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Ulcerative colitis surgery may create new target for disease

Wed, 02/03/2021 - 09:40
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A surgical procedure meant to counter ulcerative colitis, may trigger a second immune system attack, a study by researchers at NYU Grossman School of Medicine has reported. Colon tissue damaged by the disease is routinely addressed with a "J-pouch" procedure wherein a pouch is surgically constructed from nearby, healthy small intestine tissue to replace the damaged section of the colon. The procedure is designed to restrain the inflammatory attack on the colon, but more than half of these patients, unfortunately, go on to develop inflammation in the J-pouch (pouchitis).

Led by researchers at NYU Grossman School of Medicine, the study showed that some immune cells attacking the colon in ulcerative colitis are the same types attacking the J-pouch. Several varieties of immune cells were found swarming both organs in numbers as high as five times those seen in healthy tissue.

"Our findings suggest that since ulcerative colitis and pouchitis are biologically similar, they may be treated by the same drugs, even though the diseases originate in different parts of the gut," explained study co-lead author, Dr Jordan Axelrad, assistant professor in the Department of Medicine at NYU Langone Health. He added that starting with the most promising drugs can give medical providers a head start at combating pouchitis and avoiding complications from delayed treatment.

For their study, ‘Single Cell Transcriptional Survey of Ileal-Anal Pouch Immune Cells from Ulcerative Colitis Patients’, published in the journal Gastroenterology, the researchers analysed tissues from patients with and without pouchitis and from patients with ulcerative colitis using single-cell RNA sequencing (scRNA-seq) to define how the intestinal immune system is distinctly organised during pouchitis.

They examined pouch lamina propria CD45+ hematopoietic cells from intestinal tissues of ulcerative colitis patients with (n=15) and without an ileal pouch-anal anastomosis (n=11). Further in silico meta-analysis was performed to generate transcriptional interaction networks and identify biomarkers for patients with inflamed pouches.

They also analysed the gene activity of 56,000 individual cells using an experimental method called RNA sequencing and claim it is the most detailed analysis of the pouchitis cellular immune response to date, and enabled them to track step-by-step genetic activity in a single cell in any given moment.

"Since using this RNA-sequencing technique has improved our understanding of treatment options for one kind of inflammatory bowel disease, we can likely use it to assess how effective treatments are for related issues like Crohn's disease," explained study co-senior author, Dr Ken Cadwell, associate professor in the Skirball Institute of Biomolecular Medicine at NYU Langone.

In addition to tissue-specific signatures, they identified a population of IL1B/LYZ+ myeloid cells and FOXP3/ BATF+ T cells that distinguish inflamed tissues which they further validated in other single cell RNA-seq datasets from inflammatory Bowel Disease patients. Cell type specific transcriptional markers obtained from single-cell RNA-sequencing was used to infer representation from bulk RNA sequencing datasets, which further implicated myeloid cells expressing IL1B and S100A8/A9 calprotectin as interacting with stromal cells, and Bacteroidiales and Clostridiales bacterial taxa. They found that non-responsiveness to anti-integrin biologic therapies in ulcerative colitis patients was associated with the signature of IL1B+/ LYZ+ myeloid cells in a subset of patients.

Cadwell cautions that since the investigation focused only on immune cells, it remains unclear how other cells within the J-pouch, such as those that make up the organ's lining, may behave during pouchitis. He added that the research team plans to evaluate the same patients before and after J-pouch surgery to see how the immune cell landscape changes over time as inflammation develops.

"With our newfound understanding of pouchitis, we can also begin to uncover why some people develop it in the first place and how to prevent it," noted study co-lead author,  Joseph Devlin, a doctoral candidate at NYU.

Devlin added that overall, inflammatory bowel diseases progress over time and often resist treatment. By removing a colon damaged by ulcerative colitis, surgeons hope to give the body a chance to start over with fresh tissue unaffected by the disease. As a result, experts were unclear why the new J-pouch would develop an immune reaction.