Dysregulated glucocorticoid-responsive immune genes in peripheral blood mononuclear cells as a shared molecular signature of autism spectrum disorder and irritable bowel syndrome.

Overview

Authors: Kuo Zhang¹, Fangfang Mou¹, Jing Liu¹, Jianzhong Wang¹

ORCID iDs: Kuo Zhang

Qinhuangdao Maternity and Child Health Hospital, Qinhuangdao, Hebei, China

Journal: PloS one, volume 21, issue 7, article e0353181

Dates: received 29 December 2025; accepted 19 June 2026; published online 9 July 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1371/journal.pone.0353181 · PMID 42424309 · PMCID PMC13349188 · OpenAlex W7167809265

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: genetics / omics (modality), human (organism), autism (population), cellular / molecular (subfield)

Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Connectivity, Graphs, fMRI & imaging, Spectral & time-frequency

MeSH: Autism Spectrum Disorder*, Glucocorticoids*, Irritable Bowel Syndrome*, Leukocytes, Mononuclear*, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Humans, Male, MicroRNAs, Signal Transduction, Transcriptome (* major topic)

Topic: Autism Spectrum Disorder Research (Cognitive Neuroscience, Neuroscience), according to OpenAlex

Citations: not cited yet (Europe PMC); 58 references in the paper

Abstract

Background: Autism spectrum disorder (ASD) is frequently accompanied by gastrointestinal (GI) disturbances resembling irritable bowel syndrome (IBS). While dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and impaired glucocorticoid-responsive immune (GRI) signaling are proposed links between these disorders, the precise molecular mechanisms remain poorly understood.

Methods: We performed an integrative transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from ASD and IBS cohorts. Our approach combined single-sample Gene Set Enrichment Analysis (ssGSEA), differential expression profiling, weighted gene co-expression network analysis (WGCNA), and machine-learning-based feature selection. We utilized single-cell RNA sequencing to resolve cellular sources, while transcription factor, miRNA, and Connectivity Map (CMap) analyses identified regulatory mechanisms and potential drug candidates for reversing GRI-associated signatures.

Results: GRI-associated transcriptional activity was markedly elevated in the ASD group and moderately upregulated in the IBS group. Network and enrichment analyses revealed a convergence of immune recognition and cytokine signaling pathways. We identified four core genes—LRFN1, NUAK2, TMEM154, and GAPT—that consistently discriminated disease status. These genes were primarily expressed in monocytes, natural killer (NK) cells, and B cells. Regulatory analysis implicated stress-responsive transcriptional control and extensive miRNA modulation in these processes. CMap analysis identified RN-486, saracatinib, and batimastat as compounds predicted to restore GRI homeostasis.

Conclusions: These findings define a shared GRI-associated molecular signature linking systemic stress adaptation to immune dysregulation along the brain–gut axis. This study provides novel mechanistic insights and identifies potential transcriptomic biomarkers and therapeutic targets addressing the shared molecular architecture between ASD and IBS.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

geo:GSE124549 — at NCBI GEO; found in the text, “Identification of GRI-associated co-expression…”

Data Availability

All data generated or analyzed in the present study are included in the article and supplementary materials. The publicly available PBMC-based datasets supporting the findings are as follows: GSE124549 (IBS GRI dataset), GSE63379 (IBS dataset), GSE77103 (ASD dataset), GSE217850 (ASD medication-free single-cell RNA-seq dataset, collected before oral medication), and single-cell sex- and age-matched controls GSM6616992 and GSM6616995 from GSE214865, all available via the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/); additionally, the ASD dataset E-MTAB-13871 is available via ArrayExpress (https://www.ebi.ac.uk/biostudies/arrayexpress).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 13 MeSH terms, 52 references.

Cite

This paper

Zhang, K., Mou, F., Liu, J., & Wang, J. (2026). Dysregulated glucocorticoid-responsive immune genes in peripheral blood mononuclear cells as a shared molecular signature of autism spectrum disorder and irritable bowel syndrome. PloS one, 21(7), e0353181. https://doi.org/10.1371/journal.pone.0353181

BibTeX

@article{zhang2026dysregulated, author = {Zhang, Kuo and Mou, Fangfang and Liu, Jing and Wang, Jianzhong}, title = {{Dysregulated glucocorticoid-responsive immune genes in peripheral blood mononuclear cells as a shared molecular signature of autism spectrum disorder and irritable bowel syndrome}}, journal = {PloS one}, year = {2026}, month = jul, volume = {21}, number = {7}, pages = {e0353181}, publisher = {PLOS}, issn = {1932-6203}, doi = {10.1371/journal.pone.0353181}, url = {https://doi.org/10.1371/journal.pone.0353181}, pmid = {42424309}, pmcid = {PMC13349188} }

RIS

TY - JOUR AU - Zhang, Kuo AU - Mou, Fangfang AU - Liu, Jing AU - Wang, Jianzhong TI - Dysregulated glucocorticoid-responsive immune genes in peripheral blood mononuclear cells as a shared molecular signature of autism spectrum disorder and irritable bowel syndrome T2 - PloS one J2 - PLoS One PY - 2026 DA - 2026/07/09 VL - 21 IS - 7 SP - e0353181 SN - 1932-6203 PB - PLOS DO - 10.1371/journal.pone.0353181 UR - https://doi.org/10.1371/journal.pone.0353181 LA - en ER -

CSL-JSON

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