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Challenges and opportunities in inflammatory bowel disease: from current therapeutic strategies to organoid-based models

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Abstract

Background

Inflammatory bowel disease (IBD) is an increasingly prevalent global health concern that has garnered substantial attention. However, the underlying mechanisms are still unclear and the current treatments have significant limitations. Intestinal organoids provide an in vitro model to explore the pathogenesis, test the therapeutic effects, and develop regenerative treatments as well as offer the potential to transform drug discovery of IBD.

Methods

To advance our understanding of the whole story of IBD spanning from the pathogenesis to the current therapeutic strategies and latest advancements, a comprehensive search of major databases including PubMed, Scopus, and Web of Science was conducted to retrieve original articles and reviews related to IBD, organoids, pathogenesis and therapy.

Results

This review deciphers the etiopathogenesis and the current therapeutic approaches in the treatment of IBD. Notably, critical aspects of intestinal organoids in IBD, such as their potential applications, viability, cell renewal ability, and barrier functionality are highlighted. We also discuss the advances, limitations, and prospects of intestinal organoids for precision medicine.

Conclusion

The latest strides made in research about intestinal organoids help elucidate intricate aspects of IBD pathogenesis, and pave the prospective avenues for novel therapeutic interventions.

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Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

IBD:

Inflammatory bowel disease

UC:

Ulcerative colitis

CD:

Crohn's disease

IEC:

Intestinal epithelial cell

3D:

Three-dimensional

IELs:

Intraepithelial lymphocytes

REF-3-γ:

Regenerating family member 3γ

MUC2:

Mucin 2

TJ:

Tight junction

Gna12:

Guanine nucleotide-binding protein subunit-12

ZO-1:

Zonula occludens-1

Cldn2:

Claudin2

ER:

Endoplasmic reticulum

URP:

Unfolded protein response

STAT3:

Signal transducer and activator of transcription 3

NF-κB:

Nuclear factor κB

ATG16L1:

Autophagy-related 16 like 1

IRGM:

Immune-realted guanosine triphosphatase M protein

DCs:

Dendritic cells

TLR2:

Toll-like receptor 2

ILCs:

Innate lymphoid cells

TNF:

Tumor necrosis factor

IFN:

Interferon

RORC:

RAR-related orphan receptor C

AHR:

Aryl hydrocarbon receptor

MAdCAM-1:

Mucosal addressin cell adhesion molecule-1

Th cells:

T helper cells

Treg:

Regulatory T cells

SCFAs:

Short-chain fatty acids

IL-22BP:

Interleukin-22 binding protein

hIL-22:

Human interleukin-22

HIF-1α:

Hypoxia-inducible factor-1α

DSS:

Dextran sulfate sodium

PHD:

Prolyl hydroxylases

GSDMB:

Gasdermin B

PDGF-A:

Platelet-derived growth factor A

FAK:

Focal adhesion kinase

HA:

Hyaluronan

GAGs:

Glycosaminoglycans

ECM:

Extracellular matrix

MMPs:

Matrix metalloproteinases

JAK:

Janus kinase

PTPN2:

Protein tyrosine phosphatase non-receptortype-2

S1PR:

Sphingosine 1-phosphate receptors

GBP-307:

Guanylate binding protein 307

CCR9:

C–C chemokine receptor 9

rhIL-10:

Recombinant human interleukin-10

TGF-β:

Transforming growth factor β

PDE4:

Phosphodiesterase 4

3′,5′-cAMP:

Cyclic adenosine monophosphate

MSCs:

Mesenchymal stem cells

HSCs:

Hematopoietic stem cells

PEI:

Polyethylenimine

MONs:

Mesoporous organosilica nanoparticles

cfDNA:

Cell-free DNA

ROS:

Reactive oxygen species

TRAF6:

Tumor necrosis factor receptor-associated factor 6

IRAK1:

Interleukin-1 receptor-associated kinase 1

TNBS:

2,4,6-Trinitrobenzene sulfonic acid

LATS1:

Large tumor suppressor kinase 1

BAs:

Bile acids

FMT:

Fecal microbiota transplantation

5-HTP:

5-Hydroxytryptoph

iPSCs:

Induced pluripotent stem cells

ISCs:

Intestinal stem cells

TTC7A:

Tetratricopeptide repeatdomain 7A

SMAD4:

Suppressor of mothers against decapentaplegic homolog 4

MLCK:

Myosin lightchain kinase

PPI:

Proton pump inhibitor

MLC:

Phosphor-myosin light chain

MAPK:

Mitogen-activated protein kinase

CS:

Systemic corticosteroids

ATM:

Ataxia-telangiectasia mutated proteins

YAP1:

Yes-associatedprotein1

SOD3:

Superoxide dismutase 3

MLKL:

Mixed lineage kinase domain-like protein

LRH-1:

Liver receptor homolog 1

NKG2D:

Naturalkiller group2, member D

PBMCs:

Peripheral blood mononuclear cells

TP53:

Tumor protein 53

IGF-1:

Insulin-like growth factor-1

PI3K:

Phosphoinositide 3-kinase protein kinase B

PGE2:

Prostaglandin E2

COX:

Cyclooxygenase

CXCL1:

C-X-C motif chemokine1

EP4:

Prostaglandin E2 receptor 4

ATAC:

Assay of transposase accessible chromatin

TEAD:

Transcriptional enhanced associate domain

LPMCs:

Lamina propria mononuclear cells

UCP4:

Uncoupling protein 4

PBAs:

Primary bile acids

SBAs:

Secondary bile acids

TGR5:

Takeda G protein-coupled receptor 5

I3C:

Indole-3-carbin

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Funding

This study was supported by the Science and Technology Plan Project of Wenzhou, China (Grant Numbers Y20220045, Y20220389), Zhejiang Province Natural Science Foundation of China (Grant Number LTGY23H100001), National Natural Science Foundation of China (Grant Number 81901660), and Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province (2022E10022).

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  1. Lingjie Kong, Siyan Chen, Shenghao Huang and Anzhe Zheng contributed equally to this work.

Authors and Affiliations

  1. School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Lingjie Kong, Shenghao Huang & Anzhe Zheng

  2. School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Siyan Chen

  3. Laboratory Animal Center, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Sheng Gao

  4. Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Jianzhong Ye

  5. School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Chunyan Hua

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CH and SG conceived this Review. LK, SH, SC, and AZ searched the literature and drafted the manuscript. SC and SH completed the drawing of the Figures. SG edited the manuscript, JY and CH revised the manuscript. All authors contributed to the article and approved the submitted version.

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Kong, L., Chen, S., Huang, S. et al. Challenges and opportunities in inflammatory bowel disease: from current therapeutic strategies to organoid-based models. Inflamm. Res. 73, 541–562 (2024). https://doi.org/10.1007/s00011-024-01854-z

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