Multimodal MRI and multiomics reveal high-risk neurophenotype in brain-gut circuits as therapeutic target for Crohn's disease

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dc.contributor.authorLi, Xuehua
dc.contributor.authorZhang, Ruonan
dc.contributor.authorShen, Xiaodi
dc.contributor.authorLin, Shaochun
dc.contributor.authorWang, Chuhuai
dc.contributor.authorZheng, Weikai
dc.contributor.authorKong, Weimiao
dc.contributor.authorLin, Zihao
dc.contributor.authorLi, Rongchang
dc.contributor.authorLiu, Caiguang
dc.contributor.authorCao, Xin
dc.contributor.authorHuang, Li
dc.contributor.authorHe, Weitao
dc.contributor.authorLin, Jinjiang
dc.contributor.authorWang, Haijie
dc.contributor.authorLi, Zhoulei
dc.contributor.authorIacucci, Marietta
dc.contributor.authorGhosh, Subrata
dc.contributor.authorPeng, Zhenpeng
dc.contributor.authorSun, Canhui
dc.contributor.authorChen, Minhu
dc.contributor.authorYang, Guang
dc.contributor.authorWang, Yejun
dc.contributor.authorMao, Ren
dc.contributor.authorFeng, Shi Ting
dc.contributor.funder2023 SKY Imaging Research Fund of the Chinese International Medical Foundation
dc.contributor.funderFundamental Research Funds for the Central Universities
dc.contributor.funderChina International Medical Foundation, CIMF, Z‐2014‐07‐2301
dc.contributor.funderNational Key Research and Development Program of China, NKRDPC, 2023YFC2507300
dc.contributor.funderBasic and Applied Basic Research Foundation of Guangdong Province, 2026A1515012338-2023B1515020070-2023A1515011097
dc.contributor.funderSpecial Project for Research and Development in Key areas of Guangdong Province, 2023B1111040003
dc.contributor.funderSun Yat-Sen University, SYSU, 24ykqb003
dc.contributor.funderNational Natural Science Foundation of China, NSFC, 82271958-82072002-82222010-82572164-82270693-82471948-82070680
dc.date.accessioned2026-07-09T11:00:01Z
dc.date.available2026-07-09T11:00:01Z
dc.date.issued2026-07
dc.description.abstractThe brain-gut axis shapes Crohn's disease (CD) pathogenesis, yet CD-associated neurophenotypes lack defined clinical and mechanistic significance. This work aimed to define these neurophenotypes, assess their prognostic impact, elucidate neurophenotype-driven progression mechanisms using multi-omics, and validate their therapeutic potential in vivo. 109 CD patients were prospectively recruited from two centers and underwent baseline multimodal neuro-MRI, MR enterography, ileocolonoscopy, and fecal/blood sample collection. The neurophenotypes were characterized using a multimodal neuro-MRI model developed from 13 of 13,870 features. 83 patients were followed up for disease progression, with repeated brain-gut assessments. Multi-omics (fecal microbiome/metabolomics, serum metabolomics/neurotransmitters) were used to decode the mechanisms underlying neurophenotype-driven progression. Dextran sulfate sodium (DSS)-induced colitis mice with different neurophenotypes were treated with repeated transcranial magnetic stimulation (rTMS) to explore its therapeutic potential. Multimodal neuro-MRI accurately mapped CD-specific neural signatures, stratifying patients into high-risk (neurophenotype score ≥ 0.45) and low-risk neurophenotypes with robust cross-center validity (training cohort AUC = 0.842, test cohort AUC = 0.824). High-risk neurophenotype was identified as an independent predictor of accelerated disease progression (Hazard ratio = 15.46, p = 0.030), independent of intestinal inflammation. Integrated multi-omics revealed that the high-risk neurophenotype contributed to CD progression through microbial-metabolic-neurotransmitter networks where tryptophan emerged as the central regulatory hub. Serum tryptophan levels were negatively correlated with neurophenotype severity and intestinal disease progression. rTMS targeting high-risk neurophenotype in DSS-induced colitis mice elevated tryptophan levels and ameliorated intestinal disease activity. This study redefines the high-risk neurophenotype as a sustained pathogenic driver rather than a mere phenomenon, proposing brain-gut axis modulation as a promising therapeutic strategy distinct from conventional anti-inflammatory approaches.en
dc.description.sponsorshipThis study was financially supported by National Natural Science Foundation of China (82572164, 82270693, 82471948, 82271958, 82072002, 82070680, and 82222010), Guangdong Basic and Applied Basic Research Foundation (2023B1515020070, 2023A1515011097, and 2026A1515012338), National Key R&D Program of China (2023YFC2507300), Key Area Research and Development Program of Guangdong Province (2023B1111040003), Fundamental Research Funds for the Central Universities, Sun Yat-sen University (24ykqb003), and 2023 SKY Imaging Research Fund of the Chinese International Medical Foundation (Z-2014-07-2301). The funders of the study played no role in study design, data collection, data analysis, data interpretation, or writing of the report. This study was financially supported by National Natural Science Foundation of China (82572164, 82270693, 82471948, 82271958, 82072002, 82070680, and 82222010), Guangdong Basic and Applied Basic Research Foundation (2023B1515020070, 2023A1515011097, and 2026A1515012338), National Key R&D Program of China (2023YFC2507300), Key Area Research and Development Program of Guangdong Province (2023B1111040003), Fundamental Research Funds for the Central Universities, Sun Yat‐sen University (24ykqb003), and 2023 SKY Imaging Research Fund of the Chinese International Medical Foundation (Z‐2014‐07‐2301). The funders of the study played no role in study design, data collection, data analysis, data interpretation, or writing of the report.
dc.description.versionPublished Version
dc.format.extent20
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide70122
dc.identifier.authororcidLi, Xuehua
dc.identifier.authororcidZhang, Ruonan
dc.identifier.authororcidShen, Xiaodi
dc.identifier.authororcidLin, Shaochun
dc.identifier.authororcidWang, Chuhuai
dc.identifier.authororcidZheng, Weikai
dc.identifier.authororcidKong, Weimiao
dc.identifier.authororcidLin, Zihao
dc.identifier.authororcidLi, Rongchang
dc.identifier.authororcidLiu, Caiguang
dc.identifier.authororcidCao, Xin
dc.identifier.authororcidHuang, Li
dc.identifier.authororcidHe, Weitao
dc.identifier.authororcidLin, Jinjiang
dc.identifier.authororcidWang, Haijie
dc.identifier.authororcidLi, Zhoulei
dc.identifier.authororcidIacucci, Marietta
dc.identifier.authororcidGhosh, Subrata
dc.identifier.authororcidPeng, Zhenpeng
dc.identifier.authororcidSun, Canhui
dc.identifier.authororcidChen, Minhu
dc.identifier.authororcidYang, Guang
dc.identifier.authororcidWang, Yejun
dc.identifier.authororcidMao, Ren
dc.identifier.authororcidFeng, Shi Ting
dc.identifier.citationLi, X, Zhang, R, Shen, X, Lin, S, Wang, C, Zheng, W, Kong, W, Lin, Z, Li, R, Liu, C, Cao, X, Huang, L, He, W, Lin, J, Wang, H, Li, Z, Iacucci, M, Ghosh, S, Peng, Z, Sun, C, Chen, M, Yang, G, Wang, Y, Mao, R & Feng, S T 2026, 'Multimodal MRI and multiomics reveal high-risk neurophenotype in brain-gut circuits as therapeutic target for Crohn's disease', Interdisciplinary Medicine, vol. 4, no. 4, e70122, pp. 1-20. https://doi.org/10.1002/inmd.70122
dc.identifier.doi10.1002/inmd.70122
dc.identifier.endpage20
dc.identifier.issn2832-6237
dc.identifier.issued4
dc.identifier.journaltitleInterdisciplinary Medicine
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/19036
dc.identifier.volume4
dc.language.isoen
dc.publisherWiley-VCH Verlag
dc.relation.urihttps://www.scopus.com/pages/publications/105041730486
dc.rights© 2026, the Author(s). Interdisciplinary Medicine published by Wiley-VCH GmbH on behalf of Nanfang Hospital, Southern Medical University. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.accessrightsopen access
dc.rights.licensenameAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.statusPeer reviewed
dc.subjectCrohn's disease
dc.subjectIntestinal disease progression
dc.subjectMultimodal MRI
dc.subjectNeurophenotype
dc.subject[APCMicrobiome]
dc.subject[Medicine]
dc.titleMultimodal MRI and multiomics reveal high-risk neurophenotype in brain-gut circuits as therapeutic target for Crohn's diseaseen
dc.typeArticle (peer-reviewed)
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