Gustave Roussy, ClinicObiome, Villejuif, France.
INSERM U1015, Equipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France.
Cancer Discov. 2022 Apr 1;12(4):1128-1151. doi: 10.1158/2159-8290.CD-21-0999.
Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.
Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873.
肠道菌群失调与肠道和肠道外恶性肿瘤有关，但致癌作用如何以及如何使微生物组发生组成性变化使其受益仍然是一个悬而未决的难题。在这里，我们表明恶性过程可导致回肠黏膜萎缩，伴有绒毛微血管收缩，与副交感神经信号对胆碱能信号的优势有关。肿瘤发生的快速发作引起回肠细胞中 REG3γ 的释放爆发，以及短暂的上皮屏障通透性，最终导致明显且持久的以革兰氏阳性梭菌属为主的菌群失调。β-肾上腺素能受体的药理学阻断或 Adrb2 基因、万古霉素的遗传缺陷，或肿瘤携带者与无肿瘤同窝仔的共同饲养，可防止癌症引起的回肠炎，最终减缓肿瘤生长动力学。癌症患者具有这种以梭菌属为主的应激性回肠炎的独特特征。因此，应激性回肠炎是肠道外恶性肿瘤的相关疾病，需要特定的治疗方法。
肠道菌群失调是否促进肿瘤发生以及它如何控制肿瘤进展仍然是悬而未决的问题。我们表明，50%的可移植肠道外恶性肿瘤引发了β-肾上腺素能受体依赖性回肠黏膜萎缩，伴有肠道通透性增加、持续的梭菌属相关菌群失调和癌症生长。万古霉素或普萘洛尔可预防与癌症相关的应激性回肠炎。本文在本期特色文章中重点介绍，第 873 页。
