Receptor-Side Neuroimmune Remodeling in IBD: Participant-Level Associations with Metabolite-Sensing Programs and Colorectal Neoplasia Context

Background: Microbial metabolite sensing and neuroimmune signaling are increasingly recognized as interacting components of the mucosal response in inflammatory bowel disease (IBD). However, their organization across individuals and the cellular compartments carrying the relevant receptor machinery remain incompletely understood. We investigated whether metabolite-sensing host programs covary with neuroimmune receptor-side mucosal states at the participant level and whether the corresponding receptor transcripts map to defined mucosal compartments. Methods: HMP2 mucosal transcriptomes were analyzed at the participant level to evaluate prespecified relationships between metabolite-sensing and neuroimmune receptor-side host programs. Receptor-side neuroimmune remodeling was operationalized as cross-sectional participant-level host-program organization together with compartmental localization of the corresponding receptor transcripts, rather than longitudinal change or receptor activation. The stability and interpretation of these relationships were examined through diagnosis/inflammation adjustment, participant-grouped explanatory modeling, and tissue-composition sensitivity analyses. Complementary metabolomic, single-cell, UC, and colorectal-neoplasia datasets were used to examine synchronized metabolic associations, receptor-transcript localization, and the broader disease context of the identified mucosal programs. The microbiome, metabolomic, and transcriptomic datasets were obtained from multiple independent public cohorts. Results: Among 251 HMP2 biopsies from 90 participants, 13 of 20 prespecified host–program associations passed FDR correction in participant-mean analyses, and 13 of 20 remained supported after diagnosis/inflammation adjustment, with 12 associations shared between the two analyses. The strongest relationships connected the SCFA receptor/barrier-response program with the inflammation-associated reactive/glial-adjacent state (ρ = 0.727) and the CGRP/adrenomedullin-family receptor-side score (ρ = 0.552), and connected the AHR-response context with the same receptor-side score (ρ = 0.531). Single-cell analyses localized CALCRL, RAMP2, and RAMP3 mainly to endothelial cells, VIPR1 to epithelial cells, and VIPR2 to stromal cells. The attenuation of incremental model fit after composition-proxy conditioning further indicated that this organization is closely embedded in mucosal tissue ecology. Matched metabolomic and premalignant-cohort analyses provided complementary evidence on the scope of this framework but did not extend it to synchronized metabolite coupling or neoplastic progression. Conclusions: Participant-level associations and compartment-resolved receptor localization support a cross-sectional receptor-side neuroimmune remodeling framework in IBD. The convergence of host-program organization and cellular localization prioritizes specific receptor–compartment relationships for spatial validation, functional receptor perturbation, and prospectively matched stool–mucosal studies.