微生物学报

肠道微生物和宿主肠道干细胞互作机制的研究进展

PDF下载

郭芳申 , 甄文瑞 , 张祎 , 马彦博 , 李旺

微生物学报 | 综述 2026,66(2): 560-577

收起

微生物学报 | 综述 2026, 66(2): 560-577

肠道微生物和宿主肠道干细胞互作机制的研究进展

全屏

郭芳申, 甄文瑞, 张祎, 马彦博, 李旺

作者信息

河南科技大学动物科技学院，河南洛阳

Advances in the interaction mechanisms between gut microbiota and host intestinal stem cells

Fangshen GUO, Wenrui ZHEN, Yi ZHANG, Yanbo MA, Wang LI

Affiliations

College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, China

出版时间: 2026-02-04 doi: 10.13343/j.cnki.wsxb.20250648

文章导航

摘要

收起

肠黏膜上皮细胞种类和数量的稳定维持着肠道形态和功能的正常，而肠道上皮细胞稳态依赖位于隐窝处肠道干细胞(intestinal stem cells, ISCs)的不断增殖、分化和迁移。肠道共生微生物与ISCs相互作用，共同维持肠道生态稳定。ISCs分化形成的肠上皮细胞(intestinal epithelial cells, IECs)通过分泌免疫球蛋白、黏蛋白等调控肠道微生物的组成与功能。肠道共生微生物通过微生物相关分子模式(如脂磷壁酸、脂多糖)及微生物代谢物(如短链脂肪酸、胆汁酸)等构成了独特的肠道微环境，进而调控宿主ISCs功能及成熟细胞亚群稳态。基于肠道微生物靶向调控宿主ISCs功能以维护肠道健康已成为当前的研究热点。因此，本文重点阐述ISCs对肠道微生物区系的影响，以及肠道微生物及其代谢物对宿主ISCs增殖分化命运的调控作用，以期加深对肠道微生物和宿主ISCs相互作用的理解，为肠道功能及健康的调控提供理论参考。

关键词

肠道干细胞 / 肠道微生物 / 微生物代谢物

Abstract

收起

The gut structure and functional performance rely on the stable type and quantity of gut mucosal epithelial cells, whose stability depends on continuous proliferation, differentiation, and migration of intestinal stem cells (ISCs) located in the crypts. Interactions between gut microbiota and ISCs support the homeostasis of the gut ecosystem. Intestinal epithelial cells (IECs) differentiated from ISCs influence the composition and function of gut microbiota through secreting immunoglobulins, mucins, etc. Meanwhile, the microorganism-associated molecular patterns (such as lipoteichoic acid and lipopolysaccharides) and metabolites (such as short-chain fatty acids and bile acids) from gut microbiota form the unique gut microenvironment to regulate the activity of ISCs and the homeostasis of IECs. Regulating the activity of ISCs and gut health by modifying gut microbiota has become a focus of current research. Thus, this review elaborates on the impact of ISCs on the gut microbiota as well as the regulatory roles of gut microbiota and related metabolites on the proliferation and differentiation fate of ISCs, aiming to broaden the understanding of the interaction between gut microbiota and ISCs. It is expected to provide strategies and targets for the regulation on gut health.

Key words

intestinal stem cells / gut microbiota / microbial metabolites

引用本文

郭芳申, 甄文瑞, 张祎, 马彦博, 李旺. 肠道微生物和宿主肠道干细胞互作机制的研究进展. 微生物学报, 2026 , 66 (2) : 560 -577 . DOI: 10.13343/j.cnki.wsxb.20250648

Fangshen GUO, Wenrui ZHEN, Yi ZHANG, Yanbo MA, Wang LI. Advances in the interaction mechanisms between gut microbiota and host intestinal stem cells[J]. Acta Microbiologica Sinica, 2026 , 66 (2) : 560 -577 . DOI: 10.13343/j.cnki.wsxb.20250648

正文

收起

动物肠道上皮细胞(intestinal epithelial cells, IECs)主要由位于绒毛端的成熟上皮细胞、隐窝处的潘氏细胞与肠道干细胞(intestinal stem cells, ISCs)构成。肠道成熟上皮细胞可分为两大类，即吸收型细胞亚群(如肠细胞和M细胞等)和分泌型细胞亚群(如杯状细胞、潘氏细胞、Tuft细胞、肠内分泌细胞等)^[1]。不同类型的肠道上皮细胞协同发挥消化吸收和屏障防御功能。外界刺激会引起肠道上皮细胞衰老及损伤，因此ISCs不断分化产生子代细胞，对于黏膜上皮细胞的更新以及维持肠道形态和功能的正常发挥着不可替代的作用^[2]。作为宿主的“第二基因组”，肠道微生物是调控宿主ISCs增殖分化的重要因素^[3]。抗生素干预及无菌条件下动物ISCs分化形成子代细胞的能力受损^[4-5]。此外，肠道微生物相关分子模式[如脂磷壁酸(lipoteichoic acid, LTA)、脂多糖(lipopolysaccharide, LPS)等]及微生物代谢物[如色氨酸代谢物、短链脂肪酸(short-chain fatty acids, SCFAs)等]也参与构成可调控ISCs功能的干细胞龛^[6]。肠道共生微生物和ISCs的相互作用对于保障宿主肠道健康意义重大。因此，了解肠道微生物及其代谢产物和ISCs的相互作用，阐明肠道微生物调控ISCs增殖分化及肠道更新能力的机制对于利用微生态策略调控宿主肠道健康至关重要。

1 肠道干细胞

收起

1.1 肠道干细胞的分类

20世纪70年代，Cheng等^[2]发现隐窝底部的潘氏细胞之间存在1种细长的细胞，将其命名为隐窝基底柱状细胞；这类细胞可产生子代细胞，并持续沿隐窝-绒毛轴迁移形成新的肠道上皮细胞，因此也被称为肠道干细胞。肠道干细胞可分为2类：位于隐窝基底位置，由富含亮氨酸重复序列的G蛋白偶联受体5 (leucine-rich repeat-containing G-protein coupled receptor 5, Lgr5)标记的活化ISCs (Lgr5⁺ ISCs)；以及位于隐窝“+4”位置，由B细胞特异性白血病病毒插入位点(B cell-specific moloney murine leukemia virus integration site 1, Bmi-1)标记的储备ISCs (Bmi-1⁺ ISCs)^[1,7]。目前，也有学者使用嗅觉调节素4 (olfactomedin 4, Olfm4)或achaete-scute家族bHLH转录因子2 (achaete-scute family bHLH transcription factor 2, Ascl2)标记Lgr5⁺ ISCs，使用同源域蛋白同源盒(homeodomain-only protein homeobox, Hopx)、小鼠端粒酶逆转录酶(mouse telomerase reverse transcriptase, mTert)或富亮氨酸的重复序列和免疫球蛋白样结构域1 (leucine rich repeats and immunoglobulin like domains 1, Lrig1)标记Bmi-1⁺ ISCs^[7-8]。肠道更新依赖位于隐窝底部的Lgr5⁺ ISCs的增殖及分化，而位于隐窝“+4”位置的Bmi-1⁺ ISCs常处于静息状态^[9]。在不利条件下，当Lgr5⁺ ISCs受到损伤时静息的Bmi-1⁺ ISCs可产生子细胞，补充受损的Lgr5⁺ ISCs和肠道上皮细胞^[10]。因此，储备ISCs被认为是组织修复的后备干细胞。同时，在上皮损伤诱发的再生反应中未彻底分化的分泌和吸收型祖细胞也会去分化成为Lgr5⁺ ISCs以维持ISCs池稳态^[11]。

1.2 肠道干细胞的调控通路

Lgr5⁺ ISCs的增殖分化维持着肠道组织的更新。肠道上皮细胞、间充质细胞、免疫细胞和微生物等产生的调控ISCs更新、增殖和分化的信号分子所组成的微环境被称为干细胞生态位，主要包括Notch、Wnt、骨形态发生蛋白(bone morphogenetic protein, BMP)和表皮细胞生长因子(epidermal growth factor, EGF)等信号分子(图1)^[1]。干细胞之间会竞争肠道生态位，被“挤出”干细胞区的细胞在接触到不同浓度的分化调控因子时会发生分化^[12]。具体而言，当Lgr5⁺ ISCs细胞受到Notch信号通路效应分子hes家族bHLH转录因子1 (hes family bHLH transcription factor 1, Hes1)的刺激后，ISCs先转化为过渡放大(transit amplify, TA)细胞，进而分化为肠细胞^[13]。当细胞未受到Notch信号通路的刺激时会分化成分泌型肠上皮细胞祖细胞。迁移离开干细胞区的分泌型祖细胞在接收到Wnt信号刺激后会在上皮细胞之间的Eph-ephrin作用下返回隐窝底部，成为潘氏细胞^[14]。未受到Wnt蛋白刺激的分泌型祖细胞则分化成为杯状细胞、肠内分泌细胞或Tuft细胞。M细胞的分化不受Notch和Wnt通路的影响，主要是由派尔集合淋巴结中核因子受体激活因子-κB配体(receptor activator for nuclear factor-kappa B ligand, RANKL)直接刺激形成^[1]。

Notch信号通路是决定Lgr5⁺ ISCs分化命运的关键信号通路^[15]。Notch信号的激活依赖于配体呈递细胞和受体细胞之间的直接接触。因此，Notch配体如delta样配体(delta-like ligand, Dll) 1和Dll4主要由与ISCs相邻的间充质细胞和潘氏细胞提供^[16-17]。Notch配体和受体之间的相互作用会诱导受体细胞内形成Notch胞内结构域(Notch intracellular domain, NCID)^[18]。NCID与细胞核中免疫球蛋白κJ区重组信号结合蛋白(recombination signal binding protein for immunoglobulin kappa J region, RBPJ)结合，从而激活Hes1表达；Hes1通过抑制细胞周期蛋白依赖性激酶抑制剂p27KIP1和p57KIP2的表达促进Lgr5⁺ ISCs和TA细胞的快速增殖，最终使ISCs分化成为吸收型肠上皮细胞^[19]。无调性bHLH转录因子1 (atonal bHLH transcription factor 1, ATOH1)，也被称为小鼠无调性同源物1 (mouse atonal homolog 1, MATH1)，是促进Lgr5⁺ ISCs向分泌型肠道上皮细胞分化的转录因子。Notch信号通路靶基因Hes1是ATOH1的转录抑制因子，因此Notch的激活会通过抑制ATOH的表达，进而抑制Lgr5⁺ ISCs分化为分泌型肠道上皮细胞^[20]。

Wnt/β-catenin与Notch信号通路协同调控Lgr5⁺ ISCs的增殖分化命运。Wnt信号通路的激活可以上调ATOH1的表达，诱导Lgr5⁺ ISCs分化为分泌型肠道上皮细胞^[21]。潘氏细胞可产生Wnt3a，肠道间质细胞如Foxl1⁺、Gli1⁺或αSMA⁺细胞可以产生Wnt2b、Wnt4和Wnt5a等激活Wnt/β-catenin信号通路^[22-23]。Wnt配体与位于ISCs细胞膜上的Frizzled-LDL受体相关蛋白(LDL receptor related protein, LRP) 5/6受体复合物结合^[24]。复合物的形成会引起β-catenin从APC/Axin/GSK-3β复合体上解离并在胞内聚积；之后β-catenin入核，与TCF/LEF结合进而启动c-Myc和Cyclin D1等靶基因的表达，激活Lgr5⁺ ISCs的增殖和分化^[25]。

R-spondin也是ISCs生态位的重要组成成分。R-spondin可与Lgr5结合形成R-spondin-Lgr5复合物，该复合物作用于E3泛素连接酶Rnf43和ZNRF3，弱化其对Frizzled受体的抑制作用，从而增强Wnt信号通路的激活^[26-27]。与Wnt的来源一致，R-spondin主要由Foxl1⁺细胞分泌^[28]。

EGF是调节ISCs活性的一种外源性因子，主要由潘氏细胞和基质细胞分泌^[29]。EGF通过与膜受体酪氨酸激酶家族的ErbB1-4结合介导细胞通路转导，相关配体主要包括EGF、转化生长因子-α (transforming growth factor-α, TGF-α)、双调节蛋白(amphiregulin, AREG)、表观原(epigen, EPGN)、肝素结合EGF样生长因子(heparin-binding epidermal growth factor-like growth factor, HB-EGF)、表皮调节蛋白(epiregulin, EREG)、β细胞蛋白(betacellulin, BTC)和神经调节蛋白(neuregulin, NRG)等^[30-31]。EGF配体具有受体结合特异性，具体而言，EGF、TGF-α、AREG和EPGN与ErbB1受体特异性结合，HB-EGF、EREG和BTC与ErbB1和ErbB4特异性结合，NRG1和NRG2与ErbB3和ErbB4特异性结合，NRG3和NRG4与ErbB4特异性结合^[32]。EGF配体同ErbB受体结合后，引起受体细胞特定酪氨酸残基磷酸化^[33]。磷酸化残基通过激活丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)、磷脂酰肌醇3激酶-蛋白激酶B (phosphatidylinositol 3-kinase-protein kinase B, PI3K-AKT)和非受体型酪氨酸蛋白激酶-信号转导及转录激活因子(Janus kinase-signal transducer and activator of transcription, JAK-STAT)等通路，调控ISCs的增殖和分化^[34]。

BMP属于转化生长因子家族，由肠道间充质细胞产生，主要类型为BMP2和BMP4等。BMP2和BMP4与骨形态发生蛋白受体1A型(bone morphogenetic protein receptor type 1A, BMPR1A)结合激活SmaD蛋白，抑制Lgr5⁺ ISCs增殖，促进其分化^[35]。同时，隐窝周围的基质细胞，包括肌成纤维细胞和平滑肌细胞可分泌BMP抑制剂，如Noggin、Chorordins和Gremlins等，促进ISCs的增殖和更新^[36]。与Wnt信号相反，BMP浓度由隐窝底部至绒毛顶端逐渐升高，两者以冗余的方式建立ISCs分化生态梯度^[1]。

2 肠道干细胞对肠道微生物的影响

收起

Notch信号通路是决定ISCs分化命运的首要因素，其激活会促进ISCs向肠细胞分化^[15]。肠道固有层浆细胞分泌的多聚免疫球蛋白A (polymeric immunoglobulin A, pIgA)通过与肠细胞表达的多聚免疫球蛋白受体(polymeric immunoglobulin receptor, pIgR)结合运送到上皮细胞顶端膜，进而转化为分泌型免疫球蛋白A (secretory immunoglobulin A, sIgA)^[37]。sIgA可通过凝集或抑制细菌鞭毛蛋白(flagellin, Flg)的形成，进而限制潜在致病菌如分段丝状细菌和变形杆菌的生长；还可包裹共生菌如阿克曼氏菌属(Akkermansia)和乳杆菌属(Lactobacillus)等，增强其在肠黏膜中的黏附和定殖^[38-40]。肠碱性磷酸酶(intestinal alkaline phosphatase, IAP)主要由小肠细胞产生，通常被认为是肠细胞的标志物^[41]。IAP可将肠腔内微生物鞭毛蛋白、脂多糖、DNA中未甲基化的胞嘧啶-磷酸-鸟嘌呤序列(CpG-DNA)和腺苷酸二磷酸(uridine diphosphate, UDP)等去磷酸化以减弱其抗原活性和诱发肠道炎症反应的能力^[42-43]。同时，去磷酸化的LPS会阻碍Toll样受体(Toll like receptor, TLR)信号通路的激活，下调核因子κB (nuclear factor kappa-B, NF-κB)和促炎性细胞因子的表达^[44]。IAP也发挥调控肠道微生物区系组成的作用。IAP敲除小鼠肠道内好氧性革兰氏阴性细菌和总体细菌数量显著降低，而补充IAP能促进共生细菌的生长并抑制有害细菌的生长^[45-46]。

Notch信号通路的抑制会促进分泌型肠道上皮细胞亚群的形成^[15]。杯状细胞可分泌黏蛋白Mucin-2，参与构成肠道黏膜层^[47]。肠道黏液作为肠道共栖微生物的营养利用与栖息位点，构成了肠道的微生物屏障^[48-49]。潘氏细胞通过TLR和核苷酸结合寡聚化结构域(nucleotide binding oligomerization domain containing, NOD)样受体(NOD-like receptor, NLR)等模式识别受体(pattern recognition receptors, PRRs)感知微生物，进而释放抗菌肽来增强肠道抗菌防御功能。潘氏细胞主要分泌的抗菌肽是α-防御素，其通过破坏细菌的外膜，改变膜通透性及电导率，起到杀菌作用^[50]。溶菌酶通过破坏细菌细胞壁肽聚糖中的β-1,4-糖苷键，使细胞壁破裂，从而发挥杀菌作用^[51]。类似地，C型凝集素可与肽聚糖结合，产生对革兰氏阳性菌的杀伤作用^[52]。M细胞是肠道重要的抗原呈递细胞，其可摄取肠腔内抗原并呈递给免疫细胞如树突状细胞^[53]、巨噬细胞和B细胞等，从而诱导肠道免疫应答反应^[54-55]。总之，ISCs增殖分化功能相关调控因子通过改变肠道上皮细胞组成发挥对肠道微生物的调控作用。

3 肠道微生物对肠道干细胞的影响

收起

肠道共生微生物对ISCs增殖分化和黏膜上皮的更新起重要调控作用。研究表明无菌小鼠和抗生素处理的动物肠道上皮细胞增殖以及迁移活性降低，肠道成熟细胞亚群如杯状细胞和肠内分泌细胞数量减少^[56-57]。相反，无菌果蝇的肠内分泌细胞数量增多，而成肠细胞数量减少^[58]，这些差异可能由于不同物种间ISCs调控通路的不同所致。总而言之，肠道共生微生物对ISCs的增殖分化以及肠道成熟细胞谱系的形成具有重要调控作用。

3.1 微生物相关分子模式对肠道干细胞的影响

细菌细胞壁中的脂磷壁酸、LPS和胞壁酰二肽(muramyl dipeptide, MDP)等是宿主ISCs增殖分化及黏膜上皮细胞更新的重要调节因子(图2)。TLR和NLR在肠上皮细胞、内分泌细胞、免疫细胞以及ISCs中均有表达，通过识别病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)介导宿主对微生物的应答反应^[59-60]。TLR2可识别微生物来源的LTA和肽聚糖等^[61]。Riehl等^[62]发现来自鼠李糖乳杆菌(L. rhamnosus)的LTA通过TLR2刺激环氧化酶-2 (cyclooxygenase-2, COX-2)⁺间充质干细胞分泌前列腺素E2 (prostaglandin E2, PGE2)，保护ISCs免受辐射诱导的肠细胞凋亡。Hou等^[63]发现枯草芽孢杆菌(Bacillus subtilis)以LTA-TLR2依赖性方式抑制Notch通路激活，进而促进小鼠肠道分泌型上皮细胞亚群的形成。此外，TLR2促进葡聚糖硫酸钠(dextran sulphate sodium, DSS)刺激的小鼠肠道杯状细胞的再生，并通过诱导肠三叶因子3 (trefoil factor family-3, TFF3)表达抑制天冬氨酸特异性的半胱氨酸蛋白水解酶(cysteinyl aspartate specific proteinase, Caspase)-9介导的肠黏膜细胞凋亡^[64]。TLR4信号通路可抑制Wnt3a表达和受体LRP6的活性，抑制Wnt信号通路的激活^[65]。Sodhi等^[66]发现LPS通过激活TLR4促进糖原合成酶激酶-3β (glycogen synthase kinase-3β, GSK-3β)磷酸化，降低新生小鼠小肠β-catenin的表达从而抑制小鼠肠道的增殖活性。此外，LPS通过TLR4-β干扰素TIR结构域衔接蛋白(TIR-domain-containing adaptor inducing interferon-β, TRIF)依赖方式刺激p53上调的凋亡因子(p53 up-regulated modulator of apoptosis, PUMA)的表达，引起ISCs凋亡^[59]。类似地，小鼠大肠中定殖于隐窝处的核心微生物群以TLR4依赖的方式激活受体相互作用的丝氨酸-苏氨酸激酶3 (receptor-interacting serine-threonine kinase 3, RIPK3)介导的坏死性凋亡，抑制ISCs增殖^[67]。然而，TLR4的过表达会导致小鼠Lgr5⁺ ISCs中β-catenin的核积聚，引起小鼠ISCs和上皮细胞增殖能力的增加^[68]。类似地，细菌LPS、鞭毛蛋白和LTA与TLR的相互作用可上调ISCs中NADPH氧化酶1 (NADPH oxidase 1, NOX1)的表达，产生活性氧(reactive oxygen species, ROS)进而激活表皮生长因子受体(epidermal growth factor receptor, EGFR)表达从而引起ISCs的增殖以及肠黏膜损伤修复^[69-70]。DSS刺激下，TLR4通过激活COX-2/PGE2/EGFR信号通路从而刺激肠道上皮细胞的增殖^[71-72]。由此可知，不同来源配体激活的TLR4信号通路对ISCs的调控作用不同，同时不同生理状态下ISCs对TLR信号通路的响应也有差异。TLR对Notch信号通路的表达也具有调控作用。TLR4信号通路的沉默会降低小鼠肠道Notch配体的活性，从而导致Notch通路靶基因Hes1表达的下调^[64,73-74]。细菌鞭毛蛋白是TLR5的天然配体。Jones等^[75]发现，Flg通过激活TLR5上调丝裂原活化蛋白激酶磷酸酶7 (mitogen-activated protein kinase phosphatases 7, MKP-7)的表达，从而缓解小鼠肠黏膜损伤和细胞凋亡。此外，来自植物乳杆菌(L. plantarum) NCU116的胞外多糖可以通过增加ISCs的数量和分化能力，恢复结肠炎小鼠的肠道稳态^[76]。

核苷酸结合寡聚化结构域2 (nucleotide binding oligomerization domain containing 2, NOD2)是识别细菌胞壁酰二肽(muramyl-dipeptide, MDP)的关键受体，其在肠道潘氏细胞、免疫细胞和Lgr5⁺ ISCs中均表达^[77]。NOD2对ISCs损伤的保护作用依赖微生物来源的MDP^[78]。Nigro等^[78]研究发现MDP通过NOD2提高氧化应激状态下ISCs的存活和肠上皮再生。类似地，MDP通过NOD2激活自噬相关蛋白16L1 (autophagy related 16 like 1, ATG16L1)，从而促进辐射诱导的Lgr5⁺ ISCs线粒体自噬和ROS的清除^[79-81]。此外，NOD2对于肠道黏液的分泌也至关重要。NOD1/2双突变小鼠的Mucin-2表达水平降低，而NOD1/2激动剂的联合使用则促进其表达^[82]。总之，NOD受体驱动了应激状态下肠道干细胞的存活与黏膜上皮修复。

3.2 微生物代谢物对肠道干细胞的影响

3.2.1 短链脂肪酸

肠道微生物可利用宿主肠道内未消化的碳水化合物发酵产生短链脂肪酸，主要有乙酸盐、丙酸盐和丁酸盐等^[83]。SCFAs可通过激活游离脂肪酸受体(free fatty acid receptor, FFAR)促进肠道杯状细胞形成、肠道黏液的分泌以及抗菌肽如再生家族成员3γ (regenerating family member 3 gamma, RegIIIγ)和β-防御素等的产生^[84-86]。类似地，菊粉饲喂的小鼠结肠内乙酸、丙酸和丁酸等SCFAs含量显著提高，同时其结肠ISCs增殖和分化活性增强^[87]。黏蛋白降解菌嗜黏蛋白阿克曼氏菌(A. muciniphila)产生的乙酸通过激活FFAR2和FFAR3促进小鼠Lgr5⁺ ISCs的增殖以及小肠潘氏细胞和杯状细胞的形成^[56,88]。Bilotta等^[89]发现，丙酸能通过抑制组蛋白去乙酰化酶(histone deacetylase, HDAC)、激活FFAR2和STAT3等途径增加肠道上皮细胞的极化，促进成熟谱系细胞沿着隐窝-绒毛轴迁移。此外，丙酸能刺激肠上皮细胞Mucin-2表达，增强肠道黏液屏障功能^[90-91]。在DSS诱导的小鼠结肠炎模型中梭菌XIV (Clostridia clusters XIV)分泌的丙酸能缓解ISCs损伤，维持黏膜屏障功能^[92]。丁酸主要由普氏栖粪杆菌(Faecalibacterium prausnitzii)和罗斯拜瑞氏菌(Roseburia)等产生^[93]。肠道中多数丁酸盐被肠道上皮细胞用于β-氧化和三羧酸循环(tricarboxylic acid cycle, TCA)以提供能量，同时降低肠道内氧气含量(图3)^[94-95]。Donohoe等^[96]发现，添加丁酸能缓解无菌小鼠由于丁酸缺乏导致的ISCs能量代谢紊乱和细胞自噬。丁酸代谢产生的生理性缺氧微环境可维持肠道缺氧诱导转录因子-1α (hypoxia inducible factor-1α, HIF-1α)的表达，进而调控杯状细胞Mucin-2的表达和分泌^[95,97]。肠上皮细胞对丁酸的利用可形成代谢屏障，维持隐窝内低浓度丁酸盐水平^[96]。适宜浓度的丁酸盐可通过抑制HDAC提高细胞周期负调节因子Foxo3表达，进而抑制ISCs的异常增殖^[98]。类似地，普氏栖粪杆菌(F. prausnitzii)来源的丁酸可以通过下调HDAC3表达抑制ISCs向Tuft细胞的分化^[99]。此外，过量的丁酸盐可诱导肠上皮细胞热休克蛋白(heat shock proteins, HSP)的表达，从而干扰Wnt信号通路的激活和ISCs稳态^[100]。在卵清蛋白致敏小鼠模型中丁酸盐抑制肠上皮细胞中ROS的产生，下调Notch配体Jagged1的表达从而抑制Notch通路的激活^[101]。

乳酸和琥珀酸盐等SCFAs的中间代谢物也是ISCs增殖分化的调节分子。乳酸菌产生的乳酸以G蛋白偶联受体81 (G protein-coupled receptor 81, GPR81)依赖性方式激活Wnt/β- catenin通路，促进ISCs的增殖^[102-103]。琥珀酸盐对肠道的影响存在争议。琥珀酸盐可抑制肠上皮增殖，诱发肠道炎症反应，进而引起肠道黏膜损伤^[104-106]。然而，相反的研究结果表明，肠道微生物来源的琥珀酸盐通过参与TCA来诱导Tuft细胞形成，从而减轻克罗恩病小鼠回肠炎症反应和屏障功能损伤^[107]。类似地，琥珀酸通过激活琥珀酸受体1 (succinate receptor 1, SUCNR1)，改善高脂饲喂小鼠肠道杯状细胞的产生和黏液的分泌障碍^[108]。

3.2.2 胆汁酸

胆汁酸是肝脏以胆固醇为原料合成的胆烷酸物质。在肝细胞中直接合成的胆汁酸称为初级胆汁酸，包括胆酸(cholic acid, CA)、鹅脱氧胆酸(chenodeoxycholic acid, CDCA)及其与甘氨酸或牛磺酸的结合物^[109]。次级胆汁酸是初级胆汁酸经肠道细菌7α-脱羟作用所形成的胆汁酸，主要包括脱氧胆酸(deoxycholic acid, DCA)和石胆酸(lithocholic acid, LCA)及其与甘氨酸或牛磺酸的结合物^[110]。根据合成途径和结构的不同，胆汁酸可分为12α-羟基化胆汁酸(12α-OH BAs, CA、DCA及其结合物)和非12α-OH BAs [CDCA及其衍生物熊去氧胆酸(ursodeoxycholic acid, UDCA)、石胆酸及其结合物]^[111]，两者对ISCs的增殖分化功能具有相反的调控作用(图4)。在炎症性肠病(inflammatory bowel disease, IBD)个体中胆酸通过抑制过氧化物酶体增殖物激活受体α (peroxisome proliferators-activated receptor α, PPARα)的活性，抑制脂肪酸氧化和Lgr5⁺ ISCs的自我更新^[112]。奥贝胆酸(obeticholic acid, OCA)可通过法尼醇X受体(farnesoid X receptor, FXR)-细胞色素P450家族8亚家族B成员1 (cytochrome P450 family 8 subfamily B member 1, CYP8B1)信号通路恢复受损的黏膜上皮更新能力^[112]。高脂饲喂诱发的DCA循环水平提高会引起小鼠肠道内质网应激，从而降低ISCs增殖和分化为杯状细胞的能力^[113]。类似地，DCA可通过FXR依赖机制引起类固醇受体辅激活因子(steroid receptor coactivator, Src)/EGFR/细胞外信号调节激酶(extracellular signal regulated kinases, Erk)蛋白失活从而抑制肠细胞增殖^[114]。与之相反，在受损肠道的上皮再生过程中非12α-OH胆汁酸LCA通过G蛋白偶联受体TGR5激活Src/Yes相关蛋白(Yes-associated protein, YAP)和下游靶标基因促进ISCs更新和肠内分泌细胞的形成^[115]。类似地，UDCA通过抑制FXR活性并增加结肠上皮细胞囊性纤维化跨膜传导调节因子(cystic fibrosis transmembrane conductance regulator, CFTR) Cl通道的表达，以促进肠黏膜愈合^[116]。Yamada等^[117]发现，一种具有维生素D样活性的石胆酸衍生物可上调肠道类器官发育成熟标志基因CYP3A4的表达。总之，12α-羟基化胆汁酸如胆酸与非12α-羟基化胆汁酸如脱氧胆酸和石胆酸等对ISCs增殖和分化功能具有不同的调控作用，两者共同构成维持肠道干细胞稳态的胆汁酸调控微环境。

3.2.3 色氨酸代谢物

色氨酸侧链上的吲哚基团可被宿主和微生物代谢为吲哚衍生物，如色胺、吲哚、3-甲基吲哚、吲哚-3-乳酸(indole-3-lactic acid, ILA)、吲哚-3-乙酸(indole-3-acetic acid, IAA)、吲哚-3-丙酸(indolyl-3-propionic acid, IPA)、吲哚-3-丙烯酸(3-indoleacrylic acid, IA)、吲哚-3-甲醛(indole-3-aldehyde, IAld)和吲哚-3-乙醇(3-indoleethanol, IE)等^[118-119]。这些代谢物可激活芳香烃受体(aryl hydrocarbon receptor, AhR)和孕烷X受体(pregnane X receptor, PXR)等^[119-120]。AhR在小鼠Lgr5⁺ ISCs中高度表达，其可通过上调E3泛素连接酶Rnf43和Znrf3表达进而抑制Wnt/β- catenin信号通路的激活^[121-122]，因此Ahr^-/-小鼠表现出β-catenin表达异常升高，胃肠道出现炎症反应、增生和肿瘤等情况^[123-124]。在体和离体研究发现，吲哚-3-甲醇(indole-3-carbinol, I3C)以AhR依赖方式调控Wnt信号通路的激活，抑制ISCs的异常增殖^[122,125]。此外，肠道微生物如乳杆菌(Lactobacillus)、梭菌(Clostridium)和双歧杆菌(Bifidobacterium)等可以分解色氨酸，产生吲哚、色胺和IAld等激活AhR，进而产生白细胞介素(interleukin, IL)-22^{[118,126-128]}。IL-22可以活化STAT3信号通路，刺激Lgr5⁺ ISCs增殖分化以修复受损的肠黏膜^[126]。类似地，肠道微生物色氨酸代谢产物IAld通过促进ISCs的增殖来缓解断奶仔猪肠道发育受损^[129]。罗素氏消化链球菌(Peptostreptococcus russellii)产生的吲哚-3-丙烯酸可以激活AhR，增强结肠炎小鼠肠道杯状细胞的增殖和Ki67的表达^[130]。近期也有研究发现，色氨酸代谢产物5-羟基吲哚乙酸(5-hydroxyindole acetic acid, 5HIAA)和犬尿氨酸等通过激活AhR信号通路来缓解小鼠结肠炎^[131-132]。别样杆菌属(Alistipes)色氨酸代谢物吲哚及其衍生物(吲哚-3-乙醛、吲哚丙酮酸和IAA)激活AhR/ARNT信号通路，上调老龄鼠肠道干细胞标记物Lgr5的表达^[133]。结直肠癌患者相关研究发现，不动杆菌(Acinetobacter)分泌的IAA通过AhR-Wnt-β-catenin轴抑制干细胞的更新，维持干细胞稳态^[134]。此外，微生物来源的5-羟色胺通过5-羟色胺2A受体(5-HT2A receptor, HTR2A)和HTR3A激活巨噬细胞产生PGE2，PGE2通过前列腺素E2受体亚型1 (PGE2 receptor 1, EP1)和EP4促进ISCs的Wnt/β-catenin信号表达，以促进ISCs的自我更新^[135]。

3.2.4 多胺

多胺类物质由细菌利用鸟氨酸或精氨酸产生，主要包括腐胺、亚精胺和精胺等^[136-137]。多胺类物质如腐胺可直接作为能量来源促进肠道上皮细胞的更新^[138]。Bardócz等^[138]发现肠细胞摄取的腐胺约30%可转化为琥珀酸参与ISCs能量代谢。同时，多胺类物质可通过抑制TGF-β/Smads信号传导，上调Wnt信号通路从而促进ISCs的增殖^[139-141]。

4 总结与展望

收起

综上所述，ISCs稳态及宿主肠道健康与肠道共生微生物密切相关。肠道细菌及其代谢物可通过模式识别受体、G蛋白偶联受体和芳香烃受体等调控肠道干细胞的分化、更新，以及肠道的发育和损伤后修复等。因此，加强ISCs和肠道菌群相互作用及其机制研究具有重要意义。抗生素干预或无菌动物模型是研究肠道微生物与ISCs相互作用的常用方法，但这些策略通常难以揭示发挥关键作用的核心菌株。通过构建模拟宿主肠道菌群结构和功能的合成微生物群落可为解析特定关键微生物对ISCs的调控机制提供有效策略。3D类器官培养技术和器官芯片的发展为ISCs与肠道微生物之间的相互作用提供了新的体外研究途径，但类器官的封闭性结构对于微生物和ISCs的互作研究局限较大。此外，类器官体外培养体系中缺乏完整的肠道微环境组分，肠道免疫系统和神经系统等如何调节ISCs命运的具体机制还需深入研究。ISCs是肠道抵御病原体的关键，不同病原体通过何种策略操控ISCs更新和分化活性，以及肠道共生微生物如何介导这些影响，相关研究还需深入。

基金

收起

河南省自然科学基金青年项目(252300421652)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

BEUMER

, CLEVERS

. Cell fate specification and differentiation in the adult mammalian intestine[J]. Nature Reviews Molecular Cell Biology, 2020, 22(1): 39-53.

[2]

CHENG

, LEBLOND

. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine I. Columnar cell[J]. American Journal of Anatomy, 1974, 141(4): 461-479.

[3]

LUO

, LI

, WANG

, YANG

, WANG

, ZHAO

, DU

, CHEN

, SHEN

, ZHAO

, ZENG

, WANG

, CHEN

, LI

, SUN

, GU

, WEN

, XIAO

, WU

. The role of intestinal stem cell within gut homeostasis: focusing on its interplay with gut microbiota and the regulating pathways[J]. International Journal of Biological Sciences, 2022, 18(13): 5185-5206.

[4]

ZHOU

, YU

, CAO

, YU

, LIN

, HONG

, JIANG

, CHEN

, MI

, ZHANG

, LI

. Lactobacillus salivarius promotion of intestinal stem cell activity in hens is associated with succinate-induced mitochondrial energy metabolism[J]. mSystems, 2022, 7(6): e0090322.

[5]

SCHOENBORN

, von FURSTENBERG

, VALSARAJ

, HUSSAIN

, STEIN

, SHANAHAN

, HENNING

, GULATI

. The enteric microbiota regulates jejunal Paneth cell number and function without impacting intestinal stem cells[J]. Gut Microbes, 2019, 10(1): 45-58.

[6]

, CHEN

, JOHNSTON

, MA

. Gut microbiota-stem cell niche crosstalk: a new territory for maintaining intestinal homeostasis[J]. iMeta, 2022, 1(4): e54.

[7]

BARKER

, van

ES JH

, KUIPERS

, KUJALA

, van den BORN

, COZIJNSEN

, HAEGEBARTH

, KORVING

, BEGTHEL

, PETERS

, CLEVERS

. Identification of stem cells in small intestine and colon by marker gene Lgr5[J]. Nature, 2007, 449(7165): 1003-1007.

[8]

MONTGOMERY

, CARLONE

, RICHMOND

, FARILLA

, KRANENDONK

MEG

, HENDERSON

, BAFFOUR-AWUAH

, AMBRUZS

, FOGLI

, ALGRA

, BREAULT

. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(1): 179-184.

[9]

BLOEMENDAAL

ALA

, BUCHS

, GEORGE

, GUY RJ. Intestinal stem cells and intestinal homeostasis in health and in inflammation: a review[J]. Surgery, 2016, 159(5): 1237-1248.

[10]

, QI

, WEI

, RAO

, LUO

, ZOU

, MI

, ZHANG

, LI

. Krüppel-like factor 5 activates chick intestinal stem cell and promotes mucosal repair after impairment[J]. Cell Cycle, 2023, 22(19): 2142-2160.

[11]

AYYAZ

, KUMAR

, SANGIORGI

, GHOSHAL

, GOSIO

, OULADAN

, FINK

, BARUTCU

, TRCKA

, SHEN

, CHAN

, WRANA

, GREGORIEFF

. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell[J]. Nature, 2019, 569(7754): 121-125.

[12]

RITSMA

, ELLENBROEK

SIJ

, ZOMER

, SNIPPERT

, de SAUVAGE

, SIMONS

, CLEVERS

, van RHEENEN

. Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging[J]. Nature, 2014, 507(7492): 362-365.

[13]

SHROYER

, HELMRATH

, WANG

, ANTALFFY

, HENNING

, ZOGHBI

. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis[J]. Gastroenterology, 2007, 132(7): 2478-2488.

[14]

BATLLE

, HENDERSON

, BEGHTEL

, van den BORN

MMW

, SANCHO

, HULS

, MEELDIJK

, ROBERTSON

, van de WETERING

, PAWSON

, CLEVERS

. β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB[J]. Cell, 2002, 111(2): 251-263.

[15]

FRE S, HUYGHE

, MOURIKIS

, ROBINE

, LOUVARD

, ARTAVANIS-TSAKONAS

. Notch signals control the fate of immature progenitor cells in the intestine[J]. Nature, 2005, 435(7044): 964-968.

[16]

SANTOS

AJM

, LO YH, MAH AT, KUO

. The intestinal stem cell niche: homeostasis and adaptations[J]. Trends in Cell Biology, 2018, 28(12): 1062-1078.

[17]

DEMITRACK

, SAMUELSON

. Notch regulation of gastrointestinal stem cells[J]. The Journal of Physiology, 2016, 594(17): 4791-4803.

[18]

BRAY

. Notch signalling in context[J]. Nature Reviews Molecular Cell Biology, 2016, 17(11): 722-735.

[19]

RICCIO

, van GIJN

, BEZDEK

, PELLEGRINET

, van

ES JH

, ZIMBER-STROBL

, STROBL

, HONJO

, CLEVERS

, RADTKE

. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2[J]. EMBO Reports, 2008, 9(4): 377-383.

[20]

JENSEN

, PEDERSEN

, GALANTE

, HALD

, HELLER

, ISHIBASHI

, KAGEYAMA

, GUILLEMOT

, SERUP

, MADSEN

. Control of endodermal endocrine development by Hes-1[J]. Nature Genetics, 2000, 24(1): 36-44.

[21]

TIAN

, BIEHS

, CHIU

, SIEBEL

, WU

, COSTA

, de SAUVAGE

, KLEIN

. Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis[J]. Cell Reports, 2015, 11(1): 33-42.

[22]

FARIN

, van

ES JH

, CLEVERS

. Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells[J]. Gastroenterology, 2012, 143(6): 1518-1529.e7.

[23]

VALENTA

, DEGIRMENCI

, MOOR

, HERR

, ZIMMERLI

, MOOR

, HAUSMANN

, CANTÙ

, AGUET

, BASLER

. Wnt ligands secreted by subepithelial mesenchymal cells are essential for the survival of intestinal stem cells and gut homeostasis[J]. Cell Reports, 2016, 15(5): 911-918.

[24]

GAMMONS

, RENKO

, JOHNSON

, RUTHERFORD

, BIENZ

. Wnt signalosome assembly by DEP domain swapping of dishevelled[J]. Molecular Cell, 2016, 64(1): 92-104.

[25]

LIU

, XIAO

, NIU

, LI

, ZHANG

, ZHOU

, SHU

, YIN

. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities[J]. Signal Transduction and Targeted Therapy, 2022, 7: 3.

[26]

KOO BK, SPIT

, JORDENS

, LOW TY, STANGE

, van de WETERING

, van

ES JH

, MOHAMMED

, HECK

AJR

, MAURICE

, CLEVERS

. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors[J]. Nature, 2012, 488(7413): 665-669.

[27]

HAO

, XIE

, ZHANG

, CHARLAT

, OSTER

, AVELLO

, LEI

, MICKANIN

, LIU

, RUFFNER

, MAO

, MA

, ZAMPONI

, BOUWMEESTER

, FINAN

, KIRSCHNER

, PORTER

, SERLUCA

, CONG

. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner[J]. Nature, 2012, 485(7397): 195-200.

[28]

KANG

, YOUSEFI

, GRUENHEID

. R-spondins are expressed by the intestinal stroma and are differentially regulated during Citrobacter rodentium- and DSS-induced colitis in mice[J]. PLoS One, 2016, 11(4): e0152859.

[29]

SATO

, van

ES JH

, SNIPPERT

, STANGE

, VRIES

, van den BORN

, BARKER

, SHROYER

, van de WETERING

, CLEVERS

. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts[J]. Nature, 2010, 469(7330): 415-418.

[30]

DOWNWARD

, YARDEN

, MAYES

, SCRACE

, TOTTY

, STOCKWELL

, ULLRICH

, SCHLESSINGER

, WATERFIELD

. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences[J]. Nature, 1984, 307(5951): 521-527.

[31]

PLOWMAN

, CULOUSCOU

, WHITNEY

, GREEN

, CARLTON

, FOY L, NEUBAUER

, SHOYAB

. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family[J]. Proceedings of the National Academy of Sciences of the United States of America, 1993, 90(5): 1746-1750.

[32]

ABUD

, CHAN

, JARDÉ

. Source and impact of the EGF family of ligands on intestinal stem cells[J]. Frontiers in Cell and Developmental Biology, 2021, 9: 685665.

[33]

LEMMON

, SCHLESSINGER

, FERGUSON

. The EGFR family: not so prototypical receptor tyrosine kinases[J]. Cold Spring Harbor Perspectives in Biology, 2014, 6(4): a020768.

[34]

IWAKURA

, NAWA

. ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson’s disease[J]. Frontiers in Cellular Neuroscience, 2013, 7: 4.

[35]

, LI

, ZHAO

, XU

, LIU

, LI

, ZHANG

, WANG

, YANG

, XIE

, LI

, HAN

, CHEN

. BMP restricts stemness of intestinal Lgr5⁺ stem cells by directly suppressing their signature genes[J]. Nature Communications, 2017, 8: 13824.

[36]

KOSINSKI

, LI

VSW

, CHAN

ASY

, ZHANG

, HO C, TSUI

, CHAN

, MIFFLIN

, POWELL

, YUEN

, LEUNG

, CHEN

. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors[J]. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(39): 15418-15423.

[37]

吴元霞, 孙静, 葛良鹏, 李周权, 张进威. SIgA与哺乳动物肠道菌群互作的研究进展[J]. 生命科学, 2023, 35(6): 733-742.

, SUN

, GE

, LI

, ZHANG

. Progress in the interaction between SIgA and mammalian gut flora[J]. Chinese Bulletin of Life Sciences, 2023, 35(6): 733-742 (in Chinese).

[38]

GOGUYER-DESCHAUMES

, WAECKEL

, KILLIAN

, ROCHEREAU

, PAUL

. Metabolites and secretory immunoglobulins: messengers and effectors of the host-microbiota intestinal equilibrium[J]. Trends in Immunology, 2022, 43(1): 63-77.

[39]

MATHIAS

, CORTHÉSY

. N-Glycans on secretory component: mediators of the interaction between secretory IgA and Gram-positive commensals sustaining intestinal homeostasis[J]. Gut Microbes, 2011, 2(5): 287-293.

[40]

YANG

, PALM

. Immunoglobulin A and the microbiome[J]. Current Opinion in Microbiology, 2020, 56: 89-96.

[41]

HODIN

, CHAMBERLAIN

, MENG

. Pattern of rat intestinal brush-border enzyme gene expression changes with epithelial growth state[J]. The American Journal of Physiology, 1995, 269(2 Pt 1): C385-C391.

[42]

HAMARNEH

, MOHAMED

, ECONOMOPOULOS

, MORRISON

, PHUPITAKPHOL

, TANTILLO

, GUL SS, GHAREDAGHI

, TAO

, KALIANNAN

, NARISAWA

, MILLÁN

, van der WILDEN

, FAGENHOLZ

, MALO

, HODIN

. A novel approach to maintain gut mucosal integrity using an oral enzyme supplement[J]. Annals of Surgery, 2014, 260(4): 706-714.

[43]

CHEN

, MALO

, MOSS

, ZELLER

, JOHNSON

, EBRAHIMI

, MOSTAFA

, ALAM

, RAMASAMY

, WARREN

, HOHMANN

, HODIN

. Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2010, 299(2): G467-G475.

[44]

GHOSH

, WANG

, YANNIE

, GHOSH

. Intestinal barrier dysfunction, LPS translocation, and disease development[J]. Journal of the Endocrine Society, 2020, 4(2): bvz039.

[45]

MALO

, ALAM

, MOSTAFA

, ZELLER

, JOHNSON

, MOHAMMAD

, CHEN

, MOSS

, RAMASAMY

, FARUQUI

, HODIN

, MALO

, EBRAHIMI

, BISWAS

, NARISAWA

, MILLÁN

, WARREN

, KAPLAN

, KITTS

, HOHMANN

, et al. Intestinal alkaline phosphatase preserves the normal homeostasis of gut microbiota[J]. Gut, 2010, 59(11): 1476-1484.

[46]

MIZUMORI

, HAM M, GUTH

, ENGEL

, KAUNITZ

, AKIBA

. Intestinal alkaline phosphatase regulates protective surface microclimate pH in rat duodenum[J]. The Journal of Physiology, 2009, 587(14): 3651-3663.

[47]

HANSSON

. Mucins and the microbiome[J]. Annual Review of Biochemistry, 2020, 89: 769-793.

[48]

MOTTA

, WALLACE

, BURET

, DERAISON

, VERGNOLLE

. Gastrointestinal biofilms in health and disease[J]. Nature Reviews Gastroenterology & Hepatology, 2021, 18(5): 314-334.

[49]

STAHL

, TREMBLAY

, MONTERO

, VOGL

, XIA

, JACOBSON

, MENENDEZ

, VALLANCE

. The Muc2 mucin coats murine Paneth cell granules and facilitates their content release and dispersion[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2018, 315(2): G195-G205.

[50]

AYABE

, SATCHELL

, WILSON

, PARKS

, SELSTED

, OUELLETTE

. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria[J]. Nature Immunology, 2000, 1(2): 113-118.

[51]

, BALASUBRAMANIAN

, LAUBITZ

, TONG

, BANDYOPADHYAY

, LIN

, FLORES

, SINGH

, LIU

, MACAZANA

, ZHAO

, BÉGUET-CRESPEL

, PATIL

, MIDURA-KIELA

, WANG

, YAP GS, FERRARIS

, WEI

, BONDER

, HÄGGBLOM

, et al. Paneth cell-derived lysozyme defines the composition of mucolytic microbiota and the inflammatory tone of the intestine[J]. Immunity, 2020, 53(2): 398-416.e8.

[52]

DARNAUD

, dos SANTOS

, GONZALEZ

, AUGUI

, LACOSTE

, DESTERKE

, de HERTOGH

, VALENTINO

, BRAUN

, ZHENG

, BOISGARD

, NEUT

, DUBUQUOY

, CHIAPPINI

, SAMUEL

, LEPAGE

, GUERRIERI

, DORÉ

, BRÉCHOT

, MONIAUX

, et al. Enteric delivery of regenerating family member 3 alpha alters the intestinal microbiota and controls inflammation in mice with colitis[J]. Gastroenterology, 2018, 154(4): 1009-1023.e14.

[53]

SCHULZ

, PABST

. Antigen sampling in the small intestine[J]. Trends in Immunology, 2013, 34(4): 155-161.

[54]

KOMBAN

, STRÖMBERG

, BIRAM

, CERVIN

, LEBRERO-FERNÁNDEZ

, MABBOTT

, YRLID

, SHULMAN

, BEMARK

, LYCKE

. Activated Peyer’s patch B cells sample antigen directly from M cells in the subepithelial dome[J]. Nature Communications, 2019, 10: 2423.

[55]

REBOLDI

, ARNON

, RODDA

, ATAKILIT

, SHEPPARD

, CYSTER

. IgA production requires B cell interaction with subepithelial dendritic cells in Peyer’s patches[J]. Science, 2016, 352(6287): aaf4822.

[56]

PARK

, KOTANI

, KONNO

, SETIAWAN

, KITAMURA

, IMADA

, USUI

, HATANO

, SHINOHARA

, SAITO

, MURATA

, MATOZAKI

. Promotion of intestinal epithelial cell turnover by commensal bacteria: role of short-chain fatty acids[J]. PLoS One, 2016, 11(5): e0156334.

[57]

GUO

, QIAO

, HU

, HUANG

, BI

, ABBAS

, ZHEN

, GUO

, WANG

. Yeast cell wall polysaccharides accelerate yet in-feed antibiotic delays intestinal development and maturation via modulating gut microbiome in chickens[J]. Journal of Animal Science and Biotechnology, 2025, 16(1): 14.

[58]

BRODERICK

, BUCHON

, LEMAITRE

. Microbiota-induced changes in Drosophila melanogaster host gene expression and gut morphology[J]. mBio, 2014, 5(3): e01117-14.

[59]

NEAL

, SODHI

, JIA

, DYER

, EGAN

, YAZJI

, GOOD

, AFRAZI

, MARINO

, SLAGLE

, MA

, BRANCA

, PRINDLE

, GRANT

, OZOLEK

, HACKAM

. Toll-like receptor 4 is expressed on intestinal stem cells and regulates their proliferation and apoptosis via the p53 up-regulated modulator of apoptosis[J]. Journal of Biological Chemistry, 2012, 287(44): 37296-37308.

[60]

HISAMATSU

, SUZUKI

, REINECKER

, NADEAU

, McCORMICK

, PODOLSKY

. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells[J]. Gastroenterology, 2003, 124(4): 993-1000.

[61]

LEBEER

, VANDERLEYDEN

, de KEERSMAECKER

SCJ

. Host interactions of probiotic bacterial surface molecules: comparison with commensals and pathogens[J]. Nature Reviews Microbiology, 2010, 8(3): 171-184.

[62]

RIEHL

, ALVARADO

, EE XP, ZUCKERMAN

, FOSTER

, KAPOOR

, THOTALA

, CIORBA

, STENSON

. Lactobacillus rhamnosus GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells[J]. Gut, 2019, 68(6): 1003-1013.

[63]

HOU

, JIA

, LIN

, ZHU

, XIE

, YU

, LI

. Bacillus subtilis programs the differentiation of intestinal secretory lineages to inhibit Salmonella infection[J]. Cell Reports, 2022, 40(13): 111416.

[64]

PODOLSKY

, GERKEN

, EYKING

, CARIO

. Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency[J]. Gastroenterology, 2009, 137(1): 209-220.

[65]

, PATEL

, SODHI

, HACKAM

. Novel role for the innate immune receptor Toll-like receptor 4 (TLR4) in the regulation of the Wnt signaling pathway and photoreceptor apoptosis[J]. PLoS One, 2012, 7(5): e36560.

[66]

SODHI

, SHI

, RICHARDSON

, GRANT

, SHAPIRO

, PRINDLE

, BRANCA

, RUSSO

, GRIBAR

, MA

, HACKAM

. Toll-like receptor-4 inhibits enterocyte proliferation via impaired β-catenin signaling in necrotizing enterocolitis[J]. Gastroenterology, 2010, 138(1): 185-196.

[67]

NAITO

, MULET

, de CASTRO

, MOLINARO

, SAFFARIAN

, NIGRO

, BÉRARD

, CLERC

, PEDERSEN

, SANSONETTI

, PÉDRON

. Lipopolysaccharide from crypt-specific core microbiota modulates the colonic epithelial proliferation-to-differentiation balance[J]. mBio, 2017, 8(5): e01680-17.

[68]

SANTAOLALLA

, SUSSMAN

, RUIZ

, DAVIES

, PASTORINI

, ESPAÑA

, SOTOLONGO

, BURLINGAME

, BEJARANO

, PHILIP

, AHMED

, KO J, DIRISINA

, BARRETT

, SHANG

, LIRA

, FUKATA

, ABREU

. TLR4 activates the β-catenin pathway to cause intestinal neoplasia[J]. PLoS One, 2013, 8(5): e63298.

[69]

Van der POST

, BIRCHENOUGH

GMH

, HELD

. NOX1-dependent redox signaling potentiates colonic stem cell proliferation to adapt to the intestinal microbiota by linking EGFR and TLR activation[J]. Cell Reports, 2021, 35(1): 108949.

[70]

ALAM

, LEONI

, WENTWORTH

, KWAL

, WU

, ARDITA

, SWANSON

, LAMBETH

, JONES

, NUSRAT

, NEISH

. Redox signaling regulates commensal-mediated mucosal homeostasis and restitution and requires formyl peptide receptor 1[J]. Mucosal Immunology, 2014, 7(3): 645-655.

[71]

FUKATA

, CHEN

, KLEPPER

, KRISHNAREDDY

, VAMADEVAN

, THOMAS

, XU

, INOUE

, ARDITI

, DANNENBERG

, ABREU

. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine[J]. Gastroenterology, 2006, 131(3): 862-877.

[72]

HSU

, FUKATA

, HERNANDEZ

, SOTOLONGO

, GOO T, MAKI

, HAYES

, UNGARO

, CHEN

, BREGLIO

, XU

, ABREU

. Toll-like receptor 4 differentially regulates epidermal growth factor-related growth factors in response to intestinal mucosal injury[J]. Laboratory Investigation, 2010, 90(9): 1295-1305.

[73]

SODHI

, NEAL

, SIGGERS

, SHO S, MA

, BRANCA

, PRINDLE

, RUSSO

, AFRAZI

, GOOD

, Brower-SINNING

, FIREK

, MOROWITZ

, OZOLEK

, GITTES

, BILLIAR

, HACKAM

. Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice[J]. Gastroenterology, 2012, 143(3): 708-718.e5.

[74]

WAR

, SAKAMOTO

, LEIFER

. TLR9 is important for protection against intestinal damage and for intestinal repair[J]. Scientific Reports, 2012, 2: 574.

[75]

JONES

, SLOANE

, WU

, LUO

, KUMAR

, GEWIRTZ

, NEISH

. Flagellin administration protects gut mucosal tissue from irradiation-induced apoptosis via MKP-7 activity[J]. Gut, 2011, 60(5): 648-657.

[76]

ZHOU

, ZHANG

, QI

, HONG

, XIONG

, WU

, GENG

, XIE

, NIE

. Exopolysaccharides from Lactobacillus plantarum NCU116 facilitate intestinal homeostasis by modulating intestinal epithelial regeneration and microbiota[J]. Journal of Agricultural and Food Chemistry, 2021, 69(28): 7863-7873.

[77]

PETNICKI-OCWIEJA

, HRNCIR

, LIU

, BISWAS

, HUDCOVIC

, TLASKALOVA-HOGENOVA

, KOBAYASHI

. Nod2 is required for the regulation of commensal microbiota in the intestine[J]. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(37): 15813-15818.

[78]

NIGRO

, ROSSI

, COMMERE

, JAY P, SANSONETTI

. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration[J]. Cell Host & Microbe, 2014, 15(6): 792-798.

[79]

LEVY

, DEUTSCH

, SANSONETTI

, NIGRO

. 74P The bacterial receptor NOD2 mediates LGR5⁺ intestinal stem cells protection against irradiation via mitophagy activation[J]. Annals of Oncology, 2019, 30: v21.

[80]

LEVY

, STEDMAN

, DEUTSCH

, DONNADIEU

, VIRGIN

, SANSONETTI

, NIGRO

. Innate immune receptor NOD2 mediates LGR5⁺ intestinal stem cell protection against ROS cytotoxicity via mitophagy stimulation[J]. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117(4): 1994-2003.

[81]

LEE

, CHOI

, KANG

, SHIN

, KIM

, PARK

, HONG

. NOD2 supports crypt survival and epithelial regeneration after radiation-induced injury[J]. International Journal of Molecular Sciences, 2019, 20(17): 4297.

[82]

WANG

, KIM

, DENOU

, GALLAGHER

, THORNTON

, SHAJIB

, XIA

, SCHERTZER

, GRENCIS

, PHILPOTT

, KHAN

. New role of nod proteins in regulation of intestinal goblet cell response in the context of innate host defense in an enteric parasite infection[J]. Infection and Immunity, 2015, 84(1): 275-285.

[83]

MORRISON

, PRESTON

. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism[J]. Gut Microbes, 2016, 7(3): 189-200.

[84]

HOLMBERG

, FEENEY

, PRASOODANAN

P K V

, PUÉRTOLAS-BALINT

, SINGH

, WONGKUNA

, ZANDBERGEN

, HAUNER

, BRANDL

, NIEMINEN

, SKURK

, SCHROEDER

. The gut commensal Blautia maintains colonic mucus function under low-fiber consumption through secretion of short-chain fatty acids[J]. Nature Communications, 2024, 15: 3502.

[85]

WANG

, CAI

, WANG

, WU

, SUN

, WANG

, XU

, XUE

, CAO

, ZHANG

, ZHU

, LIN

, ZHANG

, YUAN

, ZHAO

, GAO

, YU

, BI

, NING

, WANG

,et al. Bacteroides methylmalonyl-CoA mutase produces propionate that promotes intestinal goblet cell differentiation and homeostasis[J]. Cell Host & Microbe, 2024, 32(1): 63-78.e7.

[86]

ZHAO

, CHEN

, WU

, SUN

, BILOTTA

, YAO

, XIAO

, HUANG

, EAVES-PYLES

, GOLOVKO

, FOFANOV

, D’SOUZA

, ZHAO

, LIU

, CONG

. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3[J]. Mucosal Immunology, 2018, 11(3): 752-762.

[87]

CORRÊA

, CASTRO

, FACHI

, NIRELLO

, EL-SAHHAR

, IMADA

, PEREIRA

, PRAL

, ARAÚJO

NVP

, FERNANDES

, MATHEUS

, de SOUZA FELIPE

, dos SANTOS PEREIRA GOMES AB, de OLIVEIRA

, de REZENDE RODOVALHO

, de OLIVEIRA

SRM

, de ASSIS

, OLIVEIRA

, dos SANTOS MARTINS

, MARTENS

, et al. Inulin diet uncovers complex diet-microbiota-immune cell interactions remodeling the gut epithelium[J]. Microbiome, 2023, 11(1): 90.

[88]

DUAN

, WU

, WANG

, TAN

, HOU

, QIAN

, HAN

, HOU

. Fucose promotes intestinal stem cell-mediated intestinal epithelial development through promoting Akkermansia-related propanoate metabolism[J]. Gut Microbes, 2023, 15(1): 2233149.

[89]

BILOTTA

, MA

, YANG

, YU

, ZHAO

, ZHOU

, YAO

, DANN

, CONG

. Propionate enhances cell speed and persistence to promote intestinal epithelial turnover and repair[J]. Cellular and Molecular Gastroenterology and Hepatology, 2021, 11(4): 1023-1044.

[90]

YAO

, CAI

, FEI

, YE

, ZHAO

, ZHENG

. The role of short-chain fatty acids in immunity, inflammation and metabolism[J]. Critical Reviews in Food Science and Nutrition, 2022, 62(1): 1-12.

[91]

XIA

, HAN

, WANG

, GUO

, WU

, HUANG

, LI

, ZHU

. Oral administration of propionic acid during lactation enhances the colonic barrier function[J]. Lipids in Health and Disease, 2017, 16(1): 62.

[92]

BAJIC

, NIEMANN

, HILLMER

, MEJIAS-LUQUE

, BLUEMEL

, DOCAMPO

, FUNK

, TONIN

, BOUTROS

, SCHNABL

, BUSCH

, MIKI

, SCHMID

, van den BRINK

MRM

, GERHARD

, STEIN-THOERINGER

. Gut microbiota-derived propionate regulates the expression of Reg3 mucosal lectins and ameliorates experimental colitis in mice[J]. Journal of Crohn’s and Colitis, 2020, 14(10): 1462-1472.

[93]

LOUIS

, HOLD

, FLINT

. The gut microbiota, bacterial metabolites and colorectal cancer[J]. Nature Reviews Microbiology, 2014, 12(10): 661-672.

[94]

ROEDIGER

. Utilization of nutrients by isolated epithelial cells of the rat colon[J]. Gastroenterology, 1982, 83(2): 424-429.

[95]

KELLY

, ZHENG

, CAMPBELL

, SAEEDI

, SCHOLZ

, BAYLESS

, WILSON

, GLOVER

, KOMINSKY

, MAGNUSON

, WEIR

, EHRENTRAUT

, PICKEL

, KUHN

, LANIS

, NGUYEN

, TAYLOR

, COLGAN

. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function[J]. Cell Host & Microbe, 2015, 17(5): 662-671.

[96]

DONOHOE

, GARGE

, ZHANG

, SUN

, O’CONNELL

, BUNGER

, BULTMAN

. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon[J]. Cell Metabolism, 2011, 13(5): 517-526.

[97]

, YEOM

, LIM YH. Specific activation of hypoxia-inducible factor-2α by propionate metabolism via a β-oxidation-like pathway stimulates MUC₂ production in intestinal goblet cells[J]. Biomedicine & Pharmacotherapy, 2022, 155: 113672.

[98]

KAIKO

, RYU SH, KOUES

, COLLINS

, SOLNICA-KREZEL

, PEARCE

, OLTZ

, STAPPENBECK

. The colonic crypt protects stem cells from microbiota-derived metabolites[J]. Cell, 2016, 165(7): 1708-1720.

[99]

ESHLEMAN

, RICE

, POTTER

, WADDELL

, HASHIMOTO-HILL

, WOO V, FIELD

, ENGLEMAN

, LIM HW, SCHUMACHER

, FREY

, DENSON

, FINKELMAN

, ALENGHAT

. Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity[J]. Immunity, 2024, 57(2): 319-332.e6.

[100]

UCHIYAMA

, SAKIYAMA

, HASEBE

, MUSCH

, MIYOSHI

, NAKAGAWA

, HE

, LICHTENSTEIN

, NAITO

, ITOH

, YOSHIKAWA

, JABRI

, STAPPENBECK

, CHANG

. Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development[J]. Scientific Reports, 2016, 6: 32094.

[101]

SHI

, MAO

, SONG

, WANG

, ZHANG

, XU

, GU

, YAO

, LIU

, RAGHAVAN

, WANG

. Butyrate alleviates food allergy by improving intestinal barrier integrity through suppressing oxidative stress-mediated Notch signaling[J]. iMeta, 2025, 4(3): e70024.

[102]

OKADA

, FUKUDA

, HASE

, NISHIUMI

, IZUMI

, YOSHIDA

, HAGIWARA

, KAWASHIMA

, YAMAZAKI

, OSHIO

, OTSUBO

, INAGAKI-OHARA

, KAKIMOTO

, HIGUCHI

, KAWAMURA

, OHNO

, DOHI

. Microbiota-derived lactate accelerates colon epithelial cell turnover in starvation-refed mice[J]. Nature Communications, 2013, 4: 1654.

[103]

LEE

, KIM

, LEE

, KIM

, KANG

, YANG

, BAEK

, SUNG

, PARK

, HWANG

, O E, KIM

, LIU

, KAMADA

, GAO

, KWEON

. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development[J]. Cell Host & Microbe, 2018, 24(6): 833-846.e6.

[104]

FUKUI

, SHIMOYAMA

, TAMURA

, YAMAMURA

, SATOMI

. Mucosal blood flow and generation of superoxide in rat experimental colitis induced by succinic acid[J]. Journal of Gastroenterology, 1997, 32(4): 464-471.

[105]

INAGAKI

, ICHIKAWA

, SAKATA

. Inhibitory effect of succinic acid on epithelial cell proliferation of colonic mucosa in rats[J]. Journal of Nutritional Science and Vitaminology, 2007, 53(4): 377-379.

[106]

WANG

, HU

, CHENG

, GAO

, LIU

, MANI

, TANG

, IYER

, GAO

, SUN

, ZHOU

, YU

, WEINBERG

, ZHANG

, CONG

, DULAI

, ZHANG

, LIU

, FANG

. Succinate drives gut inflammation by promoting FOXP3 degradation through a molecular switch[J]. Nature Immunology, 2025, 26(6): 866-880.

[107]

BANERJEE

, HERRING

, CHEN

, KIM

, SIMMONS

, SOUTHARD-SMITH

, ALLAMAN

, WHITE

, MACEDONIA

, MCKINLEY

, RAMIREZ-SOLANO

, SCOVILLE

, LIU

, WILSON

, COFFEY

, WASHINGTON

, GOETTEL

, LAU

. Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation[J]. Gastroenterology, 2020, 159(6): 2101-2115.e5.

[108]

, HUANG

, ZHANG

, REN

, ZHANG

, ZHU

, YU

. Succinate signaling attenuates high-fat diet-induced metabolic disturbance and intestinal barrier dysfunction[J]. Pharmacological Research, 2023, 194: 106865.

[109]

HEGYI

, MALÉTH

, WALTERS

, HOFMANN

, KEELY

. Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease[J]. Physiological Reviews, 2018, 98(4): 1983-2023.

[110]

RIDLON

, HARRIS

, BHOWMIK

, KANG

, HYLEMON

. Consequences of bile salt biotransformations by intestinal bacteria[J]. Gut Microbes, 2016, 7(1): 22-39.

[111]

CAI

, RIMAL

, JIANG

, CHIANG

JYL

, PATTERSON

. Bile acid metabolism and signaling, the microbiota, and metabolic disease[J]. Pharmacology & Therapeutics, 2022, 237: 108238.

[112]

CHEN

, JIAO

, LIU

, LUO

, WANG

, GUO

, TONG

, LIN

, SUN

, WANG

, HE

, ZHANG

, XU

, WANG

, ZUO

, DING

, HE

, GONZALEZ

, XIE

. Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal[J]. Cell Stem Cell, 2022, 29(9): 1366-1381.e9.

[113]

HUANG

, XIONG

, XU

, WU

, XU

, CAI

, LU

, ZHOU

. Bile acids elevated by high-fat feeding induce endoplasmic reticulum stress in intestinal stem cells and contribute to mucosal barrier damage[J]. Biochemical and Biophysical Research Communications, 2020, 529(2): 289-295.

[114]

DOSSA

, ESCOBAR

, GOLDEN

, FREY

, FORD

, GAYER

. Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2016, 310(2): G81-G92.

[115]

SORRENTINO

, PERINO

, YILDIZ

, ALAM G

, SLEIMAN M

BOU

, GIOIELLO

, PELLICCIARI

, SCHOONJANS

. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration[J]. Gastroenterology, 2020, 159(3): 956-968.e8.

[116]

MROZ

, LAJCZAK

, GOGGINS

, KEELY

. The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2018, 314(3): G378-G387.

[117]

YAMADA

, MASUNO

, KAGECHIKA

, TANATANI

, KANDA

. A novel lithocholic acid derivative upregulates detoxification-related genes in human induced pluripotent stem cell-derived intestinal organoids[J]. Biological & Pharmaceutical Bulletin, 2022, 45(11): 1720-1724.

[118]

ROAGER

, LICHT

. Microbial tryptophan catabolites in health and disease[J]. Nature Communications, 2018, 9: 3294.

[119]

AGUS

, PLANCHAIS

, SOKOL

. Gut microbiota regulation of tryptophan metabolism in health and disease[J]. Cell Host & Microbe, 2018, 23(6): 716-724.

[120]

VENKATESH

, MUKHERJEE

, WANG

, LI

, SUN

, BENECHET

, QIU

, MAHER

, REDINBO

, PHILLIPS

, FLEET

, KORTAGERE

, MUKHERJEE

, FASANO

, le

VEN J

, NICHOLSON

, DUMAS

, KHANNA

, MANI

. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4[J]. Immunity, 2014, 41(2): 296-310.

[121]

PARK

, CHOI

, KIM

, CHEONG

, JEONG

. AhR activation by 6-formylindolo [3,2-b] carbazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibit the development of mouse intestinal epithelial cells[J]. Environmental Toxicology and Pharmacology, 2016, 43: 44-53.

[122]

METIDJI

, OMENETTI

, CROTTA

, LI

, NYE E, ROSS

, LI

, MARADANA

, SCHIERING

, STOCKINGER

. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity[J]. Immunity, 2018, 49(2): 353-362.e5.

[123]

FERNANDEZ-SALGUERO

, WARD

, SUNDBERG

, GONZALEZ

. Lesions of aryl-hydrocarbon receptor-deficient mice[J]. Veterinary Pathology, 1997, 34(6): 605-614.

[124]

KAWAJIRI

, KOBAYASHI

, OHTAKE

, IKUTA

, MATSUSHIMA

, MIMURA

, PETTERSSON

, POLLENZ

, SAKAKI

, HIROKAWA

, AKIYAMA

, KUROSUMI

, POELLINGER

, KATO

, FUJII-KURIYAMA

. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in Apc^Min/+ mice with natural ligands[J]. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(32): 13481-13486.

[125]

PARK

, LEE

, HWANG

, KIM

. Indole-3-carbinol promotes goblet-cell differentiation regulating Wnt and Notch signaling pathways AhR-dependently[J]. Molecules and Cells, 2018, 41(4): 290-300.

[126]

HOU

, YE

, LIU

, HUANG

, YANG

, TURNER

, YU

. Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22[J]. Cell Death & Differentiation, 2018, 25(9): 1657-1670.

[127]

IHEKWEAZU

, ENGEVIK

, RUAN

, SHI

, FULTZ

, ENGEVIK

, CHANG-GRAHAM

, FREEBORN

, PARK

, VENABLE

, HORVATH

, HAIDACHER

, HAAG

, GOODWIN

, SCHADY

, HYSER

, SPINLER

, LIU

, VERSALOVIC

. Bacteroides ovatus promotes IL-22 production and reduces trinitrobenzene sulfonic acid-driven colonic inflammation[J]. The American Journal of Pathology, 2021, 191(4): 704-719.

[128]

QIU

, ZHOU

. Aryl hydrocarbon receptor promotes RORγt⁺ Group 3 ILCs and controls intestinal immunity and inflammation[J]. Seminars in Immunopathology, 2013, 35(6): 657-670.

[129]

ZHANG

, CHEN

, GUO

, LI

, ZHANG

, WANG

, ZHU

, YU

. The gut microbial metabolite indole-3-aldehyde alleviates impaired intestinal development by promoting intestinal stem cell expansion in weaned piglets[J]. Journal of Animal Science and Biotechnology, 2024, 15(1): 150.

[130]

WLODARSKA

, LUO

, KOLDE

, D’HENNEZEL

, ANNAND

, HEIM

, KRASTEL

, SCHMITT

, OMAR

, CREASEY

, GARNER

, MOHAMMADI

, O’CONNELL

, ABUBUCKER

, ARTHUR

, FRANZOSA

, HUTTENHOWER

, MURPHY

, HAISER

, VLAMAKIS

, et al. Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation[J]. Cell Host & Microbe, 2017, 22(1): 25-37.e6.

[131]

ZHONG

, SUN

, HUO

, XU

, YANG

, WU

, LIU

, WU

, LI

. The gut microbiota-aromatic hydrocarbon receptor (AhR) axis mediates the anticolitic effect of polyphenol-rich extracts from Sanghuangporus [J]. iMeta, 2024, 3(2): e180.

[132]

, WEI

, RAN

, LIU

, YI

, GONG

, LIU

, GONG

, LI

, GAO

. The gut microbiota-xanthurenic acid-aromatic hydrocarbon receptor axis mediates the anticolitic effects of trilobatin[J]. Advanced Science, 2025, 12(10): 2412234.

[133]

WANG

, WANG

, LI

, LU

, TANG

, YANG

, WANG

, ZHAO

, LIU

, ZHANG

, SUN

. Alistipes senegalensis is critically involved in gut barrier repair mediated by Panax ginseng neutral polysaccharides in aged mice[J]. Advanced Science, 2025, 12(36): e16427.

[134]

ZHANG

, PENG

, GOSWAMI

, LI

, DANG

, XING

, FENG

, NIGRO

, LIU

, MA

, LIU

, YANG

, JIANG

, YANG

, BARKER

, SANSONETTI

, KUNDU

. Intestinal crypt microbiota modulates intestinal stem cell turnover and tumorigenesis via indole acetic acid[J]. Nature Microbiology, 2025, 10(3): 765-783.

[135]

ZHU

, LU

, WU

, FAN

, LIU

, ZHU

, GUO

, DU

, LIU

, TIAN

, FAN

. Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons[J]. Cell Research, 2022, 32(6): 555-569.

[136]

BEKEBREDE

, KEIJER

, GERRITS

WJJ

, BOER

VCJ

. The molecular and physiological effects of protein-derived polyamines in the intestine[J]. Nutrients, 2020, 12(1): 197.

[137]

LÖSER

, EISEL

, HARMS

, FÖLSCH

. Dietary polyamines are essential luminal growth factors for small intestinal and colonic mucosal growth and development[J]. Gut, 1999, 44(1): 12-16.

[138]

BARDÓCZ

, GRANT

, BROWN

, PUSZTAI

. Putrescine as a source of instant energy in the small intestine of the rat[J]. Gut, 1998, 42(1): 24-28.

[139]

RAO

, LI

, BASS

, WANG

. Expression of the TGF-beta receptor gene and sensitivity to growth inhibition following polyamine depletion[J]. American Journal of Physiology Cell Physiology, 2000, 279(4): C1034-C1044.

[140]

LIU

, SANTORA

, RAO

, GUO

, ZOU

, ZHANG

, TURNER

, WANG

. Activation of TGF-beta-Smad signaling pathway following polyamine depletion in intestinal epithelial cells[J]. American Journal of Physiology Gastrointestinal and Liver Physiology, 2003, 285(5): G1056-G1067.

[141]

, ZHANG

, TONG

, TAWFIK

, ROSS

, SCOVILLE

, TIAN

, ZENG

, HE

, WIEDEMANN

, MISHINA

, LI

. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling[J]. Nature Genetics, 2004, 36(10): 1117-1121.

2026年第66卷第2期

PDF下载

280

115

引用本文

BibTeX

文章信息

doi: 10.13343/j.cnki.wsxb.20250648

接收时间：2025-08-23
首发时间：2026-02-05
出版时间：2026-02-04

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2025-08-23
录用日期：2025-10-04

基金

the Henan Provincial Natural Science Foundation Youth Program(252300421652)

河南省自然科学基金青年项目(252300421652)

作者信息

河南科技大学动物科技学院，河南洛阳

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/wswxb/CN/10.13343/j.cnki.wsxb.20250648

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT