Participant-level analysis of HMP2 mucosal transcriptomes supports a cross-sectional framework of receptor-side neuroimmune remodeling in IBD, in which metabolite-sensing programs covary with neuroimmune receptor-side states and receptor transcripts map to specific mucosal compartments, though this organization is embedded in tissue ecology and was not extended to synchronized metabolite coupling or neoplastic progression.
Most prespecified associations between metabolite-sensing and neuroimmune receptor-side host programs were supported in participant-mean analyses and after diagnosis/inflammation adjustment.
The SCFA receptor/barrier-response program showed the strongest association with the inflammation-associated reactive/glial-adjacent state.
The SCFA receptor/barrier-response program and the AHR-response context were both associated with the CGRP/adrenomedullin-family receptor-side score.
Single-cell analyses localized neuroimmune receptor transcripts to distinct mucosal compartments.
Conditioning on tissue-composition proxies attenuated incremental model fit, indicating the host-program organization is closely embedded in mucosal tissue ecology.
Matched metabolomic and premalignant-cohort analyses did not extend the framework to synchronized metabolite coupling or neoplastic progression.
The findings support a cross-sectional, not longitudinal or activation-based, receptor-side neuroimmune remodeling framework and prioritize receptor-compartment relationships for further validation.
This study looked at gut biopsy gene-activity data from people with inflammatory bowel disease (IBD) and others in a large public dataset (251 biopsies from 90 participants). It asked whether genes involved in sensing microbial products, such as short-chain fatty acids and compounds that activate the aryl hydrocarbon receptor, tend to move together with genes for receptors involved in nerve-immune signaling. Many of the planned comparisons did hold up: 13 of 20 were statistically supported, and a similar number remained after accounting for diagnosis and inflammation. The strongest links were between the short-chain fatty acid sensing and barrier-response program and an inflammation-linked, glial-like state. Using single-cell data, the researchers also found that different receptor genes are mainly found in different cell types. Some were mostly in blood-vessel lining cells (CALCRL, RAMP2, RAMP3), one in gut lining cells (VIPR1), and one in supporting stromal cells (VIPR2). However, the associations weakened when the researchers accounted for the mix of cell types in the tissue, suggesting the patterns are closely tied to overall tissue makeup. This research suggests a map of which receptors and cell types may be involved in gut nerve-immune-metabolite interactions in IBD. It does not show cause and effect, receptor activation, or change over time. Metabolite measurements and colorectal-neoplasia datasets did not extend the findings to matched metabolite coupling or cancer progression. The results mainly point to targets for future lab and spatial studies.
Hu H, Xu K, Yuan X, Lei Z, Lu Y. (2026). Receptor-Side Neuroimmune Remodeling in IBD: Participant-Level Associations with Metabolite-Sensing Programs and Colorectal Neoplasia Context.. International journal of molecular sciences. https://doi.org/10.3390/ijms27209179