{
  "abstract": "Background Intestinal fibrosis, a hallmark complication of Crohn’s disease (CD), frequently progresses to stricture formation and surgical intervention. Fibroblast metabolic reprogramming is important in organ fibrosis. However, its role in intestinal fibrogenesis of CD remains elusive.Objective We aim to explore the metabolic reprogramming of fibroblasts and its upstream regulators during intestinal fibrosis of CD.Design We performed metabolome, single-cell RNA sequencing and spatial transcriptome on paired mucosal and submucosal tissue from the strictured and adjacent non-strictured intestinal segments. The candidate metabolite and metabolic enzymes were verified in primary human intestinal myofibroblasts (HIMFs) and dextran sulfate sodium-induced intestinal fibrotic mice. Next, we identified fibrosis-associated circPLCE1 to regulate the pentose phosphate pathway (PPP) using the circRNA transcriptome. Finally, we studied the functions and mechanisms of circPLCE1 using metabolome, transcriptome, metabolic flux, seahorse assay and RNA pull-down assay in HIMFs and fibroblast-specific circPLCE1 knockdown mice.Results Multilayer integrated analysis identified activation of PPP in fibroblasts during intestinal fibrosis of CD. Specifically, xylulokinase (XYLB)-generated xylulose-5-phosphate (Xu5P) promoted extracellular matrix synthesis by epigenetic upregulation of collagen transcription. Moreover, downregulation of circPLCE1 in fibroblasts activated PPP, resulting in increased glycolysis, nicotinamide adenine dinucleotide phosphate production and aggravated intestinal fibrosis in vitro and in vivo. Mechanistically, circPLCE1 directly bound the domain-I of XYLB and competitively inhibited its enzymatic activity. Decreased circPLCE1 restored XYLB activity and accumulation of Xu5P in intestinal fibrosis.Conclusion Our findings delineate a circPLCE1/XYLB/Xu5P axis in fibroblasts which orchestrates PPP and fibrogenesis, unveiling a novel therapeutic target for intestinal fibrosis of CD.",
  "authors": [
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China"
      ],
      "name": "Longyuan Zhou"
    },
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China"
      ],
      "name": "Jing Nie"
    },
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China"
      ],
      "name": "Zhiyin Feng"
    },
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China"
      ],
      "name": "Rongchang Li"
    },
    {
      "affiliations": [
        "Shenzhen Qianhai Taikang Hospital, Shenzhen, Guangdong, China",
        "Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China"
      ],
      "name": "Pingxin Zhang"
    },
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China"
      ],
      "name": "Sinan Lin"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Yao Zhang"
    },
    {
      "affiliations": [
        "Inflammation and Immunity NC22, Cleveland Clinic Foundation, Cleveland, Ohio, USA"
      ],
      "name": "Florian Rieder"
    },
    {
      "affiliations": [
        "Sun Yat-Sen Memorial Hospital Department of Urology, Guangzhou, Guangdong, China"
      ],
      "name": "Changhao Chen"
    },
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China",
        "Shenzhen Qianhai Taikang Hospital, Shenzhen, Guangdong, China"
      ],
      "name": "Minhu Chen"
    },
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China"
      ],
      "name": "Ren Mao"
    }
  ],
  "title": "Fibroblast pentose phosphate pathway activation upon decreased circPLCE1 exacerbates intestinal fibrosis in Crohn’s disease",
  "uid": "6fbc0192-35ba-5d0a-832b-e70022bb4241"
}