PO.PR01.04 · 预防研究

红甘蓝汁重编程肠道微生物组并增强丁酸盐产生以预防结直肠癌

Red cabbage juice reprograms the gut microbiome and enhances butyrate production to prevent colorectal cancer

编号 3619 展板 5 时间 4/20 02:00–05:00 区域 Section 36 主讲 Satyanarayana Rachagani, PhD

分会场 Metabolism and Microbiome in Cancer Initiation and Prevention

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作者与单位 Authors & Affiliations

Bineet Narayan¹, Yariswamy Manjunath², Nagabhhishek Sirpu Natesh², Chayanee Chanpanich³, Parsa Ghadermazi⁴, BLAKE ARCIGA⁵, Samarth Kansara⁶, Ajay Tosh⁷, John Ulbrich⁶, Mary Kate Grossmann⁶, Hwang Jiwon⁶, Van Nguyen⁸, Vikas Satyananda⁹, Jussuf T. Kaifi⁹, Joshua Chan⁴, Satyanarayana Rachagani⁶

¹University of Missouri, Columbia, MO,²University of Missouri - Columbia, Columbia, MO,³Biomedical engineering, Colorado State University, Fort collins, CO,⁴Biomedical Engineering, Colorado State University, Fort Collins, CO,⁵Nextgen PHI, University of Missouri, Columbia, Columbia, MO,⁶Dept. Veterinary Medicine and Surgery, University of Missouri - Columbia, Columbia, MO,⁷Nextgen PHI, University of Missouri, Columbia, MO,⁸Pathology, University of Missouri, Columbia, MO,⁹Surgery, University of Missouri, Columbia, MO

摘要 Abstract

中文摘要

背景结直肠癌（CRC）仍是美国癌症相关死亡的第二大原因，西方饮食诱导的肠道菌群失调被认为参与其发病机制。针对肠道微生物组的早期干预提供了一种有前景的预防策略。增强短链脂肪酸（SCFA）（如丁酸盐）产生的饮食方法已成为潜在的化学预防措施。本研究通过在基因工程 CRC 小鼠模型中考察红甘蓝汁（RCJ）对微生物组成、丁酸盐产生的影响，并利用 CRC 患者来源类器官（PDO）考察其转化相关性，来研究 RCJ 的预防效果。方法将他莫昔芬诱导型 APC fl/fl；Cdx-Cre ER（AC）CRC 小鼠随机分组，通过口服灌胃接受磷酸盐缓冲液（PBS）或 RCJ，持续 10 周。随后给小鼠注射他莫昔芬以诱导 CRC，并监测体重减轻和腹泻情况。在终点，收集结肠组织和盲肠内容物用于免疫组织化学（IHC）、宏基因组谱分析，并通过 GC-MS/MS 定量粪便 SCFA。同时，建立来自 CRC 患者的 PDO，并用 RCJ 单独或与化疗药物奥沙利铂或 5-氟尿嘧啶（5-FU）联合进行处理，在 IncuCyte 平台上实时监测，并通过 IHC 评估治疗反应（增殖和凋亡）。结果与 PBS 组相比，RCJ 显著减少了 AC 小鼠的息肉和肿瘤进展并改善了生存。RCJ 处理小鼠的结肠上皮中黏膜保护性黏蛋白 Muc2 和 Muc4 的表达增强。鸟枪法测序揭示了琥珀酸-丁酸代谢途径的富集、粪便琥珀酸和丁酸的升高以及产丁酸梭菌（Clostridia）等的丰度增加。用 6% RCJ 处理 PDO 抑制了 PDO 的生长、数量和大小（经 IncuCyte 分析），为 CRC 预防提供了转化相关性。此外，RCJ 与奥沙利铂联合治疗较 RCJ 单独、RCJ + 5-FU 或培养基对照显著减少了类器官的数量、大小和面积，提示 RCJ 可能增强化疗对抗 CRC 类器官生长的治疗反应。IHC 图像证实了这些效果，显示治疗后增殖减少、凋亡增加。结论 RCJ 调节肠道微生物组并增强丁酸盐产生，这与临床前 CRC 模型中肿瘤负荷的降低相关。它还对 CRC PDO 的生长、数量和大小发挥抑制作用。值得注意的是，RCJ 增强了奥沙利铂在 PDO 中的疗效，提示其克服化疗耐药的潜力。这些发现凸显了 RCJ 作为靶向肠道微生物组-SCFA 相互作用的饮食干预以及 CRC 预防中辅助化学预防剂的转化潜力，尤其是在高危手术人群中。

查看英文原文 English abstract

Background Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality in the United States, with Western diet-induced gut dysbiosis implicated in its pathogenesis. Early interventions targeting the gut microbiome offer a promising prevention strategy. Dietary approaches that enhance short-chain fatty acid (SCFA) production like butyrate, have emerged as potential chemopreventive measures. This study investigated the preventive efficacy of red cabbage juice (RCJ) in a genetically engineered mouse model of CRC by examining its effects on microbial composition, butyrate production and its translational relevance using CRC patient-derived organoids (PDOs). Methods Tamoxifen inducible APC fl/fl ;Cdx-Cre ER (AC) mice for CRC were randomized to receive either phosphate-buffered saline (PBS) or RCJ as oral gavage for 10 weeks. Then, mice were injected with tamoxifen to induce CRC and monitored for weight loss and diarrhea. At the endpoint, colon tissues and cecal contents were collected for immunohistochemistry (IHC), metagenomic profiling, and fecal SCFA quantification by GC‑MS/MS. In parallel, PDOs from CRC patients were developed and treated with RCJ alone or in combination with chemotherapeutic agents oxaliplatin or 5-fluorouracil (5-FU) and monitored in real-time on an IncuCyte platform and therapy responses (proliferation and apoptosis) were evaluated by IHC. Results RCJ significantly reduced polyps and tumor progression in AC mice and improved survival compared to PBS group. Enhanced expression of mucosal protective mucins Muc2 and Muc4 in the colonic epithelium of RCJ-treated mice. Shotgun sequencing revealed enrichment of succinate-to-butyrate metabolic pathways, elevated fecal succinate, butyrate and abundance of butyrate-producing Clostridia etc. Treatment of PDOs with 6% RCJ inhibited PDO growth, number, size as analyzed by IncuCyte provided us with its translational relevance for CRC prevention. Further, RCJ and oxaliplatin combination therapy significantly reduced organoid number, size, area vs. RCJ alone, RCJ + 5-FU, or media control, suggesting that RCJ may enhance the therapeutic response of chemotherapy to combat CRC organoids growth. IHC images confirmed these effects, showing decreased proliferation, and increased apoptosis upon the treatment. Conclusions RCJ modulates the gut microbiome and enhances butyrate production, correlating with reduced tumor burden in a preclinical CRC model. It also exerts inhibitory effect on CRC PDO growth, number, size. Notably, RCJ enhances the efficacy of oxaliplatin in PDOs, suggesting its potential to overcome chemoresistance. These findings underscore the translational potential of RCJ as a dietary intervention targeting gut microbiome-SCFA interactions and an adjunctive chemopreventive agent in CRC prevention, particularly in at-risk surgical populations.

利益披露 Disclosure

C. Chanpanich, None.. P. Ghadermazi, None.. B. Arciga, None.. S. Kansara, None.. A. Tosh, None.. J. Ulbrich, None.. M. Grossmann, None.. H. Jiwon, None.. V. Nguyen, None.. V. Satyananda, None.. J. T. Kaifi, None.. J. Chan, None.. S. Rachagani, None.

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