Omega-3 fatty acids prevent early-life antibiotic exposure-induced gut microbiota dysbiosis and later-life obesity

When young children are treated with antibiotics, they receive a double-edged sword. Antibiotics kill both good and bad bacteria, eliminating disease but also changing the balance of microbes within our intestines.

Chronic antibiotic exposure can lead to obesity by disrupting the bacterial community within the gut, and omega-3 fatty acids are known to benefit gut bacteria. Researchers sought to determine if omega-3 supplementation could prevent later-life obesity caused by early antibiotic exposure.

To test this theory, they used fat-1 mice, a transgenic strain that turns omega-6 into omega-3. These mice were compared to wild type mice. Both groups were given antibiotic treatment, and then fed a diet high in saturated fat, omega-6, and carbohydrates, comparable to a western diet. Fat-1 mice maintained healthier gut microbial communities, and better resisted colonization by harmful bacteria. As they grew older, fat-1 mice gained less weight, and were overall healthier than the wild type mice fed an identical diet.

These results show that a high-fat, high-carbohydrate diet is harmful to health, and impairs the body's ability to recover after antibiotic exposure. However, omega-3 supplementation, when combined with a healthy diet, promotes a vibrant gut microbial profile and fosters improved long-term health.

What was the question you were asking/problem you were trying to solve in your study?

The gut microbial community plays a large role in overall health, and contributes to factors such as weight gain and chronic low-grade inflammation. Antibiotics wipe out both harmful and beneficial bacteria in the body, and it’s been found that young children without established gut microbial communities are susceptible to weight gain after antibiotic use.

Since omega-3 influences gut microbial diversity, we sought to understand the relationship between tissue concentration of omega-3 fatty acids and the after-effects of antibiotic use.  Do increased levels of tissue omega-3 polyunsaturated fatty acids prevent antibiotic-induced changes to the gut microbiota and consequently prevent obesity later in life?

What methods did you use?

We exposed both fat-1 and wild type (WT) mice to azithromycin, a common antibiotic, at 5 weeks old for two weeks. All mice were then allowed to recover for 6 weeks. For the following 14 weeks, all mice were fed a high-carbohydrate, high-fat diet, comparable to today’s Western diet. They were monitored for changes in their gut bacteria, weight gain or obesity development, insulin resistance, serum lipid profile (markers of cardiovascular health such as triglycerides and cholesterol) and fatty liver disease.

What was unique about your approach?

This research used the transgenic fat-1 mouse model, developed in our lab a few years ago. This mouse model contains the fat-1 gene from C. elegans, which allows mice to endogenously convert omega-6 into omega-3 fatty acids.

Fat-1 mice are unique because most mammals are not able to synthesize omega-3 fatty acids. Using fat-1 mice, all study subjects received identical diets, eliminating many confounding factors in nutrition research. This allowed for a well-controlled study, since all factors and conditions of our fat-1 and control mice were identical except for tissue levels of omega-3 fatty acids.

What did you find out?

We found that young fat-1 mice, with increased levels of tissue omega-3 PUFA, had a more resilient gut microbial community. They displayed reversal of antibiotic induced gut dysbiosis and reduced development of obesity later in life. These differences are attributable to differential tissue levels of omega-3.

In addition, the fat-1 mice on a western diet maintained improved overall health. They showed less insulin resistance, healthier blood lipid profiles, and much less fatty liver development compared to control WT mice. These results indicate that a higher omega-3 tissue levels protect against the development of many chronic diseases, and provides resistance against obesity.

Did anything surprise you about the results?

Our results show that mice with higher tissue levels of omega-3 are able to better resist opportunistic colonization by harmful bacteria after antibiotic administration. However, all mice showed drastic changes to their microbial communities after eating a Western diet.

Both Fat-1 and WT mice showed an increase in the relative amount of Firmicute bacteria, which in greater numbers is associated with weight gain. Although Fat-1 mice maintained their gut microbial balance better than WT mice, it seems that a high-carbohydrate high-fat Western diet is still harmful to overall health, particularly in conjunction with early-life antibiotic use.

What will be the next step in the process?

Considering these findings, it would be beneficial to next test a similar hypothesis in humans. Given the growing rate of obesity and increased antibiotic exposure throughout the world, omega-3 can prevent obesity resulting from early-life antibiotics. Clinical trials can strengthen these findings with implications for improving overall human health. In the meantime, people can incorporate omega-3s into their daily diets by eating more fish, leafy vegetables, and nuts and seeds—specifically flax, chia and walnuts.

This would be especially beneficial early in life, and in tandem with antibiotic use, to maintain gut health and prevent obesity.

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