Background: Toll‐like receptors (TLRs) are a family of fundamental pattern recognition receptors in the innate immune system, constituting the first line of defense against endogenous and exogenous antigens. The gut microbiota, a collection of commensal microorganisms in the intestine, is a major source of exogenous antigens. The components and metabolites of the gut microbiota interact with specific TLRs to contribute to whole‐body immune and metabolic homeostasis.Objective: This review aims to summarize the interaction between the gut microbiota and TLR signaling pathways and to enumerate the role of microbiota dysbiosis‐induced TLR signaling pathways in obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC).Results: Through the recognition of TLRs, the microbiota facilitates the development of both the innate and adaptive immune systems, while the immune system monitors dynamic changes in the commensal bacteria to maintain the balance of the host‐microorganism symbiosis. Dysbiosis of the gut microbiota can induce a cascade of inflammatory and metabolic responses mediated by TLR signaling pathways, potentially resulting in various metabolic and inflammatory diseases.Conclusion: Understanding the crosstalk between TLRs and the gut microbiota contributes to potential therapeutic applications in related diseases, offering new avenues for treatment strategies in conditions like obesity, IBD, and CRC.

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with a relapsing nature and complex etiology. Bioinformatics analysis has been widely applied to investigate various diseases. This study aimed to identify crucial differentially expressed genes (DEGs) and explore potential therapeutic agents for UC. Methods: The GSE47908 and GSE55306 colon tissue transcriptome gene datasets were downloaded from the Gene Expression Omnibus-NCBI (GEO) database. GEO2R and Gene Set Enrichment Analysis (GSEA) were used to screen for DEGs in patients with UC compared to the normal population based on weighted gene co-expression network analysis (WGCNA). GO-BP analysis and KEGG enrichment analysis were performed on the intersecting differential genes via the Metascape website, while hub genes were analyzed by STRING11.0 and Cytoscape3.7.1. The expression of hub genes was verified in the dataset GSE38713 colon tissue specimens. Finally, the gene expression profiles of the validation set were analyzed by immuno-infiltration through the ImmuCellAI online tool, and the CMap database was used to screen for negatively correlated small molecule compounds. Results: A total of 595 and 926 genes were screened by analysis of GSE47908 and GSE55306 datasets, respectively. Combined WGCNA hub module intersection yielded 12 hub genes (CXCL8, IL1β, CXCL1, CCL20, CXCL2, CXCR2, LCN2, SELL, AGT, LILRB3, MMP3, IDO1) associated with the pathogenesis of UC. GSEA analysis yielded intersecting pathways for both datasets (colorectal cancer pathway, base excision repair, cell cycle, apoptosis). GO-BP and KEGG enrichment analyses were performed to obtain key biological processes (inflammatory response, response to bacteria, leukocyte activation involved in the immune response, leukocyte–cell adhesion, apoptosis, positive regulation of immune effector processes) and key signaling pathways (cytokine–cytokine receptor interactions, IBD, NOD-like receptor signaling pathways). The immune cell infiltration analysis suggested that the incidence of UC was mainly related to the increase in CD4+T cells, depletion of T cells, T follicular helper cells, natural killer cells, γδ T cells and the decrease in CD8 naive T cells, helper T cells 17 and effector T cells. The CMap database results showed that small molecule compounds such as vorinostat, roxarsone, and wortmannin may be therapeutic candidates for UC. Conclusions: This study not only aids in early prediction and prevention but also provides novel insights into the pathogenesis and treatment of UC.

Inflammatory bowel disease (IBD) is associated with alterations in the intestinal luminal environment that may modify the composition of fecal water (FW) and its capacity to induce DNA damage. The aim of this study was to identify FW metabolites associated with DNA damage and aryl hydrocarbon receptor (AhR) activity and to investigate whether shared metabolic pathways may link these responses in patients with IBD. FW samples from 80 IBD patients and 20 healthy controls were analyzed. DNA damage in Caco-2 cells following FW exposure was assessed using the comet assay, AhR activity using the ethoxyresorufin-O-deethylase assay, and FW metabolites by using liquid chromatography–mass spectrometry. Metabolite signatures associated with DNA damage and AhR activity were identified separately, and subsequent pathway analysis revealed overlapping metabolic pathways, prompting further investigation of AhR-associated tryptophan metabolites. Kynurenine was inversely associated with AhR activity but positively associated with DNA damage in IBD, whereas serotonin was positively related to AhR activity and was protective against FW-induced DNA damage. Indoles did not significantly contribute to FW-induced DNA damage. These findings suggest that inflammation-associated alterations in tryptophan metabolism are associated with altered AhR signaling and epithelial DNA damage in IBD.