Impact of Omega-3 Fatty Acids on Lipidomics and Gut Microbiome in Patients with Type 2 Diabetes

Background

Type 2 Diabetes (T2D) is a common metabolic disorder worldwide, often accompanied by lipid abnormalities such as hypertriglyceridemia (HTG). Lipid abnormalities are significant risk factors for cardiovascular disease (CVD), especially high triglyceride (TG) levels, which are closely associated with the occurrence of cardiovascular events. Although statins have achieved remarkable success in controlling cholesterol, hypertriglyceridemia remains a critical clinical issue.

Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found abundantly in fish oil, have shown potential in reducing triglyceride levels. However, the effects of fish oil supplementation on lipidomics and gut microbiome in T2D patients, as well as the mechanisms by which these factors collectively regulate triglyceride levels, remain unclear. Additionally, there is significant variability in individual responses to fish oil supplementation, and the reasons for this heterogeneity are not fully understood.

To address these knowledge gaps, Jieli Lu and colleagues conducted a randomized double-blind placebo-controlled trial to investigate the impact of fish oil supplementation on lipidomics and gut microbiome in T2D patients with HTG and to identify baseline characteristics that predict the efficacy of fish oil in lowering triglycerides.

Source of the Paper

This study was conducted by scholars from multiple institutions, including the Institute of Endocrine and Metabolic Diseases at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, BGI Research, and BGI Genomics, among others. It was published in the journal Med on January 10, 2025.

Study Design and Results

1. Study Design and Participants

The study included 309 Chinese patients with T2D and HTG, who were randomly divided into a fish oil group (153 participants) and a placebo group (156 participants) for a 12-week intervention. The fish oil group received 4 grams of fish oil daily, while the placebo group received corn oil. The primary outcome was changes in serum triglyceride levels and lipidomic profiles, while secondary outcomes included changes in the gut microbiome and other metabolic variables.

2. Clinical Outcomes

The results showed that after 12 weeks, the fish oil group experienced a significant reduction in triglyceride levels, decreasing by an average of 1.51 mmol/L (95% confidence interval: -2.01 to -1.01), significantly better than the placebo group’s reduction of 0.66 mmol/L (p=0.02). Additionally, the fish oil group showed a more significant improvement in low-density lipoprotein cholesterol (LDL-C).

3. Lipidomics Analysis

Using ultra-high performance liquid chromatography-high-resolution mass spectrometry, the research team found that fish oil intervention significantly altered the serum lipid profile. After fish oil supplementation, 56.6% of lipids significantly decreased, particularly low-unsaturated triglycerides, phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and ceramides (Cers). Moreover, lipids containing EPA and DHA increased significantly in the fish oil group.

4. Gut Microbiome Analysis

Gut microbiome analysis revealed that fish oil supplementation had minimal effects on microbial diversity and overall composition. However, baseline gut microbiota characteristics could significantly predict the efficacy of fish oil in lowering triglycerides. The researchers constructed a Gut Microbiota Triglyceride Index (GMTGI) based on 112 TG-associated species, finding that patients with higher baseline GMTGI values responded better to fish oil.

5. Predictive Models and Mechanism Exploration

Through random forest models, the researchers discovered that baseline gut microbiota characteristics outperformed clinical phenotypes and lipid features in distinguishing responders (Rs) from non-responders (Nrs) to fish oil. Certain baseline microbial features and metabolic pathways (such as L-histidine degradation pathway III) were significantly associated with triglyceride reduction. Furthermore, mediation analysis indicated that specific lipid metabolites played a crucial role in mediating the relationship between baseline microbial features and fish oil efficacy.

Conclusion and Significance

This study systematically revealed the impact of fish oil supplementation on lipidomics and gut microbiome in T2D patients and highlighted the importance of baseline gut microbiota characteristics as predictors of fish oil efficacy. This not only provides new scientific evidence for the application of fish oil in managing T2D and HTG but also points towards personalized nutritional intervention strategies.

Key Highlights

1. Significant Reduction in Triglyceride Levels: Fish oil supplementation significantly reduced triglyceride levels in T2D patients, validating its effectiveness in lipid management.
2. Lipidomics Changes: The study comprehensively revealed the profound impact of fish oil on the serum lipid profile in T2D patients, particularly the increase in highly unsaturated triglycerides and decrease in low-unsaturated triglycerides.
3. Association Between Gut Microbiome and Lipid-Lowering Efficacy: Baseline gut microbiota characteristics were found to significantly predict the efficacy of fish oil in lowering triglycerides, offering new insights into personalized interventions.
4. Innovative Research Methods: Random forest models and mediation analysis were employed to explore the complex relationships between gut microbiota, lipid metabolism, and fish oil efficacy.

Limitations and Future Directions

The study was conducted exclusively on a Chinese population, and further validation is needed to generalize the findings to other racial/ethnic groups. Additionally, the relatively short intervention period limits conclusions about long-term effects. Future studies should involve diverse populations and longer intervention periods to validate and extend these findings.

This research deepens our understanding of the application of fish oil in T2D patients and provides important scientific support for personalized nutritional interventions based on gut microbiota.