Shiyuan Lu

Objective Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC. Design 18 F-FDG ( 18 F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum -induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1. Results We have found F . nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function. Conclusion F. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum .

Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.

BACKGROUND: Mitochondrial dysfunction has been linked to the development of inflammatory bowel disease (IBD), but the genetic pathophysiology was not fully elucidated. We employed Mendelian randomization and colocalization analyses to investigate the associations between mitochondrial-related genes and IBD via integrating multi-omics. METHODS: Summary-level data of mitochondrial gene methylation, expression and protein abundance levels were obtained from corresponding methylation, expression and protein quantitative trait loci studies, respectively. We obtained genetic associations with IBD and its two subtypes from the Inflammatory Bowel Disease Genetics Consortium (discovery), the UK Biobank (replication), and the FinnGen study (replication). We performed summary-data-based Mendelian randomization analysis to assess the associations of mitochondrial gene-related molecular features with IBD. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. FINDINGS: After integrating the multi-omics data between mQTL-eQTL and eQTL-pQTL, we identified two mitochondrial genes, i.e., PARK7 and ACADM, with tier 1 evidence for their associations with IBD and ulcerative colitis (UC). PDK1 and FISI genes were associated with UC risk with tier 2 and tier 3 evidence, respectively. The methylation of cg05467918 in ACADM was associated with lower expression of ACADM, which fits with the positive effect of cg05467918 methylation on UC risk. Consistently, the inverse associations between gene methylation and gene expression were also observed in PARK7 (cg10385390) and PDK1 (cg17679246), which were corroborated with the protective role in UC. At circulating protein level, genetically predicted higher levels of PARK7 (OR 0.36, 95% CI 0.25-0.52) and HINT1 (OR 0.47, 95% CI 0.30-0.74) were inversely associated with IBD risk; genetically predicted higher level of HINT1 was associated with a decreased risk of Crohn's disease (CD) (OR 0.26, 95% CI 0.14-0.49) and a higher level of ACADM (OR 0.67, 95% CI 0.55-0.83), PDK1 (OR 0.63, 95% CI 0.49-0.81), FIS1 (OR 0.63, 95% CI 0.47-0.83) was associated with a decreased risk of UC. INTERPRETATION: We found that the mitochondrial PARK7 gene was putatively associated with IBD risk, and mitochondrial FIS1, PDK1, and ACADM genes were associated with UC risk with evidence from multi-omics levels. This study identified mitochondrial genes in relation to IBD, which may enhance the understanding of the pathogenic mechanisms of IBD development. FUNDING: XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and Healthy Zhejiang One Million People Cohort (K-20230085).