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Crohn's Disease Forum » Parents of Kids with IBD » Bacteria link between Crohns and spondyloarthritis


05-21-2017, 12:48 PM   #1
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Bacteria link between Crohns and spondyloarthritis


The investigators found that patients with Crohn's disease and spondyloarthritis had higher levels of Th17 cells, and that a protein called IL-23 triggers their activity. With the recent FDA approval of an anti-IL-23 medication for Crohn's disease called ustekinumab, the findings may help physicians select therapies that target symptoms of both the bowels and the joints in these patients, Dr. Longman said.

"Just sequencing the gut flora gives you an inventory of the bacteria, but does not tell you how they are perceived by the host immune system," said co-author Dr. Kenneth Simpson, professor of small animal medicine at Cornell's College of Veterinary Medicine whose laboratory characterized the E. coli identified in the study. "This approach is giving you a functional readout versus just an inventory."

Dr. Longman led the translational study along with co-author Dr. Ellen Scherl, director of the Roberts Center at NewYork-Presbyterian and Weill Cornell Medicine and the Jill Roberts Professor of Medicine at Weill Cornell Medicine, in collaboration with HSS rheumatologists and co-authors Dr. Lisa Mandl and Dr. Sergio Schwartzman. Initial funding for the work was provided by a Cornell University and Weill Cornell Medicine pilot seed grant to foster collaborations between researchers in Ithaca and New York City, and has since been funded by the New York Crohn's Foundation, the Charina Endowment Fund, the Center for Advanced Digestive Care, the Jill Roberts Institute for Research in IBD, and the National Institutes of Health.

"We knew there was smoke but we didn't know where the fire was," said Dr. Simpson, who added that each collaborator provided unique expertise to uncover the findings. "If we can block the ability of bacteria to induce inflammation, we may be able to kick Crohn's disease and spondyloarthritis into remission."

"In IBD therapy, this is a step toward precision medicine -- to be able to clinically and biologically characterize a subtype of disease and then select the medicine that would best fit the patient with this type of inflammation," Dr. Longman added. "The results of this innovative study will start to inform our decision of which of our available medications will give the best chance of helping the individual patient."

From
https://www.sciencedaily.com/release...0209133304.htm
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05-21-2017, 12:54 PM   #2
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NEW YORK (Reuters Health)—An adherent-invasive E. coli pathotype present in the bowel may contribute to the development of Crohn’s disease-associated spondyloarthritis, researchers say.

“Clinical symptoms, including extra-intestinal manifestations, in Crohn’s disease offer a portal into the microbial, immune, and genetic mechanisms underlying disease pathogenesis,” Dr. Randy S. Longman from Weill Cornell Medical College in New York City tells Reuters Health.

“Our work highlights the potential role for host-microbe interactions that drive systemic inflammation in Crohn’s-associated peripheral spondyloarthritis,” he says.

Alterations in the intestinal microbiome seen in inflammatory bowel disease have suggested a role for the microbiome as a driver of systemic inflammation, Dr. Longman and colleagues note in Science Translational Medicine, online on Feb. 8. But the microbiome in Crohn’s disease-associated spondyloarthritis (SpA) has not been well characterized, they add.1

The team used a recently developed technique (IgA-seq), which couples the sorting of IgA-coated microbiota with 16S ribosomal RNA sequencing, to characterize the microbiome of 59 Crohn’s disease patients with and without SpA.

Although there were no significant differences in overall microbiome diversity between patients with and without SpA, there was a positive correlation between SpA and Proteobacteria and Enterobacteriaceae abundance.

IgA-seq revealed a significant enrichment of E. coli that were similar in genotype and phenotype to an adherent-invasive E. coli (AIEC) pathotype.

Although these AIEC did not induce overt intestinal disease in a mouse model, despite robust colonization, they were broadly adherent to the epithelial mucosa.

Intestinal colonization with these Crohn’s disease-SpA-derived AIEC promoted mucosal Th17 immunity, induced systemic Th17 immunity, and promoted joint inflammation.

“In addition, our study found the presence of a virulence gene called pduC in AIEC isolates from patients with CD-SpA,” Dr. Longman explains. “This gene allows these bacteria to forage for fucose metabolites abundant in the intestinal mucous layer and promote close association with the epithelial layer. When we genetically knock out this gene in one of our isolates, we prevent these bacteria from inducing Th17 cells. This exciting finding highlights a potential bacterial metabolic pathway that can be therapeutically targeted to alter Th17 induction.”

“Importantly, our work highlights the activation of the IL-23/Th17 pathway in patients with Crohn’s disease-associated peripheral spondyloarthritis,” he says. “With the recent approval of anti-IL-23 biologic therapy in Crohn’s disease, our findings may offer a guide for helping to select biologic therapy.”

Dr. Laurent Dubuquoy from Lille Inflammation Research International Center at Lille University in France, who studies chronic bowel inflammation and inflammatory joint disease, tells Reuters Health by email, “The pathogenic mechanisms induced by AIEC are far from clear despite the clear demonstration of its importance in [Crohn’s disease] pathophysiology.”



“The main message for physicians should be to focus less on microbiota changes but focus more on host response to this intestinal flora, at least in the context of inflammatory bowel diseases [IBD] and their extraintestinal complications,” Dr. Dubuquoy concludes. “This should help to choose more-targeted therapies.”

“Early detection of this immune response against AIEC appears an interesting marker to predict extraintestinal complication of [Crohn’s disease],” he adds. “This should allow the earlier use of targeted therapy and then increase its efficacy.”

From


http://www.the-rheumatologist.org/ar...loarthritis/2/
05-21-2017, 12:56 PM   #3
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Peripheral spondyloarthritis (SpA) is a common extraintestinal manifestation in patients with active inflammatory bowel disease (IBD) characterized by inflammatory enthesitis, dactylitis, or synovitis of nonaxial joints. However, a mechanistic understanding of the link between intestinal inflammation and SpA has yet to emerge. We evaluated and functionally characterized the fecal microbiome of IBD patients with or without peripheral SpA. Coupling the sorting of immunoglobulin A (IgA)-coated microbiota with 16S ribosomal RNA-based analysis (IgA-seq) revealed a selective enrichment in IgA-coated Escherichia coli in patients with Crohn's disease-associated SpA (CD-SpA) compared to CD alone. E. coli isolates from CD-SpA-derived IgA-coated bacteria were similar in genotype and phenotype to an adherent-invasive E. coli (AIEC) pathotype. In comparison to non-AIEC E. coli, colonization of germ-free mice with CD-SpA E. coli isolates induced T helper 17 cell (TH17) mucosal immunity, which required the virulence-associated metabolic enzyme propanediol dehydratase (pduC). Modeling the increase in mucosal and systemic TH17 immunity we observed in CD-SpA patients, colonization of interleukin-10-deficient or K/BxN mice with CD-SpA-derived E. coli lead to more severe colitis or inflammatory arthritis, respectively. Collectively, these data reveal the power of IgA-seq to identify immunoreactive resident pathosymbionts that link mucosal and systemic TH17-dependent inflammation and offer microbial and immunophenotype stratification of CD-SpA that may guide medical and biologic therapy.


From

https://www.ncbi.nlm.nih.gov/m/pubmed/28179509/
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