PO.CL04.01 · 临床研究
依赖微生物群的复杂膳食多糖降解抑制炎性衰老和结直肠癌易感性
Microbiota-dependent complex dietary polysaccharide degradation suppresses inflammaging and colorectal cancer susceptibility
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
衰老与全身性低度炎症（炎性衰老，inflammaging）以及对感染、慢性疾病和结直肠癌（CRC）易感性的增加相关。年龄相关的肠道菌群失调导致有益微生物代谢产物尤其是短链脂肪酸（SCFAs）的减少，从而形成促炎的肠道微环境，促进肿瘤发生。恢复微生物平衡并增强SCFA生成的膳食策略可能减轻炎性衰老和CRC风险。肠道菌群对复杂膳食多糖（CDPs）的发酵可以生成对宿主有益的代谢产物，包括SCFA，并有助于维持上皮屏障完整性和抑制衰老相关炎症。在本研究中，我们使用来自酵母的高纯度β-葡聚糖（BGs）（酵母β-1,3/1,6-葡聚糖；YBG）和来自微藻的β-葡聚糖（藻类β-1,3-葡聚糖；副淀粉，PM），证明CDP降解过程在体外和体内改变了菌群组成和代谢产物谱，在CRC的氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）模型中抑制了衰老相关炎症和癌症易感性。使用BGs的膳食处理显著改变了肠道微生物组成，尤其是增加了Akkermansia muciniphila（一种已知可产生SCFAs的黏蛋白降解细菌）的丰度。以BGs处理的老龄小鼠粪便微生物培养物显示抗炎代谢产物水平升高、促炎因子水平降低。经BGs处理的老龄小鼠显示结直肠肿瘤负荷和疾病严重程度显著降低。对BG处理小鼠结肠组织的批量RNA测序显示，癌基因、转移相关基因和促炎细胞因子的表达受到抑制，同时抗炎细胞因子以及Muc2（一个参与黏蛋白生成和肠屏障功能的关键基因）的表达升高。我们的研究结果提示，CDP降解过程可以使衰老的肠道菌群恢复活力，重建宿主有益代谢产物的生成和肠道完整性，并抑制炎性衰老。正在进行的使用无菌动物和类结肠器官（colonoid）培养物的研究旨在进一步阐明肠道菌群降解CDP调节肠道完整性、炎症和CRC易感性的机制。总体而言，这项工作证明了以微生物群为靶点的膳食策略在促进健康衰老、使肠道菌群恢复活力以及降低老年人群CRC风险方面的潜力。
查看英文原文 English abstract
Aging is associated with systemic low-grade inflammation (inflammaging) and increased susceptibility to infections, chronic diseases, and colorectal cancer (CRC). Age-associated gut dysbiosis contributes to a decline in beneficial microbial metabolites, particularly short-chain fatty acids (SCFAs), fostering a pro-inflammatory intestinal microenvironment that promotes tumorigenesis. Dietary strategies that restore microbial balance and enhance SCFA production could mitigate inflammaging and CRC risk. Fermentation of complex dietary polysaccharides (CDPs) by gut microbiota can generate host-beneficial metabolites, including SCFA, and help maintain epithelial barrier integrity and suppress aging-associated inflammation. In this study, using high-pure beta-glucans (BGs) from yeast (yeast beta-1,3/1,6-glucan; YBG) and microalgae (algal beta-1,3-glucan; paramylon, PM), we show that the CDP degradation process alters microbiota composition and metabolite profiles in vitro and in vivo, suppresses aging-associated inflammation and cancer susceptibility in the azoxymethane/dextran sulfate sodium (AOM/DSS) model of CRC. Dietary treatment using BGs significantly altered gut microbial composition, notably increasing the abundance of Akkermansia muciniphila , a mucin-degrading bacterium known to produce SCFAs. Fecal microbial cultures of aged mice with BGs showed elevated levels of anti-inflammatory metabolites and reduced levels of pro-inflammatory factors. Aged mice treated with BGs showed significantly lower colorectal tumor burden and disease severity. Bulk RNA sequencing of colon tissue of BG-treated mice revealed suppressed expression of oncogenes, metastasis-related genes, and pro-inflammatory cytokines, along with increased expression of anti-inflammatory cytokines and Muc2 , a key gene involved in mucin production and gut barrier function. Our findings suggest that the CDP degradation process can rejuvenate the aging gut microbiota, restore host beneficial metabolite production and gut integrity, and suppress inflammaging. Ongoing studies using gnotobiotic animals and colonoid cultures aim to further elucidate the mechanisms by which CDP degradation by gut microbiota modulates gut integrity, inflammation, and CRC susceptibility. Collectively, this work demonstrates the potential of microbiota-targeted dietary strategies for promoting healthy aging, rejuvenating gut microbiota, and reducing CRC risk in elderly populations.
利益披露 Disclosure
R. Jalandra, None..
M. Bhattacharjee, None..
R. Maurya, None..
R. R. Gudi, None..
J. S. Gilliard, None..
C. Westwater, None..
C. Vasu, None.