bluuebunny/crossref_metadata_2025 huggingface dataset:
DEVELOPMENT AND VALIDATION OF A MACHINE LEARNING TOOL FOR EARLY DIAGNOSIS OF INFLAMMATORY BOWEL DISEASE IN THE PRIMARY CARE SETTING: A POPULATION BASED STUDY
Authors: Ber Tahel Ilan , Tov Amir Ben , Gazit Sivan , Steinberg-Koch Shlomit , Getz Benny , Jenudi Yonatan , Underberger Dan , Ramni Or , Ben-Horin Shomron
Published: January 2022

BACKGROUND

Although 3,000,000 Americans are afflicted with Inflammatory Bowel Disease (IBD) encompassing Crohn’s Disease (CD) and Ulcerative Colitis (UC)1, timely diagnosis is a challenge due to non-specific and overlapping symptoms.2 More than 20% of patients may be initially misdiagnosed3 causing delayed diagnosis and treatment, potentially leading to increased risk of complications2 and irreversible mucosal damage.4 Artificial intelligence (AI) models can alert physicians to patients who would otherwise be misdiagnosed, potentially improving patient outcomes and reducing costs. We aimed to develop PredictAI, a proprietary AI Gradient Boosted Decision Tree based machine learning algorithm and test its accuracy in identifying undiagnosed CD and UC in the primary care setting.

METHODS

This was a retrospective study of 2,471,267 patients’ electronic medical records (EMR) from Maccabi Healthcare Services in Israel. Sufficient data was available between the years 2010-2020, of which 2 consecutive years (2015-2016) were pre-assigned to the test set. Inclusion criteria were: (i) CD or UC ICD code as defined by Maccabi’s Registry,5 (ii) no other autoimmune disease diagnosis, (iii) at least 4 years of data antedating first suspicion by primary care physician (PCP) of IBD were available. First suspicion was defined as any diagnostic test, procedure, or referral to a specialist, indicating suspicion of IBD. Here we included adult data only.

RESULTS

Of 2,471,267 patients, 1,214 had a first-time diagnosis of IBD and available antedating data in the years 2015-2016. Of these, PredictAI identified 126, 120, 104, 93 patients 1, 2, 3 and 4 years prior to initial PCP suspicion, respectively. For CD, it predicted 83/229 (36%) of patients 1 year prior to PCP initial suspicion of disease, 70/211 (33%) patients 2 years prior, 60/179 (33%) patients 3 years prior and 56/148 (38%) patients 4 years prior. Discriminatory accuracy area under the curve (AUC) was 76%, 75%, 75% and 78%, 1, 2, 3 and 4 years before initial PCP suspicion, respectively (Figure 1). Corresponding early-identification ratio and discriminatory accuracy for UC was 42/238 (17%, AUC=71%), 50/225 (22%, AUC=70%), 44/187 (23%, AUC=72%) 37/161 (23%, AUC=74%), for 1,2,3 and 4 years before initial PCP suspicion of UC, respectively (Figure 2). Specificity for CD and UC each was above 90%.

CONCLUSIONS

PredictAI accurately identified CD and UC diagnosis in 17-38% of patients presenting to primary care up to 4 years prior to PCP’s initial suspicion, potentially reducing time to diagnosis.
REAL-TIME CONTINUOUS REPORTING OF IBD BIOMARKERS IN SWEAT
Authors: Jagannath Badrinath , Pali Madhavi , Lin Kai-chun , Sankhala Devangsingh , Sardesai Abha , Muthukumar Sriram , Prasad Shalini
Published: January 2022

INTRODUCTION

Calprotectin and C-reactive protein (CRP) are key biomarkers to assess a flare-up and inflammation in IBD patients. Flare-ups in IBD patients can create excruciating pain, discomfort, and occur in a random way. Therefore, continuous monitoring of these biomarkers in real-time can aid in providing active feedback and decision support on the health state for better IBD patient management. This work demonstrates a novel way of empowering IBD patients with actionable data through capturing temporal profiles of IBD markers (Calprotectin and CRP) from sweat for patient-driven outcomes.

MATERIALS AND METHODS

10 healthy and one IBD subject were recruited in compliance with an approved IRB at UT Dallas. The levels of Calprotectin were quantified using the SWEATSENSER and ELISA. The basal levels of Calprotectin were compared between healthy and IBD cohort. Further, the wearable SWEATSENSER was used to measure CRP and Calprotectin continuously for a minimum of 6 hours. The levels of the study biomarkers were compared between healthy and IBD subjects to determine the statistical significance in differentiating between both the cohorts.

RESULTS

CRP levels between healthy and IBD subjects were measured through continuous monitoring using the SWEATSENSER for up to 24 hours over multiple days. Figure 1A shows a comparison between healthy (n=108 data points) and IBD (n=43 data points) CRP levels in sweat and a statistically significant difference between(p<0.05) was achieved. The levels were computed as a time-average of every 2 hours. Further, healthy calprotectin levels ranged 379 ng/mL while, the basal levels in IBD subject were reported to be 620 ng/mL as demonstrated in Figure 1B. The basal levels of calprotectin were significantly different between healthy and IBD subjects confirming the first proof-of-feasibility of real-time monitoring of IBD markers from sweat in detecting elevated IBD levels and an impending flare-up.

CONCLUSION

The SWEATSENSER device can differentiate the marker levels between healthy and IBD subjects. The developed device can be useful in better management of IBD patients by monitoring biomarker levels in real-time to report an impending flare-up. Further, the feasibility of real-time monitoring of CRP and Calprotectin using SWEATSENSER enables actionable data to patients during transition from remission to relapse of the disease. This is the first in-human demonstration of a wearable technology for tracking and stratification between healthy and IBD subjects.
AMINO ACID SENSING PATHWAYS IN INFLAMMATORY BOWEL DISEASE
Authors: Solanki Sumeet , Lee Jun-Hee , Shah Yatrik
Published: January 2022

IBD is a chronic inflammatory disease of the gastrointestinal tract affecting millions of people worldwide. The last few decades have seen rapid increase of IBD cases in the US contributing to exorbitant health-care costs and morbidity rates. IBD comprises of two major subtypes: ulcerative colitis and Crohn’s disease. Although the etiology of IBD is not completely understood, a complex interaction of environmental, genetic, immune, and gut microbial factors contributes to its pathogenesis. These factors ultimately converge to disrupt intestinal epithelial cell homeostasis, compromising mucosal barrier function, leading to unresolved relapsing inflammatory injury. Poor dietary habits such as Western diet are thought to play a pivotal role in the development of colitis. A healthy and balanced diet is important in management of the disease. Epidemiological and experimental studies demonstrate that high-protein diet triggers inflammatory flares and colitis patients are often advised to reduce animal dietary protein. However, colitis patients are also at high risk of a protein malnutrition. Thus, the precise mechanisms by which low dietary protein increases incidence of colitis and/or aggravate already established disease remains unknown.

Our preliminary findings suggest that low dietary protein intake aggravated dextran sulfate sodium (DSS)-induced colitis with reduced body weight, colon length and increased histological injury. Dietary habits impact intestinal epithelial cell homeostasis and regeneration process in the event of an injury. The mechanistic target of rapamycin complex 1 (mTORC1), a ‘master’ regulator of cell growth participates in intestinal tissue regeneration. Remarkably, studies inhibiting mTORC1 activity have shown to disrupt the regenerative capacity of intestinal epithelium and increased susceptibility to colitis while activating mTORC1 had a positive effect. As amino acids potently activate mTORC1, we assessed and found that low dietary protein significantly reduce colonic mTORC1 activation. The newly discovered GAP activity towards Rags (GATOR1 & GATOR2) complexes act as amino acid sensing pathways by which mTORC1 activity is modulated. GATOR1 is a negative regulator, whereas GATOR2 is a positive regulator of mTORC1. CRISPR/CAS9 knockout of Wdr24 (GATOR2) led to inactivation of mTORC1 under amino acid culture conditions. Next, we investigated the role of amino acid sensing pathway in colitis models and found that disruption of intestinal epithelial specific GATOR2 complex (Wdr24ΔIE) attenuated mTORC1 activity and increased susceptibility to colitis. These findings suggest that low protein diet impacts colitis by modulating the intestinal epithelial amino acid sensing pathway.
CORRELATION OF PUCAI BETWEEN MAYO ENDOSCOPIC AND GEBOES PATHOLOGY SCORES IN ASSESSING DISEASE ACTIVITY OF PEDIATRIC PATIENTS WITH UC AMONG HISPANICS AND NON-HISPANICS
Authors: Durazo Francisco , Michail Sonia
Published: January 2022

BACKGROUND

Disease activity in ulcerative colitis (UC) has traditionally been assessed by clinical scoring systems, including the pediatric ulcerative colitis activity index (PUCAI), a non-invasive, reliable way to monitor disease severity and the therapeutic efficacy of interventions in pediatric UC. Practice guidelines have recommended the use of PUCAI in routine clinical pediatric care. Therefore, we aim to investigate the correlation of PUCAI with the endoscopic assessment of disease activity (Mayo endoscopic score) and histologic features of mucosal inflammation (Geboes pathology grading score) in a Hispanic pediatric UC population compared to a non-Hispanic pediatric population.

METHODS

We conducted a retrospective study in pediatric patients aged 7 - 21 with UC enrolled at Children’s Hospital of Los Angeles. We first assess the distribution of the PUCAI, the Mayo, and the Geboes grading scales of disease activity (0=remission, 1=mild, 2=moderate, 3=severe) of the Physician Global Assessment (PGA). Reviewed data was collected directly from the physician report or calculated retrospectively using clinic notes. Although different pathologists graded the samples, the Geboes score is used as a department-wide standard for grading UC. Spearman correlation coefficient was assessed to measure the degree of linear association between two order-valued variables. Bootstrap simulations were used to calculate 95% confidence intervals, and approximate permutation tests were applied to compare these correlations between Hispanics and Non-Hispanics.

RESULTS

In total, 172 patients fit our inclusion criteria. Overall, a modest correlation between PUCAI with the Mayo endoscopic and Geboes pathology grading scores was observed (0.72 and 0.68). The PUCAI-Endoscopic correlations were 0.65 and 0.79 for Hispanics and non-Hispanics, respectively (p-value of difference = 0.084). The correlations between Geboes pathology and PUCAI grading scores were weaker but still larger for non-Hispanics (0.73) than Hispanics (0.64). A linear relationship between PUCAI scores and the two gradings scores, Mayo endoscopy and Geboes pathology, is shown in Figure 1 (p for trend < 0.001).

CONCLUSION

Endoscopic/pathology disease severity generally correlates with clinical disease activity measured by PUCAI score. The PUCAI correlated well with the endoscopy/pathology scores in severe clinical disease, and an agreement was less robust in assessing UC patients’ mild to moderate disease activity. However, the strength of the association varies by ethnic background. Hence, caution should be exercised when using the PUCAI score to assess UC disease activity in Hispanic pediatric patients.
POINT-OF-CARE INTESTINAL ULTRASOUND FOR THE DETECTION OF POSTOPERATIVE CROHN’S DISEASE ENDOSCOPIC RECURRENCE
Authors: Dolinger Michael , Stauber Zachary , Spencer Elizabeth , Kayal Maia , Pittman Nanci , Colombel Jean-Frederic , Dubinsky Marla
Published: January 2022

BACKGROUND

In patients with Crohn’s disease (CD), following an ileocolic resection (ICR), colonoscopy is the gold standard for the detection of endoscopic recurrence (ER). Colonoscopy, however, is invasive and not easily accepted by patients for repeated monitoring. In contrast, transabdominal intestinal ultrasound (IUS) is non-irradiating, non-invasive, and easy to repeat. The goal of this study was to assess the accuracy of IUS for ER in CD.

METHODS

This was a cross-sectional study of CD patients who underwent point-of-care IUS during a postoperative follow-up clinic visit within 30 days of a planned colonoscopy. Parameters on IUS included bowel wall thickness (BWT), bowel wall hyperemia (BWH), layer stratification, inflammatory fat, lymphadenopathy, and complications. C-reactive protein (CRP), fecal calprotectin (FC), endoscopic healing index (EHI) and Harvey Bradshaw Index (HBI) were also measured. ER was defined as a Rutgeerts Score (RS) ≥ i2. Primary outcome was the association between IUS parameters and ER. Secondary outcomes were the association of IUS parameters with other markers of disease activity. Univariable analysis – Fisher’s exact, Wilcoxon Rank Sum and Spearman correlation coefficient tested associations with ER. Area under the receiver operator curve (ROC) was used to determine optimal cut-off values for BWT to accurately identify ER.

RESULTS

Eighteen CD patients (9 female; 29 [19-40] years old), underwent IUS examination 45 [29-99] months post-ICR. All patients underwent endoscopy within 30 days of IUS examination, four (22%) for the first time post-ICR. Seven (39%) patients were on ustekinumab, four (22%) on adalimumab, two (11%) on infliximab, one (6%) on vedolizumab, and four (22%) on no therapy. ER was found in eight (44%) patients. BWT and BWH in the neo-terminal ileum and BWH at the ileocolic anastomosis were the only IUS parameters associated with ER (Table 1). BWT was 4.0 [3.2-4.8] mm in patients with ER vs. 2.0 [1.5-2.6] mm without (p=0.04). Neo-terminal ileum BWH was abnormal in six (75%) patients with ER vs. 0% without (p=0.007). BWT of 3.2 mm was the optimal cut point for predicting ER with an: AUROC of 0.82, positive predictive value of 100%, negative predictive value of 97.3%, sensitivity of 75%, and specificity of 100% (Figure 1) vs. a CRP of 10.4 mg/L (AUROC = 0.54) or FC of 1146 μg/g (AUROC = 0.56). Significant correlations were observed between neo-terminal ileum BWT and RS (ρ=0.51, p=0.04) and between BWT and CRP (ρ=-0.56, p=0.023), but not BWT and FC (ρ=-0.04, p=0.91), BWT and EHI (ρ=-0.04, p=0.91), or BWT and HBI (ρ=0.09, p=0.75).

CONCLUSIONS

IUS is a feasible, accurate, non-invasive monitoring tool for detection of postoperative CD recurrence. Larger prospective studies are needed to determine how IUS can be integrated in the monitoring of CD patients after surgery.
ANEMIA TREATMENT PATTERNS AND OUTCOMES AMONG A NATIONAL COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Brooks Carolyn , Sansgiry Shubhada , Hou Jason
Published: January 2022

BACKGROUND

Anemia is a common complication of inflammatory bowel disease (IBD) and can have a significant negative impact on quality of life by causing fatigue and reduced exercise tolerance. However, system wide patterns of anemia recognition and treatment are lacking. The aim of our study is to identify practice patterns of screening for anemia, assessment of iron stores, and administration of iron repletion therapy among a national cohort of patients with IBD.

METHODS

We conducted a retrospective cohort study of patients with IBD in the national Veterans Affairs (VA) dataset from 2000-2017. IBD patients were identified using a previously validated algorithm using administrative codes for Crohn’s disease (CD) and ulcerative colitis (UC). Laboratory values, patient demographics, and medical treatment data were extracted from the national VA datasets. Anemia was defined as hemoglobin < 13 g/dL in males and < 12g/dL in females. Initial observation of anemia during the study period was considered index anemia date. Analyses were descriptive of proportion of IBD patients with anemia, treatment, or outcomes. Temporal trends were presented as number patients by calendar year.

RESULTS

Of the 89,687 patients with IBD identified from 2000-2017, 50,781 (56%) were found to have anemia at least once during the study period. The number of IBD patients with anemia increased five-fold during the study period from 3,260 to 15,579 unique patients per calendar year. Testing for iron deficiency among patients with anemia was low- only 36% of anemic patients had iron studies completed within 6 months of anemia result. Of anemic patients who completed iron studies, the vast majority (89%) were consistent with iron deficiency anemia. Of patients with low iron stores, only 23% of patients received iron therapy within 6 months of lab result. Of patients with anemia, only 19% had anemia resolve within 1 year. Hospitalization within 5 years was observed in 30% of patients with anemia, with 60% of hospitalizations occurring within 1 year of index anemia date. IBD-associated surgery within 5 years of index anemia date was observed in only 2% of patients.

CONCLUSIONS

In a large national cohort of IBD patients, anemia is a common and undertreated complication, and is frequently followed by hospitalization and steroid use. Although iron deficiency is the most common cause of anemia, adequate iron testing and treatment is lacking, which may contribute to the low rates of anemia resolution. Interventions to improve anemia testing and treatment for iron deficiency anemia are needed.
CHRONIC COLITIS IN MICE INDUCES KIDNEY INJURY: TRANSLATIONAL IMPLICATIONS FOR IBD
Authors: Ducasa Gloria , Hazime Hajar , Fernandez Irina , Brito Nivis , Santander Ana , Burgueno Juan , Abreu Maria
Published: January 2022

Approximately 4-23% of patients with IBD develop renal complications such as nephrolithiasis, glomerulonephritis, and tubulointerstitial nephritis, which may lead to chronic kidney disease (CKD). Furthermore, it has been shown that younger age of IBD diagnosis increases risk for CKD development and this association is not linked to use of common therapeutic agents for the treatment of IBD, suggesting a disease mediated association of IBD to CKD. IBD is characterized by increased intestinal epithelial permeability. Interestingly, recent literature suggests that gut microbiome regulation plays a role in the development of CKD progression. However, the mechanisms contributing to IBD-mediated CKD have yet to be elucidated. We aimed to establish a model of colitis-mediated kidney injury and to elucidate the role of the microbiome on IBD-mediated CKD development.

Two distinct mouse models were used. BL/6 mice were treated with 2% dextran sodium sulfate for 6 days and euthanized, emulating an acute colitis model (A-DSS). We also utilized a chronic colitis model where BL/6 mice underwent three, five-day cycles of 2% dextran sodium sulfate (C-DSS) with a five-day recovery in between each cycle. Spot urines were collected on a weekly basis for albuminuria analysis. Kidneys and intestines were harvested at time of euthanasia. RNA was extracted for gene expression analysis and tissue samples were collected for histological assessment with oil-red-o (ORO) for lipid droplet analysis.

A-DSS mice did not experience any difference in kidney inflammatory markers, although intestinal inflammation was increased, as compared to control mice. A-DSS mice also did not demonstrate any difference in bacterial translocation to the kidney. Conversely, C-DSS mice (n=7) experienced an increase in inflammatory genes (IL1B and TNF) both in RNA extracted from colon and kidney sections as compared to control mice (n=4). C-DSS mice (n=3) demonstrated increased bacterial translocation (p=0.0003) to the kidney which was associated with increased albumin to creatinine ratios (p=0.0076) as compared to control mice (n=3). ORO staining of whole kidney sections demonstrated that C-DSS mice have increased lipid content as compared to control mice.

These data demonstrate that chronic colitis leads to changes in kidney inflammation and physiology seen in renal insufficiency including albuminuria. Furthermore, intestinal inflammation causes increased intestinal epithelial permeability and elevated bacterial translocation to the kidney, which has not been previously described. These data suggest that IBD may increase inflammation in a remote organ possibly through bacterial translocation. Additional studies are underway to identify if this colitis-mediated kidney injury is due to overall bacterial burden or specific bacterial content.
MICROSCOPIC COLITIS IS ASSOCIATED WITH DECREASED BONE DENSITY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Chaisidhivej Natapat , Jaroenlapnopparat Aunchalee , Ponvilawan Ben , Tantivit Nessa , Goldberg Michael E
Published: January 2022

INTRODUCTION

Although, microscopic colitis (MC) can be considered as spectrum of inflammatory bowel disease (IBD), MC is very different in many aspects; in terms of risk factors, symptoms, course of disease, treatment, and complication. Low bone mineral density (BMD) is previously known as complication of IBD. There are few data about MC and risk of bone density loss. We conduct this systematic review and meta-analysis to determine the association between MC and low BMD.

METHODS

A comprehensive literature review was conducted using the MEDLINE, and EMBASE databases through October 2021 to identify studies that demonstrated association between clinical outcomes of interest, MC and low BMD. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method.

RESULTS

After two rounds of review, four studies met our eligibility criteria and were included in analysis. The result showed statistically significant association between MC and low bone density (pooled OR = 2.15, 95% CI: 1.06 - 4.38, p = 0.03) The forest plots and funnel plots are shown below.

CONCLUSIONS

Our meta-analysis found significant association between MC and low bone density. Therefore, this data may suggest that BMD screening could be applied for MC patients, and such patients may have benefit from calcium and vitamin D supplementation. Further studies should be done to determine the significance of this issue.
SEROLOGICAL RESPONSES TO SARS-COV-2 VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE: A PROSPECTIVE COHORT STUDY
Authors: Quan Joshua , Ma Christopher , Panaccione Remo , Kanji Jamil , Tipples Graham , Sharifi Nastaran , van Huyssteen Michelle , Markovinovic Ante , Turnbull LeeAnn , Bindra Gurmeet , Mahoney Douglas , Ingram Richard , Hracs Lindsay , Coward Stephanie , Windsor Joseph , Buie Michael , Chan Melissa , Ferraz Jose , Lu Cathy , Mathivanan Meena , Novak Kerri , Seow Cynthia , Shukla Tushar , Kaplan Gilaad
Published: January 2022

BACKGROUND

The immune response of SARS-CoV-2 vaccines is uncertain in those with Inflammatory Bowel Disease (IBD) due to a diverse array of immune-modifying therapies that vary in the mechanism of immunosuppression.

AIM

We aimed to quantify the serological response to SARS-CoV-2 vaccines in those with IBD and determine antibody levels across varying therapeutic options.

METHODS

Individuals with IBD who received first and/or second dose of a COVID-19 vaccine (Pfizer-BioNTech, Moderna, and/or AstraZeneca) were assessed for serological response (2–4 weeks after first dose; 2–8 weeks after second dose and 8–18 weeks after second dose) using the SARS-CoV-2 IgG II Quant assay to the spike protein of SARS-CoV-2. The cohort was stratified based on age, sex, vaccine received, IBD type, IBD therapeutic, and prior confirmed diagnosis of COVID-19. The primary outcome was seroconversion defined as IgG levels of ≥50 AU/mL. Secondarily, we evaluated the geometric mean titer (GMT) with 95% confidence intervals (CI).

RESULTS

Table 1 describes the characteristics of individuals with IBD (n=464) with serological data following the first dose (n=266) and/or second dose (n=303) of a COVID-19 vaccine. After the first dose of the vaccine, 81.6% seroconverted, with the lowest first-dose conversion rates in patients taking anti-TNF monotherapy (79.7%), anti-TNF combination therapy (52.9%), and corticosteroids (50.0%) (Table 1). Overall, 98.4% of the cohort seroconverted within 2–8 weeks of the second dose, with 94.6% seropositive within 8–18 weeks of the second dose. Seroconversion after second dose was consistently high across all medication classes (range: 94.6%–100.0%), except for oral corticosteroids (62.5%). GMT levels significantly increased (p<0.0001) from first dose (1679 AU/mL) to second dose at 2–8 week (7943 AU/mL) but fell significantly (<0.0001) to 3565 AU/mL 8–18 weeks from second dose (Table 1, Figure 1). GMT levels 2–8 weeks after second dose were higher in those with prior COVID-19 (12,729 AU/mL), but lower in those receiving anti-TNF combination therapy (4231 AU/mL) and oral corticosteroids (5996 AU/mL) (Table 1).

CONCLUSION

Seroconversion rates following full-regimen vaccination are high in patients with inflammatory bowel disease across all medication classes except for anti-TNF combination therapy and oral corticosteroids. Antibody titres and seroconversion rates tend to decrease after 8 weeks post-full vaccination, which is consistent across medication classes.
NEW OXPHOS REGULATING COMPOUND – AUPHOS – INCREASES MITOCHONDRIAL COMPLEXES EXPRESSION IN MURINE AND HUMAN INTESTINAL EPITHELIAL CELLS
Authors: Elsayed Ahmed , Abomhya Ahmed , Avdiushko Margarita , Kapur Neeraj , Awuah Samuel , Barrett Terrence , Goretsky Tatiana
Published: January 2022

INTRODUCTION

Mitochondrial dysfunction in intestinal epithelial cells (IEC) is a critical driver in the failure to heal chronic ulceration in IBD(1). OXPHOS is important for differentiation and cell polarity in repairing IEC(2,3). The development of new IBD drugs that improve mitochondria function would potentially accelerate mucosal repair and enhance overall clinical management of refractory patients. For this study, we tested the efficacy of a novel oral agent (AuPhos) that localized to mitochondria where it increases respiration (Wempe et al CCC, 2022) and mitochondrial energy production.

METHODS

Colonic IEC proteins from control and AuPhos-treated DSS mice were examined as described elsewhere (Wempe et al CCC, 2022). Both human biopsy and tissues from mice with reduced IEC mitochondria [VilCre/mTmG/TFAMfl/fl (IEC-TFAM-/-)](Abomhya et al CCC 2022) were incubated with AuPhos (0.2; 0.5; 1 μM for biopsies and 0.5 μM for mice) or vehicle for 3 hrs. at +4oC with rotation. N=4 mice/group.

RESULTS

In membranous IEC fractions of control mice, AuPhos increased protein expression of mitochondrial complexes (Mito-Cpx) (V – 50%, III – 52%, IV – 40%). DSS treatment decreased baseline expression dramatically (V – 62%, III – 56%, II - 69%; IV – 75%). AuPhos in DSS mice increased expression of complex V by 48%, III – 35%, II – 68%, IV – 55% {A,B}. Expression of transcriptional factors PGC1a and Nrf2, which regulate mitochondria biogenesis, were increased in nuclear IEC fractions of DSS mice by 50% and 43% respectively {C,D}. Mito-Cpx and TFAM levels increased in AuPhos-treated human biopsies in a dose dependent manner {E}. AuPhos normalized mitochondrial complex levels in tissue (3h) taken from mice with attenuated mitochondrial respiration (IEC-TFAM-/-).

CONCLUSION

AuPhos increases expression of mitochondrial complexes in human and in two different murine models. The results of biochemical signaling studies suggest increased mitochondrial respiration enhances PGC1a and Nrf2 levels which are upstream of TFAM, the major transcription factor for mitochondrial biogenesis. Our lab is currently investigating this novel compound as a means for improving mucosal metabolism and accelerating mucosal repair in IBD. (Wempe et al CCC, 2022)

1 Kugathasan, S. et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet389, 1710-1718, doi:10.1016/S0140-6736(1730317-3) (2017).

2 Rodriguez-Colman, M. J. et al. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature543, 424-427, doi:10.1038/nature21673 (2017).

3 Schell, J. C. et al. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol19, 1027-1036, doi:10.1038/ncb3593 (2017).
ALTERED MICROBIAL BIOGEOGRAPHY IN INNATE IMMUNE-MEDIATED COLITIS
Authors: Boger-May Antonia , La Torre Diana La , Ruley-Haase Katelyn , English Lauren , Roncagli Connor , Reed Theodore , Hoffman Hunter , Overstreet Anne-Marie , Boone David
Published: January 2022

We have developed an innate immune model of colitis that occurs in the absence of adaptive immunity, is early-onset, 100% penetrant, chronic, and dependent on microbes. villin-TNFAIP3 transgenic mice, crossed to RAG1-/- mice (aka TRAG mice) develop innate immune-mediated colitis that is not observed in villin-TNFAIP3 or RAG1-/- littermates. Antibiotic treatment prevents colitis in TRAG mice. Thus, we sought to investigate the microbes that drive chronic innate immune colitis in the absence of adaptive immunity. To examine the spatial organization of bacteria, mucus and intestinal epithelium, bacteria and mucus were localized in Methyl-Carnoys-fixed sections of WT, villin-TNFAIP3, RAG1-/- and TRAG colons and mucus layers were collected by laser capture microdissection (LCM) for evaluation of bacterial populations. To test antibiotic effectiveness in colitis prevention, TRAG mice were treated with single antibiotic solutions of ampicillin, neomycin, metronidazole, or vancomycin, or with all antibiotics combined in a cocktail, and colitis was scored along the proximal-distal axis of the colon. Microbial populations along the proximal-distal axis of the gut were compared between RAG1-/- and TRAG mice by 16S sequencing.

Microbial invasion of the mucus layer was abundant in villin-TNFAIP3 and in TRAG mice, but not WT or RAG1-/- mice. LCM indicated that a subset of microbes, of the classes Gammaproteobacteria and Actinobacteria, were over-represented in the mucus layer of TRAG mice. These included increased abundance of genera Serratia, Acinetobacter, Pseudomonas and Corynebacterium and decreased Bifidobacterium. Differences in antibiotic effectiveness were observed along the proximal-distal axis of the colon, with neomycin being most effective in prevention of inflammation in the cecum, while ampicillin was most effective in the distal colon. The proximal-distal communities of microbes in RAG1-/- mice were distinct and tightly grouped within the cecum, proximal colon, and distal colon, whereas this structure was lost in TRAG mice. In the RAG1-/- gut, the relative abundance along the proximal-distal axis decreased for Firmicutes (mainly Lachnospiraceae and Ruminococcacaea) and Proteobacteria (mainly Helicobacteriaceae and Desulfovibrionbacteriaceae) but increased for Actinobacteria (mainly Bifidobacteriaceae) and Bacteroidetes (mainly Bacteroidales). Unlike RAG1-/- mice, in TRAG mice the abundance of Bacteroidetes decreased along the proximal-distal gut axis. TRAG mice had higher abundance of Bifidobacterium animalis, Bacteroidetes acidifaciens and Lactobacilli and lower abundance of Lachnospiraceae, along the proximal-distal axis of the gut, compared to RAG1-/-mice.

The cross-sectional and proximal-distal biogeography of microbes in RAG1-/- mice is disrupted in TRAG mice, which may contribute to the innate colitis observed in this model.
GPX3 IS REQUIRED TO MEDIATE PROTECTIVE EFFECTS OF GPX1 LOSS IN COLITIS
Authors: Blunt Koral , Jacobse Justin , Allaman Margaret , Washington Mary , Goettel Jeremy , Wilson Keith , Williams Christopher , Short Sarah
Published: January 2022

Reactive oxygen species (ROS) have long been known to contribute to the development and severity of Inflammatory Bowel Disease. However, more recent data indicates ROS may not always be pathogenic, and in fact ROS may be necessary for intestinal homeostasis. Thus, the role of ROS in the intestine, and antioxidant proteins which regulate ROS, may be contextual and dose-dependent.

Members of the glutathione peroxidase (GPx) family are antioxidants that reduce hydrogen peroxide to water. Previously, we determined that loss of GPx1, the most widely expressed GPx, protected against dextran sodium sulfate (DSS)-induced colitis and augmented intestinal proliferation. To better understand how a stepwise increase in ROS may affect intestinal phenotypes, Gpx1-/- mice were next crossed with Gpx3 null mice to yield double-knockout (DKO) mice. First, we assessed baseline proliferation, apoptosis, and DNA damage in the colon. Interestingly, while Gpx1-/- mice displayed increased proliferation compared to WT mice, this was not observed in the DKO mice. Furthermore, Gpx1-/- mice had no change in apoptosis or DNA damage, yet both were increased in DKO mice. Together, these data suggest DKO mice lose the survival benefits of GPx1 loss upon greater reduction of antioxidant capabilities.

Next, we assessed the effects of combined GPx1 and GPx3 loss in the context of inflammation and colitis. At baseline, multiplex cytokine profiling identified higher levels of colitis-associated cytokines, including IL-12, CCL4, and CCL5, in DKO mice as compared to either Gpx1-/- or WT cohorts. Pro-inflammatory changes were more pronounced upon aging, as one-year-old DKO mice showed higher levels of TNF-α and IL-17, as well as histologic evidence of chronic inflammation which was absent in similarly aged WT mice. Next, we tested the effects of experimental DSS colitis. Here, while Gpx1-/- mice had less severe injury in the DSS colitis model, DKO mice showed more pronounced weight loss and a trend towards shortened colons as compared to WT mice. Finally, altered ROS-mediated signaling is known to impact interactions with the microbiota, and increased microbial diversity is associated with protection from colitis. To establish whether loss of GPx1 and GPx3 impacted the gut microbiome, stool was harvested from WT, Gpx1-/-, and DKO mice and bacterial DNA was assessed by 16S RNA sequencing. Interestingly, and in line with less severe colitis, Gpx1-/- mice had increased diversity and evenness compared to WT mice, whereas there was no change between WT and DKO mice. Taken together, these data indicate that GPx3 is required to mediate the anti-inflammatory effects of GPx1 loss. Furthermore, combinatorial GPx loss induces greater colonic inflammation at baseline and during DSS-induced colitis, highlighting dose-dependent effects of ROS and antioxidant capacity in the intestine.
NIPEP-IBD; A SYNTHETIC PEPTIDE TARGETING NOVEL MOLECULE, INTEGRIN BETA 1, TO RESTITUTE INTESTINAL EPITHELIAL CELLS FOR INFLAMMATORY BOWEL DISEASE (IBD) TREATMENT
Authors: Kim Deogil , Lee Dong Woo , Jeong Eui Kyun , Lee Hoo Cheol , Park Yoon Shin , Lee Jue Yeon , Chung Chong Pyung , Park Yoon Jeong
Published: January 2022

Under Inflammatory bowel disease (IBD), impaired intestinal barrier from lumen is highly associated with ongoing IBD symptoms and it also contributes as a precursor for IBD. Current IBD therapeutics lack on mucosal regeneration, which the unmet needs could be the next first in class therapeutics for IBD. Here, we propose NIPEP-IBD, a synthetically modified peptide that promotes adhesion, migration, and differentiation of intestinal epithelial cells via interaction of integrin beta 1. From NIBEC’s specialized peptide discovery platform screening, specifically sequenced peptide has been selected for regenerative functional peptide, termed NIPEP-IBD. NIPEP-IBD selectively targeted and bound to integrin beta 1 protein, and its interaction was also verified in vitro, using immunoprecipitation and immunofluorescence assays on epithelial cells. Consequently, NIPEP-IBD increased integrin beta 1 expression, followed by phosphorylated FAK and RhoA proteins. As FAK-RhoA signaling pathway is known to modulate cytoskeletal rearrangement and maturation of epithelial cells, tight junction markers and rapid wound closure of epithelial cells was accelerated by NIPEP-IBD induction. The effect of NIPEP-IBD was further analyzed in vivo IBD model. DSS-induced colitis mouse model was used to analyze therapeutic effect of NIPEP-IBD in each IP and PO administration, and impaired mucosa layer by DSS was recovered by NIPEP-IBD, verified with H&E staining. Moreover, NIPEP-IBD treated mice showed reduced immune cell infiltration in colon tissue and reduced pro-inflammatory cytokines in plasma. In vivo fluorescence imaging system was further used to track distribution of NIPEP-IBD, and NIPEP-IBD specifically binds to impaired epithelium, co-localized with integrin beta 1 protein. The following GLP toxicity studies, ADME studies, and PK studies demonstrated that safety of NIPEP-IBD was verified as a therapeutic agent. Therefore, NIPEP-IBD is a safe and effective therapeutic peptide on IBD patients by restituting epithelial layer of colon and maintain its remission.
SELECTION OF MICROBIOME-DERIVED PEPTIDES THROUGH MULTI-TECHNOLOGY META-ANALYSIS, BINDING, AND FUNCTIONAL ASSAYS, IDENTIFIES PEPTIDES WITH THERAPEUTIC POTENTIAL THAT MODULATE IMMUNE RESPONSES AND DISEASE
Authors: Lin Michelle , Kim Eun Ok , Desnoyer Jill , Narayan Nicole , Ravichandar Jayamary , Lau Sabina , Hwang Bum-Yeol , Johnson Amy Jo , Willcoxon Michi , DeSantis Todd , Dabbagh Karim , Yamamoto Lynn
Published: January 2022

Microbiome-driven drug discovery holds great promise for therapeutic development. However, identification of disease-associated microbiome-host interactions are challenging, owing largely to the complexity of a diverse community and the myriad of direct and indirect interactions through which the microbiome can influence its host. Moreover, inflammatory bowel disease (IBD) is a heterogeneous disease with a complex diagnosis, and multiple etiologies, pathologies, and treatment responses. Finding robust associations between IBD and the microbiome has proven difficult. Using a systematic computational pipeline, we identified bacterially-derived peptides that were consistently increased in non-IBD samples and improved colitis in mouse models. To identify concordant changes in 15 IBD cohorts with 21 datasets, we used a novel multi-technology meta-analysis (MTMA) procedure and a curated reference database (StrainSelect). From these strains’ genomes and from metagenomic assemblies, the encoded bacterial peptides were synthesized and screened to find those which interact with the human immune system. Using phage panning, peptide libraries were assessed in a large scale screen using primary human cells to identify those that bind to our cells of interest such as T cells. Peptides that demonstrated binding were then screened in functional assays to identify bioactive peptides that influence cytokine production. Peptides with strong effects and cross-reacted to mouse cells also showed efficacy in mouse models of IBD. Identification of bioactive peptides demonstrates that a workflow in which i) a standardized computational pipeline is employed to identify peptides that are consistently decreased in IBD patients, ii) peptides are first screened by their ability to bind to cells of interest, and iii) peptides are then screened for functional activity, results in bioactive peptides with therapeutic potential.
THE SYNTHETIC GLYCAN KB295 OPTIMIZES MICROBIOME COMPOSITION AND FUNCTION IN ULCERATIVE COLITIS – RESULTS FROM A PROOF OF PRINCIPLE HUMAN STUDY
Authors: Meisner Jeffrey , Bransford Toni , Miller Kelsey , Lee Jackson , Jose Adarsh , Giuggio Michael , McComb Megan , Humphries Eric , Rosini Madeline , Wingertzahn Mark , Shanahan Fergus , van Hylckama Vlieg Johan E T , Dowling Mark
Published: January 2022

The pathogenesis of ulcerative colitis (UC) involves genetic susceptibility, immune-mediated tissue injury and environmental factors including disturbances of the gut microbiota. Nearly all current approved therapies modify host immunity, rather than directly targeting the microbiota. Fecal microbiota transplantation provides encouraging evidence for the therapeutic potential of gut microbiome modulation. Bacteria in the GI tract are ecologically differentiated by their ability to use specific glycans as growth substrates, making glycans a promising and safe alternative to target the microbiome. To explore this, we used an ex vivo fecal microbiota culture system to identify a synthetic glycan (KB295) with desirable microbiological activity and conducted a proof of principle study of safety and tolerability of KB295 in patients with UC.

Fecal microbial communities from healthy subjects were incubated anaerobically with and without (negative control) KB295. KB295 increased short chain fatty acid (SCFA) production across ten fecal samples to a median concentration of 47.0 mM compared to 15.2 mM with the negative control in culture supernatants, including increases in acetate, propionate, and butyrate in all cases. Metagenomic sequencing of the ex vivo fecal pellets revealed that KB295 depleted pathobionts in the family Enterobacteriaceae to a median relative abundance of 10.8% compared to 38.2% with the negative control. Pathobiont depletion was associated with enrichments of diverse genera in the phyla Bacteroidetes and Firmicutes.

Twelve patients with mild to moderate UC were enrolled in an open-label single-arm study with an 8-week intake of KB295. KB295 was well tolerated with generally mild adverse events, and only one AE resulted in discontinuation. The most frequently occurring adverse events were changes in bowel habit, flatulence, and headache. Fecal calprotectin and lactoferrin decreased by median values of 69.0% (n=11) and 86.0% (n=6), respectively, from screening to the end of the KB295 intake. Consistent with the ex vivo preclinical findings, of the subjects for whom we have data to date, the relative abundance of the fecal pathobiont family Enterobacteriaceae decreased from five participants, and the commensal genus Parabacteroides was enriched in four of five participants.

These results establish a proof of principle for the glycobiological modulation of gut microbiome composition and function and provide insight into the potential utility of this strategy in patients with ulcerative colitis. The safety, tolerability, and encouraging evidence for reduced inflammation with KB295 call for a Phase 2 study, which is planned.
INCIDENTALLY DIAGNOSED ASYMPTOMATIC CROHN’S DISEASE: LONG-TERM CLINICAL OUTCOMES OF UNTREATED PATIENTS
Authors: Grinman Ana , Ungar Bella , Lahat Adi , Kopylov Uri , Eliakim Rami , Ben-Horin Shomron
Published: January 2022

BACKGROUND

Crohn’s disease (CD) is occasionally diagnosed in asymptomatic patients undergoing colonoscopy for other reasons, but their clinical outcomes and optimal management remain poorly defined.

METHODS

A retrospective cohort study of asymptomatic patients with incidental diagnosis of CD. The primary outcome was defined as the occurrence of a clinical flare. Secondary outcomes included time to clinical flare, time to initiation of corticosteroids or immunomodulators/biologics, and rate of surgery.

RESULTS

Of the 2558 patients in Sheba IBD registry, 53 asymptomatic patients with incidental diagnosis of CD were identified (median age 50 (41.75-57), 52% males, 32/53 with L1, 9/53 L2, 11/53 L3,1/53 L4, 41/53 B1, 10/53 B2, 2/53 B3, 1 with perianal disease). Most patients (48/53) did not receive any treatment after diagnosis. Of these untreated patients, 43/48 (89.5%) had not experienced a flare over a median follow-up of 4.5 years (IQR 2-8, range 1-15 years). None of the patients with over 8 years follow-up (n=14) experienced a flare. When comparing the group of patients with or without immediate post-diagnosis initiation of treatment (n=5, n=48, respectively), there was no difference in survival time without flare (p=0.3). Of the 48 patients without immediate treatment, immunomodulators/biologics were initiated in 4(8.3%) during follow-up. Surgery for CD occurred in 2 patients during the follow-up. None of the parameters examined, including age, CRP, ileal versus other locations, or having a complicated phenotype (B2/B3 versus B1) was found to predict a clinical flare later on.

CONCLUSION

Many asymptomatic patients with an incidental diagnosis of Crohn’s disease can probably be followed-up without immediate treatment. Although the majority remain asymptomatic and without complications during follow-up, close monitoring for disease progression is prudent.
INFLAMMATORY BOWEL DISEASE IN APPALACHIA: AN INVESTIGATION INTO DISPARATE OUTCOMES WITHIN THE STATE OF KENTUCKY
Authors: Perry Courtney , Rhudy Christian , Flomenhoft Deborah , Talbert Jeffrey , Barrett Terrence
Published: January 2022

INTRODUCTION

Inflammatory Bowel Disease (IBD) affects an estimated 3.1 million US adults, with an increasing prevalence in recent years1. Of these, 1.1 million live in the CDC classified “Southern” region, which includes the state of Kentucky. The eastern portion of the state is part of the Appalachian region, a low-resourced area with a dense, vulnerable population. The majority of Kentucky’s Appalachian counties are classified as distressed (ranked bottom 10% in the US based on economic development), and suffer a higher prevalence of chronic disease2. To our knowledge, there is no published data quantifying the healthcare burden of IBD or evaluating disease outcomes in this vulnerable community.

METHODS

We utilized the hospital inpatient discharge and outpatient services databases available through the healthcare cost and utilization project (HCUP) to assess outcomes among patients with a diagnosis of either Crohn’s disease (CD) or Ulcerative Colitis (UC) in the state of Kentucky. Outcomes of interest were aggregated at the county level and included number of hospital admissions, number of total outpatient visits and visits to an emergency department, inpatient and outpatient surgeries. Data was reported as number of incident visits per 100,000 population/year, collected between the years 2009-2019.

RESULTS

We found that CD patients residing in Appalachian counties were more likely to be admitted to the hospital (42.72 vs. 29.69, p-value= 0.0001), require inpatient surgery (6.91 vs 5.35, p-value= 0.006), and be admitted for abdominal pain as a complication of their disease (3.82 vs 2.28, p-value = 0.0031) than non-Appalachians. Appalachian CD patients also had a higher number of ER visits (84.06 vs. 52.64, p-value = 0.0102), outpatient surgery visits (161.24 vs 112.35, p-value = 0.0024), and clinic visits for abdominal pain (39.8 vs 24.34, p-value=0.0002) than non-Appalachians. UC patients in Appalachian counties were more likely to require inpatient surgery (1.36 vs 0.74, p-value 0.0007) than non-Appalachians. There was no significant difference in rates of fistula, perforation, or malabsorption in either CD or UC based on Appalachian county data.

CONCLUSION

These data support the notion of disparate outcomes in IBD based on Appalachian county residence in the state of Kentucky. This was most striking when evaluating Crohn’s disease in Appalachians, as evidenced by hospital admissions, surgeries, and ER visits. Appalachian inpatients with UC had a significantly higher rate of surgical resection. These findings highlight a need for aggressive investigation into root causes of these disparate outcomes, with particular attention to identifying and subsequently alleviating barriers to IBD care. Whether these data infer treatment of Appalachian IBD patients should be managed more aggressively earlier in the disease course awaits further investigation.