SUMMARY Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA−SEQ) and show that high IgA−coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA−SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with pre-defined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA−coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

Highlights Pig peripheral neuritis trauma model mimics cutaneous human pathologies. Pig skin anatomically similar to humans, unlike rodent. Pig PNT model provides better data than rodent for translational pain research.

CB 2 cannabinoid receptors (CB 2 ) are a promising therapeutic target that lacks unwanted side effects of CB 1 activation. However, the cell types expressing CB 2 that mediate these effects remain poorly understood. We used transgenic mice with CB 2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB 2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. Structurally distinct CB 2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB 2 EGFP reporter mice with established neuropathy. Antiallodynic effects of AM1710 were blocked by SR144528, a CB 2 antagonist with limited CNS penetration. Intraplantar AM1710 administration suppressed paclitaxel-induced neuropathic nociception in CB 2 EGFP but not CB 2 knockout mice, consistent with a local site of antiallodynic action. mRNA expression levels of the anti-inflammatory cytokine interleukin-10 were elevated in the lumbar spinal cord after intraplantar AM1710 injection along with the proinflammatory cytokine tumor necrosis factor alpha and chemokine monocyte chemoattractant protein-1. CB 2 EGFP , but not wildtype mice, exhibited anti-GFP immunoreactivity in the spleen. However, the anti-GFP signal was below the threshold for detection in the spinal cord and brain of either vehicle-treated or paclitaxel-treated CB 2 EGFP mice. EGFP fluorescence was coexpressed with CB 2 immunolabeling in stratified patterns among epidermal keratinocytes. EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB 2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.

Background There are limited data on how vedolizumab (VDZ) impacts extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD). The aim of this study was to determine the clinical outcomes of EIMs after initiation of VDZ for patients with IBD. Methods A multicenter retrospective study of patients with IBD who received at least 1 dose of VDZ between January 1, 2014 and August 1, 2019 was conducted. The primary outcome was the rate of worsening EIMs after VDZ. Secondary outcomes were factors associated with worsening EIMs and peripheral arthritis (PA) specifically after VDZ. Results A total of 201 patients with IBD (72.6% with Crohn disease; median age 38.4 years (interquartile range, 29-52.4 years); 62.2% female) with EIMs before VDZ treatment were included. The most common type of EIM before VDZ was peripheral arthritis (PA) (68.2%). Worsening of EIMs after VDZ occurred in 34.8% of patients. There were no statistically significant differences between the worsened EIM (n = 70) and the stable EIM (n = 131) groups in term of age, IBD subtype, or previous and current medical therapy. We found that PA was significantly more common in the worsening EIM group (84.3% vs 59.6%; P < 0.01). Worsening of EIMs was associated with a higher rate of discontinuation of VDZ during study follow-up when compared with the stable EIM group (61.4% vs 44%; P = 0.02). Treatment using VDZ was discontinued specifically because of EIMs in 9.5% of patients. Conclusions Almost one-third of patients had worsening EIMs after VDZ, which resulted in VDZ discontinuation in approximately 10% of patients. Previous biologic use or concurrent immunosuppressant or corticosteroid therapy did not predict EIM course after VDZ.