Effect of tocotrienol and tocopherol regulation by the microbiome on colitis-associated cancer.

Abstract

e15512 Background: The association between inflammatory bowel disease (IBD) and a higher risk of colorectal cancer (CRC) has been well established, and is commonly attributed to chronic inflammation and a predisposition to genomic instability ( Feagins et al., 2009 ). Independently, an altered gut microbiome has been evidenced in both IBD ( Halfvarson et al., 2017 ) and CRC ( Marchesi et al., 2011 ). It is unknown whether the altered the IBD-associated microbiome is able to directly influence carcinogenesis via an inflammation-independent mechanisms. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. 2,081 stool samples from adults with IBD and 2,000 stool samples from healthy adults were included. Shannon’s Diversity Index was used to consider within-sample diversity, and PERMANOVA and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Differential abundance analysis was used to identify species significantly associated with IBD, and a database built on existing literature was used to consider their metabolic products and interactions with known human oncogenes and tumour suppressor genes. Results: Our results show a clearly separation of the IBD microbiome from the healthy population (PERMANOVA p = 0.01), as well as a collapse in Shannon diversity (p < 2.2e-16). Compared to the healthy microbiome, 79 species were significantly (FDR < 0.01) enriched in the IBD stool microbiome, including: Bacteroides fragilis, Bacteroides vulgatus, Bacteroides uniformis, Escherichia coli, Veillonella parvula, Enterococcus faecalis, Fusobacterium mortiferum, and Fusobacterium ulcerans, all of which have previously been evidenced to be enriched in CRC ( Randa et al., 2023 , Bi et al., 2022 , Du et al., 2022 ). Conversely, 115 species were enriched in healthy subjects, including several bacteria with probiotic and anti-tumourigeneic potential such as: Segatella copri, Roseburia inulinivorans, Lactobacillus rogosae, and Coprococcus comes ( Sarah et al., 2022 , Kang et al., 2023 , Campisciano et al., 2020 , Yang et al., 2019 ) Two of the bacteria enriched in the healthy group are producers of both delta-tocotrienol and gamma-tocopherol. These vitamin E isoforms have been implicated in suppression of cancer invasion and proliferation ( Ya et al., 2008 ), in part through NFkB signalling ( Ling et al., 2012 ). Conclusions: This work suggests that that IBD-associated microbiome may contribute to colorectal cancer risk via the suppression of vitamin E isoform signalling, a mechanism that is independent from inflammation. This could present a highly targetable way of mediating CRC-risk in the IBD population.