intestinal organoids generated from mice. This epigenetic mosaicism was detected by measuring allele specific expression in organoids grown from different individuals and from spatially different regions of the mouse intestine. This epigenetic mechanism has been observed in more than 25% of autosomal genes in mouse and in human cell lines and is called autosomal monoallelic expression (MAE). Allelic imbalance in MAE genes is clonally stable, persisting for multiple organoid passages and is regulated partially by DNA methylation. Our findings suggest how non-genetic variation leads to formation of developmental clones (or patches) within an individual that could then cause a wide range of functional diversity, thereby driving phenotypic variability. This will point the ways to affect epigenetic differences in intestinal tissue for disease prevention.
PRO-INFLAMMATORY MOLECULAR AND INFLAMMATORY MECHANISMS OF SULFUR METABOLISM IN IBD-RELEVANT CLOSTRIDIA SPECIES
Authors: Suarez Gabriel , Liu Bo , Herzog Jeremy , Sartor Ryan
Published: January 2021

Sulfur metabolism is emerging as a signature of IBD gut microbiota. Overrepresentation of sulfur-reducing bacteria (SRB) in IBD results in SRB-derived epithelial toxic H2S production that can overwhelm the body’s detoxification capacity, leading to impaired cellular respiration by inhibiting oxygen binding to mitochondrial cytochrome-c-oxidase. Butyrate potently inhibits SRBs and H2S, yet IBD patients have reduced short chain fatty acid (SCFA) production. More critically, H2S blocks butyrate oxidation, the primary energy source of colonocytes; butyrate oxidation deficiency is a defining characteristic of IBD. Since cysteine is the preferred substrate for H2S production by SRBs, a cysteine-rich environment provided by either a high protein diet or local intestinal mucus degradation promotes ideal conditions for SRB establishment and proliferation. SRBs can catabolize other sulfur-containing compounds critical for immune homeostasis and cellular health, such as taurine-conjugated bile acids and the “master antioxidant” glutathione, leading to further toxic H2S production. However, the molecular underpinnings of sulfur metabolism by specific bacterial genera is understudied in IBD. Results: Using a combination of in-vivo and in-vitro screening to detect the relative induction of interleukin 10 (IL-10) and interferon g (IFNg) by 19 resident bacterial strains isolated from a healthy human donor, we identified 4 bacterial strains that induce a low IL-10/IFNg ratio. These 4 strains (low group), but not 3 bacterial strains that induce a high IL-10/IFNg ratio, induce colitis in selectively colonized gnotobiotic Il10-/- mice (Fig.1A). Two of these 4 disease-inducing strains, Clostridium perfringens (A12) and Clostridium bolteae (B6), produce high concentrations of H2S in monoassociated mice (Fig.1B). In-vitro H2S production by these strains is dependent on cysteine (Fig.1C). C. perfringens and C. bolteae each induce colitis in monoassociated Il10-/- mice (Fig.1D). We are dissecting the sulfur metabolic pathways in C. perfringens and C. bolteae and their contribution to inflammatory processes by interrupting key genes predicted to contribute to H2S production, cysteine catabolism and bile acid metabolism. We will use these mutants in both in-vitro and in-vivo Il10 -/- gnotobiotic mice models to characterize their metabolic and inflammatory profiles. We have created several mutants using Targetron gene editing, including the dissimilatory sulfate reductase (Δdsr), a putative sulfonate membrane transporter (ΔssuA), anaerobic sulfite reductase (ΔasrA) and bile salt hydrolase (Δbsh). Conclusions: H2S producing bacterial strains can induce experimental colitis. Our planned mechanistic studies will determine the metabolic routes for H2S production by specific aggressive bacteria to guide novel therapeutic or dietary interventions to improve IBD prognosis.
A NOVEL LANGERIN EXPRESSING TYPE 2-CONVENTIONAL DENDRITIC CELL IS SIGNIFICANTLY DECREASED IN CROHN’S DISEASE
Authors: Doyle Chloe , Bertram Kirstie , Rhodes Jake , Cunningham Anthony , Ctercteko Grahame , Byrne Scott , Harman Andrew
Published: January 2021

Crohn’s disease is a chronic relapsing auto-inflammatory condition of the gastrointestinal tract that primarily affects young individuals with an increasing incidence rate. There is still no cure for Crohn’s disease and current treatment-options are limited to controlling inflammatory molecules such as TNF. Unfortunately, these biologics can produce significant side effects and not all patients respond to anti-TNF treatment. New treatments are therefore urgently needed. Targeting the cells and molecules of the immune system still represents the most promising approach which is why we have conducted an in-depth study of the immune cells and molecules associated with a healthy intestinal immune system and compared that to what is happening in Crohn’s disease.

Our group has privileged access to large human ileum explants as well as draining lymph node samples isolated from patients undergoing colorectal surgery to remove Crohn’s affected tissue. We have designed and optimised enzymatic tissue digestion protocols to isolate these cells in an immature state with minimal receptor cleavage. We have also developed high-parameter flow and mass cytometry panels to comprehensively identify and characterise all known subsets of mononuclear phagocytes (MNP), innate lymphoid cells, mucosal-associated invariant T cells, natural killer cells and T and B lymphocytes.

We have discovered that the newly described Langerin+ type 2-conventional dendritic cell (cDC2) is significantly decreased in Crohn’s affected ileum compared to healthy ileum. Furthermore, we have shown this decrease corresponds with lower TGF-b levels, a known driver of Langerin expression. After 7 days of co-culture, sorted Langerin+ cDC2 induced significantly higher levels of IL-17 and IL-22 in allogenic naïve CD4+ T cells compared to other MNP subsets, including cDC2 which did not express Langerin. These differentiated T cells expressed high levels of RORt and aryl hydrocarbon receptor (AHR) – transcription factors that are associated with CD4+ T helper 17 cells, implying that they may play a crucial role in intestinal barrier repair and regeneration that is absent in Crohn’s disease. Together these results suggest that Langerin+ cDC2 may have an anti-inflammatory role in human tissue and their reduction in Crohn’s disease may contribute to the pathogenesis of this disease, highlighting a potential therapeutic target for Crohn’s disease.
NEUTROPHILS ALTER DSB REPAIR PATHWAY IN INFLAMED MUCOSA TO PROMOTE COLON CARCINOGENESIS
Authors: Bui Triet , Butin-Israeli Veronika , Hanauer Stephen , Sebag Julien , Sumagin Ronen
Published: January 2021

Due to exacerbated inflammation and recurring tissue injury patients with Inflammatory Bowel Disease (IBD) are at higher risk of developing colorectal cancer (CRC). Although, PMN infiltration of the intestinal mucosa is a hallmark of IBD, and is associated with tissue injury, the contribution of PMNs to CRC and more so to IBD associated CRC is not known. We recently showed that PMNs can acutely exacerbate tissue injury and promote genomic instability by promoting miR-23a and miR-155-dependent accumulation of double-strand breaks (DSBs) and inhibition of DSB-repair by homologous recombination (HR). We now demonstrate that in chronic gut inflammation and recurring epithelial injury, as seen in IBD, via similar miRNA-dependent mechanism, PMNs alter DNA damage responses (DDR) to promote CRC progression. In murine model of Colitis-associated CRC (Azoxymethane, AOM/Dextran sodium sulfate, DSS) and human CRC xenografts, intratumoral PMNs intriguingly, functional dualism, suppressing tumor onset, but promoting tumor cell survival and growth in progressive tumors. The observed PMN effects were mediated by persistent suppression of HR-mediated DSB repair. HR suppression by PMNs, initially resulted in elevated replication stress and increased tumor cell apoptosis, however, longer term, altered DDR transcriptional profile and facilitated the upregulation of DSB repair by non-homologous end-joining (NHEJ). NHEJ upregulation enhanced CRC progression and tumor cell survival. PMN depletion, CRSPER-mediated deletion of miR-155 responsive sequence in RAD51 (preserves HR activity) or inhibition of NHEJ by small molecule inhibitors increased tumor cell death and diminished tumor development. Collectively, our data define a novel link between PMN-mediated mucosal injury and colon carcinogenesis.
OBSTRUCTED LYMPHATIC TRANSPORT AND LEAKAGE DRIVEN BY MESENTERIC TERTIARY LYMPHOID ORGANS IS A FEATURE OF CROHN’S DISEASE MOUSE MODEL
Authors: Czepielewski Rafael , Erlich Emma , Onufer Emily , Young Shannon , Kim Ki-Wook , Wang Peter , Bala Shashi , Hsieh Chyi-Song , Zinselmeyer Bernd , Davis Michael , Randolph Gwendalyn
Published: January 2021

Pioneer reports of Crohn’s disease (CD) suggested that impaired lymphatic flow might drive its pathogenesis but remains unsettled. Nodules of tertiary lymphoid organs (TLO) are found in association with collecting lymphatic vessels (CLVs) of the mesentery that normally conducts lymph outflow from the intestine. Whether TLOs affect lymph transport is unknown. In the TNFΔARE mouse model of Crohn’s-like ileitis, TLOs are found in valves regions. Using lymphatic reporters and photoconversion to study cell trafficking from the intestine, our findings indicated that TLOs halts immune cells traveling from the inflamed ileum to the lymph node, effectively trapping DCs, B, and T cells, and impacting the development of microbe tolerogenic regulatory T cells. Lymphatic transport defects were intrinsic to the CLVs because the soluble fluorescent tracer’s passage through TLO was also blocked. Lymph blockage promoted retrograde lymphatic flow returning towards the gut wall due to incapable valves. Moreover, significant lymph leakage was found, specifically at the TLOs. Neutralizing anti-TNF mAb treatment into TNFΔARE mice is ineffective in eliminating TLOs or restoring lymphatic trafficking when administered in female mice with advanced disease. In males, the therapy was able to restore forward flow to the lymph node. However, even in the presence of TNF inhibition, both sexes demonstrated TLO lymph leakage. Thus, mesenteric TLOs that form during chronic ileitis drive broadly impaired lymph transit of molecules and cells from the intestine that is only partially reversible by neutralizing the cytokine cascade underlying the disease and establish a perennial tissue alteration.
ALBUMIN-BASED NANOPARTICLES FOR DRUG COMBINATION IN INFLAMMATORY BOWEL DISEASE
Authors: Zhang Sufeng , Cho Won Joon , Jin Amy , Korzenik Josh , Lennerz Jochen , Traverso Carlo
Published: January 2021

Despite recent therapeutic advances in the treatment of inflammatory bowel disease (IBD), the off-target systemic side effects of small-molecule drugs or biologics remain problematic. Targeting the site of intestinal inflammation offers an approach to maximize potential therapeutic benefits while minimizing systemic side effects. Importantly, drug combination provides the possibility of tackling IBD through different pathways that could improve the treatment outcome. Here we introduced an inflammation-targeting drug delivery system utilizing albumin-based nanoparticles (NPs) for drug combination with relevance for IBD treatment. The pathophysiological features of the inflamed mucosa in IBD include the disrupted mucosal barrier and increased intestinal permeability; inflammation of the colonic mucosa is also accompanied by an in-situ secretion and accumulation of positively charged proteins at the site of inflammation 1, 2. We formulated the NPs using human serum albumin (HSA) with heparin coating (termed as HEP-HSA NPs) to increase the negative surface charge to interact with the accumulated positively charged proteins at the inflamed mucosa. Both small-molecule drugs and biologics were chosen to be encapsulated in these NPs, including budesonide (BUD), vancomycin (Vanco), and granulocyte macrophage colony-stimulating factor (GM-CSF). As an example of drug combination, we loaded BUD and GM-CSF simultaneously in the HEP-HSA NPs. The dual-drug loaded HEP-HSA NPs exhibited a higher anti-inflammatory effect than both of the single-drug loaded NPs in vitro and selectively bound to the inflamed intestine after enema administration in vivo in a murine model of colitis. Importantly, analyses of the physicochemical characteristics and targeting capacities of these NPs indicate that HEP coating modulates NP binding to the inflamed intestine, providing a foundation for future development of inflammation-targeting NP formulations 3. Furthermore, by analyzing disease parameters in individual mice, we also investigated the correlation between NP targeting and disease activity in the inflamed colon, which provides an approach to further our understanding on the underlying interactions between NPs and the biological interface in colitis.

References:

1. Tirosh B, Khatib N, Barenholz Y, et al. Transferrin as a luminal target for negatively charged liposomes in the inflamed colonic mucosa. Mol Pharm 2009;6:1083–91.

2. Zhang S, Ermann J, Succi MD, et al. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease. Sci Transl Med 2015;7:300ra128.

3. Zhang S, Cho WJ, Jin AT, et al. Heparin-Coated Albumin Nanoparticles for Drug Combination in Targeting Inflamed Intestine. Adv Healthc Mater 2020;9:e2000536.
A WHOLE FOOD, ANTI-INFLAMMATORY DIET ESTABLISHES A BENEFICIAL GUT MICROBIOME IN INFLAMMATORY BOWEL DISEASE PATIENTS
Authors: Olednzki Barbara , Bucci Vanni , Cawley Caitlin , Maldonado-Contreras Ana
Published: January 2021

Background and Aims

The inflammatory bowel disease-anti-inflammatory diet (IBD-AID) is a whole food diet designed to favor the development of an anti-inflammatory microbiome and to assist with remission in patients suffering from inflammatory bowel disease (IBD). Herein, we evaluated the effect of the IBD-AID on the gut microbiome and defined the impact of specific foods on bacteria depleted in IBD patients, as well as the clinical response to the IBD-AID.

Methods

A single-arm, pre-post intervention trial was performed. After a baseline period, a dietary intervention was initiated. We collected stool and blood samples throughout the study and assessed dietary intake and disease severity. We applied advanced computational approaches to define and model complex interactions between the diet, microbiota, and response to the IBD-AID.

Results

A dense dataset comprising 553 dietary records and 340 stool samples was compiled from 22 subjects participating in the study. The IBD-AID favored bacteria that are normally depleted in IBD cohorts and capable of producing short-chain fatty acids (SCFAs). Consumption of non-starchy vegetables, nuts, and seeds positively correlated with increased abundance of SCFA-producing bacteria, including Roseburia hominis, Eubacterium eligens,and Faecalibacterium prausnitzii. Half of the subjects completing the intervention with high diet adherence (>60%) reported a positive clinical response to the IBD-AID, with a subset of bacterial species predicting diet-induced reduction of symptoms with 67% accuracy. After the intervention, subjects also exhibited a reduction of circulating inflammatory markers.

Conclusions

The IBD-AID favors the growth of SCFA-producing bacteria that are depleted during IBD dysbiosis. The microbiome signatures emerging after the IBD-AID can predict response to the diet.
SER-287, AN INVESTIGATIONAL MICROBIOME THERAPEUTIC FOR PATIENTS WITH ACTIVE MILD-TO-MODERATE ULCERATIVE COLITIS, PRODUCES REMISSION ASSOCIATED METABOLITES, REDUCES INTESTINAL EPITHELIAL IL-8 SECRETION AND PROTECTS EPITHELIAL BARRIER FUNCTION IN VITRO
Authors: Martínez Asunción , Balasubramanian Divya , Piña Ambar , Kieser Karen , Narendar Priyanka , Abdulaziz Ahmad , O’Brien Edward , Henn Matthew
Published: January 2021

Background

In a Phase 1b study of mild-to-moderate ulcerative colitis (UC) (Henn et al. Gastro 2020), oral daily dosing of SER-287, a purified consortium of Firmicutes spores administered after vancomycin pre-conditioning, led to significantly higher rates of clinical remission compared to placebo (40% versus 0%, respectively; p=0.024). Engraftment, defined as SER-287 spore germination and growth of metabolically-active bacteria, was associated with remission and shifts in disease relevant microbe-associated metabolites. To better understand the mechanism underlying these favorable clinical observations, we evaluated metabolite production by SER-287 and their impact on specific inflammatory pathways and barrier epithelial integrity in vitro.

Methods

Three SER-287 lots and a negative control pro-inflammatory consortium including three strains isolated from UC subjects (Escherichia coli, Bifidobacterium dentium, and Streptococcus parasanguinis) were grown in vitro in a complex medium designed to mimic the nutrient composition found in the human colon. Culture supernatants were assessed for the presence of anti-inflammatory and remission associated metabolites by GC-MS or LC-MS. Anti- and pro-inflammatory activities were determined by measuring IL-8 secretion, an inflammatory cytokine whose expression is elevated in UC patients, by HT29 epithelial cells after incubation with bacterial supernatants in the presence or absence of TNF-α. Epithelial integrity was assayed by measuring FITC-dextran leakage in a trans-well culture of differentiated primary human colonic epithelial cells challenged with IFN-γ in the presence or absence of culture supernatants.

Results

When cultured in vitro, all SER-287 lots tested produced the anti-inflammatory short-chain fatty acids butyrate and propionate and other metabolites associated with remission in the Phase 1b trial, including tryptophan metabolites, bile acids and medium-chain fatty acids. SER-287 culture supernatants significantly reduced IL-8 secretion in TNF-α stimulated HT29 cells while the pro-inflammatory consortium increased IL-8 secretion compared to TNF-α alone (Figure 1A). SER-287 lots induced minimal IL-8 secretion in the absence of TNF-α while the pro-inflammatory consortium strongly induced IL-8 (Figure 1B). SER-287 supernatants significantly decreased IFN-γ-mediated barrier disruption, while the pro-inflammatory consortium was not protective (Figure 2).

Conclusions

Production of remission-associated metabolites, reduction of epithelial inflammation, and protection from epithelial barrier damage are shown to be pharmacological properties of SER-287 which may underlie the mechanism of action of this microbiome therapeutic for mild-to-moderate UC.
SARS-COV-2 INFECTION AND SEROCONVERSION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE PATIENTS
Authors: Ruan Wenly , Ihekweazu Faith , Walsh Seema , Karam Lina , Wyatt Allyson , Nguyen Huyen , Kellermayer Richard
Published: January 2021

Background

As the Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to evolve, its influence on specific patient populations suffering from chronic disorders becomes increasingly important. Patients with inflammatory bowel disease (IBD) are commonly immunosuppressed with immunomodulators, biologics, and steroids. Therefore, IBD patients have been considered as a risk population for COVID-19. Yet, emerging epidemiologic data may indicate otherwise. It is still unclear, however, how COVID-19 infection affects IBD patients and how seroconversion against the virus might take place depending upon disease states and treatments. We describe a single center cohort of pediatric IBD patients with COVID-19, a subset of whom were tested for seroconversion subsequent to the laboratory test supported infection.

Methods and Results

The electronic medical records of pediatric IBD patients who tested positive for SARS-CoV-2 by nasopharyngeal swab based PCR testing were included in the study. The clinical course of IBD, concurrent medications, COVID-19 related symptoms, SARS-CoV-2 testing date, and SARS-CoV-2 IgG antibody testing date and result were examined.

A total of 13 pediatric IBD patients at Texas Children’s Hospital tested positive for SARS-CoV-2. Patient demographics and specifics of IBD disease and management are detailed in table 1. Management was not altered in any of these patients in response to the positive COVID-19 test. Seven (53.8%) had symptoms including fever, sore throat, fatigue, loss of taste, dizziness, loss of smell, abdominal pain, and/or diarrhea; six (46.2%) were asymptomatic. No patients required hospitalization attributed to COVID-19. Of the 13 patients, 6 (46.2%) have been already tested for seroconversion. Four (67.7%) had elevated SARS-CoV-2 IgG of whom 3 patients (50%) had acute and resolved symptoms; one (16.7%) had an ambiguous serology (reactive total IgG and IgM but negative IgG and IgM individually), and one (16.7%) had nonreactive antibody titers. Seroconversion was tested between 0.4, or 4 to 13.7 weeks after initial positive SARS-CoV-2 PCR testing. The close antibody testing at 0.4 weeks had the ambiguous results. Serologic testing for the additional cases is pending.

Conclusions

We describe a cohort of pediatric IBD patients with COVID-19 ranging from 1 week to 4 months after infection whose disease course has not been significantly affected. A large proportion of patients tested for seroconversion were found to mount a detectable IgG based immune response in spite of their medical immunosuppression. More research needs to be performed to evaluate the importance of seroconversion with relation to disease course andCOVID-19 reinfection in pediatric IBD patients.
THE SAFETY, TOLERABILITY, AND EFFECTIVENESS OF BIOLOGICS/SMALL MOLECULE THERAPY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE AND CIRRHOSIS
Authors: Li Muyi , Khan Sameer , Proctor Deborah , Gaidos Jill , Al-Bawardy Badr
Published: January 2021

Introduction

Biologic agents and small molecules have been shown to be effective and relatively safe in the treatment of inflammatory bowel disease (IBD). However, data is lacking regarding the use of these agents in patients with IBD and concomitant cirrhosis. The aim of this study is to examine the safety, tolerability and effectiveness of biologics and small molecules in patients with IBD and concomitant cirrhosis.

Methods

This is a retrospective study of adult patients diagnosed with both IBD and cirrhosis (by liver biopsy or Fibroscan) treated with biologic agents or small molecule agents between 2012 and 2020 within the Yale-New Haven Hospital system. We included patients on tofacitinib or any of the following biologic agents: infliximab, adalimumab, certolizumab pegol, golimumab, vedolizumab, ustekinumab. Primary outcomes were rates of adverse events (infection, infusion reaction, IBD-related hospitalization) and mortality. Secondary outcomes were clinical remission (defined by the physician global assessment) and mucosal healing (Mayo endoscopic score of 0 or 1 for ulcerative colitis (UC) and absence of erosion/ulcerations in Crohn’s disease (CD)).

Results

A total of 18 patients (72% CD, 28% UC) with median age of 50 (26–73) years were included (Table 1). Decompensated cirrhosis was present in 33.3% of the population prior to initiation of biologic/small molecule therapy. The most common etiology of cirrhosis was primary sclerosing cholangitis at 38.9%.

IBD therapy included: infliximab/adalimumab (44.5%), vedolizumab (27.7%), and ustekinumab (22.2%) and tofacitinib (5.6%). A total of 4 patients (22.2%) were on concomitant corticosteroid therapy and 3 on combination therapy with thiopurines (Table 2).

Adverse events occurred in 27.7% (n=5; 1 infusion reaction and 4 infections). The 4 patients with infections included: 2 on infliximab/adalimumab, 1 on ustekinumab, 1 on vedolizumab. Two of these patients were on concomitant thiopurines and 1 on corticosteroid. Biologic therapy was stopped in 3 patients, 2 for non-response and 1 for an infusion reaction. Mortality rate was 11% and all were liver-related.

Clinical remission was achieved in 66.7% and mucosal healing was noted in 72.7% (8/11).

Conclusions

In this cohort of patients with IBD and cirrhosis, biologic/small molecule therapies were effective for IBD. Approximately a quarter of patients experienced adverse events that were mainly due to infections. Larger studies are needed to elucidate the relative safety of different biologic agents and small molecules in IBD patients with cirrhosis.
VISCERAL ADIPOSE TISSUE INFLUENCES ANTI-TUMOR NECROSIS FACTOR (TNF) TREATMENT RESPONSE IN IBD
Authors: Gu Phillip , Chhabra Avneesh , Chhittajallu Punya , Chang Christopher , Mendez Denisse , Gilman Andrew , Fudman David , Xi Yin , Feagins Linda
Published: January 2021

Background

Data describing the effect of obesity on anti-TNF treatment response in inflammatory bowel disease (IBD) are conflicting. This likely reflects the shortcomings of using body mass index (BMI) to capture an individual’s adipose stores. Recent studies have found visceral adipose tissue (VAT), not BMI, is associated with IBD-related complications and post-operative recurrence. However, the relationship between VAT and treatment response is unclear. We aim to evaluate the effect of VAT on anti-TNF treatment response.

Methods

IBD patients starting anti-TNF agents between 1/1/2009 to 7/31/2019 at two academic medical centers were included. Three-dimensional VAT volume was measured from CT scans with Aquarius (iNtuition, Foster City, CA). Patients were categorized by predefined volume cutoffs: <1500cm3, 1500-2999cm3, >3000cm3. Primary outcomes included composite endpoint of corticosteroid-free response (CFR) at 6 and 12 months defined by meeting one of the following: a) clinical response based on Harvey Bradshaw Index for Crohn’s disease (CD) or Lichtiger score for ulcerative colitis (UC) b) endoscopic improvement based on ulcer healing for CD and Mayo score for UC compared to baseline or c) 50% improvement or normalization of CRP or fecal calprotectin. Secondary outcomes included IBD-related surgery at 6 and 12 months. We performed a multivariable logistic regression on CFR and surgery, adjusting for age, gender, IBD diagnosis, disease duration, active tobacco use, and immunomodulator exposure, to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI).

Results

We included 182 patients. Table 1 summarizes differences in baseline characteristics. There were no differences in CFR at 6 months. Compared to those with VAT volume <1500cm3, patients with VAT volume 1500-2999cm3 were significantly more likely to achieve CFR at 12 months (aOR 3.27, [95%CI 1.26–8.5]), but not for those with VAT volume >3000cm3 (aOR 0.45, [95%CI 0.13–1.50], Figure 1b). With respect to surgery within 6 months, patients with volume >3000cm3 were significantly more likely to undergo surgery than those with VAT volume <1500cm3 (aOR: 7.99 [95%CI 1.49–2.94]), while there was no significant difference with patients with VAT volume 1500-2999cm3 (aOR: 0.63 [95%CI 0.14–2.78]). While not statistically significant, a similar trend was observed at 12 months with those with VAT volume >3000cm3 having the highest risk of surgery (aOR: 3.55 [95%CI 0.87–14.61], Figure 1c and d).

Conclusion

In this retrospective, multicenter, cohort study, we found VAT influences treatment response but not in a dose-dependent manner as previously hypothesized. If confirmed by future prospective studies, VAT may be employed as a biomarker to better inform treatment decisions and improve outcomes, especially considering the growth of artificial intelligence in medical imaging.
DETERMINANTS OF INFLAMMATORY BOWEL DISEASE PATIENT SATISFACTION AFTER TRANSITION TO VIRTUAL VISITS
Authors: Ghafari-Saravi Afsoon , Rabizadeh Shervin , Dubovsky Alan , Miller Shaun , Melmed Gil , van Deen Welmoed
Published: January 2021

Introduction

Due to COVID-19, traditional inflammatory bowel disease (IBD) patient and provider office-based interactions have shifted to telemedicine platforms to address the ongoing healthcare needs of this population. As telehealth services continue to expand, a better understanding of patient satisfaction is required in order to optimize the patient experience for IBD patients.

Methods

We analyzed patient satisfaction data from a metropolitan tertiary hospital’s IBD outpatient clinic. Three questions were compared between in-person and virtual visits: “Did this provider listen carefully to you?”, “Did this provider seem to know the important information about your medical history?”, and “Using any number from 0 to 10, where 0 is the worst provider possible and 10 is the best provider possible, what number would you rate this provider?” We performed Fisher’s exact tests to analyze differences in top-box satisfaction scores between in-person and virtual visits. A qualitative analysis of open-ended questions was performed to identify key satisfaction themes.

Results

We collected satisfaction data from 309 in-person medical visits and 202 telehealth visits. Top-box satisfaction scores for provider listening and provider medical history decreased overall from in-person to virtual visits, while overall provider ratings remained the same (Figure 1). Decreases were larger among males than among females for both provider listening and provider knowledge (Table 1). After excluding patients who reported problems with the video connection or video quality, no statistically significant changes in top-box scores were found between in-person and telehealth visits (Figure 1). Open-ended answers where overwhelmingly positive, but care coordination issues and technical problems were perceived as barriers.

Discussion

We identified a decrease in patient satisfaction with telehealth visits compared to in-person visits, particularly among males. This decrease was not observed after adjusting for those experiencing technical issues with their visit. Efforts to improve telehealth technology platforms, patient preparation for telehealth visits, and provider education regarding handling technology glitches during a visit may help improve overall patient satisfaction with virtual IBD visits.
HEPATITIS VACCINATION AND ANTIBODY STATUS AMONG U.S. ADULTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Moon Jooyoung , Moon Hanna
Published: January 2021

Background

It is difficult to predict when inflammatory bowel disease (IBD) patients will need to receive immunosuppressive therapy. The use of immunosuppressants increases the risks of opportunistic infection and re-activation of viral replication. Hepatitis A (HAV) and B (HBV) are still endemic in certain areas of the world, and the latter has the potential to induce fulminant hepatitis with hepatic failure in the immunocompromised. Thus, it is important to routinely screen IBD patients for hepatitis and recommend appropriate vaccinations for those who are seronegative for antibodies.

Methods

We performed a retrospective analysis with data from the National Health and Nutrition Survey (NHANES) from 2009 to 2010. We identified participants who reported whether they were told by a doctor or other health professional that they have IBD. We excluded those who did not provide pertinent information and those who did not know their vaccination status. For the purpose of statistical analysis, vaccination status was stratified as either complete or incomplete. Complete vaccination for HAV was defined as at least 2 doses, and that for HBV was defined as 3 doses. Incomplete vaccination was defined as the aggregate of inadequate doses, no doses, and refusal.

Results

HAV vaccination data was available in 48 IBD and 4303 non-IBD participants. Complete HAV vaccination was 14.6% among IBD patients, compared to 26.4% for non-IBD participants (odds ratio [OR] 0.47; 95% confidence interval [CI], 0.21–1.06). There were 55 IBD and 4443 non-IBD participants with known anti-HAV antibody status, and seropositivity was similar for both groups (41.8% vs. 42.4%, p=0.93). HBV vaccination data was available in 50 IBD and 4349 non-IBD participants. Complete HBV vaccination was 26.0% among IBD participants, compared to 34.4% among non-IBD participants (OR 0.67; 95% CI, 0.35–1.26). The presence of anti-HBV surface antibody was reported in 58 IBD and 4666 non-IBD participants, and seropositivity in the IBD group was less than the non-IBD group (17.2% vs. 23.5%, p=0.26).

Conclusion

Patients with IBD have lower rates of hepatitis vaccination and lower seropositivity for hepatitis antibodies. The current American College of Gastroenterology guidelines recommend the assessment and completion of HBV vaccination schedule prior to initiating biologic therapy. The European Crohn’s and Colitis Organisation is stricter on the timing of these preemptive measures and recommends doing so at the time of IBD diagnosis. A small number of studies have suggested that seroconversion following vaccination may be reduced in IBD patients, but even so, the vaccination rates need to be improved greatly. To do so, gastroenterologists and primary care physicians should systematically educate IBD patients on the importance of hepatitis vaccination and recommend routine testing for seronegative patients.
PATIENTS WITH INFLAMMATORY BOWEL DISEASE PERSPECTIVE ON COVID-19 AND HEALTH CARE SERVICE DURING THE PANDEMIC
Authors: Opheim Randi , Moum Kristian , Moum Bjørn
Published: January 2021

Background

Patients with inflammatory bowel diseases (IBD) have experienced changes to the routine management of their conditions during the coronavirus disease (COVID-19) pandemic. The disease as well IBD treatment frequently require immunosuppressant medications, which could increase their risk of infection. The aim of this study was to determine patients’ experience of the health care service, including the restrictions of hospitals visits made in Norway from Mars 12th 2020.

Method

From June 18 to September 18 2020, all patients at the IBD outpatient clinic at Oslo University Hospital in Norway on biological therapy or other immunosuppressant’s were included. A questionnaire including patients concerns regarding their disease, medical therapy and COVID-19, as well as their health care service needs in follow-up during the COVID-19 pandemic.

Results

Altogether 506 IBD patients answered a paper-based questionnaire. The mean age was 40.78 (SD 14.71), 289/506 (57%) men, ulcerative colitis 199/506 (39%), Crohn’s disease 307/506 (61%). Sixty-three patients (12.5%) used biological therapy in combination with azathioprine or steroids. Ninety-one (18.2%) were in obligated quarantine with negative test. Five patients (4.9%) tested positive to SARS- CoV-2 of the 98 patients tested, (1.0% of the total sample). One third of the IBD patients perceived they had increased risk for being infected by SARS- CoV-2 because of the immunosuppressive drugs they used. Nonetheless, 496/506 (98.6%) of the patients adhered to continuing their medication. One-hundred and sixty-one (32.3%) voluntarily isolated, and 21/506 (4.2%) was in sick leave being afraid of being infected. Furthermore, 20/506 (4.0%) cancelled their consultation because they were afraid of being infected from SARS- CoV-2 at the hospital. The hospital changed physical consultation to telephone consultation for 75/506 (15.0%) of the patients. Thirty-eight patients (7.6%) reported that they were afraid of going to the hospital because of restrictions due to the COVID-19 pandemic, and 18/506 (3.6%) did not feel safe when at hospital. Approximately half of the IBD patients (219/506) were satisfied with the information provided by physician about medical treatment for IBD and Covid-19 while 398/506 (77.3%) were satisfied with the information from health-care providers about restrictions due to COVID-19. There were no statistical differences between Crohn’s disease and ulcerative colitis.

Conclusion

IBD patients on biological treatment and immunosuppressives took precautions because of fear of being infected with SARS- CoV-2. At the same time, they adhere to medical treatment regimens and follow-up at the hospital. Most patients were satisfied with the information they received from physicians and other health-care workers. One percent tested positive to SARS-CoV-2.
THE IMPLEMENTATION OF A PILOT STUDY OF A STANDARDIZED INFLAMMATORY BOWEL DISEASE CURRICULUM FOR GASTROENTEROLOGY FELLOWS
Authors: Mulgund Aditi , Beniwal-Patel Poonam
Published: January 2021

Introduction

There is a need for standardization of the inflammatory bowel disease (IBD) training curriculum in gastroenterology fellowship. This training varies by program and in many cases may be insufficient to provide advanced care in IBD. Prior data has shown only 28% of trainees feel satisfied with their IBD exposure and few feel comfortable with the management of pouches, stomas, and pregnant or post-operative patients. The current approach to IBD education varies widely by training program and may include didactic sessions, web-based education, or clinical exposure. Because of the increase in IBD prevalence and rapid change to the treatment armamentarium, fellows need to be uniformly trained in IBD. There is a need for a standardized curriculum for IBD training across all gastroenterology fellowships.

Methods

We created an IBD curriculum for our categorical gastroenterology fellows based off the core IBD competencies recommended by the Crohn’s and Colitis Foundation Rising Educators, Academicians, and Clinicians Helping Inflammatory Bowel Disease (REACH-IBD) group. Unique learning objectives and learning resources were provided during the IBD month, each year of fellowship. A pre-test and post-test was administered during the IBD month.

Results

The core competencies assessed in pre-survey data is shown in table 1. Preliminary data showed that only one trainee close to the end of training felt comfortable with most aspects of IBD management. The remaining trainees closer to the beginning of their fellowship were less comfortable with most aspects of IBD management (Table 1). First year fellows had most difficulty with identifying serious infections associated with advanced therapies for IBD and noting which laboratory testing is needed for monitoring. Second- and third-year fellows did well with assessment and management of the IBD patient, but had difficulty with advanced management of post-surgical or pregnant patient (Fig. 1).

Conclusion

This single-center prospective study implemented a novel comprehensive IBD curriculum as part of the IBD training month. Through real-time assessment, specific strengths and areas for further improvement were identified so additional training could be provided. The limitation of the study is the small sample size and limited follow up. Further models in IBD education during gastroenterology fellowship need to be explored.

Pre-rotation survey, administered to trainees to assess where they feel weakness lies

Bar graph demonstrating individual scores and average scores for post-rotation test, separated by year
PERFORMANCE CHARACTERISTICS OF A FRET-BASED IMMUNOASSAY FOR QUANTITATION OF INFLIXIMAB ON A POINT-OF-CARE INSTRUMENT SYSTEM
Authors: Ong Edgar , Huang Ruo , Kirkland Richard , Hale Michael , Mimms Larry
Published: January 2021

Introduction

A fast (<5 min), time-resolved fluorescence resonance energy transfer (FRET)-based immunoassay was developed for the quantitative detection of infliximab (IFX) and biosimilars for use in therapeutic drug monitoring using only 20 µL of fingerstick whole blood or serum at the point-of-care. The Procise IFX assay and ProciseDx analyzer are CE-marked. Studies were performed to characterize analytical performance of the Procise IFX assay on the ProciseDx analyzer.

Methods

Analytical testing was performed by spiking known amounts of IFX into negative serum and whole blood specimens. Analytical sensitivity was determined using limiting concentrations of IFX. Linearity was determined by testing IFX across the assay range. Hook effect was assessed at IFX concentrations beyond levels expected to be found within a patient. Testing of assay precision, cross-reactivity and potential interfering substances, and biosimilars was performed. The Procise IFX assay was also compared head-to-head with another CE-marked assay: LISA-TRACKER infliximab ELISA test (Theradiag, France). The accuracy of the Procise IFX assay is established through calibrators and controls traceable to the WHO 1st International Standard for Infliximab (NIBSC code: 16/170).

Results

The Procise IFX assay shows a Limit of Blank, Limit of Detection, and Lower Limit of Quantitation (LLoQ) of 0.1, 0.2, and 1.1 µg/mL in serum and 0.6, 1.1, and 1.7 µg/mL in whole blood, respectively. The linear assay range was determined to be 1.7 to 77.2 µg/mL in serum and whole blood. No hook effect was observed at an IFX concentration of 200 µg/mL as the value reported as “>ULoQ”. Assay precision testing across 20 days with multiple runs and reagent lots showed an intra-assay coefficient of variation (CV) of 2.7%, an inter-assay CV of <2%, and a total CV of 3.4%. The presence of potentially interfering/cross-reacting substances showed minimal impact on assay specificity with %bias within ±8% of control. Testing of biosimilars (infliximab-dyyb and infliximab-abda) showed good recovery. A good correlation to the Theradiag infliximab ELISA was obtained for both serum (slope=1.01; r=0.99) and whole blood (slope=1.01; r=0.98) samples (Figure 1).

Conclusion

Results indicate that the Procise IFX assay is sensitive, specific, and precise yielding results within 5 minutes from both whole blood and serum without the operator needing to specify sample type. Additionally, it shows very good correlation to a comparator assay that takes several hours and sample manipulation to yield results. This makes the Procise IFX assay ideal for obtaining fast and accurate IFX quantitation, thus allowing for immediate drug level dosing decisions to be made by the physician during patient treatment.
IMPACT OF DIET ON INFLAMMATORY BOWEL DISEASE SYMPTOMS: AN ADOLESCENT VIEWPOINT
Authors: Zangara Megan , Bhesania Natalie , Liu Wei , Cresci Gail , Kurowski Jacob , McDonald Christine
Published: January 2021

Background

Dietary modification shows promise as therapy in inflammatory bowel disease (IBD); however, it is unknown whether adolescents are interested in a dietary approach.

Methods

Cross-sectional survey of adolescents with IBD ages 14–21 on disease knowledge, dietary habits, and perceptions of diet therapy.

Results

A total of 132 subjects (48.5% female), mean age of 17.8 years and median disease length of 5 years (range 0, 16), completed the survey. Diet was perceived as a symptom trigger by 59.8% of subjects, and 45.4% had tried using diet as a treatment for symptom resolution, often without physician supervision and with limited success. Overall, subjects reported following a diet significantly more often than documented in the electronic medical record (EMR) by the physician (25.0% vs. 15.0%, p=0.033), with 72% agreement between subject response and EMR documentation on current status of diet modification (AC1=0.59, CI=0.45, 0.73). Subjects experiencing active disease symptoms as determined by Manitoba IBD Index were more likely to be currently modifying their diet compared to subjects without active disease symptoms (OR = 4.11, CI=1.58, 10.73, p=0.003). The subjects reporting unsuccessful dietary modification compliancy (25.7%, n=34) most commonly cited perceived lack of improvement in their IBD symptoms as the primary reason for stopping the diet (48.4%, n=15).

Conclusions

Adolescents with IBD perceive a relationship between diet and disease symptoms and are interested in dietary modification as a symptom management option. Our study suggests that a large proportion of adolescent IBD patients may already be attempting dietary modification, and therefore would be receptive to a modified dietary plan under the guidance of their gastroenterologist and dietitian. Much is still unknown about how dietary modification will fit in with current treatment regimens, but patient interest informs us that it is necessary to continue development and research of this promising therapeutic option.