Cytokines and Biologic Therapy in Patients with Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders, including Crohns’ disease (CD) and ulcerative colitis (UC), both characterized by a clinical relapsing course and an immune-mediated pathogenesis [...]

Serological Response to BNT162b2 and ChAdOx1 nCoV-19 Vaccines in Patients with Inflammatory Bowel Disease on Biologic Therapies; A Multi-Center Prospective Study

Introduction Immunogenicity of SARS-CoV-2 vaccines in patients with inflammatory bowel disease (IBD) on biologics are not well studied. The goal of this study is to measure serological response to BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD receiving different biologic therapies. Method We performed a multi-center prospective study between August 1st, 2021, and September 15th, 2021. We measured seropositivity of SARS-CoV2 antibodies, SARS-CoV-2 IgG and neutralizing antibody concentrations, in patients with IBD receiving biologic therapies between 4-10 weeks after second dose or 3-6 weeks after first dose of vaccination with BNT162b2 or ChAdOx1 nCoV-19 vaccines. Results There were 126 patients enrolled (mean age, 31 years; 60% male; 71% Crohns disease, 29% ulcerative colitis). 92 patients were vaccinated with BNT162b2 vaccine (73%) and 34 patients with ChAdOx1 nCoV-19 vaccine (27%). The proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving 2 doses of the vaccine in patients treated with infliximab and adalimumab were 44 out of 59 patients (74.5%) and 13 out of 16 patients (81.2%), respectively. Whereas the proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving two doses of the vaccine in patients treated with ustekinumab and vedolizumab were 100% and 92.8%, respectively. In patients receiving infliximab and adalimumab, the proportion of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels after two-dose vaccination was 40 out of 59 patients (67.7%) and 14 out 16 patients (87.5%), respectively. Whereas the proportions of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels were 12 out of 13 patients (92.3%) and 13 out of 14 patients (92.8%) in patients receiving ustekinumab and vedolizumab. Conclusion: The majority of patients with IBD on infliximab, adalimumab, and vedolizumab seroconverted after two doses of SARS-CoV-2 vaccination. All patients on ustekinumab seroconverted after two doses of SARS-CoV-2 vaccine. BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 are both likely to be effective after two doses in patients with IBD on biologics. A follow up larger studies are needed to evaluate if decay of antibodies occurs over time.

Military Aviators with Inflammatory Bowel Diseases Continued Flying

INTRODUCTION: Military aviators are likely to be first diagnosed with inflammatory bowel diseases (IBD) during military service. Current recommendations support continuing flying with restrictions, but risks may be significant. The aim of the study was to document the long-term results of aviators newly diagnosed with IBD. METHODS: A prospective observational study over a 23-yr period included all Israeli Air Force (IAF) aviators with IBD. Primary end point was the qualification and safety to continue operational flying following IBD diagnosis. RESULTS: Subjects were 16 male aviators with an average follow-up of 130 mo. Average age was 27 (2045) and average time from symptoms onset to final diagnosis was 7.3 mo. Eight (50%) patients had Crohns disease (CD), and the other eight had ulcerative colitis (UC). Eight (50%) were high performance platform aviators. Two patients received biologic treatment, two were treated with repeated corticosteroid courses, and four with immunosuppressive therapy. Two patients underwent surgery and four needed different lengths of hospitalizations. Eight (50%) aviators (3 CD, 5 UC) were grounded for a mean of 177 d (5590). Altogether grounding for IBD aviators was 46/2087 mo (2.2%). Most grounding periods were short term and reversible. All aviators continued flying under annual monitoring or as needed and no compromise of their abilities was documented. CONCLUSIONS: All aviators were able to continue flying and no events of sudden incapacitation or severe disabling flares have been seen among patients. Our study findings support the current recommendation to continue flying when IBD is in stable remission. Tehori O, Koslowsky B, Gabbai D, Shapira S, Ben-Ari O. Military aviators with inflammatory bowel diseases continued flying. Aerosp Med Hum Perform. 2021; 92(10):831834.

Identification of topoisomerase as a precision-medicine target in chromatin reader SP140-driven Crohns disease

How mis-regulated chromatin directly impacts human immunological disease is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing chromatin reader whose loss-of-function associates with Crohns disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). However, mechanisms underlying SP140-driven pathogenicity and therapeutic approaches that rescue SP140 remain unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOP) that maintains heterochromatin and immune cell fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, genome instability, severely compromised lineage-defining and microbe-inducible innate transcriptional programs and defective bacterial killing. Pharmacological inhibition of TOP1 or TOP2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1 or TOP2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a repressor of topoisomerases and reveal repurposing of TOP inhibition as a precision strategy for reversing SP140-driven immune disease.

Pharmacotherapy of inflammatory bowel diseases: efficacy performance and safety management

Treatment of inflammatory bowel diseases IBD (Crohns disease, ulcerative colitis) is aimed at achieving clinical, endoscopic and histological remission, minimizing surgical complications, and ensuring a normal quality of life. However, the use of medical treatment is potentially associated with various adverse events, among which infectious complications, malignant neoplasms, as well as myelotoxicity, hepatotoxicity, skin lesions and others. The risk of side effects depends on the type of drug therapy (5-aminosalicylates, thiopurines, biologicals, etc.), the duration of treatment, the presence of extra-intestinal manifestations, etc. The article provides an overview of data on both the effectiveness and frequency of various side effects of the main classes of drugs in IBD, presents methods of investigation which can predict the effectiveness and development of side effects, the implementation of which can be considered as a variant of personalized therapy in IBD.

Quantifying the antimicrobial activity of CRISPR-Cas9-accA modified ΔB. subtilis mutants against V. harveyi and E. Coli

Probiotics are increasingly popular, currently. Probiotics have been described with the ability to treat many disorders of the gastrointestinal tract (GIT) such as irritable bowel syndrome (IBS)and Crohns disease. Types of probiotics include bacterial strains from Lactobacillus and Bifidobacterium. Probiotics can restore balance to gut microbiota by outcompeting pathogenic bacteria for nutrients and secrete antimicrobials to eliminate these bacterial pathogens. However, the viability of most advertised probiotics lose their potency due to being freeze dried into powders during storage or for consuming. Many probiotics become ineffective and produce lower CFUs while traversing through the gastric acids of the digestive system. For these reasons, this study sought to enhance the antimicrobial response of a highly potent probiotic known as Bacillus subtilis. B. subtilis has been used to treat many disorders of the gut and secrete many antimicrobials lethal for pathogenic microbes. B. subtilis was genetically modified to express CRISPR-Cas9 nuclease deletion of the accA gene B.subtilis mutants, which inhibits expression of an essential accA gene a part of the fatty acid synthesis (FAS) metabolic pathway. The CRISPR-Cas9-accA B.subtilis mutants were co-cultured with V. harveyi and E. Coli. Bacterial growth, biofilm formation, antimicrobial activity, and antibiotic resistance were quantified. It was found that B. subtilis mutants co-cultured with V. harveyi and E. Coli lessened bacterial growth, amplified biofilm with V. harveyi, reduced biofilm formation of E. Coli, the co-cultures with the mutants lacked antimicrobial activity, and increased the antibiotic resistance of V. harveyi and E. Coli. It can be concluded that there is an immense potential for using genetically engineered probiotic strains to enhance the antimicrobial activity of B. subtilis, which can amplify the reduction of pathogenic bacteria. However, the safety and frugality of using B. subtilis as a probiotic requires further consideration.

COMPREHENSIVE ANALYSIS OF TOLL-LIKE RECEPTORS IN ULCERATIVE COLITIS AND CROHNS DISEASE

Болезнь внутреннего восприятия (язвенный колит и болезнь Крона) является основной проблемой гастроэнтерологии. Они характеризовались неизвестной этиологией, сложным патогенезом, рецидивом с рецидивами по течению по жизни и часто приводящим к инвалидности. Вместе с тем, особенности этих заболеваний в Казахстане остаются слабо изученным направлением, анализ патологии носит исключительно характерный характер. Internal perception disease (ulcerative colitis and Crohn's disease) is the main problem of gastroenterology. They were characterized by an unknown etiology, complex pathogenesis, relapse with relapses throughout life and often leading to disability. At the same time, the features of these diseases in Kazakhstan remain poorly studied, the analysis of pathology is extremely characteristic.

Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD); however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequence data from more than 30,000 CD cases and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

Adolescent autism and autoimmune diagnoses linked to infant gut bacteria whose prevalence is associated with at-risk genetics and/or diet

The earliest predictors of future autoimmune diseases are a series of autoantibodies that are rarely evaluated and very within and between diseases. In addition, autoantibodies often appear just prior to disease onset. All of these factors make it difficult to apply interventions that might prevent disease. Earlier predictors of disease are needed. Here, a general population cohort was used to assess whether gut bacterial biomarkers could be identified prior to disease. Gut microbiome analysis on 1,741 one-year old Swedish children was performed on samples collected in the late 1990s. These children were then followed for 18 years for the incidence of five autoimmune diseases and autism. Specific bacterial strains in the gut microbiome of one-year-old children have been identified as exclusive to the 96 subjects (cases) who acquired type 1 diabetes, celiac disease, hypothyroidism, Crohns disease, juvenile idiopathic arthritis, or autism over their next 18 years. None of these strains were found in the 1,645 children (controls) who did not acquire any of these diseases. Ten other strains were exclusive to those who remained disease-free. In most cases, the presence or absence of these bacteria were strongly associated with: 1) high-risk class II human leukocyte antigen (HLA) alleles; 2) dietary factors; or 3) a combination of HLA genetics and diet. These results have three significant implications: 1) certain class II HLA haplotypes may serve as bacterial gatekeepers early in life, altering microbiome composition thereby creating the potential for dysbiosis and inflammation; 2) the gut microbiome dysbiosis and inflammation during infancy, largely derived from host HLA genetics and diet, may be a common precedent to all five autoimmune diseases and autism; and 3) HLA gatekeeping may prevent gut colonization of beneficial bacteria in those genetically at-risk individuals who could most benefit from probiotic therapy.