Cause Of Crohn Research Articles

Personalized Medicine In Chron's Disease

Crohn's disease is an autoimmune disease that has no complete cure. Although the disease has no cure, there are many different ways to treat it. The cause of Crohn's disease is not entirely known yet. However, researchers suspect that a mutation in the NOD2 gene causes Crohn's, and they have found many statistics to prove that the Nucleotide Binding Oligomerization DomainCcontaining 2 (NOD2) is the reason for Crohn's. Many other genes contribute to the cause of Crohn’s, but for this research paper, NOD2 is the main focus. NOD2 is a crucial gene in the immune system; because of its vital role, a mutation in this gene can have many effects. This paper will first discuss Crohn's and why NOD2 is essential. A popular and emerging topic in the field of medicine is personalized medicine. Personalized medicine is using or changing an individual's gene to help treat or cure the disease the individual is fighting. This paper will explore the details of personalized medicine and its different types. Personalization transforms the field of healthcare since perspectives are changing. Instead of everyone getting the same medication no matter how their body reacts to it, personalized medicine can provide a unique and personal treatment for the disease. To conclude, the paper will address and analyze the effect of personalized medicine on Crohn's disease and its impact.

A261 INVESTIGATING THE RELATIONSHIP BETWEEN AIR POLLUTION AND BIOMARKERS OF CROHN’S DISEASE IN CANADA

Abstract Background The cause of Crohn's disease (CD) remains unclear. Studies suggest a potential connection between CD and air pollution, with a higher occurrence of CD found in areas with higher pollution levels. Aims Our study sought to explore this potential connection by investigating the relationship between components of air pollution and biomarkers indicative of CD risk. Methods In total, 2,256 healthy first-degree relatives of patients with CD were recruited as part of the CCC-GEM Project. We assessed baseline samples of gut permeability using the urinary fractional excretion ratio of lactulose-to-mannitol (LMR), subclinical inflammation via fecal calprotectin (FCP), and stool microbiome using 16S-rRNA sequencing. Air pollutant (n=8) concentrations were obtained from the National Air Pollution Surveillance Database. We used postal code to estimate air pollutant exposure via inverse distance weighting, averaging data for one (pollutant1-month), three (pollutant3-months), and twelve months (pollutant12-months) prior to recruitment. We used generalized estimating equation models to find associations between pollutant exposure and LMR, FCP, and microbiome composition, adjusting for age, sex, air pollutant seasonality, familial income, and familial relationships. Significance was set at pampersand:003C0.05, and false discovery rate (q) correction was applied to microbiome analysis. Results We observed a negative association between particulate matter (PMµg/m3), PM101-month, and PM103-months and LMR (β=-0.06[-0.09, -0.01], p=6.0×10-3 and β=-0.05[-0.07, -0.01], p=7.6×10-4), and a positive association between PM103-months and FCP (β=0.05[0.001, 0.10], p=0.04). 12-month pollutant exposure was associated with seven microbial taxa in a logit model. Notably, Carbon monoxide (CO)12-months was associated with Oscillospiraceae UCG_003 (β=3.49[1.53, 5.46], q=0.03). PM2512-months was associated with Marvinbryantia (β=0.12[0.06, 0.18], q=0.02). PM1012-months was associated with Moryella (β=0.07[0.03, 0.10], q=0.02). Nitrogen dioxide (NO)12-months was associated with Coprobacter and Ruminococcaceae UBA1819 (β=0.05[0.02, 0.07], q=0.03 and β=0.05[0.02, 0.08], q=0.04). NOX12-months was also associated with Ruminococcaceae_UBA1819 as well as Intestinimonas (β=0.03[0.01, 0.04], q=0.04 and β=0.03[0.01, 0.04], q=0.02). Conclusions Air pollutant exposure was associated with biomarkers of gut inflammation, barrier function, and microbiome composition. A shorter exposure (1/3 months) primarily affected FCP and LMR, while longer-term exposure (12 months) exerted a discernible impact on the microbiome. These findings suggest that exposure to air pollution may modulate the gut barrier function, inflammation, and the gut microbiome, biomarkers that are associated with the development of CD. Funding Agencies Crohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Leona M. and Harry B. Helmsley Charitable Trust, Dr. Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases

P321 Development and validation of an Integrated Risk Score for future risk of Crohn’s disease in healthy first-degree relatives: The CCC-GEM Project, a multicentre prospective cohort study

Abstract Background Although the cause of Crohn’s disease (CD) is unknown, recent studies have identified a number of biomarkers associated with the risk of developing CD in healthy at-risk individuals. Establishing a combined prediction model that stratifies the future risk of CD in healthy at-risk individuals is the first step towards disease prevention and a better understanding of the preclinical phase of CD. Methods We recruited healthy first-degree relatives (FDRs) of persons with CD from 2008-2017 as part of the global multicenter prospective Crohn’s and Colitis Canada Genetic Environmental Microbial (CCC-GEM) Project. After collecting demographic information, blood, urine, and stool samples at recruitment, participants were followed for the development of CD. A GEM-integrative risk score (GEM-IRS), using random survival forest modeling that combined the baseline variables (demographics, measures of gut inflammation – fecal calprotectin, intestinal barrier function – urinary fractional excretion ratio of lactulose to mannitol, and fecal microbiome composition and predicted functional capacities – based upon 16S rDNA sequencing and PICRUSt2) to estimate time-to-CD onset, was derived and subsequently validated in two independent testing cohorts. Results Among 2,619 FDRs followed for a median of 6.8 years, 61 (2.3%) developed CD. The GEM-IRS, developed on the training cohort (n= 1,170), upon validation, showed a c-statistic of 0.789 in the pooled-testing cohorts (0.786 in the North American Testing cohort (n=1,141) and 0.804 in the Israeli Cohort (n=308)). The 4th quartile group compared to the rest had significantly increased risk of CD (hazard ratio [HR] 6.42, 95% confidence interval [CI], 3.10-13.30) in the pooled-testing cohorts (HR 5.89, 95% CI, 2.70-12.85 in North American Testing cohort; HR 10.7, 95% CI 1.24-92.65 in Israeli cohort). Furthermore, the GEM-IRS predicted CD in pre-specified subgroups of FDRs with minimal subclinical inflammation (fecal calprotectin<50 ug/g) or normal barrier function measures (lactulose/mannitol ratio<0.025), and up to 7 years before diagnosis in the pooled-testing cohort. Conclusion The GEM-IRS, which includes biomarkers of gut inflammation, intestinal barrier function, and the gut microbiome, is a valid risk stratification tool for predicting future development of CD in healthy first-degree relatives of persons with CD. The score may be used to guide preventative care for healthy first-degree relatives.

Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn’s disease

BackgroundDisrupted intestinal epithelial barrier is one of the major causes of Crohn’s disease (CD). Novel molecular targets for intestinal epithelial barrier are essential to treatment of CD. Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is an adhesion molecule that regulates cell adhesion, migration, and enterocyte differentiation. However, the function and mechanism of TMIGD1 in CD and intestinal epithelial barrier has rarely been studied. Furthermore, the association between TMIGD1 and the clinical features of CD remains unclear.MethodsTranscriptome analysis on colonic mucosa from CD patients and healthy individuals were performed to identify dysregulated genes. Multi-omics integration of the 1000IBD cohort including genomics, transcriptomics of intestinal biopsies, and serum proteomics identified the association between genes and characteristics of CD. Inflammation was assessed by cytokine production in cell lines, organoids and intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice. Epithelial barrier integrity was evaluated by trans-epithelium electrical resistance (TEER), paracellular permeability, and apical junction complex (AJC) expression. Co-immunoprecipitation, GST pull-down assays, mass spectrometry, proteomics, and transcriptome analysis were used to explore downstream mechanisms.ResultsMulti-omics integration suggested that TMIGD1 was negatively associated with inflammatory characteristics of CD. TMIGD1 was downregulated in inflamed intestinal mucosa of patients with CD and mice colitis models. Tmigd1INT-KO mice were more susceptible to chemically induced colitis. In epithelial cell lines and colonic organoids, TMIGD1 knockdown caused impaired intestinal barrier integrity evidenced by increased paracellular permeability and reduced TEER and AJC expression. TMIGD1 knockdown in intestinal epithelial cells also induced pro-inflammatory cytokine production. Mechanistically, TMIGD1 directly interacted with cytoplasmic BAF nuclear assembly factor 1 (BANF1) to inhibit NF-κB activation. Exogenous expression of TMIGD1 and BANF1 restored intestinal barrier function and inhibited inflammation in vitro and in vivo. TMIGD1 expression predicted response to anti-TNF treatment in patients with CD.ConclusionsOur study demonstrated that TMIGD1 maintained intestinal barrier integrity and inactivated inflammation, and was therefore a potential therapeutic target for CD.

Gut Microbiome Composition Is Associated With Future Onset of Crohn’s Disease in Healthy First-Degree Relatives

The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P= .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

Sarcoidosis, Mycobacterium paratuberculosis and Noncaseating Granulomas: Who Moved My Cheese.

Clinical and histological similarities between sarcoidosis and tuberculosis have driven repeated investigations looking for a mycobacterial cause of sarcoidosis. Over 50 years ago, "anonymous mycobacteria" were suggested to have a role in the etiology of sarcoidosis. Both tuberculosis and sarcoidosis have a predilection for lung involvement, though each can be found in any area of the body. A key histopathologic feature of both sarcoidosis and tuberculosis is the granuloma-while the tuberculous caseating granuloma has an area of caseous necrosis with a cheesy consistency; the non-caseating granuloma of sarcoidosis does not have this feature. This article reviews and reiterates the complicity of the infectious agent, Mycobacterium avium subsp. paratuberculosis (MAP) as a cause of sarcoidosis. MAP is involved in a parallel story as the putative cause of Crohn's disease, another disease featuring noncaseating granulomas. MAP is a zoonotic agent infecting ruminant animals and is found in dairy products and in environmental contamination of water and air. Despite increasing evidence tying MAP to several human diseases, there is a continued resistance to embracing its pleiotropic roles. "Who Moved My Cheese" is a simple yet powerful book that explores the ways in which individuals react to change. Extending the metaphor, the "non-cheesy" granuloma of sarcoidosis actually contains the difficult-to-detect "cheese", MAP; MAP did not move, it was there all along.

Ursolic Acid and Solasodine as Potent Anti-Mycobacterial Agents for Combating Paratuberculosis: An Anti-Inflammatory and In Silico Analysis.

Mycobacterium avium subspecies paratuberculosis (MAP) infection in domestic livestock causes persistent diarrhea, weight loss, and death and is also a potential cause of Crohn's disease (CD) in humans; notably, treatments against MAP are insufficient, costly, and can cause adverse reactions. Hence, plant-derived bioactive constituents have been taken into consideration in this regard. Herein, we present the results of two bioactive constituents (Solasodine and Ursolic acid) that were evaluated for their safety and efficacy against MAP protein (Dephospho-Coenzyme A kinase (DPCK) by utilizing in vitro assays and different tools of in silico biology. The ADME/t-test, the drug-likeness property test, pharmacophore modelling, and PASS prediction have proven that both the constituents have better binding capacities than the available antibiotic drugs used to target protein inhibition pathways. Through our observations, it can be inferred that these two phytochemicals can be adequately used to treat paratuberculosis, thereby combating inflammatory bowel disorders (IBD) of an autoimmune nature.

Causes of Crohn's Disease

Crohn’s Disease is a type of inflammatory bowel disease that affects the small intestine. The causes of Crohn’s Disease are not fully known, but research has shown that the main causes are an immune response due to the overproduction of signaling molecules, environmental factors and lifestyle, and a person’s genetics/microbial environment. A hyper-inflammatory immune response causing immune cells to attack intestinal epithelial cells due to the overproduction of cytokines can result in discomfort for the patient and can even cause perforations in the intestinal epithelial layer. There has also been work that shows a correlation between a person’s diet and the development of Crohn’s Disease. Diets containing high levels of fat and sugar have been shown to negatively affect the small intestine, whereas diets high in fiber have prompted protective effects against Crohn’s Disease. Additionally, smoking has been shown to have adverse effects on the small intestine since the inhaled chemicals can break down the protective mucosal layer, leaving the epithelial cells in the intestine more susceptible to damage and inflammation. Crohn’s Disease has also been found in patients who have decreased biodiversity in the small intestine. Lastly, genetics have been shown to hold a significant link in the prevalence of Crohn’s Disease. In this review, we will discuss the mechanisms behind the key causes of Crohn’s Disease as well as discuss future research into Crohn’s Disease, focusing more on finding biological cures to the disease to prevent it from being passed down.

Cannabinoid Receptor 2 (CB2) Inverse Agonist SMM-189 Induces Expression of Endogenous CB2 and Protein Kinase A That Differentially Modulates the Immune Response and Suppresses Experimental Colitis.

The causes of Crohn’s disease (CD) and ulcerative colitis (UC), the two most common forms of inflammatory bowel disease (IBD), are multi-factorial and include dysregulation of immune cells in the intestine. Cannabinoids mediate protection against intestinal inflammation by binding to the G-protein coupled cannabinoid receptors 1 and 2 (CB1 and CB2). Here, we investigate the effects of the CB2 inverse agonist SMM-189 on dextran sodium sulfate (DSS)-induced experimental colitis. We observed that SMM-189 effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis, and increased both body weight and colon length. Treatment with SMM-189 also increased the expression of CB2 and protein kinase A (PKA) in colon lamina propria lymphocytes (LPLs). We noticed alterations in the percentage of Th17, neutrophils, and natural killer T (NKT) cells in the spleen, mesenteric lymph nodes (MLNs), and LPLs of mice with DSS-induced colitis after treatment with SMM-189 relative to DSS alone. Further, myeloid-derived suppressor cells (MDSCs) during colitis progression increased with SMM-189 treatment as compared to DSS alone or with control cohorts. These findings suggest that SMM-189 may ameliorate experimental colitis by inducing the expression of endogenous CB2 and PKA in LPLs, increasing numbers of MDSCs in the spleen, and reducing numbers of Th17 cells and neutrophils in the spleen, MLNs, and LPLs. Taken together, these data support the idea that SMM-189 may be developed as a safe novel therapeutic target for IBD.

Warm, Sweetened Milk at the Twilight of Immunity - Alzheimer's Disease - Inflammaging, Insulin Resistance, M. paratuberculosis and Immunosenescence.

This article prosecutes a case against the zoonotic pathogen Mycobacterium avium ss. paratuberculosis (MAP) as a precipitant of Alzheimer’s disease (AD). Like the other major neurodegenerative diseases AD is, at its core, a proteinopathy. Aggregated extracellular amyloid protein plaques and intracellular tau protein tangles are the recognized protein pathologies of AD. Autophagy is the cellular housekeeping process that manages protein quality control and recycling, cellular metabolism, and pathogen elimination. Impaired autophagy and cerebral insulin resistance are invariant features of AD. With a backdrop of age-related low-grade inflammation (inflammaging) and heightened immune risk (immunosenescence), infection with MAP subverts glucose metabolism and further exhausts an already exhausted autophagic capacity. Increasingly, a variety of agents have been found to favorably impact AD; they are agents that promote autophagy and reduce insulin resistance. The potpourri of these therapeutic agents: mTOR inhibitors, SIRT1 activators and vaccines are seemingly random until one recognizes that all these agents also suppress intracellular mycobacterial infection. The zoonotic mycobacterial MAP causes a common fatal enteritis in ruminant animals. Humans are exposed to MAP from contaminated food products and from the environment. The enteritis in animals is called paratuberculosis or Johne’s disease; in humans, it is the putative cause of Crohn’s disease. Beyond Crohn’s, MAP is associated with an increasing number of inflammatory and autoimmune diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis, multiple sclerosis, and rheumatoid arthritis. Moreover, MAP has been associated with Parkinson’s disease. India is one county that has extensively studied the human bio-load of MAP; 30% of more than 28,000 tested individuals were found to harbor, or to have harbored, MAP. This article asserts an unfolding realization that MAP infection of humans 1) is widespread in its presence, 2) is wide-ranging in its zoonosis and 3) provides a plausible link connecting MAP to AD.

Revealing immune responses in the Mycobacterium avium subsp. paratuberculosis-infected THP-1 cells using single cell RNA-sequencing.

Mycobacterium avium subsp. paratuberculosis (MAP) is a causative agent of Johne’s disease, which is a chronic and debilitating disease in ruminants. MAP is also considered to be a possible cause of Crohn’s disease in humans. However, few studies have focused on the interactions between MAP and human macrophages to elucidate the pathogenesis of Crohn’s disease. We sought to determine the initial responses of human THP-1 cells against MAP infection using single-cell RNA-seq analysis. Clustering analysis showed that THP-1 cells were divided into seven different clusters in response to phorbol-12-myristate-13-acetate (PMA) treatment. The characteristics of each cluster were investigated by identifying cluster-specific marker genes. From the results, we found that classically differentiated cells express CD14, CD36, and TLR2, and that this cell type showed the most active responses against MAP infection. The responses included the expression of proinflammatory cytokines and chemokines such as CCL4, CCL3, IL1B, IL8, and CCL20. In addition, the Mreg cell type, a novel cell type differentiated from THP-1 cells, was discovered. Thus, it is suggested that different cell types arise even when the same cell line is treated under the same conditions. Overall, analyzing gene expression patterns via scRNA-seq classification allows a more detailed observation of the response to infection by each cell type.

Risk of ulcerative colitis and Crohn's disease in smokers lacks causal evidence.

Smoking has been associated with opposing risks of ulcerative colitis and Crohn's disease. Whether these observational associations reflect actual causal associations, confounding, or reverse causation is unclear. Using a Mendelian randomization approach, we tested the hypothesis that smoking protects against ulcerative colitis and is a cause of Crohn's disease. We included 118,683 white Danes aged ≥ 20 from the Copenhagen General Population Study (2003-2015) and the Copenhagen City Heart Study (1991-94 and 2001-03). During follow-up until 2018, we investigated the association of smoking and CHRNA3 rs1051730, where the T-allele is strongly associated with nicotine dependence, with risk of ulcerative colitis and Crohn's disease. We identified 1312 cases of ulcerative colitis and 671 cases of Crohn's disease. Compared to never-smokers, multivariable adjusted hazard ratios (HRs) for ulcerative colitis were 1.69(95% confidence interval [CI] 1.32-2.15) in former smokers and 2.27(1.74-2.96) in current smokers. Corresponding HRs for Crohn's disease were 1.31(0.93-1.84) and 1.93(1.34-2.78), respectively. Among ever-smokers when compared to non-carriers of the CHRNA3 rs1051730 T-allele, age and sex adjusted HRs for risk of ulcerative colitis were 1.03(95%CI 0.89-1.18) in heterozygotes and 0.91(0.72-1.16) in homozygotes. Corresponding HRs for Crohn's disease were 1.05(0.87-1.28) and 1.02(0.74-1.41), respectively. In a meta-analysis combined with UK Biobank, there was no evidence that CHRNA3 rs1051730 was associated with risk of ulcerative colitis or Crohn's disease. In conclusion, current versus never-smoking was associated with unexpected 2.3-fold risk of ulcerative colitis and expected 1.9-fold risk of Crohn's disease in prospective analyses; however, genetic evidence of lifelong increased smoking intensity did not support causal relationships.

Novel NR4A1 Arg293Ser Mutation in Patients With Familial Crohn's Disease.

The underlying etiology of Crohn's disease remains unknown. The aim of this study was to identify genomic alterations associated with the development of Crohn's disease in one Japanese family with a family history of Crohn's disease. We performed whole-exome sequence and pedigree analysis of a Japanese family in which both sisters developed Crohn's disease. Whole-exome sequencing was performed using the Ion Torrent Proton™ system. Data from the Proton runs were initially processed using the Ion Torrent platform-specific pipeline software Ion Reporter. An autosomal dominant mode of inheritance was assumed, and stringent selection criteria were applied. A substitution in the NR4A1 gene at codon 293 resulting in an amino acid change from arginine to serine was identified only in the affected sisters. The impaired DNA-binding capacity of the NR4A1 protein due to an NR4A1 germline mutation may be a possible cause of Crohn's disease.

An Overview on Resistivity, Diagnostic Challenges and Zoonotic Significance of: Mycobacterium avium ssp. paratuberculosis (MAP)

Background: Mycobacterium avium ssp. paratuberculosis (MAP) is a gram-positive, contagious, rod-shaped intracellular pathogen. Methods: MAP is the etiologic agent of Johne’s disease in cattle, and has tremendous economic effect in the ruminant industry. Simultaneously, the MAP has also been suspected as a cause of Crohn’s disease in humans. Results: There has been a challenge in the diagnosis of MAP due to its long incubation period, unknown pathogenesis & cross-reactivity among its closely related sub-species. The survival of MAP inside the host macrophages & monocytes, is still unclear. Resistivity & survival of MAP in the outside environment is also high. Conclusion: Thus, more research about its pathogenesis, control, and potential role as a zoonotic pathogen must be carried out in future.

Crohn’s disease

Crohn's disease is an inflammatory bowel disease that is characterized by chronic inflammation of any part of the gastrointestinal tract, has a progressive and destructive course and is increasing in incidence worldwide. Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown. Theonset of the disease at a young age in most cases necessitates prompt but long-term treatment to prevent disease flares and disease progression with intestinal complications. Thus, earlier, more aggressive treatment with biologic therapies or novel small molecules could profoundly change the natural history of the disease and decrease complications and the need for hospitalization and surgery. Although less invasive biomarkers are in development, diagnosis still relies on endoscopy and histological assessment of biopsy specimens. Crohn's disease is a complex disease, and treatment should be personalized to address the underlying pathogenetic mechanism. In the future, disease management might rely on severity scores that incorporate prognostic factors, bowel damage assessment and non-invasive close monitoring of disease activity to reduce the severity of complications.

Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases.

Bacille Calmette–Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli’s ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis of ruminant animals and is the putative cause of Crohn’s disease of humans. MAP has been associated with an increasingly long list of inflammatory/autoimmune diseases: Crohn's, sarcoidosis, Blau syndrome, Hashimoto’s thyroiditis, autoimmune diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, lupus and Parkinson’s disease. Epidemiologic evidence points to BCG providing a “heterologous” protective effect on assorted autoimmune diseases; studies using BCG vaccination for T1D and MS have shown benefit in these diseases. This article proposes that the positive response to BCG in T1D and MS is due to a mitigating action of BCG upon MAP. Other autoimmune diseases, having a concomitant genetic risk for mycobacterial infection as well as cross-reacting antibodies against mycobacterial heat shock protein 65 (HSP65), could reasonably be considered to respond to BCG vaccination. The rare autoimmune disease, relapsing polychondritis, is one such disease and is offered as an example. Recent studies suggesting a protective role for BCG in Alzheimer’s disease are also explored. BCG-induced energy shift from oxidative phosphorylation to aerobic glycolysis provides the immunomodulating boost to the immune response and also mitigates mycobacterial infection—this cellular mechanism unifies the impact of BCG on the disparate diseases of this article.

Cows Get Crohn's Disease and They're Giving Us Diabetes.

Increasingly, Johne’s disease of ruminants and human Crohn’s disease are regarded as the same infectious disease: paratuberculosis. Mycobacterium avium ss. paratuberculosis (MAP) is the cause of Johne’s and is the most commonly linked infectious cause of Crohn’s disease. Humans are broadly exposed to MAP in dairy products and in the environment. MAP has been found within granulomas such as Crohn’s disease and can stimulate autoantibodies in diseases such as type 1 diabetes (T1D) and Hashimoto’s thyroiditis. Moreover, beyond Crohn’s and T1D, MAP is increasingly associated with a host of autoimmune diseases. This article suggests near equivalency between paucibacillary Johne’s disease of ruminant animals and human Crohn’s disease and implicates MAP zoonosis beyond Crohn’s disease to include T1D.

Identifying Crohn\u2019s disease signal from variome analysis

BackgroundAfter years of concentrated research efforts, the exact cause of Crohn’s disease (CD) remains unknown. Its accurate diagnosis, however, helps in management and preventing the onset of disease. Genome-wide association studies have identified 241 CD loci, but these carry small log odds ratios and are thus diagnostically uninformative.MethodsHere, we describe a machine learning method—AVA,Dx (Analysis of Variation for Association with Disease)—that uses exonic variants from whole exome or genome sequencing data to extract CD signal and predict CD status. Using the person-specific coding variation in genes from a panel of only 111 individuals, we built disease-prediction models informative of previously undiscovered disease genes. By additionally accounting for batch effects, we were able to accurately predict CD status for thousands of previously unseen individuals from other panels.ResultsAVA,Dx highlighted known CD genes including NOD2 and new potential CD genes. AVA,Dx identified 16% (at strict cutoff) of CD patients at 99% precision and 58% of the patients (at default cutoff) with 82% precision in over 3000 individuals from separately sequenced panels.ConclusionsLarger training panels and additional features, including other types of genetic variants and environmental factors, e.g., human-associated microbiota, may improve model performance. However, the results presented here already position AVA,Dx as both an effective method for revealing pathogenesis pathways and as a CD risk analysis tool, which can improve clinical diagnostic time and accuracy. Links to the AVA,Dx Docker image and the BitBucket source code are at https://bromberglab.org/project/avadx/.

Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity.

The fruitless search for the cause of Crohn's disease has been conducted for more than a century. Various theories, including autoimmunity, mycobacterial infection and aberrant response to food and other ingested materials, have been abandoned for lack of robust proof. This review will provide the evidence, obtained from patients with this condition, that the common predisposition to Crohn's is a failure of the acute inflammatory response to tissue damage. This acute inflammation normally attracts large numbers of neutrophil leucocytes which engulf and clear bacteria and autologous debris from the inflamed site. The underlying predisposition in Crohn's disease is unmasked by damage to the bowel mucosa, predominantly through infection, which allows faecal bowel contents access to the vulnerable tissues within. Consequent upon failure of the clearance of these infectious and antigenic intestinal contents, it becomes contained, leading to a chronic granulomatous inflammation, producing cytokine release, local tissue damage and systemic symptoms. Multiple molecular pathologies extending across the whole spectrum of the acute inflammatory and innate immune response lead to the common predisposition in which defective monocyte and macrophage function plays a central role. Family linkage and exome sequencing together with GWAS have identified some of the molecules involved, including receptors, molecules involved in vesicle trafficking, and effector cells. Current therapy is immunosuppressant, which controls the symptoms but accentuates the underlying problem, which can only logically be tackled by correcting the primary lesion/s by gene therapy or genome editing, or through the development of drugs that stimulate innate immunity.

Serological and molecular evaluation of Mycobacterium avium subspecies paratuberculosis (Johne's disease) infecting riverine-type water buffaloes (Bubalus bubalis) in the Philippines.

Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne's disease and a possible cause of Crohn's disease in humans. A total of 70 blood and fecal samples were collected from water buffaloes in selected municipalities of Nueva Ecija for ELISA and qPCR assay. Results revealed presence of antibodies of MAP in 3 serum samples for ELISA. The qPCR assay was carried out using standard curve method targeting the MAP specific insertion element IS900. Results revealed that 10 of the samples were positive for MAP DNA in qPCR. ELISA was able to detect antibodies for MAP showing 2.48% infection rate among the 70 buffaloes tested using blood serum samples. On the other hand, qPCR was able to detect MAP using IS900 showed 14.28% infection rate among buffaloes tested using fecal samples. Nucleotide sequence of isolated MAP showed high homology (99-100%) among the reported MAP isolates in the GenBank.