Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets

Narzo, Antonio Fabio Di; Houten, Sander M.; Kosoy, Roman; Huang, Ruiqi; Vaz, Frédéric M.; Hou, Ruixue; Wei, Guojian; Wang, Wenhui; Comella, Phillip; Dodatko, Tetyana; Rogatsky, Eduard; Stojmirović, Aleksandar; Brodmerkel, Carrie; Perrigoue, Jacqueline; Hart, Amy; Curran, Mark; Friedman, Joshua R.; Zhu, Jun; Agrawal, Manasi; Cho, Judy H.; Ungaro, Ryan C.; Dubinsky, Marla; Sands, Bruce E.; Suárez‐Fariñas, Mayte; Schadt, Eric E.; Colombel, Jean–Frédéric; Kasarskis, Andrew; Hao, Ke; Argmann, Carmen

doi:10.1053/j.gastro.2021.11.015

Cited by 42 publications

(27 citation statements)

References 46 publications

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“…Biopsy and blood RNA from patients with MSCCR were extracted and processed in randomised batches as previously described30 and in online supplemental methods. Coupled genotype data for the same patients were available 31. For bMIS generation, biopsy data for patients with indeterminate IBD disease were removed (n=13) and biopsies identified as inflamed in the healthy control group were also removed (n=7).…”

Section: Methodsmentioning

confidence: 99%

Biopsy and blood-based molecular biomarker of inflammation in IBD

Argmann

Hou

Ungaro

et al. 2022

Gut

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ObjectiveIBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.DesignTranscriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn’s disease, n=421 UC and 243 controls) in the Mount Sinai Crohn’s and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.ResultsbMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.ConclusionTranscriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.

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Section: Methodsmentioning

confidence: 99%

Biopsy and blood-based molecular biomarker of inflammation in IBD

Argmann

Hou

Ungaro

et al. 2022

Gut

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“…70 71 Low fibre intake has been associated with increased IBD risk, [72][73][74] and patients with IBD show a decrease in butyrate producing bacterial species, as well as a decreased expression of butyrate transporters. [75][76][77] A reduction of butyrate-producing bacteria and the dietary substrate for SCFA generation in patients with IBD may lead to loss of an antiinflammatory 'break' in the gut. In turn, it appears plausible that butyrate supplementation ameliorates the course of IBD, which is currently probed by several clinical trials with butyrate in IBD.…”

Section: Recent Advances In Basic Sciencementioning

confidence: 99%

“…Moreover, butyrate also exerts anti-inflammatory effects in the gut mucosa by inhibition of histone deacetylases and activation of G protein-coupled receptors present in gut epithelium and mucosal immune cells 70 71. Low fibre intake has been associated with increased IBD risk,72–74 and patients with IBD show a decrease in butyrate producing bacterial species, as well as a decreased expression of butyrate transporters 75–77. A reduction of butyrate-producing bacteria and the dietary substrate for SCFA generation in patients with IBD may lead to loss of an anti-inflammatory ‘break’ in the gut.…”

Section: The Diet Is a Critical Determinant Of Gut Microbial Composit...mentioning

confidence: 99%

Diet fuelling inflammatory bowel diseases: preclinical and clinical concepts

Adolph

Zhang

2022

Gut

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The diet and gut microbiota have been extensively interrogated as a fuel for gut inflammation in inflammatory bowel diseases (IBDs) in the last few years. Here, we review how specific nutrients, typically enriched in a Western diet, instigate or deteriorate experimental gut inflammation in a genetically susceptible host and we discuss microbiota-dependent and independent mechanisms. We depict the study landscape of nutritional trials in paediatric and adult IBD and delineate common grounds for dietary advice. Conclusively, the diet reflects a critical rheostat of microbial dysbiosis and gut inflammation in IBD. Dietary restriction by exclusive enteral nutrition, with or without a specific exclusion diet, is effectively treating paediatric Crohn's disease, while adult IBD trials are less conclusive. Insights into molecular mechanisms of nutritional therapy will change the perception of IBD and will allow us to enter the era of precision nutrition. To achieve this, we discuss the need for carefully designed nutritional trials with scientific rigour comparable to medical trials, which also requires action from stake holders. Establishing evidencebased dietary therapy for IBD does not only hold promise to avoid long-term immunosuppression, but to provide a widely accessible therapy at low cost. Identification of dietary culprits disturbing gut health also bears the potential to prevent IBD and allows informed decision making in food politics.

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“…In addition to restoring some lipid molecules to similar levels to controls, our results showed that Ncs strongly increased anti-inflammatory plasmalogens. Dysregulation of plasmalogen metabolism is associated with the development of obesity-related metabolic disease and inflammatory bowel disease ( 41 – 43 ). Rescue of its levels prevents hepatic steatosis and NASH (non-alcoholic steatohepatitis) by increasing fatty acid oxidation through PPARα signaling ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis

et al. 2023

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IntroductionPsoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels.MethodsThe therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action.ResultsNcs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions.DiscussionTaken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.

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Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets

Cited by 42 publications

References 46 publications

Biopsy and blood-based molecular biomarker of inflammation in IBD

Biopsy and blood-based molecular biomarker of inflammation in IBD

Diet fuelling inflammatory bowel diseases: preclinical and clinical concepts

Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis

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