Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2022 Jul 8;13(1):3964. doi: 10.1038/s41467-022-31312-5.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6 mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy.
肝细胞癌 (HCC) 是全球癌症相关死亡的主要原因，而晚期 HCC 的治疗选择有限。在这里，我们观察到肠道菌群失调会影响抗肿瘤免疫监视，并促使肝病向癌症方向发展。正如 Nlrp6 小鼠中所见，失调的微生物群会诱导肝脏单核细胞髓系来源的抑制细胞 (mMDSC) 的 Toll 样受体 4 依赖性扩增，并抑制 T 细胞丰度。这种表型可通过粪便微生物群转移传播，并且在抗生素治疗后可逆转，这表明肿瘤微环境具有高度的可塑性。虽然 Akkermansia muciniphila 的缺失与 mMDSC 的丰度相关，但它的重新引入恢复了肠道屏障功能，并强烈减少了肝脏炎症和纤维化。肝硬化患者的肝组织中细菌丰度增加，这会引起明显的转录变化，包括激活纤维炎症途径以及介导癌症免疫抑制的回路。这项研究表明，肠道微生物群密切影响肝脏炎症微环境，为癌症预防和治疗开辟了途径。
