bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIET AND ITS MICROENVIRONMENT INFLUENCE THE HEALTH OF COLON
Authors: Thomas Sunil , Mercogliano Giancarlo , Prendergast George 
Published: January 2022

Abstract
Ulcerative colitis (UC) is an autoimmune chronic inflammatory disease of the large intestine that greatly increases risks of colorectal cancer. UC is an idiopathic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire, colon. A Western diet, smoking, alcohol abuse, altered circadian rhythm and a dysbiotic microbiome is thought to induce UC. However, it is still not completely understood the factors in the diet that triggers UC. Identification of the factors associated with the diet that induce UC will lead to healthier lifestyle that prevents UC. In animal models we show that standard diet and diet rich in fiber positively influenced the health of the colon. A high fat high protein diet negatively regulated the health of the colon. A high fat high protein diet caused obesity in animals, paradoxically it also reduced the colon length significantly in these animals. Animals feeding on a high fat high protein had no energy in the fecal pellet demonstrating peinosis [hunger-like-condition; peina (Greek) hunger; osis (Greek) condition] of the colon. A high fat high protein diet also induced peripheral neuropathy in animals; whereas animals on a high fiber diet was healthy and had longer colon and no peripheral neuropathy. Bacteria of the family Erysipelotrichaceae that is related to inflammation-related disorders of the gastrointestinal tract is also high in animals fed with a high fat high protein diet; these animals also had low levels of valeric acid and propionic acid in the colon. Overall, a high fat high protein diet negatively impacts the health of the colon due to poor energy metabolism and its associated dysbiotic microbiome and metabolome.
Currently, anti-inflammatory drugs and immune suppressors are prescribed for UC treatment, side-effects and the risk of opportunistic infections limit the quality of treatment. Hence, there is a need for a new class of biologics for efficient UC treatment. Bin1 is a risk factor in UC as determined by the increase in Bin1 expression in the colon of UC patients. In animal models, we showed that attenuation of BIN1 gene protected against UC. We have developed an innovative therapeutic strategy to treat UC that acts by correcting the leaky colonic epithelial barrier function that drives chronic inflammation in this setting. Specifically, we recently showed that administration of our anti-Bin1 monoclonal antibody (Bin1 mAb 99D) is sufficient to mimic the effect of genetic downregulation of Bin1 to preserve the normal colonic mucosa in an established mouse model of UC, in comparison to control-treated mice which exhibited severe lesions and inflammatory cell influx throughout the mucosa. A diet that positively influence the colon may be beneficial during immunotherapeutic treatment of ulcerative colitis.
GENERATION OF ANTIGEN-SPECIFIC REGULATORY T CELLS BYLACTOBACILLUS SPECIES
Authors: Weingarden Alexa , Bousbaine Djenet , Chen Yiyin , Fischbach Michael 
Published: January 2022

Abstract

INTRODUCTION
There is a need for novel treatments for patients with inflammatory bowel disease (IBD) who do not respond to medical therapy. It is likely that IBD arises from dysfunctional interactions between the mucosal immune system and the gut microbiome, and manipulation of this interaction is therefore a promising therapeutic target. Signaling through the T cell receptor (TCR) may have a powerful role in controlling inflammation in IBD, as chimeric antigen receptor regulatory T cells (Tregs) which recognize colitis-associated antigens have been demonstrated to control inflammation in mouse models. We hypothesized that model antigen expression by two potential Treg-inducing organisms, Lactobacillus reuteri and L. plantarum, could stimulate antigen-specific Tregs which may be able to prevent colitis. Here, we demonstrate that expression of the ovalbumin-derived model peptides OT1 and OT2 by these species are recognized in vitro by transgenic CD8 and CD4 mouse T cells specific for OT1 and OT2, respectively. We also demonstrate that OT2 expression by L. reuteri can be recognized in vivo and generate antigen-specific Tregs.

METHODS
We generated expression of OT1 and OT2 peptides in L. reuteri and L. plantarum in three subcellular locations: secreted, cell membrane-associated, and cell wall-associated. For in vitro assays, mouse dendritic cells (DCs) were pulsed with heat-killed cell pellets from each of these constructs or culture supernatant from secreted constructs, then incubated with either OT1 CD8+ or OT2 CD4+ T cells pre-stained with CellTrace Violet (CTV) for 3.5 days. For in vivo analyses, mice were gavaged with L. reuteri transformed with either empty vector or wall-associated OT2, or given ovalbumin in drinking water, followed by adoptive transfer of CTV-stained OT2 cells. OT2 cells were recovered from mesenteric lymph nodes (mLN) 7 days after adoptive transfer and stained for Foxp3.

RESULTS
All OT2 constructs induced significant in vitro proliferation (decreased CTV staining) of OT2 cells compared to strains expressing empty vector, while secreted and membrane-associated OT1 constructs induced significant proliferation of OT1 cells. In vivo, L. reuteri expressing wall-associated OT2 induced significant OT2 proliferation in mLN compared to L. reuteri transformed with empty vector. A significantly higher proportion of these proliferated cells were Tregs (Foxp3+) compared to proliferated cells in mice treated with L. reuteri transformed with empty vector.

CONCLUSION
These findings suggest that Lactobacillus species can generate antigen-specific proliferation of T cells in vitro, and that L. reuteri may be capable of inducing antigen-specific Tregs in vivo. Expression of antigens by this species may represent a method of generating tolerance in the intestine, which could lead to novel therapies for controlling inflammation in IBD.
MIRIKIZUMAB REDUCES ABDOMINAL PAIN IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE
Authors: Loftus Edward , Pollack Paul , Hunter Theresa , Shan Mingyang , Chan Lai-Shan , Deckard Deanilee , Cross Raymond 
Published: January 2022

Abstract

BACKGROUND
Mirikizumab (miri), an anti-IL-23p19 inhibitor, has demonstrated efficacy in patients with ulcerative colitis and moderately to severely active Crohn’s disease (CD) in a Phase 2, randomised, double-blind, placebo-controlled study (NCT02891226). This analysis evaluated the effect of miri versus placebo (PBO) on worst abdominal pain (AP) utilising an 11-point AP Numeric Reporting Scale (AP NRS).

METHODS
During induction, patients were randomised 2:1:1:2 to receive PBO, 200mg, 600mg, or 1000mg miri administered intravenously (IV) every four weeks (Q4W). At week (W)12, patients entered a blinded maintenance treatment. Patients who received miri during induction and achieved ≥1 point improvement in Simple Endoscopic Score for Crohn’s Disease (SES-CD) at W12 were randomised 1:1 to either continue induction treatment (IV 200mg, 600mg, 1000mg miri Q4W) or receive 300mg miri Q4W administered subcutaneously (SC) for 40W (maintenance). Because of small patient numbers, the randomised maintenance groups results were combined for those who continued the same IV induction treatment (All IV-C) and those who were randomised to SC treatment (All SC). SES-CD non-improvers (NI/1000mg IV Miri) and patients who received PBO (PBO/1000mg IV Miri) during induction received 1000mg miri IV Q4W during maintenance. Patients recorded “worst AP in the past 24 hours” each day using an 11-point AP NRS (0=no pain to 10=worst possible pain) on an electronic diary. The Pain NRS is a valid, reliable, and responsive patient reported outcome that can be used to assess pain among patients with CD. Weekly average score was calculated and compared to placebo using a mixed model for repeated measures (MMRM) for visits in the induction period. Observed change in Pain NRS is presented for maintenance.

RESULTS
Significant reduction in AP NRS was reported by patients treated with 600mg miri compared to patients treated with placebo at W8 (least square mean difference ± standard error [95% confidence interval]: -1.01 ± 0.4 [-1.87, -0.14], p=0.02) (Table 1) and in all miri treatment groups: 200mg (-0.92 ± 0.4 [-1.80, -0.03], p=0.04), 600mg (-1.23 ± 0.4 [-2.11, -0.36], p=0.006) and 1000mg (-0.86 ± 0.4 [-1.57, -0.15], p=0.02) miri versus PBO at W12 (Table 1). Patients who received miri during induction continued to show improvements at W52 (Table 1). Patients treated with PBO/1000mg IV during maintenance reported similar improvements to patients who received miri from W0-52 (Table 1).

CONCLUSION
Using an 11-point Abdominal Pain Numeric Reporting Scale, mirikizumab treatment was associated with statistically significant improvements in abdominal pain when compared to placebo after 12 weeks in patients with moderately to severely active Crohn’s disease. Additional numeric reductions in abdominal pain were observed through 52 weeks in all mirikizumab treated patient groups.
UTILITY OF FIBROSCAN IN ULCERATIVE COLITIS?
Authors: Jain Shubham , Nair Sujit , Chandnani Sanjay , Junare Parmeshwar , Debnath Prasanta , Rane Siddhesh , Patel Sameet , Rathi Pravin 
Published: January 2022

Abstract

INTRODUCTION
Ulcerative colitis (UC) is associated with liver disorders due to various etiologies. Some are diagnosed on basis of deranged liver function tests, imaging, and/or histology. Data on fibroscan in UC is scarce. A previous study had shown no significant differences in liver stiffness (LS) on fibroscan between the inflammatory bowel disease (IBD) cases and non-IBD control groups.

AIMS
We aimed to evaluate UC patients for the prevalence of clinically significant liver disease which is defined by an increased liver stiffness measurement (LS) ≥8 kPa using transient elastography (TE) and to evaluate the effect of UC treatment on liver stiffness at 6 months.

METHODS
All individuals (UC and non-IBD) had their LS recorded using FibroScan® (EchoSense, Paris, France) by a single-blinded operator trained in TE.

RESULTS
120 UC patients and 60 non-IBD control subjects were included. All demographic variables were comparable between the two groups. Thirty-five UC patients (29.9%) had an LS over 8 kPa at baseline and 24 had persistently elevated LS at 6 months after treatment. This suggests a significant reduction in TE values among 31.4% of cases after starting treatment. Four patients had LS in the cirrhotic range (&gt;14 kPa). On fibroscan, difference in LS (mean ± standard deviation in group UC = 7.57 ± 2.77 vs non-IBD group = 5.37 ± 2.32, p &lt; .001).

CONCLUSION
TE in UC at the time of diagnosis can detect clinically significant fibrosis. With treatment, TE values regress below &lt;8 kpa in a significant proportion of patients.
LONG TERM OUTCOMES OF PARTIAL ENTERAL NUTRITION THERAPY IN CHILDREN WITH CROHN’S DISEASE
Authors: Vellanki Srisindu , Borcich Anthony , Agawu Atu , Stoner Natalie , Lindsey Albenberg 
Published: January 2022

Abstract

BACKGROUND
Partial enteral nutritional therapy (PEN, defined as 80% of daily caloric intake from formula) has shown similar efficacy in inducing remission for pediatric Crohn’s Disease (CD) in comparison to exclusive enteral nutrition (EEN, defined as 100% of daily caloric intake from formula). Long-term outcomes of PEN are not well defined in the literature We aimed to study the long-term outcomes of PEN as defined by the number of patients still on maintenance PEN at 1 and 2 years after initiation.

METHODS
This was a retrospective cohort study using electronic medical record data at a large pediatric academic center. Patients diagnosed with CD between ages 7-19 years at PEN initiation with available follow-up data were included. Exclusion criteria were diagnoses of ulcerative colitis or indeterminate colitis, concomitant treatment with systemic steroids (prednisone (or equivalent) dose &gt; 20 mg daily), biologics, or immunomodulators. Data collected included demographic and IBD characteristics as well as details of PEN therapy. We calculated the one and two-year PEN persistence rates and used Kaplan-Meier methods to produce survival curves of PEN persistence with adjustment for censoring.

RESULTS
Between 2009 and 2021, forty-nine participants met inclusion criteria (out of 114 assessed for inclusion). Participants were mostly white (n = 38, 77%), and male (n = 30, 61%). The mean age at CD diagnosis was 11.4 years (standard deviation, SD: 2.9 years) and the mean age at PEN initiation was 12.1 years (SD: 2.6 years). The most common reasons for PEN initiation were primary induction (n = 30, 61%), family/patient preference to avoid other medications (n = 26, 53%), and failure of primary medical therapy (n = 10, 20%). The most chosen formula type for PEN therapy was partially hydrolyzed formulas (n = 30, 61%), followed by standard formulas with whole intact proteins (n = 16, 33%). The one-year PEN persistence rate was 51% (26/49) and the two-year persistence rate was 25% (12/49) (table1). The median time on PEN was 1.3 years (IQR: 0.6 – 2.2 years) (Figure 1). The most common reasons for discontinuation were disease relapse/progression (n=32/41,78%) and treatment non-adherence (n =8/41, 20%). A small number of individuals discontinued due to formula intolerance (n = 3/41,7%). The most common medical therapies escalated to were infliximab (n =21/41, 51%), and adalimumab (n = 8/41, 20%) when PEN was discontinued.

DISCUSSION
Our study suggests that PEN therapy can be used as potential long-term treatment strategy for mild pediatric Crohn’s disease while avoiding corticosteroids and side-effects common with other IBD therapies. Secondary analysis is underway to understand predictors of response or failure to PEN therapy such as disease location/ distribution, type of formula, and the amount of calories from food vs. formula.
TOWARDS A COMMON VALIDATED METHODOLOGY FOR HISTOLOGIC MEASUREMENT OF MUCOSAL HEALING IN ULCERATIVE COLITIS: INTRODUCING A NEW PROJECT OF THE BIOMARKERS CONSORTIUM OF THE FOUNDATION FOR THE NIH
Authors: Honig Gerard 
Published: January 2022

Abstract
Ulcerative colitis is a chronic, debilitating disease characterized by damage to the mucous membrane (mucosa) lining the lower gastrointestinal tract. Endoscopic and histological evidence of healing of the damaged mucosa, referred to as mucosal healing, is increasingly accepted as an important endpoint in clinical practice and in clinical trials due to its association with improved clinical outcomes. In fact, in a draft guidance to industry, the Food and Drug Administration encouraged incorporating histologic evaluation in ulcerative colitis clinical trials. However, there is no community consensus regarding how to define mucosal healing and the field lacks standardized protocols for measuring this treatment target endpoint. Standardized assessment of histologic disease activity in clinical trials is challenging for many reasons, including variability in collection of mucosal biopsies (e.g., number and location), lack of fully validated histology scoring systems, and absence of standard definitions of histologic improvement and remission. The lack of standardized measurement of mucosal healing constitutes a major challenge for drug development and negatively impacts optimization of clinical management for patients. Therefore, the Biomarkers Consortium of the Foundation for the National Institutes of Health recently launched a consortium project, with governmental, nonprofit and industry partners, to address this gap by establishing a common methodology for a histologic measurement of mucosal healing in ulcerative colitis. The project will: 1) Establish the optimum number and locations of biopsies required to determine histological inflammation in ulcerative colitis; 2) Establish a standardized histopathologic measurement of mucosal healing that correlates with clinical outcomes; and 3) Develop an automated machine learning-based methodology for histopathological scoring of mucosal healing. The final results of this project will contribute to a consensus methodology with the goal of establishing a regulatory standard for future industry-sponsored clinical trials, with the potential to contribute to improved tools for clinical monitoring of disease activity in ulcerative colitis.
NON-IMMUNE MEDIATED MUSCULOSKELETAL DISEASE IN INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Schwartzman Monica , Schwartzman Sergio 
Published: January 2022

Abstract

BACKGROUND
Musculoskeletal (MSK) disease is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD); however, the full spectrum of MSK manifestations remains poorly characterized. The published literature is predominately focused on peripheral and axial inflammatory spondyloarthritis (SpA). However, the prevalence of more common, non-inflammatory MSK conditions, such as osteoarthritis (OA) and fibromyalgia (FM), has not been formally reported. In the general population, the prevalence of OA and FM are 10-14% and 2-3%, respectively.

OBJECTIVE
To evaluate the prevalence of OA and FM in the published literature in IBD.

METHODS
A systematic literature review of articles assessing the prevalence of MSK disease in IBD was performed using multiple databases through September 2021. References of included articles were searched for additional pertinent studies.

RESULTS
773 abstracts were screened and 94 studies included. Studies were heterogeneous precluding meta-analysis. Regarding study design, 36% were retrospective, 51% cross-sectional and 13% longitudinal. Median age at the time of the study was 41 years (range 29-51) and 49% (range 31%-100%) were male. The median number of IBD patients in each study was 243 (range 44-56,097). The prevalence of SpA (range) in the reviewed studies was: ankylosing spondylitis (AS) 3.5% (1%-27%), axial SpA 9.2% (1%-46%), and peripheral SpA 15.6% (1%-49%). Only 20/94 studies (21%) stated the term OA in any part of the paper. Of these, 20% excluded OA, 15% used the term OA but did not specifically exclude or identify patients with OA in the results, 5% reported that OA data was unavailable and 60% described the prevalence of OA in the results. In the studies that described OA in the results, median prevalence of OA was 12% (range 0.4%-23.4%). Only 7/94 studies (8%) described FM in any part of the paper, and all described the prevalence of FM in the results with a median prevalence of 2.2% (range 0.8%-12%).

CONCLUSION
While OA and FM are common conditions in the general population, most studies did not formally evaluate for these conditions in patients with IBD. When assessed, the median prevalence of OA was consistent with the general population, and additionally higher than the prevalence of AS and axial SpA in patients with IBD. The prevalence of FM was consistent with the general population. Although both rheumatologists and gastroenterologists need to recognize the importance of SpA, it is as important to understand that the most common MSK disease in IBD may be non-inflammatory. This distinction is critical, as treatment of IBD patients incorrectly diagnosed with inflammatory SpA may subject patients unnecessarily to medication adverse events, while undertreatment of patients with unrecognized SpA may lead to preventable disease morbidity.
MATRIX METALLOPROTEINASE (MMP-9) INDUCED INCREASE IN INTESTINAL EPITHELIAL TIGHT JUNCTION BARRIER IS MEDIATED BY EGFR ACTIVATION
Authors: Al-Sadi Rana , Engers Jessica , Haque Mohammad 
Published: January 2022

Abstract

BACKGROUND
The defective intestinal tight junction (TJ) barrier has a key pathogenic factor in Crohn’s disease (CD) and other inflammatory conditions of the gut. Clinical studies in CD patients have shown that a persistent increase in intestinal permeability is predictive of poor clinical outcome. Matrix metalloproteinase-9 (MMP-9) has been shown to be markedly increased in intestinal tissues of patients with CD and it has been postulated that MMP-9 plays an important role on the pathogenesis of intestinal inflammation in CD. Our recent studies suggested that MMP-9 at clinically relevant concentrations causes an increase in intestinal epithelial TJ permeability in-vitro and in-vivo by inducing intracellular signaling pathways via activating distinct basolateral membrane receptors. However, the specific protein receptors and the intracellular signaling cascades involved have not been fully identified. One of the potential protein receptors that might be a target of MMP-9 on the basolateral membrane of the intestinal epithelial cells is the epidermal growth factor receptor (EGFR), which has been shown to have opposing roles in the pathophysiology of CD.

AIMS
Therefore, our aims in this study were to examine the effect of MMP-9 on EGFR activation and delineate the role of EGRF in MMP-9 induced increase in intestinal epithelial TJ permeability by using Caco-2 monolayers as an in-vitro model system.

RESULTS
MMP-9 (400 ng/ml) caused a time-dependent increase in EGFR activation as assessed by EGFR phosphorylation, and by in-vitro kinase activity measurement of EGFR in filter-grown Caco-2 monolayers. Inhibition of EGFR by pharmacologic inhibitor, PD 153035, prevented the MMP-9 induced increase in Caco-2 TJ permeability measured by trans-epithelial resistance (TER) and mucosal-to-serosal flux of a paracellular marker dextran 10kd. MMP-9 caused a decrease in the TJ protein occludin expression. Inhibition of EGFR by PD 153035 prevented the MMP-9 induced degradation of occludin expression. In addition, the effect of EGFR activation by a known activator, NSC 228155 25, in the absence of MMP-9, caused an increase in Caco-2 TJ permeability and a decrease in occludin expression.

CONCLUSION
Our data showed that MMP-9 induced increase in intestinal epithelial TJ permeability is mediated in part by the activation of EGFR and the subsequent degradation of occludin expression. Identifying the specific membrane receptors that mediate the MMP-9 induced increase in intestinal TJ permeability could be important in developing future therapeutic strategies in IBD.