EPA and DHA may prevent type 2 diabetes!

The latest global diabetes map shows that a total of 463 million people in the world suffer from diabetes, which is equivalent to 1 in 11 adults.
The population of diabetes in mainland China has reached 116 million, ranking first in the world[1]
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In addition to the known genetic and environmental factors, the occurrence and development of diabetes is also closely related to the intestinal flora
.

Imbalance of the intestinal flora can enrich Gram-negative bacteria that release lipopolysaccharides, thereby increasing the permeability of the intestinal mucosa, causing systemic low-grade inflammation, leading to insulin resistance and diabetes [2]
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 Recently, a research team led by Professor Zhang Yu and Professor Jiao Jingjing of Zhejiang University found that the n-3 polyunsaturated fatty acids EPA and DHA can improve the hyperglycemia and insulin resistance of diabetic mice by changing the composition of intestinal microbes and microbial metabolites, and EPA The effect seems to be more obvious, and the relevant research results are published on Microbiome [3]
.

Figure 1-The screenshot on the first page of the paper mentions eicosapentaenoic acid (EPA), which may be unfamiliar to everyone
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When it comes to docosahexaenoic acid (DHA), we may automatically jump out of all kinds of milk powder advertisements in our minds
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In fact, EPA and DHA are also the main functional components of the well-known deep-sea fish oil, both of which belong to n-3 polyunsaturated fatty acids
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N-3 polyunsaturated fatty acids are essential fatty acids in the human body and important components for maintaining cell structure and function.
N-3 polyunsaturated fatty acids represented by EPA and DHA are mainly derived from marine fish such as salmon, tuna and sardines [4 ]
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In recent years, studies have found that n-3 polyunsaturated fatty acids can restore the balance of intestinal flora and reduce inflammation [5], but there are also studies suggesting that n-3 polyunsaturated fatty acids can not prevent diabetes [6], or can not improve small The intestinal flora in mice is disturbed [7]
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Therefore, in order to explore the direct and indirect effects of exogenous supplementation of EPA/DHA on the microenvironment of the intestinal flora in the diabetic state, Zhang Yu and Jiao Jingjing's research team carried out a series of experiments
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The researchers used spontaneous type 2 diabetic mice (db/db mice) caused by leptin receptor gene defects.
The mice of this strain will develop obesity, hyperglycemia, hyperlipidemia, and diabetes after 4 weeks of birth.
A series of symptoms of diabetes, its physiological and behavioral characteristics are very similar to the performance of human type 2 diabetes, and it is currently considered to be an ideal animal model for type 2 diabetes research [8]
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The results of the study showed that, compared with the control group, the hyperglycemia and insulin resistance of db/db mice with EPA/DHA added to their diet were significantly improved
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As for lipid metabolism, the researchers found that female db/db mice that were exogenously supplemented with EPA showed significant decreases in serum triglyceride (TG), total cholesterol (TC) and low-density lipoprotein (LDL-C) levels
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At the same time, db/db mice exogenously supplemented with EPA/DHA showed an increase in oxygen consumption and a decrease in respiratory exchange rate (RER), suggesting an increase in energy consumption and fat utilization
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Figure 2-EPA and DHA can significantly improve glucose homeostasis in db/db mice.
OGTT: Oral glucose tolerance test to evaluate blood glucose regulation ability; ITT: Insulin tolerance test to evaluate insulin sensitivity; PTT: Pyruvate tolerance test to evaluate liver The diversity of gut microbiota at the level of gluconeogenesis is very important to the stability and efficiency of the ecosystem.
Patients with type 2 diabetes can manifest that the abundance of gut microbes is destroyed, leading to imbalance of the flora [2]
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The supplementation of EPA/DHA can significantly increase the diversity of the intestinal flora of db/db mice and adjust the species structure of the flora
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Specifically, DHA and EPA reduce the abundance of Enterobacteriaceae and conditional pathogens containing lipopolysaccharides, such as Staphylococcus, Streptococcus and Klebsiella
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At the same time, EPA and DHA can enrich the Bifidobacterium and Lactobacillus flora that fight endotoxemia and inflammation, and can also increase the red bug flora that is negatively correlated with glutamate levels.
The abundance of Coriobacteriaceae increases the abundance of Barnesiella and Clostridium which are related to bile acid production, as well as the enrichment of certain short-chain fatty acid (SCFAs) producing bacteria
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It is worth noting that there are gender differences in the influence of EPA/DHA on the composition of the bacterial flora
.

 Figure 3-EPA and DHA can regulate the composition of the intestinal flora of db/db mice.
Through KEGG analysis of the intestinal microbiome and metabolome, the researchers found that the glutamate metabolism pathway is the main metabolic pathway regulated by DHA/EPA.
Animal experiments have also confirmed that EPA can reduce L-glutamate levels and reduce β-cell apoptosis induced by glutamate
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Combined with the results of the study, it is suggested that DHA/EPA can enrich the red stink bug flora that is negatively correlated with the level of glutamate.
The researchers speculate that exogenous supplementation of DHA/EPA can increase the abundance of the red stink bug flora in the mouse intestine.
To accelerate the degradation of glutamate, thereby reducing β cell apoptosis
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Figure 4-EPA and DHA can reduce β cell apoptosis in db/db mice More and more studies have confirmed that the interaction between gut microbes and bile acids plays an important role in the regulation of body metabolism
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As an important signaling molecule, bile acids can control blood sugar, blood lipids and energy metabolism by binding to farnesoid derivative X receptors (FXR) in different organs, and affect intestinal hormone secretion, hepatic gluconeogenesis and intestinal flora Adjustment of structure [9]
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In this study, considering that DHA/EPA can increase the abundance of Barnesella and Clostridium related to bile acid production, KEGG analysis confirmed that the bile acid metabolism pathway is also the main metabolic pathway regulated by DHA/EPA
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Consistent with the results of the KEGG analysis, the non-targeted metabolomics method to evaluate the fecal metabolite profile of different groups also found that the content of cholic acid (CA) and chenodeoxycholic acid (CDCA) decreased significantly
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In addition, the results of qRT-PCR indicated that gluconeogenesis-related genes in the liver of diabetic mice in the DHA/EPA group, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate dehydrogenase (G6PC), had significant mRNA expression Down
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The results of qRT-PCR and Western Blot also showed that exogenous supplementation of EPA or DHA can significantly increase the expression levels of mRNA and protein of FXR and SHR in the liver of diabetic mice, and at the same time induce the phosphorylation of FoxO1
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Therefore, the research team believes that DHA/EPA can accelerate the production of primary bile acids, CA and CDCA by enriching the abundance of Barnesella and Clostridium in the mouse intestine, thereby activating the FXR-SHP-FOXO1 pathway To suppress liver gluconeogenesis
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In addition to bile acids, the researchers also found that some short-chain fatty acids, such as propionic acid and butyric acid, increased significantly after the intervention of DHA and EPA
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Previous studies have found that beneficial bacteria in the intestinal flora can break down complex carbohydrates to produce short-chain fatty acids (SCFAs), which can improve insulin resistance and glucose metabolism disorders [10]
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Researchers have also found that DHA/EPA can increase certain short-chain fatty acid (SCFAs) producing bacteria, such as Prevotella, Alloprevotella, Clostridium XlVa (Clostridium XlVa) ), Eubacterium and Intestinimonas expression, which in turn promotes the secretion of more glucagon-like protein 1 (GLP-1) from intestinal L cells, activates the insulin signaling pathway and white fat Beige to improve glucose metabolism disorders and insulin resistance in db/db mice
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In order to further explore the causal relationship between lowering blood sugar and gut microbes after DHA/EPA intervention, the researchers used fecal bacteria transplantation to "pass" the gut microbes of DHA/EPA-treated mice to antibiotic-treated db /db mice
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The results showed that mice transplanted with gut microbes after DHA/EPA treatment showed similar changes in gut microbes and at the same time restored glucose homeostasis
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 Figure 5-EPA and DHA can directly affect the growth rate of enterobacteria and red stink bugs.
In addition, although no clinical trials have been done, both db/db mice and patients with type 2 diabetes have obvious intestinal flora disorders, which are manifested as intestines.
The abundance of Bacteriaceae increases [11] and the abundance of Rhododactylis decreases [12]
.

In vitro experiments have confirmed that EPA/DHA can directly accelerate the growth rate of Rhododactylidae and reduce the growth rate of Enterobacteriaceae
.

Therefore, it can be speculated that exogenous supplementation of EPA/DHA may directly affect the human gut microbiome through a similar mechanism
.

It is worth noting that although this experiment found that adding EPA/DHA directly to the diet can significantly improve the hyperglycemia and insulin resistance of diabetic mice, whether EPA/DHA can become the "star of tomorrow" in the treatment of diabetes requires further steps.
Confirmed by clinical studies
.

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Eicosapentaenoic and docosahexaenoic acids attenuate hyperglycemia through the microbiome-gut-organs axis in db/db mice.
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Liu Haijun,Zhang Hong,Wang Xiao et al.
The family Coriobacteriaceae is a potential contributor to the beneficial effects of Roux- en-Y gastric bypass on type 2 diabetes.
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Liu Haijun,Zhang Hong,Wang Xiao et al.
The family Coriobacteriaceae is a potential contributor to the beneficial effects of Roux-en-Y gastric bypass on type 2 diabetes.
[J].
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Editor in chargeYing YuyanFront Cell Infect Microbiol, 2020, 10: 575084.
12.
Liu Haijun,Zhang Hong,Wang Xiao et al.
The family Coriobacteriaceae is a potential contributor to the beneficial effects of Roux-en-Y gastric bypass on type 2 diabetes.
[J].
Surg Obes Relat Dis, 2018, 14: 584-593.
Editor in chargeYing Yuyan