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

Abstract The 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.