A mysterious feature of Crohn’s disease (CD) is the extra-intestinal manifestation of “creeping fat” (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum . Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.

No abstract

Background Mucosal expression of IFN-γ plays a pivotal role in IBD pathogenesis and IBD-risk regions flank IFNG. The conserved IFNG rs1861494 T/C, introduces a new CpG methylation site, and is associated with disease severity and lack of therapeutic response in other infectious and immune mediated disorders, and is in linkage-disequilibrium with a UC disease severity region. It seems likely that CpG-altering SNPs modify methylation and gene expression. This study evaluated the association between rs1861494 and clinical, serologic and methylation patterns in IBD patients. Methods Peripheral T cells of UC and CD patients were genotyped for rs1861494 and analyzed for allele-specific and IFNG promoter methylation. Serum ANCA and IFN-γ secretion were measured by ELISA and nucleo-protein complex formation by EMSA. Results IFNG rs1861494 T allele carriage in IBD patients was associated with enhanced secretion of IFN-γ. T allele carriage was associated in UC with high levels of ANCA and faster progression to colectomy. In CD, it was associated with complicated disease involving a stricturing/penetrating phenotype. Likewise, IFNG rs1861494 displayed genotype specific modulation of DNA methylation and transcription factor complex formation. Conclusions This study reports the first association of IFNG rs1861494 T allele with enhanced IFN-γ secretion and known IBD clinical parameters indicative of more aggressive disease, as well as serological markers associated with treatment resistance to anti-TNF therapy in IBD patients. These data may be useful prognostically as predictors of early response to anti-TNF therapy to identify IBD patients for improved personalized therapeutics.

Our results may help to optimize the use of anti-TNF agents in clinical practice and position these therapies appropriately as clinicians strive for a more personalized approach to managing IBD.

Angiotensin-Converting Enzyme 2 (ACE2) has been identified as the host receptor for SARScoronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn's disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased ACE2 mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. ACE2 was downregulated in CD compared to controls in independent cohorts. Within CD, ACE2 expression was reduced in inflamed ileal tissue and also remarkably, from un-involved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel ACE2 expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that ACE2 downregulation is associated with inflammation and worse outcomes in CD. Methods Tissue Samples and Study SubjectsWe investigated association of ACE2 mRNA with age at collection, gender, smoking, BMI, diagnosis, CD sub-phenotypes and cytokine levels in 4 independent transcriptomic datasets of SB gene expression contingent on availability of meta-data for each cohort (see Table 1). Three of these cohorts have been described previously. In all 4 cohorts the small bowel specimens were taken from macroscopically normal appearing tissue.The 'SB139' [13] dataset was generated using whole Human Genome 4x44k Microarrays (Agilent) from formalin fixed paraffin embedded (FFPE) tissue taken from the unaffected margin of SB tissue resected during ileo-cecal or SB resection for complicated CD. Median age at time of surgery, which were all performed at Cedars-Sinai Medical Center, Los Angeles, was 32 years. The 'WashU' dataset [14] was generated by RNA-seq and similarly was generated from FFPE tissue from the unaffected proximal margin of resected CD tissues and also from FFPE from non-IBD control subjects. These subjects had a median age of 51 years at time of surgery which were all performed at the University of Washington, St Louis. The 'RISK' [15, 16] dataset was generated by RNA-seq from ileal biopsies taken from pediatric subjects in a CD inception cohort from multiple centers across North America (median age at time of biopsy 12 years). Being an inception cohort the age of diagnosis and age at specimen collection are the same. The CD subjects in RISK cohort were divided into two groups: those that had no small bowel/ileal disease (cCD) and those where the ileum was involved (iCD). The 'Cedars100' [17] dataset has not been previously published but similarly, utilized FFPE from un-involved proximal resection margins from complicated CD surgeries (performed at Cedars-Sinai Medical Center) and transcriptomics were generated by RNA-seq. All study subjects in SB139 and Cedars100 were CD; the WashU cohort consisted of CD and non-IBD controls and RISK cohort is a mix of CD, UC, and non-IBD controls.In addition we looked at the effect ...