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MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)

  • Authors:
    • Liping Liang
    • Xiaoyan Liu
    • Bang Li
    • Huyi Lei
    • Zibo Tang
    • Shijie Mai
    • Chenghai Yang
    • Yongjian Zhou
    • Shaoheng Zhang
    • Le Liu
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology and Hepatology, Guangzhou Key Laboratory of Digestive Diseases, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, P.R. China, Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China, Department of Gastroenterology, First People's Hospital of Foshan (Foshan Hospital Affiliated to Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology, Foshan, Guangdong 528000, P.R. China, Department of Hematology, The Affiliated Hospital of Shaoxing University (Shaoxing Municipal Hospital), Shaoxing, Zhejiang 312000, P.R. China, Department of Radiation Oncology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, P.R. China, Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518000, P.R. China, Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
    Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 74
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    Published online on: January 27, 2026
       https://doi.org/10.3892/ijmm.2026.5745
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Abstract

Inflammatory bowel disease (IBD) pathogenesis reflects complex interactions between host immunity and gut microbiome dynamics, with microRNAs (miRNAs) functioning as key mediators of cross‑kingdom communication. Host‑derived miRNAs modulate bacterial gene expression and reshape microbial communities, while gut microbiota influences host miRNA expression through microbial metabolites and multiple immune signaling. In IBD, dysregulated miRNAs disrupt immune homeostasis by affecting inflammatory responses, lymphocyte differentiation and epithelial barrier integrity. Yet many miRNAs exhibit context‑dependent dual functions, complicating therapeutic targeting. Despite their biomarker potential for distinguishing IBD subtypes and tracking disease activity, clinical validation faces substantial obstacles including methodological inconsistencies, patient heterogeneity and temporal expression variability. Single-target miRNA therapeutics have yielded modest clinical outcomes, exposing the resilience of regulatory networks and compensatory mechanisms that limit intervention efficacy. The bidirectional architecture of miRNA‑microbiome communication argues against reductionist approaches. Effective IBD management requires integrated strategies that address multiple regulatory nodes rather than isolated pathways. Advancing this field demands deeper investigation of temporal dynamics, spatial organization and network‑level interactions. Such understanding will inform precision medicine strategies that restore regulatory equilibrium without compromising the adaptive capacity of host‑microbiome systems. Progress depends on recognizing the integrated nature of these regulatory networks rather than treating components in isolation.

View Figures

Figure 1

Eukaryotic miRNA biogenesis and
processing pathway. The miRNA biogenesis pathway spans both nuclear
and cytoplasmic compartments. In the nucleus (left panel), miRNA
genes are transcribed to produce primary transcripts (pri-miRNA)
containing characteristic stem-loop secondary structures. The
nuclear ribonuclease Drosha processes pri-miRNA into shorter
precursor molecules (pre-miRNA). In the cytoplasm (right panel),
pre-miRNA is transported from the nucleus by Exportin-5. The
cytoplasmic ribonuclease Dicer subsequently processes pre-miRNA
into mature miRNA duplexes of approximately 22 nucleotides in
length. The mature miRNA, containing a critical 6-nucleotide seed
region for target recognition, is incorporated into the RISC to
regulate target mRNA expression through complementary base-pairing
interactions. This pathway represents the fundamental mechanism
through which host cells generate regulatory miRNAs that
participate in cross-kingdom communication with gut microbiota in
IBD pathogenesis. miRNA, microRNA; pri-miRNA, primary microRNA
transcript; pre-miRNA, precursor microRNA; RISC, RNA-induced
silencing complex; nt, nucleotides.

Figure 2

Triadic regulatory network model of
miRNA-mediated IBD pathogenesis. Central miRNA pool (orange circle)
mediates bidirectional communication between gut microbiota (green
circle, bottom left) and immune system (blue circle, bottom right),
with IBD pathogenesis resulting from network dysfunction.
Cross-kingdom regulation examples: miR-21 targets B.
thetaiotaomicron tryptophan operon, miR-142-3p promotes L.
reuteri growth, miR-30d increases A. muciniphila
abundance. Three novel hypotheses: Temporal miRNA dysregulation,
miRNA-microbiome evolutionary mismatch and regulatory network
resilience. Key miRNA targets in IBD: miR-223 targets NLRP3/C/EBPβ,
miR-155 targets C/EBPβ/SOCS1/SHIP-1/Wnt/β-catenin, miR-146a targets
IRAK1/TRAF6/NUMB/NF-κB. This framework emphasizes systems-level
dysfunction requiring network-based therapeutic approaches. A.
muciniphila, Akkermansia muciniphila; B.
thetaiotaomicron, Bacteroides thetaiotaomicron; C/EBPβ,
CCAAT/enhancer-binding protein β; IBD, inflammatory bowel disease;
IRAK1, interleukin-1 receptor-associated kinase 1; L.
reuteri, Lactobacillus reuteri; NF-κB, nuclear factor
κB; NLRP3, NOD-like receptor protein 3; NUMB, NUMB endocytic
adaptor protein; SHIP-1, SH2-containing inositol 5'-phosphatase 1;
SOCS1, suppressor of cytokine signaling 1; TRAF6, TNF
receptor-associated factor 6.

Figure 3

Host-derived and dietary-derived
miRNAs modulate gut microbiota composition. Host-secreted miRNAs
directly regulate bacterial gene expression and reshape microbial
communities. miR-515-5p and miR-1226-5p promote pathogenic bacteria
(F. nucleatum, E. coli) proliferation, while miR-21
enhances tryptophan synthesis in gut microbes but suppresses L.
reuteri growth. Dietary miRNAs from GELN containing miR-7267-3p
selectively promote beneficial L. rhamnosus growth by
targeting monooxygenase and increasing I3A levels. miR-30d enhances
A. muciniphila proliferation through upregulation of
bacterial β-galactosidase expression, demonstrating cross-kingdom
miRNA-mediated regulation of gut microbiome homeostasis. A.
muciniphila, Akkermansia muciniphila; E. coli,
Escherichia coli; F. nucleatum, Fusobacterium
nucleatum; GELN, ginger-derived exosome-like nanoparticles;
I3A, indole-3-carboxaldehyde; L. reuteri, Lactobacillus
reuteri; L. rhamnosus, Lactobacillus rhamnosus;
ycnE, monooxygenase gene; miRNA, microRNA.

Figure 4

miRNA regulation of innate and
adaptive immune responses in the intestinal microenvironment.
miRNAs differentially regulate immune cell functions in
inflammatory bowel disease pathogenesis. In innate immunity,
miR-146a suppresses NETs and macrophage M1 polarization, while
miR-155 promotes inflammatory responses. miR-34a and let-7i enhance
DC maturation, whereas miR-146a, miR-183 and miR-20a inhibit NK
cell cytotoxicity. In adaptive immunity, miR-17~92, miR-146a,
miR-31 and miR-155 promote Th1 differentiation, miR-21 drives Th2
responses and miR-155 enhances Th17 IL-17 production. miR-17,
miR-19b and miR-92a suppress Treg development, while miR-155
promotes B cell IgG production and miR-146a reduces IgA
class-switching, demonstrating complex miRNA-mediated immune
regulation in intestinal homeostasis. NETs, neutrophil
extracellular traps; Mφ, macrophage; DC, dendritic cell; NK,
natural killer cell; ILC2, innate lymphoid cell type 2; Th, T
helper cell; Treg, regulatory T cell.

Figure 5

miRNA-mediated regulation of pattern
recognition receptor signaling in IBD pathogenesis. Bidirectional
miRNA-microbiome crosstalk regulates intestinal inflammation
through modulation of PRR signaling pathways. Gut microbiota
influences host miRNA expression, while host-derived miRNAs reshape
microbial communities within the inflamed intestinal epithelium.
Multiple miRNAs (miR-10a, miR-320, miR-192, miR-495, miR-512,
miR-671) directly target NOD2 expression and suppress inflammatory
cytokine release through inhibition of the MDP-NOD2-RIPK2-NF-κB
signaling cascade. Conversely, NOD2 activation enhances miR-146a
expression, leading to NUMB protein degradation and subsequent
activation of the SHH pathway, promoting inflammatory responses.
NOD2 signaling also upregulates miR-29 expression, which suppresses
IL-12p40/IL-23 production and mitigates Th17 cell responses,
demonstrating complex feedback mechanisms between PRR signaling and
miRNA regulation in intestinal homeostasis and IBD pathogenesis.
PRR, pattern recognition receptor; MDP, muramyl dipeptide; IBD,
inflammatory bowel disease; NOD2, nucleotide-binding
oligomerization domain 2; RIPK2, receptor-interacting protein
kinase 2; NF-κB, nuclear factor κB; NUMB, NUMB endocytic adaptor
protein; SHH, Sonic Hedgehog pathway.

Figure 6

Clinical applications of miRNAs in
IBD: From biomarker discovery to therapeutic intervention.
High-throughput sequencing of miRNAs from multiple biological
samples (colonic biopsies, feces, saliva, blood) enables
comprehensive biomarker discovery and therapeutic development. For
biomarker applications, distinctive miRNA expression profiles
facilitate IBD diagnosis through identification of upregulated
miRNAs. Patient stratification distinguishes UC from CD based on
specific miRNA signatures, while disease monitoring tracks
inflammation levels and treatment responses over time. For
therapeutic applications, miRNA-based interventions include
synthetic miRNA mimics to restore beneficial miRNA function and
antagomiRs to inhibit pathogenic miRNA activity through
complementary binding to target genes. Advanced nanoparticle
delivery systems incorporating nano-size optimization, surface
modification and functionalization enhance therapeutic miRNA
stability, tissue specificity and clinical efficacy in IBD
treatment. UC, ulcerative colitis; CD, Crohn's disease; IBD,
inflammatory bowel disease; miRNA, microRNA.

Figure 7

Personalized miRNA-based IBD
management workflow. Five-step clinical workflow: ⅰ) Assessment:
multi-sample collection (blood, feces, tissue) and miRNA profiling
using RT-qPCR panels and NGS analysis; ⅱ) Diagnosis: UC vs. CD
classification, severity assessment and disease activity monitoring
using predictive markers; ⅲ) Treatment - response prediction,
personalized dosing and targeted miRNA therapeutics with
combination therapy; ⅳ) Monitoring: miRNA normalization tracking,
clinical improvement assessment, dose optimization and therapy
switching; ⅴ) Management: remission maintenance, relapse prevention
and regular surveillance with early intervention. Clinical benefits
include non-invasive biomarker detection, early disease monitoring,
personalized treatment selection, multi-target approaches and
reduced trial-and-error treatment. Current challenges encompass
protocol standardization, off-target effects management, delivery
system optimization, cost-effectiveness and regulatory approval
pathways. IBD, inflammatory bowel disease; UC, ulcerative colitis;
CD, Crohn's disease; RT-qPCR, reverse transcription quantitative
PCR; NGS, next-generation sequencing.
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Copy and paste a formatted citation
Spandidos Publications style
Liang L, Liu X, Li B, Lei H, Tang Z, Mai S, Yang C, Zhou Y, Zhang S, Liu L, Liu L, et al: <p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>. Int J Mol Med 57: 74, 2026.
APA
Liang, L., Liu, X., Li, B., Lei, H., Tang, Z., Mai, S. ... Liu, L. (2026). <p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>. International Journal of Molecular Medicine, 57, 74. https://doi.org/10.3892/ijmm.2026.5745
MLA
Liang, L., Liu, X., Li, B., Lei, H., Tang, Z., Mai, S., Yang, C., Zhou, Y., Zhang, S., Liu, L."<p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 74.
Chicago
Liang, L., Liu, X., Li, B., Lei, H., Tang, Z., Mai, S., Yang, C., Zhou, Y., Zhang, S., Liu, L."<p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 74. https://doi.org/10.3892/ijmm.2026.5745
Copy and paste a formatted citation
x
Spandidos Publications style
Liang L, Liu X, Li B, Lei H, Tang Z, Mai S, Yang C, Zhou Y, Zhang S, Liu L, Liu L, et al: <p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>. Int J Mol Med 57: 74, 2026.
APA
Liang, L., Liu, X., Li, B., Lei, H., Tang, Z., Mai, S. ... Liu, L. (2026). <p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>. International Journal of Molecular Medicine, 57, 74. https://doi.org/10.3892/ijmm.2026.5745
MLA
Liang, L., Liu, X., Li, B., Lei, H., Tang, Z., Mai, S., Yang, C., Zhou, Y., Zhang, S., Liu, L."<p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 74.
Chicago
Liang, L., Liu, X., Li, B., Lei, H., Tang, Z., Mai, S., Yang, C., Zhou, Y., Zhang, S., Liu, L."<p>MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 74. https://doi.org/10.3892/ijmm.2026.5745
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