Regulatory roles of intestinal CD4⁺ T cells in inflammation and their modulation by the intestinal microbiota

Intestinal inflammation is a major global health challenge, driving the pathogenesis of inflammatory bowel disease (IBD) and imposing a significant socioeconomic burden. Dysregulated homeostasis of intestinal CD4⁺ T cell subsets, particularly the imbalance between pro-inflammatory T helper cells (Th1, Th2, Th17, Th9) and regulatory T cells (Tregs), is a key trigger of intestinal inflammation. These immune cells orchestrate immune responses through distinct cytokine profiles (IFN-γ/IL-4/IL-17/IL-9 vs. IL-10/TGF-β). Recent studies highlight the pivotal role of the intestinal microbiota in regulating this immune axis via three primary mechanisms: 1, Short-chain fatty acids (SCFAs) induce epigenetic reprogramming by inhibiting HDACs, promoting Treg differentiation and inhibit the differentiation of Th17/Th9 cells; 2, Secondary bile acids (BAs) suppress Th17 polarization through FXR/TGR5/PXR signaling; 3, Tryptophan metabolites (indole, kynurenine) balance Th17/Treg ratios via AhR-IL-22 signaling. Microbial dysbiosis disrupts this network by secreting pathogen-associated molecular patterns (PAMPs), such as Lipopolysaccharide (LPS) and peptidoglycan (PG), which activate pathogen pattern recognition receptors (PRRs), such as TLR4/NOD2/NF-κb signaling, driving Th1/Th17 differentiation. This review summarizes recent advances in the microbiota-CD4⁺ T cell interaction and discusses therapeutic strategies to modulate the intestinal microbiota, aiming to enhance understanding of IBD pathogenesis and identify potential clinical interventions.