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<p>Hepatocellular carcinoma (HCC) is accompanied by an altered gut microbiota but whether the latter contributes to carcinogenesis is unclear. Here we show that faecal microbiota transplantation (FMT) using stool samples from patients with HCC spontaneously initiate liver inflammation, fibrosis and dysplasia in wild-type mice, and accelerate disease progression in a mouse model of HCC. We find that HCC-FMT results in gut barrier injury and translocation of live bacteria to the liver. Metagenomic analyses and bacterial culture of liver tissues reveal enrichment of the gut pathogen <i>Klebsiella pneumoniae</i> in patients with HCC and mice transplanted with the HCC microbiota. Moreover, <i>K. pneumoniae</i> monocolonization recapitulates the effect of HCC-FMT in promoting liver inflammation and hepatocarcinogenesis. Mechanistically, <i>K. pneumoniae</i> surface protein PBP1B interacts with and activates TLR4 on HCC cells, leading to increased cell proliferation and activation of oncogenic signalling. Targeting gut colonization using <i>K. oxytoca</i> or TLR4 inhibition represses <i>K</i>. <i>pneumoniae-</i>induced HCC progression. These findings indicate a role for an altered gut microbiota in hepatocarcinogenesis.</p>

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Gut–liver translocation of pathogen Klebsiella pneumoniae promotes hepatocellular carcinoma in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月2日

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  • Xueliang Wang,
  • Yi Fang,
  • Wei Liang,
  • Yuhong Cai,
  • Chi Chun Wong,
  • Junlin Wang,
  • Na Wang,
  • Harry Cheuk-Hay Lau,
  • Ying Jiao,
  • Xingyu Zhou,
  • Liufang Ye,
  • Mengmiao Mo,
  • Tao Yang,
  • Miao Fan,
  • Lei Song,
  • Heming Zhou,
  • Qiang Zhao,
  • Eagle Siu-Hong Chu,
  • Meinong Liang,
  • Weixin Liu,
  • Xin Liu,
  • Shuaiyin Zhang,
  • Haitao Shang,
  • Hong Wei,
  • Xiaoxing Li,
  • Lixia Xu,
  • Bing Liao,
  • Joseph J. Y. Sung,
  • Ming Kuang,
  • Jun Yu

摘要

Hepatocellular carcinoma (HCC) is accompanied by an altered gut microbiota but whether the latter contributes to carcinogenesis is unclear. Here we show that faecal microbiota transplantation (FMT) using stool samples from patients with HCC spontaneously initiate liver inflammation, fibrosis and dysplasia in wild-type mice, and accelerate disease progression in a mouse model of HCC. We find that HCC-FMT results in gut barrier injury and translocation of live bacteria to the liver. Metagenomic analyses and bacterial culture of liver tissues reveal enrichment of the gut pathogen Klebsiella pneumoniae in patients with HCC and mice transplanted with the HCC microbiota. Moreover, K. pneumoniae monocolonization recapitulates the effect of HCC-FMT in promoting liver inflammation and hepatocarcinogenesis. Mechanistically, K. pneumoniae surface protein PBP1B interacts with and activates TLR4 on HCC cells, leading to increased cell proliferation and activation of oncogenic signalling. Targeting gut colonization using K. oxytoca or TLR4 inhibition represses K. pneumoniae-induced HCC progression. These findings indicate a role for an altered gut microbiota in hepatocarcinogenesis.