Supplementing With the Vitamin A Metabolite Retinoic Acid Can Alleviate Negative Affective States Caused by SPI1‐Induced Immune and Metabolic Dysfunctions Following Intestinal Barrier Impairment

Abstract

ABSTRACT Ulcerative colitis (UC) and depression (DP) are significant comorbidities in epidemiological research. However, the mechanisms underlying UC‐induced DP remain poorly understood. Myeloid differentiation and retinoic acid metabolic dysregulation are implicated in both conditions, yet their interconnection in the context of comorbidity is unclear. This study investigates the role of SPI1 in mediating UC‐induced DP through the modulation of retinoic acid metabolism and hematopoietic stem cell myeloid bias, exploring the immune‐metabolic‐gut axis. This study employed multi‐technique approach to determine whether SPI1 exacerbates UC‐induced DP by influencing retinoic acid metabolism and myeloid bias. Methods included genome‐wide and proteome‐wide Mendelian randomization (MR), in vivo imaging, qRT‐PCR, metabolomics, transcriptomics, flow cytometry, behavioral tests, immunofluorescence, immunohistochemistry, in silico knockout and overexpression analyses, various machine‐learning models, molecular docking, and molecular dynamics simulations to comprehensively evaluate our hypothesis. Our findings indicate that myeloid bias in hematopoietic stem cells occurs during UC‐induced DP and is regulated by SPI1. Inhibiting SPI1 reshapes this myeloid bias and alleviates depressive phenotypes. Furthermore, SPI1 shows a significant causal relationship with retinol‐binding protein 2 (RBP2), a key player in retinoic acid metabolism. SPI1 inhibition restored Cyp26a1 levels and normalized the transcription of RBP2 and other retinoic acid metabolism‐related genes, thereby rescuing metabolic homeostasis. Exogenous administration of all‐trans retinoic acid (ATR) also corrected myeloid bias and exerted therapeutic effects against UC‐induced DP. These findings highlight the pivotal role of SPI1 in UC‐induced DP and suggest the potential of exogenous ATR supplementation as preventive or therapeutic strategy for patients with this comorbidity.

The authors' abstract, as published at the source. Food Frontiers, 2026 · DOI ↗