Role of Energy Metabolism and Mitochondrial Function in Inflammatory Bowel Disease

Özsoy, Mihriban; Stummer, Nathalie; Zimmermann, Franz; Feichtinger, René G.; Sperl, Wolfgang; Weghuber, Daniel; Schneider, Anna-Maria

doi:10.1093/ibd/izac024

Cited by 14 publications

(8 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results are of particular importance from a clinical point of view, because human intestinal mucosa from patients with CD/SC exhibited both decreased levels of HuR and PC/ISC niche dysfunction. Although defective PCs and mitochondrial impairment are commonly observed in patients with IBD (Xiao et al, 2019;Ozsoy et al, 2022), the present study demonstrates for the first time that there were significant defects in PC/ISC niche in the intestinal mucosa of patients with critical surgical disorders after HuR inhibition. Notably, abnormalities in PC/ISC niche function in the intestinal epithelium of IE-HuR −/− mouse are similar to those observed in the mucosa of patients with CD/SC.…”

Section: Discussionmentioning

confidence: 53%

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity

Xiao,

Warner,

Mallard

et al. 2023

Life Sci. Alliance

View full text Add to dashboard Cite

Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to thePhb1mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.

show abstract

Section: Discussionmentioning

confidence: 53%

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity

Xiao,

Warner,

Mallard

et al. 2023

Life Sci. Alliance

View full text Add to dashboard Cite

show abstract

“…Several studies also support these observations of altered energy metabolism including metabolites involved in the amino-acid cycle and TCA cycle; consistently, most of the studies report a significant dysregulation in TCA intermediates. − …”

Section: Resultsmentioning

confidence: 75%

Integrated Metabolomics and Proteomics of Symptomatic and Early Presymptomatic States of Colitis

Shimshoni,

Solomonov,

Sagi

et al. 2024

J. Proteome Res.

View full text Add to dashboard Cite

Colitis has a multifactorial pathogenesis with a strong cross-talk among microbiota, hypoxia, and tissue metabolism. Here, we aimed to characterize the molecular signature of the disease in symptomatic and presymptomatic stages of the inflammatory process at the tissue and fecal level. The study is based on two different murine models for colitis, and HR-MAS NMR on "intact" colon tissues and LC-MS/MS on colon tissue extracts were used to derive untargeted metabolomics and proteomics information, respectively. Solution NMR was used to derive metabolomic profiles of the fecal extracts. By combining metabolomic and proteomic analyses of the tissues, we found increased anaerobic glycolysis, accompanied by an altered citric acid cycle and oxidative phosphorylation in inflamed colons; these changes associate with inflammation-induced hypoxia taking place in colon tissues. Different colitis states were also characterized by significantly different metabolomic profiles of fecal extracts, attributable to both the dysbiosis characteristic of colitis as well as the dysregulated tissue metabolism. Strong and distinctive tissue and fecal metabolomic signatures can be detected before the onset of symptoms. Therefore, untargeted metabolomics of tissues and fecal extracts provides a comprehensive picture of the changes accompanying the disease onset already at preclinical stages, highlighting the diagnostic potential of global metabolomics for inflammatory diseases.

show abstract

“…Mitochondrial dysregulation is characteristic of and appears to necessary for inflammation (42). Additionally, mitochondrial dysregulation has previously been associated with the pathogenesis of CD and UC (43-45).…”

Section: Discussionmentioning

confidence: 99%

Genomic Insights into Pediatric Intestinal Inflammatory and Eosinophilic Disorders using Single-sell RNA-sequencing

Keever-Keigher,

Harvey,

Williams

et al. 2023

Preprint

View full text Add to dashboard Cite

Chronic inflammation of the gastrointestinal (GI) tissues underlies GI inflammatory disorders, leading to tissue damage and a constellation of painful and debilitating symptoms. These GI disorders include inflammatory bowel diseases (Crohn’s disease (CD) and ulcerative colitis (UC)), and eosinophilic disorders (eosinophilic esophagitis (EoE) and eosinophilic duodenitis (EoD)). GI inflammatory disorders can often present with overlapping symptoms necessitating the use of invasive procedures to give a proper diagnosis. This study aims to use peripheral blood mononuclear cells (PBMCs) from individuals with CD, UC, EoE, and EoD to better understand the alterations to the transcriptome of individuals with these diseases and identify potential markers of active inflammation within the peripheral blood of patients that may be useful in diagnosis. Single-cell RNA-sequencing (scRNA-seq) was performed on PBMCs isolated from the blood samples of pediatric patients diagnosed with a GI disorder, including CD, UC, EoE, EoD, and controls with histologically healthy gastrointestinal tracts. We identified 1,185 (FDR < 0.05) differentially expressed genes (DEGs) between individuals with GI disorders and controls across six distinct immune cell populations. Few patterns of gene dysregulation were common among all GI disorders, including the downregulation ofESR2in CD4+T cells compared to controls. Many DEGs showed distinct patterns of dysregulation among individuals with CD, UC, EoE, and EoD compared to controls, such as dysregulation of genes associated with oxidative stress in monocytes of individuals CD and the upregulation ofSCGB3A1in CD4+T cells in individuals with EoD. These findings indicate both overlapping and distinct alterations to the transcriptome of individuals with CD, UC, EoD, and EoE compared to controls, which provide insight as to which genes may be useful as markers for disease in the peripheral blood of patients.

show abstract

Role of Energy Metabolism and Mitochondrial Function in Inflammatory Bowel Disease

Cited by 14 publications

References 92 publications

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity

Integrated Metabolomics and Proteomics of Symptomatic and Early Presymptomatic States of Colitis

Genomic Insights into Pediatric Intestinal Inflammatory and Eosinophilic Disorders using Single-sell RNA-sequencing

Contact Info

Product

Resources

About