Glymenaki Maria, Curio Sophie, Shrestha Smeeta, Zhong Qi, Rushton Laura, Barry Rachael, El-Bahrawy Mona, Marchesi Julian R, Wang Yulan, Gooderham Nigel J, Guerra Nadia, Li Jia V
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Department of Life Sciences, Imperial College London, London, UK.
Microbiome. 2025 Feb 28;13(1):60. doi: 10.1186/s40168-025-02049-2.
Fecal abundances of Enterobacteriaceae and Enterococcaceae are elevated in patients following Roux-en-Y gastric bypass (RYGB) surgery. Concurrently, fecal concentrations of tyramine, derived from gut bacterial metabolism of tyrosine and/or food, increased post-RYGB. Furthermore, emerging evidence suggests that RYGB is associated with increased colorectal cancer (CRC) risk. However, the causal link between RYGB-associated microbial metabolites and CRC risk remains unclear. Hence, this study investigated the tyrosine metabolism of Enterobacteriaceae and Enterococcaceae strains isolated from patients post-RYGB and explored the causal effects of tyramine on the CRC risk and tumorigenesis using both human colonic cancer cell line (HCT 116) and wild-type and Apc mice.
We isolated 31 bacterial isolates belonging to Enterobacteriaceae and Enterococcaceae families from the feces of patients with RYGB surgery. By culturing the isolates in tyrosine-supplemented medium, we found that Citrobacter produced phenol as a main product of tyrosine, whereas Enterobacter and Klebsiella produced 4-hydroxyphenylacetate, Escherichia produced 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate, and Enterococcus and two Klebsiella isolates produced tyramine. These observations suggested the gut bacterial contribution to increased fecal concentrations of tyramine post-RYGB. We subsequently evaluated the impact of tyramine on CRC risk and development. Tyramine induced necrosis and promoted cell proliferation and DNA damage of HCT 116 cells. Daily oral administration of tyramine for 49 days to wild-type mice resulted in visible adenomas in 5 out of 12 mice, accompanied by significantly enhanced DNA damage (γH2AX +) and an increased trend of cell proliferation (Ki67 +) in the ileum, along with an upregulated expression of the cell division cycle gene (Cdc34b) in the colon. To evaluate the impact of tyramine on intestinal tumor growth, we treated Apc mice with the same doses of tyramine and duration. These mice showed larger colonic tumor size and increased intestinal cell proliferation and inflammation (e.g., increased mRNA expression of IL-17A and higher number of Ly6G + neutrophils) compared to water-treated Apc control mice.
Our results collectively suggested that RYGB-associated fecal bacteria could contribute to tyramine production and tyramine increased CRC risk by increasing DNA damage, cell proliferation, and pro-inflammatory responses of the gut. Monitoring and modulating tyramine concentrations in high-risk individuals could aid CRC prognosis and management. Video Abstract.
在接受Roux-en-Y胃旁路术（RYGB）的患者中，粪便中肠杆菌科和肠球菌科的丰度升高。同时，由酪氨酸和/或食物的肠道细菌代谢产生的酪胺粪便浓度在RYGB术后增加。此外，新出现的证据表明RYGB与结直肠癌（CRC）风险增加有关。然而，RYGB相关的微生物代谢产物与CRC风险之间的因果关系仍不清楚。因此，本研究调查了从RYGB术后患者分离出的肠杆菌科和肠球菌科菌株的酪氨酸代谢，并使用人结肠癌细胞系（HCT 116）以及野生型和Apc小鼠探索了酪胺对CRC风险和肿瘤发生的因果效应。
我们从接受RYGB手术患者的粪便中分离出31株属于肠杆菌科和肠球菌科的细菌菌株。通过在补充酪氨酸的培养基中培养这些菌株，我们发现柠檬酸杆菌产生苯酚作为酪氨酸的主要产物，而肠杆菌和克雷伯菌产生4-羟基苯乙酸，大肠杆菌产生4-羟基苯乳酸和4-羟基苯丙酮酸，肠球菌和两株克雷伯菌分离株产生酪胺。这些观察结果表明肠道细菌对RYGB术后粪便中酪胺浓度升高有贡献。我们随后评估了酪胺对CRC风险和发展的影响。酪胺诱导HCT 116细胞坏死并促进细胞增殖和DNA损伤。对野生型小鼠每日口服酪胺49天导致12只小鼠中有5只出现可见腺瘤，同时回肠中DNA损伤（γH2AX +）显著增强且细胞增殖（Ki67 +）有增加趋势，结肠中细胞分裂周期基因（Cdc34b）表达上调。为了评估酪胺对肠道肿瘤生长的影响，我们用相同剂量和持续时间的酪胺处理Apc小鼠。与用水处理的Apc对照小鼠相比，这些小鼠的结肠肿瘤尺寸更大，肠道细胞增殖和炎症增加（例如，IL-17A的mRNA表达增加以及Ly6G +中性粒细胞数量增加）。
我们的结果共同表明，RYGB相关的粪便细菌可能有助于酪胺的产生，并且酪胺通过增加肠道的DNA损伤、细胞增殖和促炎反应而增加CRC风险。监测和调节高危个体中的酪胺浓度可能有助于CRC的预后和管理。视频摘要。
