肠道共生生物对肠道干细胞的调节机制研究进展

doi:10.11843/j.issn.0366-6964.2025.03.005

摘要/Abstract

摘要：

肠道干细胞(intestinal stem cells, ISCs)在维持肠道稳态中起重要作用。已有研究表明，肠道共生生物(如微生物和寄生虫及其代谢产物)对宿主的干细胞调节至关重要，可通过直接或间接作用影响肠道干细胞的更新分化。本文重点阐述了肠道菌群和蠕虫及其代谢产物对ISCs的影响，并侧重总结了相关的细菌、代谢产物等对ISCs增殖分化的研究进展，旨在为未来肠道损伤治疗提供新的思路。

关键词: 肠道菌群, 肠道蠕虫, 肠道干细胞

Abstract:

Intestinal stem cells (ISCs) are vital for maintaining intestinal homeostasis. Research indicates that intestinal commensal organisms, including microorganisms and parasites, along with their metabolites, play a crucial role in regulating host stem cells. These organisms can influence the renewal and differentiation of ISCs through direct or indirect mechanisms. This article delves into the impact of intestinal microbiota, worms, and their metabolites on ISCs, and provides an overview of current research on how related bacteria and metabolites affect the proliferation and differentiation of ISCs. The goal of this review is to offer innovative insights for potential future treatments of intestinal injuries.

Key words: gut microbiota, intestinal helminth, intestinal stem cell

中图分类号:

S852.2

丁莹莹, 张嘉芸, 唐龙轩, 张少华, 郭小腊, 蒲丽霞, 牟文杰, 王帅. 肠道共生生物对肠道干细胞的调节机制研究进展[J]. 畜牧兽医学报, 2025, 56(3): 1019-1026.

DING Yingying, ZHANG Jiayun, TANG Longxuan, ZHANG Shaohua, GUO Xiaola, PU Lixia, MOU Wenjie, WANG Shuai. Research Progress on the Regulatory Mechanisms of Intestinal Commensal Organisms on Intestinal Stem Cells[J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(3): 1019-1026.

参考文献 66

1	STAPPENBECK T S , WONG M H , SAAM J R , et al. Notes from some crypt watchers: regulation of renewal in the mouse intestinal epithelium[J]. Curr Opin Cell Biol, 1998, 10 (6): 702- 709. doi: 10.1016/S0955-0674(98)80110-5
2	YAO C S , GOU X W , TIAN C X , et al. Key regulators of intestinal stem cells: diet, microbiota, and microbial metabolites[J]. J Genet Genomics, 2023, 50 (10): 735- 746. doi: 10.1016/j.jgg.2022.12.002
3	MA N , GUO P T , ZHANG J , et al. Nutrients mediate intestinal bacteria-mucosal immune crosstalk[J]. Front Immunol, 2018, 9, 5. doi: 10.3389/fimmu.2018.00005
4	GRICE E A , SEGRE J A . The human microbiome: our second genome[J]. Annu Rev Genomics Hum Genet, 2012, 13, 151- 170. doi: 10.1146/annurev-genom-090711-163814
5	VON MOLTKE J , JI M , LIANG H E , et al. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit[J]. Nature, 2016, 529 (7585): 221- 225. doi: 10.1038/nature16161
6	KARO-ATAR D , OULADAN S , JAVKAR T , et al. Helminth-induced reprogramming of the stem cell compartment inhibits type 2 immunity[J]. J Exp Med, 2022, 219 (9): e20212311. doi: 10.1084/jem.20212311
7	YOUSEFI M , LI L H , LENGNER C J . Hierarchy and plasticity in the intestinal stem cell compartment[J]. Trends Cell Biol, 2017, 27 (10): 753- 764. doi: 10.1016/j.tcb.2017.06.006
8	LI L H , CLEVERS H . Coexistence of quiescent and active adult stem cells in mammals[J]. Science, 2010, 327 (5965): 542- 545. doi: 10.1126/science.1180794
9	ROTHENBERG M E , NUSSE Y , KALISKY T , et al. Identification of a cKit⁺colonic crypt base secretory cell that supports Lgr5⁺stem cells in mice[J]. Gastroenterology, 2012, 142 (5): 1195- 1205. e6. doi: 10.1053/j.gastro.2012.02.006
10	AYYAZ A , KUMAR S , SANGIORGI B , et al. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell[J]. Nature, 2019, 569 (7754): 121- 125. doi: 10.1038/s41586-019-1154-y
11	LEY R E , LOZUPONE C A , HAMADY M , et al. Worlds within worlds: evolution of the vertebrate gut microbiota[J]. Nat Rev Microbiol, 2008, 6 (10): 776- 788. doi: 10.1038/nrmicro1978
12	HOOPER L V . Epithelial cell contributions to intestinal immunity[J]. Adv Immunol, 2015, 126, 129- 172.
13	DOMINGUEZ-BELLO M G , GODOY-VITORINO F , KNIGHT R , et al. Role of the microbiome in human development[J]. Gut, 2019, 68 (6): 1108- 1114. doi: 10.1136/gutjnl-2018-317503
14	SKELLY A N , SATO Y , KEARNEY S , et al. Mining the microbiota for microbial and metabolite-based immunotherapies[J]. Nat Rev Immunol, 2019, 19 (5): 305- 323. doi: 10.1038/s41577-019-0144-5
15	ABRAMS G D , BAUER H , SPRINZ H . Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice[J]. Lab Invest, 1963, 12, 355- 364.
16	ABO H , CHASSAING B , HARUSATO A , et al. Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration[J]. Nat Commun, 2020, 11 (1): 513. doi: 10.1038/s41467-019-14258-z
17	KUNDU P , BLACHER E , ELINAV E , et al. Our gut microbiome: the evolving inner self[J]. Cell, 2017, 171 (7): 1481- 1493. doi: 10.1016/j.cell.2017.11.024
18	NAITO T , MULET C , DE CASTRO C , et al. Lipopolysaccharide from crypt-specific core microbiota modulates the colonic epithelial proliferation-to-differentiation balance[J]. mBio, 2017, 8 (5): e01680- 17.
19	HOU Q H , YE L L , LIU H F , et al. 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 Differ, 2018, 25 (9): 1657- 1670. doi: 10.1038/s41418-018-0070-2
20	KIM S , SHIN Y C , KIM T Y , et al. Mucin degrader Akkermansia muciniphila accelerates intestinal stem cell-mediated epithelial development[J]. Gut Microbes, 2021, 13 (1): 1- 20.
21	MIGUEL-ALIAGA I , JASPER H , LEMAITRE B . Anatomy and physiology of the digestive tract of Drosophila melanogaster[J]. Genetics, 2018, 210 (2): 357- 396. doi: 10.1534/genetics.118.300224
22	PECK B C E , SHANAHAN M T , SINGH A P , et al. Gut microbial influences on the mammalian intestinal stem cell niche[J]. Stem Cells Int, 2017, 2017, 5604727.
23	MCHARDY I H , GOUDARZI M , TONG M M , et al. Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships[J]. Microbiome, 2013, 1 (1): 17. doi: 10.1186/2049-2618-1-17
24	AKHTAR M , CHEN Y , MA Z Y , et al. Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation[J]. Anim Nutr, 2021, 8, 350- 360.
25	KARO-ATAR D , GREGORIEFF A , KING I L . Dangerous liaisons: how helminths manipulate the intestinal epithelium[J]. Trends Parasitol, 2023, 39 (6): 414- 422. doi: 10.1016/j.pt.2023.03.012
26	KAIKO G E , RYU S H , KOUES O I , et al. The colonic crypt protects stem cells from microbiota-derived metabolites[J]. Cell, 2016, 165 (7): 1708- 1720. doi: 10.1016/j.cell.2016.05.018
27	WANG X Y , CAI Z L , WANG Q L , 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. doi: 10.1016/j.chom.2023.11.005
28	DUAN C H , WU J H , WANG Z , et al. Fucose promotes intestinal stem cell-mediated intestinal epithelial development through promoting Akkermansia-related propanoate metabolism[J]. Gut Microbes, 2023, 15 (1): 2233149. doi: 10.1080/19490976.2023.2233149
29	ZHU P P , LU T K , WU J Y , et al. Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons[J]. Cell Res, 2022, 32 (6): 555- 569. doi: 10.1038/s41422-022-00645-7
30	LI S T , LU C W , DIEM E C , et al. Acetyl-CoA-carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5⁺intestinal stem cell function[J]. Nat Commun, 2022, 13 (1): 3998. doi: 10.1038/s41467-022-31725-2
31	CHEN L , VASOYA R P , TOKE N H , et al. HNF4 regulates fatty acid oxidation and is required for renewal of intestinal stem cells in mice[J]. Gastroenterology, 2020, 158 (4): 985- 999. e9. doi: 10.1053/j.gastro.2019.11.031
32	SCHNEIDER K M , ALBERS S , TRAUTWEIN C . Role of bile acids in the gut-liver axis[J]. J Hepatol, 2018, 68 (5): 1083- 1085. doi: 10.1016/j.jhep.2017.11.025
33	ZENG H W , UMAR S , RUST B , et al. Secondary bile acids and short chain fatty acids in the colon: a focus on colonic microbiome, cell proliferation, inflammation, and cancer[J]. Int J Mol Sci, 2019, 20 (5): 1214. doi: 10.3390/ijms20051214
34	LIN S , WANG S T , WANG P , et al. Bile acids and their receptors in regulation of gut health and diseases[J]. Prog Lipid Res, 2023, 89, 101210. doi: 10.1016/j.plipres.2022.101210
35	KOZONI V , TSIOULIAS G , SHIFF S , et al. The effect of lithocholic acid on proliferation and apoptosis during the early stages of colon carcinogenesis: differential effect on apoptosis in the presence of a colon carcinogen[J]. Carcinogenesis, 2000, 21 (5): 999- 1005. doi: 10.1093/carcin/21.5.999
36	SORRENTINO G , PERINO A , YILDIZ E , et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration[J]. Gastroenterology, 2020, 159 (3): 956- 968. e8. doi: 10.1053/j.gastro.2020.05.067
37	SONG M , YANG Q , ZHANG F L , et al. Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR-PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria[J]. FASEB J, 2020, 34 (5): 7103- 7117. doi: 10.1096/fj.201903244R
38	MARKANDEY M , BAJAJ A , ILOTT N E , et al. Gut microbiota: sculptors of the intestinal stem cell niche in health and inflammatory bowel disease[J]. Gut Microbes, 2021, 13 (1): 1990827. doi: 10.1080/19490976.2021.1990827
39	FAN H C , WU J Q , YANG K P , et al. Dietary regulation of intestinal stem cells in health and disease[J]. Int J Food Sci Nutr, 2023, 74 (7): 730- 745. doi: 10.1080/09637486.2023.2262780
40	ALVARADO D M , CHEN B S , ITICOVICI M , et al. Epithelial indoleamine 2, 3-dioxygenase 1 modulates aryl hydrocarbon receptor and notch signaling to increase differentiation of secretory cells and alter mucus-associated microbiota[J]. Gastroenterology, 2019, 157 (4): 1093- 1108. e11. doi: 10.1053/j.gastro.2019.07.013
41	KAWAJIRI K , KOBAYASHI Y , OHTAKE F , et al. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in Apc^Min/+ mice with natural ligands[J]. Proc Natl Acad Sci U S A, 2009, 106 (32): 13481- 13486. doi: 10.1073/pnas.0902132106
42	SAHU A , GOPALAKRISHNAN L , GAUR N , et al. The 5-hydroxytryptamine signaling map: an overview of serotonin-serotonin receptor mediated signaling network[J]. J Cell Commun Signal, 2018, 12 (4): 731- 735. doi: 10.1007/s12079-018-0482-2
43	GUTKNECHT L , KRIEGEBAUM C , WAIDER J , et al. Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: convergent data from Tph2 knockout mice[J]. Eur Neuropsychopharmacol, 2009, 19 (4): 266- 282. doi: 10.1016/j.euroneuro.2008.12.005
44	MOOSSAVI S , ZHANG H Y , SUN J , et al. Host-microbiota interaction and intestinal stem cells in chronic inflammation and colorectal cancer[J]. Expert Rev Clin Immunol, 2013, 9 (5): 409- 422. doi: 10.1586/eci.13.27
45	FUKATA M , VAMADEVAN A S , ABREU M T . Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders[J]. Semin Immunol, 2009, 21 (4): 242- 253. doi: 10.1016/j.smim.2009.06.005
46	BANSAL K , TRINATH J , CHAKRAVORTTY D , et al. Pathogen-specific TLR2 protein activation programs macrophages to induce Wnt-β-catenin signaling[J]. J Biol Chem, 2011, 286 (42): 37032- 37044. doi: 10.1074/jbc.M111.260414
47	HEDAYAT M , TAKEDA K , REZAEI N . Prophylactic and therapeutic implications of toll-like receptor ligands[J]. Med Res Rev, 2012, 32 (2): 294- 325. doi: 10.1002/med.20214
48	YI H , PATEL A K , SODHI C P , et al. 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. doi: 10.1371/journal.pone.0036560
49	BURGUEÑO J F , ABREU M T . Epithelial toll-like receptors and their role in gut homeostasis and disease[J]. Nat Rev Gastroenterol Hepatol, 2020, 17 (5): 263- 278. doi: 10.1038/s41575-019-0261-4
50	NIGRO G , ROSSI R , COMMERE P H , et al. 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. doi: 10.1016/j.chom.2014.05.003
51	BAE Y S , CHOI M K , LEE W J . Dual oxidase in mucosal immunity and host-microbe homeostasis[J]. Trends Immunol, 2010, 31 (7): 278- 287. doi: 10.1016/j.it.2010.05.003
52	NATH A , CHAKRABARTI P , SEN S , et al. Reactive oxygen species in modulating intestinal stem cell dynamics and function[J]. Stem Cell Rev Rep, 2022, 18 (7): 2328- 2350. doi: 10.1007/s12015-022-10377-1
53	VAN DER POST S , BIRCHENOUGH G M H , HELD J M . NOX1-dependent redox signaling potentiates colonic stem cell proliferation to adapt to the intestinal microbiota by linking EGFR and TLR activation[J]. Cell Rep, 2021, 35 (1): 108949. doi: 10.1016/j.celrep.2021.108949
54	REEDY A R , LUO L P , NEISH A S , et al. Commensal microbiota-induced redox signaling activates proliferative signals in the intestinal stem cell microenvironment[J]. Development, 2019, 146 (3): dev171520. doi: 10.1242/dev.171520
55	TURNBAUGH P J , LEY R E , MAHOWALD M A , et al. An obesity-associated gut microbiome with increased capacity for energy harvest[J]. Nature, 2006, 444 (7122): 1027- 1031. doi: 10.1038/nature05414
56	LEE Y S , KIM T Y , KIM Y , et al. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development[J]. Cell Host Microbe, 2018, 24 (6): 833- 846. e6. doi: 10.1016/j.chom.2018.11.002
57	NAKAMURA A , KURIHARA S , TAKAHASHI D , et al. Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon[J]. Nat Commun, 2021, 12 (1): 2105. doi: 10.1038/s41467-021-22212-1
58	KING I L , LI Y . Host-parasite interactions promote disease tolerance to intestinal helminth infection[J]. Front Immunol, 2018, 9, 2128. doi: 10.3389/fimmu.2018.02128
59	MORALES R A , RABAHI S , DIAZ O E , et al. Interleukin-10 regulates goblet cell numbers through notch signaling in the developing zebrafish intestine[J]. Mucosal Immunol, 2022, 15 (5): 940- 951. doi: 10.1038/s41385-022-00546-3
60	TAKASHIMA S , MARTIN M L , JANSEN S A , et al. T cell-derived interferon-γ programs stem cell death in immune-mediated intestinal damage[J]. Sci Immunol, 2019, 4 (42): eaay8556. doi: 10.1126/sciimmunol.aay8556
61	LIN X , GAUDINO S J , JANG K K , et al. IL-17RA-signaling in Lgr5⁺intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment[J]. Immunity, 2022, 55 (2): 237- 253. e8. doi: 10.1016/j.immuni.2021.12.016
62	LINDEMANS C A , CALAFIORE M , MERTELSMANN A M , et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration[J]. Nature, 2015, 528 (7583): 560- 564. doi: 10.1038/nature16460
63	JOURDAN P M , LAMBERTON P H L , FENWICK A , et al. Soil-transmitted helminth infections[J]. Lancet, 2018, 391 (10117): 252- 265. doi: 10.1016/S0140-6736(17)31930-X
64	COAKLEY G , HARRIS N L . The Intestinal epithelium at the forefront of host-helminth interactions[J]. Trends Parasitol, 2020, 36 (9): 761- 772. doi: 10.1016/j.pt.2020.07.002
65	REYNOLDS L A , FINLAY B B , MAIZELS R M . Cohabitation in the intestine: interactions among helminth parasites, bacterial microbiota, and host immunity[J]. J Immunol, 2015, 195 (9): 4059- 4066. doi: 10.4049/jimmunol.1501432
66	HAYAKAWA Y , WANG T C . The tuft Cell-ILC2 circuit integrates intestinal defense and homeostasis[J]. Cell, 2018, 174 (2): 251- 253. doi: 10.1016/j.cell.2018.06.037

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