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菌群 - 宿主互作新突破！Gut Microbes 助力肠道稳态调控研究登顶
322 人阅读发布时间：2026-07-07 11:08
近日，天津医科大学、南开大学等多机构联合团队在国际权威期刊Gut Microbes发表重磅研究，首次揭示4 - 胍基丁酸（4-GBA）-SLC36A1 轴驱动菌群 - 宿主反馈环路调控肠道稳态的全新机制，为溃疡性结肠炎（UC）的诊疗提供了全新靶点与策略。在这项研究的核心实验环节中，爱必信 Absin abs9530 结肠类器官培养基成为关键实验工具，为肠道类器官模型的构建、功能验证及机制探索提供了稳定且高效的支撑，助力研究团队顺利取得突破性成果。
文献标题：
A 4-guanidinobutanoic acid-SLC36A1 axis drives a microbiota‒host feedback loop to regulate intestinal homeostasis
发表期刊：
Gut Microbes. (IF=11)
DOI：
10.1080/19490976.2026.2639216
使用 Absin 产品：
人正常肠类器官培养基（货号：abs9530）
一、层层递进，解锁菌群代谢物调控肠道稳态的科学逻辑
该研究围绕"肠道菌群代谢物如何调控肠道黏膜屏障稳态"这一科学问题，设计了从筛选关键分子→验证体内功能→解析分子机制→挖掘临床价值的四层递进式研究思路，逻辑严密且环环相扣：
- 筛选核心菌群代谢物：从健康人粪便中分离 297 株肠道细菌，通过结肠类器官共培养体系，筛选能上调黏液蛋白 MUC2（肠道屏障核心分子）的菌株，最终锁定Bacteroides stercorirosoris及其代谢产物 4-GBA；
- 体内验证功能与依赖性：利用 DSS 诱导结肠炎、C. rodentium感染小鼠模型，验证 4-GBA 对肠道屏障的保护作用，同时通过抗生素耗菌、粪菌移植（FMT）、Akkermansia muciniphila特异性耗竭实验，证实其作用依赖肠道菌群及黏液层；
- 解析分子调控通路：结合单细胞 RNA 测序、信号通路抑制剂干预、慢病毒介导的基因敲低 / 过表达，揭示 4-GBA 通过 SLC36A1 转运体激活 Hedgehog 信号通路，增强肠道干细胞（ISCs）功能并促进杯状细胞分化的核心机制；
- 挖掘临床转化价值：通过人类 UC 患者样本验证 SLC36A1 表达与疾病严重程度的相关性，同时发现 SLC36A1 激动剂肌氨酸可模拟 4-GBA 的保护作用，为 UC 治疗提供新方向。
整个研究中，结肠类器官模型是贯穿始终的核心实验平台，而 Absin abs9530 结肠类器官培养基则为该模型的稳定性、功能性和实验可重复性提供了关键保障。
二、四大核心成果，刷新肠道菌群 - 宿主互作认知
这项研究凭借严谨的实验设计和先进的技术手段，取得了四项突破性成果，为肠道疾病研究提供了全新视角：
成果 1：发现 4-GBA 是菌群来源的肠道屏障 "保护因子"
Bacteroides stercorirosoris产生的 4-GBA 是调控肠道稳态的关键代谢物，能显著上调结肠类器官及小鼠体内 MUC2 表达，增加杯状细胞数量（原文 Figure 1G-H），且 4-GBA 在人体中主要存在于粪便和尿液，其水平完全依赖肠道菌群（原文 Figure 1I-K），抗生素处理会显著降低其含量，粪菌移植可恢复。
成果 2：揭示 4-GBA 调控菌群结构的间接机制 —— 黏液依赖的生态位扩张
4-GBA 并非直接促进有益菌Akkermansia muciniphila生长，而是通过增强宿主黏液分泌，为其提供适宜的生存生态位，形成4-GBA→黏液分泌增加→Akkermansia富集→肠道屏障强化的正向反馈循环（原文 Figure 4），首次阐明菌群代谢物通过重塑宿主表型间接调控肠道菌群的新模式。
成果 3：鉴定 SLC36A1-Hedgehog 轴是 4-GBA 的核心调控通路
4-GBA 需通过肠道上皮细胞表面的 SLC36A1 转运体进入细胞，进而激活 Hedgehog 信号通路，上调肠道干细胞标志物（Lgr5、Ascl2）和杯状细胞分化因子（Atoh1、Spdef）（原文 Figure 5-6）；SLC36A1 基因敲低会完全阻断 4-GBA 的保护作用，证实该转运体是 4-GBA 发挥功能的 "必经之路"。
成果 4：证实 SLC36A1 是 UC 诊疗的潜在新靶点
临床样本分析显示，UC 患者结肠组织中 SLC36A1 表达显著降低，且与疾病严重程度（ESR、CRP、Mayo 内镜评分）呈负相关（原文 Figure 7D-G）；此外，SLC36A1 激动剂肌氨酸可显著减轻小鼠 DSS 诱导的结肠炎症状，为 UC 的诊断标志物开发和治疗药物研发提供了全新方向。
三、Absin abs9530：结肠类器官研究的 "稳定基石"，全程赋能核心实验
在这项研究中，爱必信 Absin abs9530 结肠类器官培养基被应用于结肠类器官的构建、细菌代谢物筛选、功能验证及机制探索等全核心实验环节（原文 2.3、2.5、3.1、3.5、3.6 节），成为实验顺利开展的关键工具，其核心作用体现在以下三大方面：
1. 支撑稳定、功能性结肠类器官模型的构建
研究人员将小鼠结肠隐窝分离后，接种于 Matrigel 中，使用Absin abs9530进行培养，成功构建了具有完整肠道上皮结构的结肠类器官模型。该培养基针对结肠类器官生长特性优化配方，含 Wnt3a、R-spondin 1、EGF 等肠道干细胞增殖与分化所需的关键细胞因子，能确保类器官在体外长期保持生理结构的完整性和细胞类型的异质性，准确模拟体内肠道上皮的生理状态，为后续实验奠定了可靠的模型基础。
2. 保障细菌代谢物筛选的准确性与可重复性
在 4-GBA 的筛选实验中，研究人员将结肠类器官与细菌上清共培养，通过检测 MUC2 表达筛选活性代谢物（原文 Figure 1）。Absin abs9530具有批次间差异小、稳定性强的特点，能让类器官在体外稳定生长并准确响应 4-GBA 的刺激，避免因培养基波动导致的实验误差，确保了从 297 株细菌中精准筛选出目标菌株及代谢物的实验结果可靠、可重复。
3. 兼容多类实验操作，支撑机制研究的全流程
在解析 4-GBA 调控机制的实验中，包括信号通路抑制剂干预（如 Hedgehog 抑制剂环巴胺）、慢病毒介导的 SLC36A1 敲低 / 过表达、类器官增殖与分化检测等（原文 Figure 5E-G、Figure 6D-J），Absin abs9530展现出ji佳的实验兼容性：既能支持类器官在药物处理、基因操作后的正常生长，又能保证类器官的功能特性不丢失，让研究人员能准确检测 4-GBA 对肠道干细胞功能、信号通路激活的调控作用，顺利解析 SLC36A1-Hedgehog 轴的核心机制。
简单来说，Absin abs9530 结肠类器官培养基凭借高活性、高稳定性、高兼容性的三大特性，成为该研究中结肠类器官模型的 "标配培养基"，为从代谢物筛选到机制解析的全流程实验提供了稳定、高效的支撑，是研究取得突破性成果的重要助力。
四、图文解析：Absin abs9530 助力的核心实验结果
图 1：4-GBA 促进结肠类器官杯状细胞分化（原文 Figure 1）
在Absin abs9530培养的结肠类器官中，4-GBA 处理后：①MUC2 mRNA 和蛋白表达显著上调（B、C、H）；②AB-PAS 染色阳性的杯状细胞数量明显增加（G）。证实 4-GBA 能特异性促进肠道黏液分泌，而这一关键筛选实验的顺利开展，依赖 abs9530 维持的类器官正常功能。
Figure 1. Commensal-derived 4-GBA expands goblet cells in colonic organoids. (A) Schematic representation of colonic organoid treated with fractionated (<3 kDa) metabolites from human gut commensal supernatants. Commensal bacterial strains were isolated from the fecal samples of healthy volunteers and taxonomically identified. Colonic organoids were exposed to <3 kDa fractions of culture supernatants derived from these strains. MUC2 expression was analyzed by qRT-PCR and immunofluorescence staining. Sodium butyrate was used as a positive control. (B and C) Colonic organoids isolated from WT mice were treated with commensal bacterial culture supernatants (25% v/v) for six consecutive days. (B) qRT-PCR analysis of MUC2 mRNA levels in colonic organoids. (C) Representative images and quantification of immunofluorescence staining against MUC2 in the indicated colonic organoid. (D and E) Untargeted metabolomics analysis of B. stercorirosoris supernatant using blank organoid medium and supernatant from the negative control strain B. intestinalis as controls. (D) KEGG enrichment analysis of 291 overlapped metabolites. (E) LC‒MS quantification of 4-GBA in the indicated supernatants. (F) qRT-PCR analysis of MUC2 mRNA levels in colonic organoids following a 4-d treatment with various metabolites at the indicated concentrations. (G and H) Colonic organoids isolated from WT mice were exposed to water (control) and 4-GBA (0.8 mM) for 4 d. (G) Alcian Blue–Periodic Acid Schiff (AB–PAS) staining in colonic organoid. (H) Representative images and quantification of immunofluorescence staining against MUC2 in colonic organoids. (I) LC‒MS quantification of 4-GBA in urine, feces, and plasma from 6 healthy volunteers. (J and K) The mice were assigned to the control (drinking water), Abx (antibiotics in the drinking water), and FMT (transplantation with healthy volunteers fecal microbiota after antibiotic treatment). Fecal samples were collected for 4-GBA quantification. (J) Schematic representation of the experimental workflow. (K) LC‒MS quantification of 4-GBA in fecal samples. The data are the mean ± SD. Scale bar: 50 μm. n = 4 (B, C, F, and H), n = 3 (E), n = 5 (G and K), n = 6 (I). One-way ANOVA (B, C, E, F, and K) or unpaired Student's t-test (G–I).
图 2：4-GBA 激活小鼠肠道干细胞增殖（原文 Figure 2）
体内实验证实 4-GBA 能增加 Lgr5-Tomato + 肠道干细胞比例和 Ki67 + 增殖细胞数量（L），上调干细胞标志物和杯状细胞分化因子（J）。而该结果的体外预实验验证，均基于Absin abs9530构建的结肠类器官模型完成，为体内实验提供了可靠的前期依据。
Figure 2. 4-GBA attenuates DSS-induced colitis. (A–G) Mice received 2% DSS in drinking water for 7 d with co-administration of either 4-GBA (150 mg/kg) or Ectoine (150 mg/kg). Analysis of disease activity index scores (A) and colon length (B) of the indicated mice. (C) Representative H&E staining analysis and quantitation of histopathological changes in colonic tissue. (D) AB–PAS staining and quantitation of colonic tissue. (E) Representative immunohistochemical analysis and quantitation of MUC2 in colonic tissue. (F) mRNA expression levels of proinflammatory cytokines and antimicrobial peptides in the colonic tissue. (G) Flow cytometry analysis of the indicated cells in mesenteric lymph nodes (MLN) and the colonic lamina propria (cLP) from the indicated mice. (H–J) WT mice received daily oral gavage of 4-GBA (150 mg/kg) for seven consecutive days. AB–PAS staining (H) and immunohistochemical analysis of MUC2 (I) in colonic tissue. (J) mRNA expression levels of Atoh1 and Spdef in the colonic tissue. (K and L) Lgr5-Tomato reporter mice received oral 4-GBA (150 mg/kg/d) or vehicle control for seven consecutive days. Tamoxifen (20 mg/kg/d, i.p.) was administered on days 5–7 to label Lgr5-Tomato+ cells. (K) Schematic of the workflow. (L) Representative images and quantification of the percentages of Tomato+ crypts and Ki-67+ cells among total crypts in mouse colon tissue. n > 15 crypts per measurement, n > 4 measurements per mouse, and n = 5 mice per group. The data are the mean ± SD. Scale bar: 10 μm or 50 μm. n = 8 (A–E, G–J), n = 5 (F and L). Two-way ANOVA (A), one-way ANOVA (B‒G) or unpaired Student's t-test (H–J, L).
图 3：SLC36A1 敲低阻断 4-GBA 对类器官的调控作用（原文 Figure 6）
在Absin abs9530培养的类器官中，慢病毒介导的 SLC36A1 敲低完全阻断了 4-GBA 的作用：①类器官形成效率和出芽能力显著降低（D）；②肠道干细胞标志物和 MUC2 表达被抑制（E）；③Ki67 + 增殖细胞和 MUC2 + 杯状细胞数量减少（G、H）。证实 SLC36A1 是 4-GBA 的关键转运体，而 abs9530 为基因操作后的类器官功能检测提供了稳定平台。
Figure 6. 4-GBA activates intestinal stemness via SLC36A1–Hedgehog signaling. (A) mRNA expression levels of SLC36A1 in organoids exposed to 4-GBA or the water control. (B) mRNA expression levels of SLC36A1 in the colonic tissue from antibiotic-treated mice following exposure to 4-GBA or the water control. (C) Representative images and quantification of immunofluorescence staining against SLC36A1 in the colonic tissue from antibiotic-treated mice following exposure to 4-GBA or the water control. (D–J) Colonic organoid isolated from WT mice (D and E, G–J) or Lgr5-Tomato reporter mice (F) were infected with lentiviral vectors encoding either scramble control or SLC36A1-targeting shRNA for 48 h, followed by 4-d exposure to 4-GBA (0.8 mM) or water control. (D) Representative images and quantification of organoid-forming efficiency and the number of buds per organoid. (E) mRNA expression levels of ISCs function markers (Lgr5, Ascl2, and Mki67) and goblet cells markers (Muc2) in the indicated organoid. (F) Tamoxifen (2 μM) was administered on days 2–4 post treatment-initiation to label Lgr5-Tomato+ ISCs. Representative images and quantification of Lgr5-Tomato+ ISCs in the indicated organoid. (G and H) Representative images and quantification of immunofluorescence staining against Ki67 (G) and MUC2 (H) in the indicated organoid. (I) mRNA expression levels of Ptch1 and Gli1 in the indicated organoid. (J) Representative images and quantification of immunofluorescence staining against Gli1 in the indicated organoid. Data are the mean ± SD. Scale bar: 10 μm or 50 μm. n = 4 (A, D–J), n = 8 (B), n = 8 (C). Unpaired Student's t-test (A‒C) or one-way ANOVA (D‒J).
五、技术赋能科研，Absin 助力肠道生物学研究新发展
肠道类器官技术作为近年来生命科学领域的热门技术，凭借其能模拟体内肠道生理状态的优势，已成为肠道菌群 - 宿主互作、肠道疾病机制、药物筛选等研究的核心工具。而优质的类器官培养基，是类器官技术应用的 "基础中的基础"。
爱必信 Absin 始终聚焦科研需求，打造高品质的类器官培养系列产品，其中abs9530 结肠类器官培养基经过大量实验验证，能为结肠类器官的长期稳定培养、功能验证、基因操作等提供全方位支持，已成为众多科研团队开展肠道类器官研究的优选产品。本次助力该研究登顶Gut Microbes，再次印证了 Absin 产品的品质与实力。
未来，Absin 将持续深耕类器官培养领域，不断优化产品配方，丰富产品系列（涵盖肠道、胃、肝脏等多种类器官培养基及配套试剂），为科研人员提供更全面、更高效的类器官培养解决方案，助力更多肠道生物学、炎症性肠病、肿瘤等领域的突破性研究成果诞生！
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