Host transcriptional signatures associated with microbial sequence signals reveal age-related decline in intestinal homeostasis

Aims To characterize age-associated alterations in intestinal barrier homeostasis by integrating host transcriptomic profiles and mucosa-associated microbial sequence signals recovered from human colonic biopsy RNA-seq datasets.Materials and methods We performed an integrative host-microbiome metatranscriptomic analysis of human colonic biopsies from adults aged 20 to >70 years (n = 238). RNA-seq libraries from four public datasets were analyzed using DESeq2, GSEA, Ingenuity Pathway Analysis (IPA), and SAHMI for differential expression, pathway enrichment, and microbial profiling.Results Aging was associated with progressive transcriptional remodeling of the intestinal barrier. Key epithelial genes regulating differentiation (GATA5), extracellular matrix (ECM) turnover (MMP9, ADAMTS4), and lipid metabolism (FABP6, LRP2, LPA) showed age-dependent dysregulation, accompanied by elevated chemokine and cytokine signaling (CXCL1, CCL19, IL17A, IL22). Pathway analyses identified enrichment of IL-17 and ECM-cytokine signaling, consistent with chronic inflammatory activation. Parallel microbial profiling revealed a shift from butyrate-producing commensals (Faecalibacterium, Roseburia, Bifidobacterium) toward mucolytic and pro-inflammatory taxa (Ruminococcus torques, Acidaminococcus intestini, Bacteroides ovatus).Conclusions This study supports a continuum model of immune, structural, and microbial remodeling associated with aging. The findings highlight mucosal host-microbe interactions as potential therapeutic targets for preserving epithelial resilience and promoting healthy aging.