From the Journals

Cellular gene profiling may predict IBD treatment response

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These insights are an important start

Inflammatory bowel diseases are complex and heterogenous disorders driven by inappropriate immune responses to luminal substances, including diet and microbes, resulting in chronic inflammation of the gastrointestinal tract. Therapies for IBD largely center around suppressing immune responses; however, given the complexity and heterogeneity of these diseases, consensus on which aspect of the immune response to suppress and which cell type to target in a given patient is unclear.

Dr. Sreeram Udayan is with the division of gastroenterology in the department of medicine at Washington University, St. Louis.

Dr. Sreeram Udayan

In this study, Jacobsen et al. profiled CD11b+ lamina propria phagocytes from biopsy specimens of patients with IBD and identified genes differentially expressed depending on the inflammation status (uninflamed vs. inflamed), tissue type (colon vs. ileum), and the type of IBD (ulcerative colitis vs. Crohn’s disease). This study is notable in that it studied CD11b+ cells from the gut, as opposed to many studies examining circulating cellular populations, and evaluated the response of these resident populations to emerging therapies for IBD. The authors find that even in patients refractory to anti-TNF-alpha therapy, the most common biologic used for IBD, CD11b+ cellular populations can be modulated, and inflammatory responses suppressed with Janus kinase inhibitors in in vitro studies, which suggests that this may be a therapeutic approach for this difficult-to-treat patient population. Beyond these objective observations, this study also could foreshadow future approaches to use intestinal biopsies to tailor immunotherapies for personalized therapy for IBD particularly in difficult to treat refractory cases.

Sreeram Udayan, PhD, and Rodney D. Newberry, MD, are with the division of gastroenterology in the department of medicine at Washington University, St. Louis.


 

FROM GASTRO HEP ADVANCES

Transcriptomic profiling of phagocytes in the lamina propria of patients with inflammatory bowel disease (IBD) may guide future treatment selection, according to investigators.

Mucosal gut biopsies revealed that phagocytic gene expression correlated with inflammatory states, types of IBD, and responses to therapy, lead author Gillian E. Jacobsen a MD/PhD candidate at the University of Miami and colleagues reported.

In an article in Gastro Hep Advances, the investigators wrote that “lamina propria phagocytes along with epithelial cells represent a first line of defense and play a balancing act between tolerance toward commensal microbes and generation of immune responses toward pathogenic microorganisms. ... Inappropriate responses by lamina propria phagocytes have been linked to IBD.”

To better understand these responses, the researchers collected 111 gut mucosal biopsies from 54 patients with IBD, among whom 59% were taking biologics, 72% had inflammation in at least one biopsy site, and 41% had previously used at least one other biologic. Samples were analyzed to determine cell phenotypes, gene expression, and cytokine responses to in vitro Janus kinase (JAK) inhibitor exposure.

Ms. Jacobsen and colleagues noted that most reports that address the function of phagocytes focus on circulating dendritic cells, monocytes, or monocyte-derived macrophages, rather than on resident phagocyte populations located in the lamina propria. However, these circulating cells “do not reflect intestinal inflammation, or whole tissue biopsies.”

Phagocytes based on CD11b expression and phenotyped CD11b+-enriched cells using flow cytometry were identified. In samples with active inflammation, cells were most often granulocytes (45.5%), followed by macrophages (22.6%) and monocytes (9.4%). Uninflamed samples had a slightly lower proportion of granulocytes (33.6%), about the same proportion of macrophages (22.7%), and a higher rate of B cells (15.6% vs. 9.0%).

Ms. Jacobsen and colleagues highlighted the absolute uptick in granulocytes, including neutrophils.

“Neutrophilic infiltration is a major indicator of IBD activity and may be critically linked to ongoing inflammation,” they wrote. “These data demonstrate that CD11b+ enrichment reflects the inflammatory state of the biopsies.”

The investigators also showed that transcriptional profiles of lamina propria CD11b+ cells differed “greatly” between colon and ileum, which suggested that “the location or cellular environment plays a marked role in determining the gene expression of phagocytes.”

CD11b+ cell gene expression profiles also correlated with ulcerative colitis versus Crohn’s disease, although the researchers noted that these patterns were less pronounced than correlations with inflammatory states

“There are pathways common to inflammation regardless of the IBD type that could be used as markers of inflammation or targets for therapy.”

Comparing colon samples from patients who responded to anti–tumor necrosis factor therapy with those who were refractory to anti-TNF therapy revealed significant associations between response type and 52 differentially expressed genes.

“These genes were mostly immunoglobulin genes up-regulated in the anti–TNF-treated inflamed colon, suggesting that CD11b+ B cells may play a role in medication refractoriness.”

Evaluating inflamed colon and anti-TNF refractory ileum revealed differential expression of OSM, a known marker of TNF-resistant disease, as well as TREM1, a proinflammatory marker. In contrast, NTS genes showed high expression in uninflamed samples on anti-TNF therapy. The researchers noted that these findings “may be used to build precision medicine approaches in IBD.”

Further experiments showed that in vitro exposure of anti-TNF refractory samples to JAK inhibitors resulted in significantly reduced secretion of interleukin-8 and TNF-alpha.

“Our study provides functional data that JAK inhibition with tofacitinib (JAK1/JAK3) or ruxolitinib (JAK1/JAK2) inhibits lipopolysaccharide-induced cytokine production even in TNF-refractory samples,” the researchers wrote. “These data inform the response of patients to JAK inhibitors, including those refractory to other treatments.”

The study was supported by Pfizer, the National Institute of Diabetes and Digestive and Kidney Diseases, the Micky & Madeleine Arison Family Foundation Crohn’s & Colitis Discovery Laboratory, and Martin Kalser Chair in Gastroenterology at the University of Miami. The investigators disclosed additional relationships with Takeda, Abbvie, Eli Lilly, and others.

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