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Can Omega-3 Fats Treat Dysbiosis?

Omega-3 fish oil supplements may help to modify the gut biome and improve gut health. In this article, Cliff delves into the research to answer the question 'can omega-3 fats treat dysbiosis?'

Key points

  • Omega-3 fats DHA and EPA modify the intestinal microbiome
  • This may result in some reduction in species diversity but this finding is not clear
  • Omega-3 fats increase relative amounts of short-chain fatty acid producing bacteria beneficial to health
  • These changes to the microbiome reduce the formation of endotoxins and reduce inflammation and immune dysfunction
  • High dose fish oil supplementation during active inflammatory bowel disease has been demonstrated to worsen sepsis in some animal models, and this finding needs to be further studied in humans

Various studies have found that the omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) found in fish oil, can reverse intestinal dysbiosis (distortion of the natural balance of microbes in the gut) by increasing beneficial bacteria species, including LactobacillusBifidobacterium, and butyrate-producing bacteria, such as Roseburia and Coprococcus. In addition, omega-3 fatty acids decrease the proportions of lipopolysaccharide and mucous producing bacteria in the gut, along with reducing inflammation and oxidative stress,1 and obesity.2

What are ‘lipopolysaccharides’?

Lipopolysaccharides (LPS) are ‘endotoxins’ (toxins originating within the body) that are found in the outer membrane of various bacteria, which can be released into the body of the host. They are linked to sepsis, inflammation, auto-immune diseases, and even obesity in humans.

Omega-3 fatty acids decrease the proportions of lipopolysaccharide and mucous producing bacteria in the gut, along with reducing inflammation and oxidative stress, and obesity.

Animal Research

Systemic and chronic inflammation can be related to ‘metabolic endotoxemia’, or toxicity resulting from gut dysbiosis and increased levels of LPS (see above). Mice fed a diet high in omega-6 fats exhibit higher levels of metabolic endotoxemia and systemic inflammation. When mice are modified to be able to convert omega-6 fats to omega-3s, both endotoxemia and inflammation are drastically reduced. Increased omega-3 fats enhance the production of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased LPS production and gut permeability (i.e. less ‘leaky gut’), and ultimately, reduced metabolic endotoxemia and inflammation.3

Mice fed a diet high in omega-6 fats exhibit higher levels of metabolic endotoxemia and systemic inflammation

Animal research (in mice) has suggested that elevated tissue levels of omega-3 fatty acids reduce body weight gain and the severity of insulin resistance, and these effects were associated with reversal of antibiotic-induced dysbiosis in the gut.4 Further research has shown that both endogenous (created within the body) and supplemental omega-3 fats (fish oil) improve diet-induced microbiome changes (along with improvements in lipid profiles and fatty-liver disease), with supplementation having a bigger effect to reshape the intestinal microbiome and increase short-chain fatty acid production, which is both beneficial to health and also indicative of positive changes to the microbiome.5  Reduced maternal n-3 PUFA exposure has also led to significantly depleted EpsilonproteobacteriaBacteroides, and Akkermansia and higher relative abundance of Clostridia.6 Mice supplemented with omega-3 fats had reduced expression of genes associated with de novo lipogenesis (creation of fats within the body) and these mice also had a greater abundance of BacteroidetesActinobateria, and Proteobacteria (which were negatively correlated with the genes associated with lipid and triglyceride synthesis).7

supplemental omega-3 fats (fish oil) improve diet-induced microbiome changes

What are short-chain fatty acids?

Short-chain fatty acids (SCFAs) have carbon chains between two and five in length. These fatty acids include acetic acid (C:2), propionic acid (C:3), butyric acid (C:4), and valeric acid (C:5). Short-chain fatty acids, especially butyric acid, are used extensively as a fuel substrate by intestinal epithelial cells.8 Butyric acid is mostly produced by microbial intestinal fermentation of dietary fibre and resistant starch. Most of the butyric acid produced by this fermentation of starches is absorbed and used directly by cells of the intestinal wall, with most of the remainder absorbed into the hepatic portal vein and transported to the liver where it can be converted to ketone bodies.9, 10 A small amount is absorbed directly from the large colon and enters systemic circulation, to be used directly by peripheral tissue.9 Butyrate reduces inflammation and cancer formation in the colon, and decreases oxidative stress, and promotes satiety.11, 12 Thus, it serves an important role in preserving the health of the colon, the microbiota, and has other beneficial effects on overall health.

Other research in rodents has shown positive from omega-3 fats in models of ulcerative colitis, an inflammatory bowel disorder. In research related to this, omega-6 fats have been shown to increase inflammation-causing bacteria such as Enterobacteriaceae, Segmented Filamentous Bacteria and Clostridia spp,13 and Helicobacter, Uncultured bacterium clone WD2_aaf07d12 (GenBank: EU511712.1), Clostridiales bacterium, Sphingomonadales bacterium and Pseudomonas species Firmicutes,14 and mice with infection-induced colitis had  greater intestinal damage, immune distortion and infiltration of pathogenic bacteria from the intestine when given omega-6 fats. In comparison, the addition of omega-3 fats to the diet, reverses the growth of these inflammatory microbial blooms and increases beneficial microbes like Lactobacillus and Bifidobacteria,13, 15  and improves immune markers.13 However, there was some suggestion that the prevention of systemic inflammation resulted in greater sepsis and mortality among omega-3 supplemented mice.13 Similarly, omega-3 supplemented mouse pups displayed positive changes to the microbiome and reduced inflammation, along with protection against oral peanut allergy, but also a tendency toward worsened responses during E. coli sepsis and had significantly worse outcomes during Staphylococcus aureus skin infection.16

In rats treated with ethanol to mimic alcohol consumption in humans, ethanol increased intestinal permeability (‘leaky gut’) and decreased numbers of faecal Bifidobacterium. However, liver damage (as indicated by liver enzymes AST and ALT activities and inflammatory markers in the liver) and leaky-gut were significantly improved in rats treated with fish oil.17

liver damage and leaky-gut were significantly improved in rats treated with fish oil

Human Research

While it seems apparent that omega-3 fatty acids affect the microbiome in humans, the impact of these fats in the gut biome is less defined in human in vivo research. The few studies thus far completed on omega-3 supplementation in humans show some consistency of changes in the gut microbiota, particularly, a decrease in Faecalibacterium, often associated with an increase in the Bacteroidetes and butyrate-producing bacteria belonging to the Lachnospiraceae family. Dysbiosis of these bacteria are commonly seen in inflammatory bowel diseases and omega-3 fats might exert beneficial effects to the microbiome in these diseases.18

In a recent case study, a 45-year-old male who consumed 600 mg of omega-3 daily for 14 days was observed to have decreased microbiome species diversity but increases in several butyrate-producing bacteria. There was an important decrease in Faecalibacterium prausnitzii and Akkermansia spp. After the intervention and ceasing omega-3 supplementation, the gut microbiota reverted to pre-study levels (after a 14-day washout).19

Total omega-3 and DHA levels in serum were associated with microbiome diversity in a study of 876 twins. (DHA Beta (SE) = 0.13 (0.04), p = 0.0006; total omega-3: 0.13 (0.04), p = 0.001). Even stronger associations were found between DHA and certain bacteria such as Lachnospiraceae family (Beta (SE) = 0.13 (0.03), p = 8 × 10−7). 20

In an open-label trial of 22 healthy volunteers, a mixed DHA/EPA formulation (4 g per day) did not result in significant changes in overall bacterial diversity but there were reversible changes in several butyrogenic bacteria; BifidobacteriumRoseburia and Lactobacillus.21

Maternal fish oil supplementation increases the omega-3 fatty acid content of breast milk and this has been demonstrated to both affect the microbiome,22, 23 and reduce inflammatory markers in the breast-fed infants.23

A mixed DHA/EPA formulation (4 g per day) did not result in significant changes in overall bacterial diversity but there were reversible changes in several butyrogenic bacteria

Conclusion

From the evidence, it appears that omega-3 supplements, especially those containing the active omega-3 metabolites DHA and EPA can modulate intestinal bacteria, and in particular increase bacteria producing beneficial short-chain fatty acids and reducing inflammation. This is likely to be of benefit to both gut and overall health. However, there is some suggestion from the animal research that the use of very high doses of these fats during active bowel disease may have some effects on increasing the risk of sepsis due to over-suppression of innate immune and inflammatory responses, although this has not been observed in humans and there is relative abundance of use of fish oil in IBD patients.

The use of fish oil, in particular, seems prudent for health overall, and particularly for the health of the microbiome.

The active omega-3 metabolites DHA and EPA can modulate intestinal bacteria, and in particular increase bacteria producing beneficial short-chain fatty acids and reducing inflammation

References

1.            Zhang Y, Zhang B, Dong L, Chang P. Potential of Omega-3 Polyunsaturated Fatty Acids in Managing Chemotherapy- or Radiotherapy-Related Intestinal Microbial Dysbiosis. Advances in Nutrition. 2018;10(1):133-47.

2.            Cui C, Li Y, Gao H, Zhang H, Han J, Zhang D, et al. Modulation of the gut microbiota by the mixture of fish oil and krill oil in high-fat diet-induced obesity mice. PloS one. 2017;12(10):e0186216.

3.            Kaliannan K, Wang B, Li X-Y, Kim K-J, Kang JX. A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia. Scientific Reports. 2015;5:11276.

4.            Kaliannan K, Wang B, Li XY, Bhan AK, Kang JX. Omega-3 fatty acids prevent early-life antibiotic exposure-induced gut microbiota dysbiosis and later-life obesity. International Journal Of Obesity. 2016;40:1039.

5.            Le Barz M, Daniel N, Varin TV, Mitchell P, Pilon G, Gauthier J, et al., editors. Transgenic production of endogenous n-3 PUFA levels compared to fish oil intake differentially improve obesity-related metabolic disorders: role of the gut microbiota. 21st European Congress of Endocrinology; 2019: BioScientifica.

6.            Robertson RC, Kaliannan K, Strain CR, Ross RP, Stanton C, Kang JX. Maternal omega-3 fatty acids regulate offspring obesity through persistent modulation of gut microbiota. Microbiome. 2018;6(1):95.

7.            Huang K-H, Nichols RG, Sebastian A, Albert I, Patterson AD, Ross AC. Gut Microbiota Increased by Omega-3 Fatty Acids is Negatively Correlated with Hepatic Lipid Metabolism-Associated Genes in mice with High Carbohydrate Diet-Induced Steatosis. The FASEB Journal. 2017;31(1_supplement):654.3-.3.

8.            Wong JMW, de Souza R, Kendall CWC, Emam A, Jenkins DJA. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol. 2006;40(3):235-43.

9.            Bourassa MW, Alim I, Bultman SJ, Ratan RR. Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health? Neuroscience Letters. 2016;625:56-63.

10.         Stilling RM, van de Wouw M, Clarke G, Stanton C, Dinan TG, Cryan JF. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem Int. 2016;99:110-32.

11.         Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 2008;27(2):104-19.

12.         Fung KY, Cosgrove L, Lockett T, Head R, Topping DL. A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate. Br J Nutr. 2012;108(05):820-31.

13.         Ghosh S, DeCoffe D, Brown K, Rajendiran E, Estaki M, Dai C, et al. Fish Oil Attenuates Omega-6 Polyunsaturated Fatty Acid-Induced Dysbiosis and Infectious Colitis but Impairs LPS Dephosphorylation Activity Causing Sepsis. PloS one. 2013;8(2):e55468.

14.         Li Q, Zhang Q, Wang C, Tang C, Zhang Y, Li N, et al. Fish Oil Enhances Recovery of Intestinal Microbiota and Epithelial Integrity in Chronic Rejection of Intestinal Transplant. PloS one. 2011;6(6):e20460.

15.         Robertson RC, Seira Oriach C, Murphy K, Moloney GM, Cryan JF, Dinan TG, et al. Omega-3 polyunsaturated fatty acids critically regulate behaviour and gut microbiota development in adolescence and adulthood. Brain, Behavior, and Immunity. 2017;59:21-37.

16.         Myles IA, Pincus NB, Fontecilla NM, Datta SK. Effects of Parental Omega-3 Fatty Acid Intake on Offspring Microbiome and Immunity. PloS one. 2014;9(1):e87181.

17.         Chen J-R, Chen Y-L, Peng H-C, Lu Y-A, Chuang H-L, Chang H-Y, et al. Fish Oil Reduces Hepatic Injury by Maintaining Normal Intestinal Permeability and Microbiota in Chronic Ethanol-Fed Rats. Gastroenterology Research and Practice. 2016;2016:10.

18.         Costantini L, Molinari R, Farinon B, Merendino N. Impact of Omega-3 Fatty Acids on the Gut Microbiota. International Journal of Molecular Sciences. 2017;18(12):2645.

19.         Noriega BS, Sanchez-Gonzalez MA, Salyakina D, Coffman J. Understanding the Impact of Omega-3 Rich Diet on the Gut Microbiota. Case Reports in Medicine. 2016;2016:6.

20.         Menni C, Zierer J, Pallister T, Jackson MA, Long T, Mohney RP, et al. Omega-3 fatty acids correlate with gut microbiome diversity and production of N-carbamylglutamate in middle aged and elderly women. Scientific Reports. 2017;7(1):11079.

21.         Watson H, Mitra S, Croden FC, Taylor M, Wood HM, Perry SL, et al. A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota. Gut. 2018;67(11):1974-83.

22.         Andersen AD, Mølbak L, Michaelsen KF, Lauritzen L. Molecular Fingerprints of the Human Fecal Microbiota From 9 to 18 Months Old and the Effect of Fish Oil Supplementation. Journal of Pediatric Gastroenterology and Nutrition. 2011;53(3):303-9.

23.         Quin CS, Pasquale DM, Barnett JA, Ghosh S, Gibson DL. A317 THE EFFECT OF OMEGA-3 PUFA ON THE DEVELOPING MICROBIOTA AND IMMUNITY OF INFANTS. Journal of the Canadian Association of Gastroenterology. 2018;1(suppl_1):551-.

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