N ew York City is the epicenter of the US coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with local population infection rates estimated at 25%. 1 The impact of COVID-19 on patients with inflammatory bowel disease (IBD) within an epicenter is not well understood. Our study aims were to compare clinical outcomes between COVID-19 patients with and without IBD and to investigate the prevalence and risk factors of COVID-19 in IBD patients.
A lthough patients with inflammatory bowel disease (IBD) reported an increased frequency of gastrointestinal (GI) symptoms following infection, 1,2 the durable impact of COVID-19 on IBD activity and the microbiome is not well defined. Our study aims were to compare clinical, endoscopic, and laboratory markers of disease activity and the fecal microbiome in IBD participants 6 months pre-and post-COVID-19.
Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via programmable Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for multiplexed detection of exposure and response to thousands of microbial protein products. Here we designed and constructed a library of 95,601 56 amino acid peptide tiles spanning a subset of environmental proteins more likely to be associated with immune responses: those with "toxin" or "virulence factor" keyword annotations. PhIP-Seq was used to profile the circulating antibodies of ~1,000 individuals against this "ToxScan" library of 14,430 toxins and virulence factors from 1,312 genera of organisms. In addition to a detailed analysis of six commonly encountered human commensals and pathogens, we study the age-dependent stability of the ToxScan profile and use a genome-wide association study (GWAS) to find that the MHC-II locus modulates the selection of bacterial epitopes. We detect previously described anti-flagellin antibody responses in a Crohn's disease cohort and identify a novel association between anti-flagellin antibodies and juvenile dermatomyositis (JDM). PhIP-Seq with the ToxScan library provides a new window into exposure and immune responses to environmental protein toxins and virulence factors, which can be used to study human health and disease at cohort scale.
Background Bacterial constituents of the intestinal microbiota can contribute to local and systemic inflammatory diseases. Crohn's disease (CD), a type of inflammatory bowel disease, can result in extraintestinal manifestations (EIM) including peripheral (CD-SpA) and axial spondyloarthritis (CD-AxSpA). Microbial contributors to CD pathogenesis can be identified by flow cytometric sorting and 16S sequencing of bacteria recognized by mucosal IgA. We expand this technique by incubating fecal samples with autologous sera, capturing bacterial species recognized by circulating IgG in a process called IgG-seq. We hypothesize that these systemically-recognized enteric bacteria are linked to development of CD-EIM. Methods Fecal samples from individuals with CD were sorted into IgG-positive and negative populations. DNA was extracted from each population, 16S sequencing performed, and sequences processed with QIIME2. Intestinal coating index (ICI) was calculated at the genus level. Serum cell-free DNA sequencing (cfDNA) was performed for a subset of samples. Results IgG-seq was conducted on 86 CD, 41 CD-SpA, and 16 CD-AxSpA samples. PCoA analysis demonstrates significant differences in microbiome composition in the three groups (P = 0.013, PERMANOVA). Relative abundances of Escherichia-Shigella and Ruminococcus are positively correlated with joint disease activity. Analysis of IgG ICI for genera present in > 10% of patients demonstrates overrepresentation of Ruminococcus, Escherichia-Shigella, and Bacteroides in IgG-recognized fractions. IgG recognition of bacteria does not cluster specifically by CD or EIM severity. cfDNA sequencing demonstrates no Ruminococcus DNA in serum, whereas E. coli DNA was detected in multiple patient sera. Conclusion IgG-seq is a robust method for identifying immune-reactive enteric bacteria; our results highlight the link between immune response to enteric bacterial genera, such as Escherichia-Shigella and Ruminococcus, and joint disease activity in CD-SpA and CD-AxSpA. While Escherichia-Shigella may induce immunity by breaching the mucosal barrier, the absence of Ruminococcus in serum cfDNA suggests immune activation at barrier sites. Further studies are needed to characterize the strain-specific features that underlie our findings. Disclosures Fardina Malik, MD, Pfizer: Advisor/Consultant Iwijn de Vlaminck, PhD, GenDX: Advisor/Consultant|GenDX: Board Member|Kanvas Biosciences: Board Member|Kanvas Biosciences: Ownership Interest|Karius Inc.: Board Member|Karius Inc.: Ownership Interest|Viracor Eurofins: Advisor/Consultant Randy S. Longman, MD, PhD, Pfizer: Advisor/Consultant.
Spondyloarthritis (SpA) is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD). Sulfasalazine (SAS) is one of the earliest medications used in IBD and its efficacy in spondyloarthritis is thought to depend on its antibacterial properties. Therefore, our study aims to diagnostically evaluate the role for the fecal microbiome in clinical response to SAS and identify microbial and immunologic therapeutic targets associated with clinical response. We have longitudinally followed IBD-SpA patients subjected to SAS therapy. Clinical data, including validated IBD and joint disease activity scores, and fecal samples from 19 patients were collected at baseline and at week 2 and 12 after SAS initiation. Metagenomic sequencing was used to define the effect of SAS on the IBD-SpA fecal microbiome and to evaluate its relationship with joint symptoms improvement. Gnotobiotic mouse models were used to test the sufficiency of the SAS effect observed in patients. Fecal microbiome of SAS-responders was distinct from that of non-responders and 6 pre-treatment microbial markers (including Faecalibacterium prausnitzii) predicted SAS-response (AUC: 0.9). SPF mice and germ-free mice colonized with patient microbiota revealed that SAS selectively reduced mucosal-associated bacteria. Gnotobiotic mouse models revealed a critical role for A. muciniphila in modulating mucosal inflammation. Our study reveals the ability of SAS to selectively target mucosal-associated bacteria and modulate the inflammatory impact of IBD-SpA associated pathobionts. This study highlights the potential use of microbial-based diagnostic tools to improve drug efficacy and therapeutic strategies for IBD-SpA.
Joint inflammation (spondyloarthritis, SpA), is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD), but the specific role for therapies targeting SpA is not well defined. Sulfasalazine (SAS) is a prodrug composed of two chemical moieties, 5-aminosalicylate and the anti-folate antibiotic sulfapyridine, with efficacy in peripheral arthritis. Our study aims to evaluate the role for the gut microbiome in clinical response of SpA to SAS and to define microbial mechanisms targeted by SAS. We longitudinally follow IBD patients with SpA who have a medical indication for SAS therapy. Clinical data and fecal samples from 22 patients were collected before initiation of SAS and at week 12 after initiation of SAS. The fecal microbiome of SAS-responders was distinct from that observed in non-responders and 6 pre-treatment microbial markers (including the short chain fatty acid (SCFA) producer Faecalibacterium prausnitzii) predicted SAS-response (AUC=0.9). Fecal metabolome of SAS responders had lower thymine and higher deoxyuridine compared to non-responders consistent with evidence of a folate trap in response to SAS treatment. SAS therapy in SPF mouse-model of chemically-induced colitis alleviated colitis in GPR 109a- and 43-dependent fashion consistent with a synergistic role for SCFA. In vitro and in vivo models revealed SAS direct regulation of F. prausnitzii transcription and metabolic function and its impact on host immune response. Collectively, these findings highlight the potential role for microbial diagnostics to improve SAS efficacy, and drug modulation of microbial markers to potentiate therapy for IBD patients with SpA. Supported by New York Crohn's Foundation
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