bluuebunny/crossref_metadata_2025_split huggingface dataset:
GENETIC OVERLAP BETWEEN INFLAMMATORY BOWEL DISEASE AND PARKINSON’S DISEASE IMPLICATES THE ROLE OF ADAPTIVE IMMUNE RESPONSE IN THEIR COMORBIDITY
Authors: Otten Thomas , Ayash Jonathan , Lee Wonjun , Cheng Haoxiang , Debebe Anketse , Hao Ke , Peters Lauren , Björkegren Johan , Kalash Olivia , Picker Mellissa , Rendon Alexa , Colombel Jean-Frederic , Saunders-Pullman Rachel , Unger Marcus , Peter Inga 
Published: January 2022

Abstract

BACKGROUND AND AIMS
Patients with inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) have been shown to be at up to a 40% increased risk of developing Parkinson’s disease (PD), a progressive neurodegenerative disorder. Even though a genetic link between IBD and PD was established through shared causal mutations in the LRRK2 gene, it cannot fully explain the observed comorbidity. The goal of this study was to further explore the genetic overlap between these two diseases.

METHODS
The polygenic risk scores (PRS), representing estimated genetic determinants for IBD, CD, UC, and PD from previously reported respective genome-wide association studies, were computed using a linear combination of the estimated effects across multiple disease-associated variants in the Parkinson’s Progression Markers Initiative (PPMI, www.ppmi-info.org/data) cohort consisting of 413 PD cases and 195 healthy controls (HC) of predominantly European ancestry. We applied a generalized linear regression model to determine the relationship between IBD-related PRS and PD status while adjusting for sex, age, ethnicity, and principal components (PC1-5). A gene-set enrichment analysis was then conducted using Enrichr to examine the biological pathways associated with the genes regulated by variants intersecting between PRS-IBD and PRS-PD in various tissues relevant to IBD and PD (whole blood, visceral adipose fat, brain, and skeletal muscles).

RESULTS
As expected, PRS-PD was significantly elevated in PD patients (odds ratio (OR) 1.76 [95% confidence interval 1.39-2.26], adjusted p=5.34e-06). We also found that PRS-IBD, PRS-CD, and PRS-UC were significantly positively associated with PD case status (OR 1.37 [1.07-1.76], adjusted p=0.01, OR 1.46 [1.15-1.87], adjusted p=0.002, OR 1.36 [1.05-1.76], adjusted p=0.02, respectively, Figure 1). Gene-set enrichment analysis of the intersecting genes between PRS-IBD and PRS-PD across the 4 different relevant tissue types consistently identified the pathways implicating susceptibility to immune-mediated diseases and infections and immune cell differentiation and processing (Figure 2).

CONCLUSION
These results further support the genetic link between IBD and PD and emphasize the role of immunity, particularly pertaining to the adaptive immune system in the pathogenesis of both diseases. This is in line with the established role of autoimmunity in IBD etiology and is consistent with recent studies implicating the autoimmune system in PD development. Moreover, our findings suggest that PRS-IBD could serve as an early biomarker of PD and help stratify high-risk IBD patients for future PD prevention interventions.
CHRONIC COLITIS ALTERS BRAIN ACTIVITY BY INDUCING HMGB1-MEDIATED PYROPTOSIS IN MICE
Authors: Mitchell Jonathon , Kim Su Jin , Howe Cody , Patel Marisa , Kim Gayoung , Heo Gwangbeom , Im Eunok , Rhee Sang 
Published: January 2022

Abstract

BACKGROUND AND AIM
Chronic gut inflammation such as inflammatory bowel diseases is thought as being associated with neurodegenerative diseases in humans. The direct evidence for and the underlying mechanism of this brain-gut interaction, however, remain elusive.

METHODS
We used manganese-enhanced magnetic resonance imaging (MEMRI) to assess brain functional activity from awake and freely moving mice. As a mouse model of chronic colitis, mice were treated with three cycles of dextran sulfate sodium. We performed the passive avoidance test, which is a fear-motivated test that assesses short-term and long-term memory. Mouse hippocampus tissues and microglial cells were subjected to GC-MS, immunofluorescence staining, ELISA, and immunoblotting analysis to examine how the inflamed gut is linked to the brain pathology.

RESULTS
We found that manganese ion uptake, indicative of Ca2+ influx into neuronal cells, and accumulation are dramatically reduced in the hippocampus of chronic colitis mice compared to control mice. Long-term memory is declined in chronic colitis mice. Neuroinflammatory signals, including IL-1β production and the activation of Caspase-1, Caspase-11, and Gasdermin (GSDM), are induced in the hippocampus of chronic colitis mice. High-mobility group box 1 (HMGB1) level is elevated both in the serum and in the hippocampus of chronic colitis mice; however, lipopolysaccharide (LPS) levels remain at low levels without significant changes in these samples. The blood-brain barrier permeability is increased in chronic colitis mice. In the presence of LPS, accordingly, HMGB1 treatment induces the activation of Caspase-11 and GSDM in mouse microglial cell line SIM-A9.

CONCLUSION
Our findings suggest that HMGB1 released from the inflamed intestine may move to the brain through the blood circulatory system; in conjunction with a low level of endogenous LPS, elevated HMGB1 can subsequently activate Caspase-mediated inflammatory responses in the brain. This study implies that chronic gut inflammation may alter brain activity in mice.
NOVEL FUNCTION OF MYELOID METHYLTRANSFERASE SMYD5 IN INFLAMMATORY BOWEL DISEASE PROGRESSION
Authors: Hou Yuning , Guan Xiaoqing , Sharma Shaligram , Li Chunying 
Published: January 2022

Abstract

Background and Aims
SET and MYND domain-containing protein 5 (SMYD5) is a lysine methyltransferase and broadly expressed across various tissues, including immune cells. However, the myeloid SMYD5 in inflammatory bowel disease is entirely unknown. Here, we interrogated the role of SMYD5 in IBD pathogenesis and progression.

METHODS
Colitis was induced in myeloid-specific Smyd5 knockout (Smyd5fl/flLyz2+/-) and floxed control (Smyd5fl/fl) mice through DSS administration in drinking water for 7 days followed by regulator drinking water for 1 day. The induction of colitis was evaluated by measuring relative body weight loss, disease activity index, and histological as well as morphological changes in the colon. The infiltration of macrophages and neutrophils was examined by immunohistochemical staining. Smyd5 depletion in the myeloid cells in Smyd5fl/flLyz2+/- mice was confirmed by quantitative real-time PCR (RT-PCR). The formation of neutrophil extracellular traps (NET) was observed by immunofluorescence microscopy in vitro and in vivo.

RESULTS
Smyd5fl/flLyz2+/- mice administered with DSS displayed a significantly worsened colitis reflected by profound body weight loss and an exaggerated disease activity compared to Smyd5fl/fl mice that received DSS. Meanwhile, Smyd5fl/flLyz2+/- mice receiving DSS exhibited severer tissue damages and immune cell infiltration compared to Smyd5fl/fl mice. In addition, more infiltrated neutrophils were observed in the colon tissues of Smyd5fl/flLyz2+/- mice than in Smyd5fl/fl mice that received DSS. However, the infiltration of macrophages was comparable between these two groups. Moreover, we also observed exaggerated NET formation when Smyd5 was silenced both in vitro and in vivo.

CONCLUSION
Our findings suggest that SMYD5 depletion in myeloid cells leads to exaggerated disease in acute experimental colitis. Furthermore, these data revealed that SMYD5 might play a critical role in suppressing inflammatory response and could serve as a potential therapeutic target in IBD.
INCREASE IN MK2 ACTIVITY IN CROHN’S DISEASE: ROLE IN THE INFLAMMATORY ACTIVATION OF FIBROBLASTS
Authors: Chulkina Marina , McAninch Steven , Ehudin Melanie , Dovat Sinisa , Koltun Walter , Yochum Gregory , Valentine John , Beswick Ellen , Pinchuk Irina 
Published: January 2022

Abstract

INTRODUCTION AND HYPOTHESIS
Mesenchymal cells known as myo-/fibroblasts (MFs) are critical immunosuppressors under gut mucosal homeostasis. Expression of immune checkpoint PD-L1 by MFs plays a key role in the control of T cell inflammatory responses. In Crohn’s disease (CD), MFs switch their activity from immunosuppressive to pro-inflammatory, where they are also known as Inflammatory Fibroblasts. However, the mechanisms responsible for these pathological changes in MF activity are unknown. Map-kinase-activated protein kinase 2 (MK2) is a major regulator of inflammation in the gut. MK2 is downstream of p38 signaling, it evokes a sub-pathway that directly regulates the production of key inflammatory cytokines implicated in CD (such as TNF-α, IL-1, and IL-6). Thus, we hypothesized that activation of MK2 signaling is critical to the pathological changes in MFs during the immunopathogenesis of CD.

METHODS
Human normal and CD tissues and derived MFs, as well as animal models relevant to CD, were used in this study. MF signaling/activity was analyzed using RNAseq, qRT-PCR, western blot (WB), cytokine/chemokine multiplex arrays, and confocal microscopy.

RESULTS
In situ analysis demonstrated an increase in MK2 activity within the inflamed compared to the non-inflamed CD and healthy control intestinal tissues, which was confirmed by WB and multiplex signaling array analysis. In situ increase in MK2 activity in CD intestinal mucosa was greatly associated with mesenchymal stromal cells that bear a “myofibroblast” phenotype (positive for α-SMA expression). An increase in MK2 activity was also observed in primary MF cultures isolated from CD (CD-MFs) when compared to normal (N-) MFs. MK2 activity within CD-MFs was also associated with a significant decrease in the expression of the immunosuppressive checkpoint PD-L1 and an increase in the expression of inflammatory CCL2 and IL-6. Inhibition of MK2 activity within CD-MFs through using the MK2-specific inhibitor PF-3644022 (10 μM) reversed the inflammatory activity of MFs. Remarkably, we observed a differential role of p38 and MK2 in the regulation of PD-L1 expression in MFs: while p38 was required for basal expression of PD-L1, activation of MK2 downregulates PD-L1 expression. These data indicate a unique role of MK2 activation in pathological reprogramming of MFs in CD. Use of MK2 inhibitor in a therapeutic modality in chronic DSS and IL-10 KO murine models of CD also significantly reduce MF-linked inflammatory responses in vivo.

CONCLUSION
Our data suggest that an increase in MK2 activity in CD is critical to the reprogramming of the MF from immunosuppressive toward pathological Inflammatory fibroblasts. Targeting MK2 activity within MFs could be a desirable strategy for improving the efficacy of current IBD therapeutic approaches.
LACTOBACILLUS MURINUS ACTIVATES THE ARYL HYDROCARBON RECEPTOR TO ATTENUATE TNF-ALPHA-INDUCED PRO-INFLAMMATORY RESPONSES IN HUMAN INTESTINAL EPITHELIAL CELLS
Authors: Ahmed Husnain , Bell Julia , Mansfield Linda 
Published: January 2022

Abstract

BACKGROUND
Anti-TNF-alpha therapy is an established treatment modality for inflammatory bowel disease (IBD). Yet up to 30% of patients do not respond to anti-TNF-alpha therapy (primary non-responders), and almost 50% of responders lose clinical efficacy over time (secondary non-responders). Furthermore, numerous safety concerns are associated with the long-term use of anti-TNF-alpha agents. Anti-TNF-alpha therapy safety concerns and the increased incidence of non-responders have driven the need to develop innovative strategies to treat IBD.

OBJECTIVE
A potential alternative to anti-TNF-alpha therapy is the use of novel probiotics capable of attenuating the damaging effects of TNF-alpha on the intestinal epithelium. We hypothesized that Lactobacillus murinus attenuates TNF-alpha induced pro-inflammatory responses and decreases barrier disruption in human intestinal epithelial cells (Caco-2) by activating the aryl hydrocarbon receptor (AhR).

METHODS
We used Caco-2 cells grown on Transwell inserts to model the human intestinal epithelial barrier. Transepithelial Electrical Resistance (TEER) was measured to evaluate the formation of tight junctions. Once TEER reached 500 ohms per cm2, the cells were considered to have formed tight junctions. To induce pro-inflammatory responses, Caco-2 cell monolayers were treated with increasing doses of TNF-alpha (0.1, 1 and 10 ng/ml). Caco-2 cell monolayers were also treated with L. murinus to test its ability to activate AhR. Two defined ligands for AhR were used as controls i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 6-formylindolo[3,2-b] carbazole (FICZ). Next, we pre-treated the Caco-2 cells with either L. murinus or defined AhR ligands for 12 hours. After pre-treatment, monolayers were stimulated with TNF-alpha for 24 hours. IL-8 and TEER were quantified as endpoints to determine treatment efficacy.

RESULTS
TNF-alpha stimulation decreased the TEER and induced the secretion of IL-8 in a dose-dependent manner thus, providing a model of intestinal inflammation. AhR was significantly activated in monolayers treated with L. murinus as well as with defined AhR ligands. Furthermore, pre-treating the cells with L. murinus or with endogenous AhR ligand attenuated the TNF-alpha induced pro-inflammatory response and decreased epithelial barrier disruption in Caco-2 cells.

CONCLUSIONS
These results indicate that TNF-alpha induced damage to the gut wall can be attenuated using novel probiotics such L. murinus or endogenous AhR ligand. These data suggest that AhR could be a novel drug target for treating IBD. These results also indicate that L. murinus may be a potential therapeutic to mitigate or treat IBD without the use of anti-TNF-alpha agents.
LONG TERM ADVERSE HEALTH OUTCOMES IN OFFSPRING FROM MOTHERS WITH INFLAMMATORY BOWEL DISEASE: A NATIONWIDE POPULATION BASED STUDY IN KOREA
Authors: Ahn Hyeong Sik , Kim Hyun Jung 
Published: January 2022

Abstract

BACKGROUND
The research on reproductive women with inflammatory bowel disease (IBD) has focused on short-term outcomes and the studies on the long-term health outcomes of the children of parents with IBD are scarce. Therefore, there is a gap in understanding the influence of parental IBD on long-term outcomes especially in growth and development of their children. The objective of this study is to assess the long-term influence of maternal IBD on disease, growth and development of their offspring.

METHODS
Using National Health Insurance Service (NHIS) which covers total population in Korea (n=50 million), we constructed a mother-child database to track healthcare utilization of their offspring. We linked National Health Screening for Infant and Children database which include growth and development information to NHIS data for subset of population. From the database, we identified IBD patients who had given live singleton births and their offspring by linking personal identification number, providing all children born alive in Korea between 2002 and 2018. Through follow-up until the age of 15, we investigated the association between maternal IBD and selected disease categories in the offspring that include neurodevelopmental disorders, metabolic, autoimmune and allergic conditions. We also assessed association to growth and development such as height and weight of the children up to 71 months of age.

RESULTS
From study database of 3 million woman who gave birth during study periods, we identified 5191 women with IBD who had 7230 children, and 1:10 matched non-IBD control. Mortality rate between IBD and non-IBD offspring was not significantly different between two groups (p&gt;0.05). We could confirm the higher risk of autoimmune diseases (risk ratio (RR); 1.5), but no significant increased risk was identified in neurodevelopmental disorders, and metabolic diseases in IBD offspring compared to non-IBD offspring. In multivariate analysis, children born to IBD mothers had an higher risk (RR: 8.1) of IBD development compared to children with non-IBD mother with but no increased risk was observed in other conditions including autism spectrum disorder, bronchial asthma, or juvenile rheumatoid arthritis. Growth failures defined as less than 3 percentiles in weight and height at 71 months of age were more prevalent in IBD offspring compared to non-IBD offspring (RR 1.53 in weight and 1.25 in height). Among IBD offspring, 5.14% and 4.25% children showed growth failure in weight and height, respectively, compared to 3.40% and 2.78% children in non-IBD offspring.

CONCLUSIONS
From the largest study that ever researched on the health offspring of IBD parents, we found the evidence of poor long-term morbidity regarding autoimmune diseases, but not in neurodevelopmental disorders. Offspring have a higher risk of developing IBD and growth failure up to age of 6.
OUTCOMES OF TOTAL PROCTOCOLECTOMY (TPC) WITH ILEAL POUCH ANAL ANASTOMOSIS (IPAA)
Authors: Petrov Jessica , Al-Bawardy Badr , Gaidos Jill , Proctor Deborah 
Published: January 2022

Abstract

BACKGROUND
Total proctocolectomy (TPC) followed by ileal pouch anal anastomosis (IPAA) is the surgery of choice for eligible ulcerative colitis patients who are refractory to medical therapy or develop complications such as adenocarcinoma or dysplasia. Although associated with excellent quality of life, IPAA can lead to complications including chronic antibiotic-refractory pouchitis, anatomical complications, and development of Crohn’s disease. These outcomes remain a clinical challenge. The aim of this study was to evaluate the rate of complications and their treatment following TPC with IPAA to assess for predictors of adverse postoperative outcomes.

METHODS
This was a single center, retrospective study from January 1,2010 to December 31, 2020. We included patients who underwent TPC with IPAA and reported at least one episode of pouchitis, some of whom also had additional complications. Chronic pouchitis was defined as recurrent episodes of biopsy-proven inflammation or as reported in the patient record based on clinical presentation and responsiveness to treatment. Crohn’s disease of the pouch was defined as pre-pouch ileitis or development of a fistula more than 6 months post-operatively. Data is presented as number of cases and proportions.

RESULTS
A total of 44 subjects who underwent IPAA (52% female, mean age 46.4 ± 11.3 years) were included. The rate of acute pouchitis was 9%, the rate of chronic pouchitis was 75%. In the chronic pouchitis group, 45% were antibiotic-dependent and 7% were antibiotic-refractory.
We found that 70% of subjects required the initiation of medical therapy to treat symptoms of pouchitis, with the majority requiring chronic antibiotics (73%) (Table). A total of 10 subjects (23%) required biologics and 10 subjects (23%) required chronic steroid therapy. Anatomic complications were noted in 23 subjects (52%), the most common being abscess/fistula formation (30%), followed by stricture formation (27%). Anatomic complications appeared more likely to occur when more time had elapsed since the original surgery. 10 subjects (23%) needed repeat surgery and 9 subjects (20%) developed Crohn’s disease of the pouch.

CONCLUSIONS
In our cohort, we found that nearly two thirds of subjects required medical therapy to treat pouchitis following IPAA including 25% requiring treatment biologic/immunosuppressant therapy. In addition, one quarter required repeat surgery for treatment of complications. Limitations of this study include a tertiary patient population and small sample size. We found a lack of standardized characterization of pouchitis with respect to symptoms and lab abnormalities. In future work, we plan to use this data to develop a prospective, multi-center study to establish a standardized database of patients who underwent IPAA. This will help better understand factors that influence outcomes and guide management.
EFFECTS OF DELAYED ENDOSCOPIES IN INFLAMMATORY BOWEL DISEASE PATIENTS DURING THE COVID-19 PANDEMIC
Authors: Young Karen , Hargunani Devesh , Poylin Vitaliy 
Published: January 2022

Abstract

OBJECTIVES
Care for many chronic conditions was altered during the COVID-19 pandemic. For patients with Inflammatory Bowel Disease (IBD), routine maintenance including endoscopies were postponed. The effects of delaying endoscopies on IBD outcomes are currently unknown. This study aimed to evaluate effects of delays of maintenance endoscopies on patients with IBD during the COVID-19 pandemic.

METHODS
This was a retrospective review of all IBD patients scheduled for routine endoscopy at Northwestern Memorial Hospital March 13, 2020 through May 31, 2020. All endoscopic examinations were canceled in this period due to COVID-19. Patients were divided between those whose endoscopies were rescheduled promptly (on-time) or postponed (delayed) after August 31, 2020. Patient outcomes were examined one year after cancellation. Primary outcomes included hospital and emergency room admissions. Secondary outcomes included need for surgery and medication changes.

RESULTS
100 patients were included in the delayed group and 150 in the on-time group, with a mean age of 47.5 and 42.8 years respectively. 59.2% had Crohn’s disease (CD), 39.2% had Ulcerative Colitis (UC) and 1.2% had indeterminate colitis. Both groups had similar initial severity scores as measured by the Harvey-Bradshaw Index in CD and the Simple Clinical Colitis Activity Index in UC. On average, the on-time group endoscopy was re-scheduled 2.8 months after closure compared to 9.1 months for the delayed group. There was no difference in the number of emergency room visits or hospital admissions during the delay. At one-year post-endoscopy, there was no difference in the number of emergency room visits between the on-time group (n=10, 6.7%) and the delayed group (n=3, 3%), p= 0.17. One-year post-endoscopy there were significantly more hospitalizations in the on-time group (n=14, 9.3%) compared to the delayed group (n=3, 3%), p=0.03. There was one malignancy in the on-time group and two in the delayed group which did not reach statistical significance. Although clinical severity scores were similar at 1 year, there were more IBD related surgeries in the on-time group (16) compared to the delayed group (4), p=0.03.

DISCUSSION
Patients with delayed endoscopies due to COVID-19 did not experience worse outcomes compared to patients whose endoscopies remained on-time. There was a trend towards increased malignancies in the delayed group, but higher number of admissions and operations in the on-time group despite similar degree of inflammation on endoscopy. Retrospective nature of this review did not allow us to evaluate all factors that may have influenced the decision for admission and surgery.

CONCLUSIONS
Controlled delay in endoscopies in patients with IBD with closely monitored re-scheduling efforts is safe and can be utilized in times of emergencies without compromising patient outcomes.