Sex-specific immune signatures in irritable bowel syndrome suggest reduced neutrophil-associated activity in males and altered interferon signaling in females
Background & Aims: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with a higher prevalence in females. While most transcriptomic studies have focused on gut mucosal biopsies, systemic transcriptional differences remain poorly understood. We investigated sex-specific whole-blood transcriptome profiles in IBS using a cross-sectional observational design.  Methods: Whole-blood bulk RNA sequencing was performed on the DNBSEQ-G400 platform. Differential expression analysis was performed separately for males and females using DESeq2 (FDR < 0.05). Functional enrichment and protein–protein interaction analyses were performed using STRING database. Cell-type enrichment scores were estimated with xCell2. Transcription factor (TF) coordination network analysis was conducted using NetREm. In silico validation was performed using three independent publicly available RNA-seq datasets from small intestine, colon, and peripheral blood mononuclear cells.  Results: We identified sex-specific transcriptional signatures. In males, genes involved in neutrophil-mediated antibacterial responses were downregulated. In females, genes involved in antiviral defense and interferon signaling pathways were downregulated, whereas neutrophil-associated pathways showed opposite regulation. Transcription factor coordination analysis revealed widespread alterations in regulatory relationships, including both shared and sex-specific TF–TF interactions. Cross-cohort comparisons revealed partial concordance across datasets, with both sexes overlapping primarily with small intestine data; males showed gene- and pathway-level overlap, whereas females showed gene-level overlap.  Conclusions: Whole-blood transcriptome profiling revealed distinct immune-related signatures in IBS, suggesting sex-specific immune modulation in IBS pathophysiology.
Background & Aims: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with a higher prevalence in females. While most transcriptomic studies have focused on gut mucosal biopsies, systemic transcriptional differences remain poorly understood. We investigated sex-specific whole-blood transcriptome profiles in IBS using a cross-sectional observational design.  Methods: Whole-blood bulk RNA sequencing was performed on the DNBSEQ-G400 platform. Differential expression analysis was performed separately for males and females using DESeq2 (FDR < 0.05). Functional enrichment and protein–protein interaction analyses were performed using STRING database. Cell-type enrichment scores were estimated with xCell2. Transcription factor (TF) coordination network analysis was conducted using NetREm. In silico validation was performed using three independent publicly available RNA-seq datasets from small intestine, colon, and peripheral blood mononuclear cells.  Results: We identified sex-specific transcriptional signatures. In males, genes involved in neutrophil-mediated antibacterial responses were downregulated. In females, genes involved in antiviral defense and interferon signaling pathways were downregulated, whereas neutrophil-associated pathways showed opposite regulation. Transcription factor coordination analysis revealed widespread alterations in regulatory relationships, including both shared and sex-specific TF–TF interactions. Cross-cohort comparisons revealed partial concordance across datasets, with both sexes overlapping primarily with small intestine data; males showed gene- and pathway-level overlap, whereas females showed gene-level overlap.  Conclusions: Whole-blood transcriptome profiling revealed distinct immune-related signatures in IBS, suggesting sex-specific immune modulation in IBS pathophysiology.
Latvian Biomedical Research and Study Centre