Astore C, Nagpal S, Gibson G. International Journal of Molecular Sciences, 2022, 23:14380, 11 pages. DOI: 10.3390/ijms232214380
Background & Rationale
Inflammatory bowel disease (IBD) involves chronic gastrointestinal inflammation, with increasing prevalence potentially linked to environmental factors including diet. Omega-3 fatty acids, polyunsaturated fatty acids (PUFAs) obtained largely from diet, may reduce inflammatory responses in IBD, though causality remains unestablished. Alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) represent notable omega-3 forms. ALA derives from plant oils whilst EPA and DHA come primarily from fish and seafood. The body converts small amounts of ALA into EPA and subsequently DHA through FADS2 and FADS1 desaturase enzymes.
Study Design
The authors performed two-sample Mendelian randomisation (MR) analysis assessing genetic associations between circulating metabolites and IBD using genome-wide association study (GWAS) summary data from large European ancestry cohorts. The exposure dataset comprised 249 circulating metabolites from UK Biobank. Three independent IBD GWAS datasets served as outcomes: Sample one from IBD-Genetics Consortium (IBD-GC), Sample two from earlier IBD-GC release, and Sample three from FinnGen. Instrumental variables were 31 IBD-associated single nucleotide polymorphisms (SNPs) in Sample one, 38 in Sample two, and 43 in Sample three. Five MR methods were employed: inverse variance weighted (IVW) as primary method, with MR-Egger, weighted median, simple mode, and weighted mode as sensitivity analyses. Statistical approaches included Cochran’s Q test, MR-Egger intercept test, leave-one-out analysis, and IVW-radial method for outlier detection.
Patient Population
The analysis utilised GWAS summary statistics from large European ancestry cohorts rather than individual participant data. Baseline clinical characteristics were not reported given the summary data nature.
Key Findings
Increased circulating omega-3 fatty acids demonstrated protective associations with IBD across all datasets. Sample one showed IVW odds ratio 0.87, Sample two 0.79, Sample three 0.86. All methods produced odds ratios below 1.0 with significance levels between 0.001 and 0.00001, except simple mode in Sample three. After removing SNPs with F-statistics below 10, significance remained between 0.00001 and 0.01. Fisher’s method combining all samples showed significance at p<0.0001 for all MR modes except simple mode. Five additional metabolites showed concordant evidence across both IBD-GC datasets: four protective (including DHA, DHA to total fatty acids ratio, omega-3 to total fatty acids ratio) and omega-6 to omega-3 ratio as risk factor. UK Biobank data showed significantly reduced omega-3 and DHA levels in IBD cases versus controls. No statistical interaction occurred between rs174564 and DHA or omega-3 fatty acids regarding IBD prevalence.
Discussion
Multiple evidence lines support robustness: replication across three independent datasets, concordant results from five MR implementations, leave-one-out analysis showing results not driven solely by rs174564, and lower omega-3 and DHA in IBD patients. The largest genetic effect involved rs174564, an intronic SNP in FADS2 encoding a desaturase protein in ALA metabolism. FADS2 expression was elevated in blood and colon in IBD-protective variant carriers. Omega-3 fatty acids are anti-inflammatory, possibly through cyclooxygenase (COX) inhibition, reducing pro-inflammatory prostaglandin production. Protection against ulcerative colitis appeared weaker than for Crohn’s disease. FADS2 haplotype differences across ancestries may explain variable omega-3 supplement trial results.
Authors’ Conclusions
Omega-3 fatty acids demonstrate significant protective associations with IBD, replicated across three datasets using multiple MR methods. Instrumental variables highlight rs174564 in FADS2, involved in ALA desaturation producing anti-inflammatory EPA and DHA. Low omega-3 to omega-6 ratio is a causal risk factor, particularly for Crohn’s disease. Limitations include need for confirmation in diverse ancestries, uncertainty regarding blood versus colon as tissue mediator, and need for one-sample MR. Results inform disease prevalence but should not imply omega-3 supplementation is curative; it may require extended administration at particular ages and likely benefits only patient subsets.
Reference
Astore C, Nagpal S, Gibson G. Mendelian Randomization Indicates a Causal Role for Omega-3 Fatty Acids in Inflammatory Bowel Disease. Int J Mol Sci. 2022;23(22):14380. doi:10.3390/ijms232214380
This Scientific Publication Summary is an objective summary of the published trial for personal and educational use. It does not constitute clinical advice, endorsement of the intervention, or a recommendation to alter clinical practice.