Abstract 3734: Associations between microbiota-derived indoles and inflammation markers among colorectal cancer patients

Abstract Introduction: Gut microbiota-derived indole metabolites, produced from dietary tryptophan, play significant roles in modulating inflammation and intestinal immune responses. However, despite emerging interest, still little is known about the roles of indoles in the context of colorectal cancer (CRC). Given the microbiome’s potential impact on CRC progression, understanding the associations between indoles and inflammatory markers may reveal novel therapeutic insights for CRC management. Methods: Pre-surgery serum samples from 77 stage I-IV CRC patients participating in the ColoCare Study, Heidelberg, have been contributed to the German PerMiCCion Consortium to measure circulating levels of indoles and cytokines using untargeted metabolomics analyses and LEGENDPLEX Cytokine Array, respectively. Multivariable linear regression models were conducted to quantify associations between Indole-3-Acetic Acid (IAA), Methyl-IAA (mIAA), 5-Hydroxyindoleacetic Acid (5-HIAA), Indole-3-Propionic Acid (IPA), Indole-3-Acetamide (IAM), Indole-3-Lactic Acid (ILA), Indole-3-Aldehyde, Indole-3-Carboxylic Acid (ICA) and 44 inflammation markers. Models were adjusted for age, sex, tumor stage, tumor site, and circulating creatinine levels. Sensitivity analyses with false discovery rate (FDR) correction were conducted to adjust for multiple testing. Results: We found mixed associations for indoles with inflammation markers. For example, IAM was positively associated with IL-6 (β =0.23, p =0.04), CD25 (β =0.68, p =0.01), Tim-3 (β =0.29, p =0.03) and Angiopoietin-2 (β =0.31, p =0.04). In contrast, IPA and ICA showed inverse associations with IL-6 (β =−0.37, p =0.01; β =−0.07, p =0.02, respectively). Strong associations between IPA and CD68 (β =1.01, p =0.02) and PDGF-AA (β =0.62, p =0.03) were observed. Additionally, IAA, 5H-IAA, and ILA were positively correlated with chemokines CXCL9, CXCL11, and CCL4 (β =0.30, p =0.02; β =0.19, p =0.01; β =0.17, p =0.03, respectively). Weak associations of ILA and mIAA with PD-L1 were found (β =0.14, p<0.01; β =0.14, p<0.01, respectively). In sensitivity analyses, associations did not remain statistically significant after FDR adjustment. Conclusion: This study highlights the varied roles of indole metabolites in CRC. Metabolites like IAM appear to foster a pro-tumor immune landscape via inflammation, immune exhaustion, and angiogenesis. While IPA and ICA may counteract these processes through anti-inflammatory effects, IPA may also have pro-angiogenic properties. IAA, 5H-IAA, and ILA seem to be involved in immune cell recruitment to the tumor site and ILA and mIAA may play a role in suppression of anti-tumor immune responses. Larger cohort studies are needed to gain a deeper understanding of the interplay between indoles and inflammatory processes during colorectal carcinogenesis which may ultimately help identify therapeutic targets for CRC. Citation Format: Victoria Damerell, Doratha A. Byrd, Sheetal Hardikar, Mmadili N. Ilozumba, Christoph Kahlert, Jane C. Figueiredo, Christopher I. Li, David Shibata, Adetunji T. Toriola, Cornelia M. Ulrich, Gianni Panagiotou, Biljana Gigic. Associations between microbiota-derived indoles and inflammation markers among colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3734.