Gene Signature–Based Approach Identified MEK1/2 as a Potential Target Associated With Relapse After Anti-TNFα Treatment for Crohn’s Disease

Gamo, Kanae; Okuzono, Yuumi; Yabuki, Masato; Ochi, Takashi; Sugimura, Kyoko; Sato, Yosuke; Sagara, Masaki; Hayashi, Hiroki; Ishimura, Yoshimasa; Nishimoto, Yuji; Murakawa, Yusuke; Shiokawa, Zenyu; Gotoh, Masayuki; Miyazaki, Takahiro; Ebisuno, Yukihiko

doi:10.1093/ibd/izy079

Cited by 5 publications

(4 citation statements)

References 61 publications

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“…8a and Supplementary Table 1 ). These data are consistent with findings from Gamo et al demonstrating elevated SPRY2 expression in adult IBD patients 43 . Furthermore, in our mucosal biopsy samples, SPRY2 levels were inversely correlated with IL33 expression (Fig.…”

Section: Resultssupporting

confidence: 93%

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

et al. 2021

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Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.

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Section: Resultssupporting

confidence: 93%

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

et al. 2021

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“…Similar results were obtained from analysis of epithelium from surgical specimens from IBD and control patients (not shown). These data are consistent with findings from Gamo et al demonstrating elevated Sprouty2 expression in adult IBD patients 39 .…”

Section: Sprouty2 Levels Are Increased In Human Ibd and Negatively Csupporting

confidence: 93%

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Schumacher

Hsieh

Liu

et al. 2020

Preprint

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Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we asked whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion led to expanded goblet and tuft cell populations. Sprouty2 loss induced PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this resulted in increased stromal IL-13+ cells. IL-13 in turn induced tuft and goblet cell expansion in vitro and in vivo. Sprouty2 was downregulated by inflammation; this appeared to be a protective response, as VillinCre;Sprouty2 F/F mice were resistant to DSS colitis. In contrast, Sprouty2 was elevated in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.

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“…Likewise, the Monoamine oxidase inhibitor Procarbazine may have the potential to modulate neurotransmitters and immune responses and BCR-ABL kinase inhibitors such as Dasatinib and RAF inhibitors like Vemurafenib, AZ-628, and PLX-4720 might indirectly impact immune pathways, offering insights into IBD modulation ( 80 , 81 ). Additionally, mTOR inhibitors, represented by WYE-354, and SYK inhibitors like Fostamatinib are under investigation for their anti-inflammatory effects ( 82 , 83 ) and MEK inhibitors, including PD-0325901 and MEK1-2-inhibitor, target pathways associated with inflammation and immune responses ( 84 ). It’s worth acknowledging the dichotomous findings regarding the impact on IBD as certain reports suggested RAF/MEK inhibitors to potentially promote IBD in humans and mice ( 85 , 86 ), while others have indicated that MEK inhibitors hold promise in improving diarrhea and histological scores in a murine colitis model ( 84 ), and RAF inhibition has induced clinical remission in CD patients ( 87 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, mTOR inhibitors, represented by WYE-354, and SYK inhibitors like Fostamatinib are under investigation for their anti-inflammatory effects ( 82 , 83 ) and MEK inhibitors, including PD-0325901 and MEK1-2-inhibitor, target pathways associated with inflammation and immune responses ( 84 ). It’s worth acknowledging the dichotomous findings regarding the impact on IBD as certain reports suggested RAF/MEK inhibitors to potentially promote IBD in humans and mice ( 85 , 86 ), while others have indicated that MEK inhibitors hold promise in improving diarrhea and histological scores in a murine colitis model ( 84 ), and RAF inhibition has induced clinical remission in CD patients ( 87 ). Lastly, compounds such as the Cannabinoid receptor antagonist O-1918, cyclooxygenase inhibitor Valdecoxib, and Histamine receptor antagonist Loratadine are all associated with anti-inflammatory pathways ( 88 – 90 ).…”

Section: Discussionmentioning

confidence: 99%

Exploring potential biomarkers and therapeutic targets in inflammatory bowel disease: insights from a mega-analysis approach

Stemmer,

Zahavi,

Kellerman

et al. 2024

Front. Immunol.

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BackgroundUnderstanding the molecular pathogenesis of inflammatory bowel disease (IBD) has led to the discovery of new therapeutic targets that are more specific and effective. Our aim was to explore the molecular pathways and genes involved in IBD pathogenesis and to identify new therapeutic targets and novel biomarkers that can aid in the diagnosis of the disease.MethodsTo obtain the largest possible number of samples and analyze them comprehensively, we used a mega-analysis approach. This involved reprocessing raw data from multiple studies and analyzing them using bioinformatic and machine learning techniques.ResultsWe analyzed a total of 697 intestinal biopsies of Ulcerative Colitis (n = 386), Crohn’s disease (n = 183) and non-IBD controls (n = 128). A machine learning analysis detected 34 genes whose collective expression effectively distinguishes inflamed biopsies of IBD patients from non-IBD control samples. Most of these genes were upregulated in IBD. Notably, among these genes, three novel lncRNAs have emerged as potential contributors to IBD development: ENSG00000285744, ENSG00000287626, and MIR4435-2HG. Furthermore, by examining the expression of 29 genes, among the 34, in blood samples from IBD patients, we detected a significant upregulation of 12 genes (p-value < 0.01), underscoring their potential utility as non-invasive diagnostic biomarkers. Finally, by utilizing the CMap library, we discovered potential compounds that should be explored in future studies for their therapeutic efficacy in IBD treatment.ConclusionOur findings contribute to the understanding of IBD pathogenesis, suggest novel biomarkers for IBD diagnosis and offer new prospects for therapeutic intervention.

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Gene Signature–Based Approach Identified MEK1/2 as a Potential Target Associated With Relapse After Anti-TNFα Treatment for Crohn’s Disease

Abstract: Our data revealed the abnormalities in anti-TNFα responders' CD colons that would be cause of recurrence of CD. Also, we provided evidence regarding MEK1/2 inhibitor as a potential treatment against CD to achieve sustainable remission.

Cited by 5 publications

References 61 publications

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Exploring potential biomarkers and therapeutic targets in inflammatory bowel disease: insights from a mega-analysis approach

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