Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis

• Published in: Cell host & microbe 2022-08, Vol.30 (8), p.1139-1150.e7
• Main Authors: Lu, Haiyang, Xu, Xiaoqiang, Fu, Di, Gu, Yubei, Fan, Rong, Yi, Hongmei, He, Xiangyi, Wang, Chaofu, Ouyang, Binshen, Zhao, Ping, Wang, Li, Xu, Pengpeng, Cheng, Shu, Wang, Zhifeng, Zou, Duowu, Han, Lizhong, Zhao, Weili
• Format: Article
• Language: English
• Subjects: B cell lymphoma; gut microbiota; inflammation; lymphoid malignancies; SCFA
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2022.07.003

Microbiota-induced tumorigenesis is well established in solid tumors of the gastrointestinal tract but rarely explored in hematologic malignancies. To determine the role of gut microbiota in lymphoma progression, we performed metagenomic sequencing on human primary gastrointestinal B cell lymphomas. We identified a distinct microbiota profile of intestinal lymphoma, with significantly decreased symbiotic microbes, particularly the genus Eubacterium and notably butyrate-producing Eubacterium rectale. Transfer of E. rectale-deficit microbiota of intestinal lymphoma patients to mice caused inflammation and tumor necrosis factor (TNF) production. Conversely, E. rectale treatment reduced TNF levels and the incidence of lymphoma in sensitized Eμ-Myc mice. Moreover, lipopolysaccharide from the resident microbiota of lymphoma patients and mice synergizes with TNF signaling and reinforces the NF-κB pathway via the MyD88-dependent TLR4 signaling, amalgamating in enhanced intestinal B cell survival and proliferation. These findings reveal a mechanism of inflammation-associated lymphomagenesis and a potential clinical rationale for therapeutic targeting of gut microbiota. [Display omitted] •E. rectale was identified as a protective factor in primary intestinal lymphoma•E. rectale prevented TNF-related intestinal inflammation by producing butyrate•E. rectale reduced the incidence of lymphoma in Eμ-Myc mice•TNF enhanced TLR4/MyD88 signaling to activate NF-κB pathway in B cells Lu et al. identified Eubacterium rectale as a protective factor in primary intestinal lymphoma. Eubacterium rectale is a butyrate-producing bacteria that inhibits intestinal inflammation, subsequently alleviating TLR4/MyD88/NF-κB signaling in B cells. Their findings revealed a mechanism of inflammation-associated lymphomagenesis and provided clinical rationale for targeting gut microbiota involved in lymphoma progression.