Contact Dr. Lu for information about cancer treatments。聯繫盧博士，獲取有關癌症治療資訊。
Dietary spinach reshapes the gut microbiome in an Apc-mutant genetic background: mechanistic insights from integrated multi-omics
Ying-Shiuan Chena Texas A&M Health, Houston, USA
,Jia Li,Rani Menon,Arul Jayaraman,Kyongbum Lee,Yun Huang,Wan Mohaiza Dashwood,Ke Zhang,Deqiang Sun &Roderick H. Dashwood
Article: 1972756 | Received 14 Apr 2021, Accepted 17 Aug 2021, Published online: 08 Sep 2021
Complex interrelationships govern the dynamic interactions between gut microbes, the host, and exogenous drivers of disease outcome. A multi-omics approach to cancer prevention by spinach (SPI) was pursued for the first time in the polyposis in rat colon (Pirc) model. SPI fed for 26 weeks (10% w/w, freeze-dried in the diet) exhibited significant antitumor efficacy and, in the Apc-mutant genetic background, β-catenin remained highly overexpressed in adenomatous polyps. However, in both wild type and Apc-mutant rats, increased gut microbiome diversity after SPI consumption coincided with reversal of taxonomic composition. Metagenomic prediction implicated linoleate and butanoate metabolism, tricarboxylic acid cycle, and pathways in cancer, which was supported by transcriptomic and metabolomic analyses. Thus, tumor suppression by SPI involved marked reshaping of the gut microbiome along with changes in host RNA-miRNA networks. When colon polyps were compared with matched normal-looking tissues via metabolomics, anticancer outcomes were linked to SPI-derived linoleate bioactives with known anti-inflammatory/ proapoptotic mechanisms, as well as N-aceto-2-hydroxybutanoate, consistent with altered butanoate metabolism stemming from increased α-diversity of the gut microbiome. In colon tumors from SPI-fed rats, L-glutamate and N-acetylneuraminate also were reduced, implicating altered mitochondrial energetics and cell surface glycans involved in oncogenic signaling networks and immune evasion. In conclusion, a multi-omics approach to cancer prevention by SPI provided mechanistic support for linoleate and butanoate metabolism, as well as tumor-associated changes in L-glutamate and N-acetylneuraminate. Additional factors, such as the fiber content, also warrant further investigation with a view to delaying colectomy and drug intervention in at-risk patients.
The gut microbiome is strongly implicated in host physiology and pathophysiology.1–3 For example, studies in germ-free models of colorectal cancer (CRC) revealed decreased bowel inflammation and tumor outcomes as compared with the corresponding animals under conventional housing conditions.4,5 Fecal microbiota transplantation was used successfully to treat recurrent Clostridium difficile infection,6 and provided benefit to patients with inflammatory bowel diseases, functional gastrointestinal disorders, and obesity.7
There is increasing interest in defining interventions that alter the gut microbiota for disease prevention and treatment. Epidemiological studies indicate that CRC is associated with low consumption of green vegetables and fiber, whereas intake of dark leafy vegetables is linked to decreased risk.8 However, little is known about how these dietary intakes influence the crosstalk between gut microbiota, host transcriptomics, and pathogenesis in the gastrointestinal tract.
Spinach (SPI) is a dark leafy green vegetable with a high chlorophyll content and other diverse bioactives.9–11 We employed an adenomatous polyposis coli (Apc)-mutant rat model12–15 to examine anticancer outcomes from dietary SPI consumption. The polyposis in rat colon (Pirc) model mimics disease progression in human familial adenomatous polyposis patients, involving spontaneous tumor development both in the colon and in the small intestine.15,16 The genetic model circumvents the need for carcinogen treatment, used previously with dietary SPI,17 and the burden of adenomatous polyps facilitates temporal tracking of tumor suppression via colonoscopy.12,14,18
We observed significant antitumor efficacy from dietary SPI consumption, and despite the Apc-mutant genetic background, β-catenin protein levels remained highly overexpressed in colon polyps. Subsequently, mechanisms were pursued linking gut microbiome to host multi-omic changes in fatty acid metabolism, the tricarboxylic acid (TCA) cycle, and pathways in cancer.
複雜的相互關係控制著腸道微生物、宿主和疾病結果的外源驅動因素之間的動態相互作用。首次在大鼠結腸息肉病 (Pirc) 模型中採用菠菜 (SPI) 預防癌症的多組學方法。餵食 26 週的 SPI（10% w/w，在飲食中冷凍乾燥）表現出顯著的抗腫瘤功效，並且在 Apc 突變的遺傳背景下，β-連環蛋白在腺瘤性息肉中仍然高度過表達。然而，在野生型和 Apc 突變型大鼠中，食用 SPI 後腸道微生物組多樣性的增加與分類組成的逆轉相吻合。宏基因組預測涉及亞油酸和丁酸代謝、三羧酸循環和癌症途徑，這得到了轉錄組學和代謝組學分析的支持。因此，SPI 的腫瘤抑制涉及腸道微生物組的顯著重塑以及宿主 RNA-miRNA 網絡的變化。當通過代謝組學將結腸息肉與匹配的外觀正常的組織進行比較時，抗癌結果與具有已知抗炎/促凋亡機制的 SPI 衍生的亞油酸酯生物活性物質以及 N-乙酰-2-羥基丁酸酯有關，這與丁酸酯代謝的改變一致來自腸道微生物組的α-多樣性增加。在 SPI 餵養大鼠的結腸腫瘤中，L-谷氨酸和 N-乙酰神經氨酸也減少了，這表明參與致癌信號網絡和免疫逃避的線粒體能量學和細胞表面聚醣發生了改變。總之，SPI 的癌症預防多組學方法為亞油酸和丁酸代謝以及 L-谷氨酸和 N-乙酰神經氨酸的腫瘤相關變化提供了機制支持。其他因素，如纖維含量，也需要進一步調查，以推遲對高危患者的結腸切除術和藥物干預。
腸道微生物群與宿主生理學和病理生理學密切相關。1-3 例如，與常規飼養條件下的相應動物相比，結直腸癌 (CRC) 無菌模型的研究顯示腸道炎症和腫瘤結果減少。4， 5 糞便微生物群移植成功用於治療復發性艱難梭菌感染，6 並為炎症性腸病、功能性胃腸道疾病和肥胖症患者帶來益處。 7
人們對定義改變腸道微生物群以預防和治療疾病的干預措施越來越感興趣。流行病學研究表明，CRC 與綠色蔬菜和纖維的攝入量低有關，而深葉蔬菜的攝入量與風險降低有關。8 然而，人們對這些膳食攝入量如何影響腸道微生物群、宿主轉錄組學和胃腸道的發病機制。
菠菜 (SPI) 是一種深綠葉蔬菜，具有高葉綠素含量和其他多種生物活性。9-11 我們採用腺瘤性息肉病大腸桿菌 (Apc) 突變大鼠模型 12-15 來檢查飲食 SPI 消費的抗癌效果。大鼠結腸息肉 (Pirc) 模型模擬了人類家族性腺瘤性息肉病患者的疾病進展，涉及結腸和小腸中的自發性腫瘤發展。15,16 遺傳模型避免了致癌物治療的需要，以前與飲食一起使用SPI,17 和腺瘤性息肉的負擔有助於通過結腸鏡檢查對腫瘤抑制的時間跟踪。12,14,18
我們觀察到飲食 SPI 消耗具有顯著的抗腫瘤功效，儘管存在 Apc 突變的遺傳背景，β-連環蛋白水平在結腸息肉中仍然高度過表達。隨後，研究人員探索了將腸道微生物組與宿主脂肪酸代謝、三羧酸 (TCA) 循環和癌症途徑的多組學變化聯繫起來的機制。