Taylor Soderborg is a 3rd year MD/PhD student at the University of Colorado Denver, School of Medicine, pursuing a PhD in integrative physiology: reproductive sciences track. Her thesis work is focused on the influence of maternal diet-induced obesity on development of the infant microbiome and how this may alter immune system development and later life obesity. She plans to pursue the obstetrics and gynecology clinical specialty.
Soderborg presented her work in poster format at the recent Keystone Symposium: Gut Microbiota Modulation of Host Physiology. Later, she answered some questions about her work for GMFH editors.
What made you decide to study the effects of a western style diet in mice and their offspring?
The western style diet [WSD] is named for the fact that it mimics the macronutrients eaten by the majority of us who live in the western world: a shocking 42% kCal fat, 0.2% cholesterol and 34% sucrose. Early microbiome studies examining diet-induced obesity have utilized a simple high fat diet (60% kCal from fat); however, most people consume both fat and sugar in excess. Together with cholesterol, these components play an important role in the excess weight gain and the metabolic complications associated with obesity in individuals who eat this diet. The WSD is also associated with microbiome “dysbiosis”.
What happens normally (to mothers and pups) when mouse mothers consume a western style diet?
We typically start animals on the WSD a month or more before they get pregnant. Once they are obese and become pregnant, weight gain is typically not different from regular chow-fed mothers, but the mothers have higher lipid levels, more inflammation, and are more likely to have higher blood sugar during pregnancy, which can be harmful if transferred to the developing fetus.
Thus, an animal born to a mother on a WSD will be slightly larger, typically with more body fat, and will show changes in the blood –a greater pro-inflammatory fatty acid profile, indicative of the mother’s diet. The infant’s microbiome during the weaning period, due to the mother’s diet during breast feeding, is also dramatically shifted to a less diverse, more dysbiotic profile. This is similar to findings in obese humans. The increased inflammation is thought to be in part driven by the elevated omega-6 and reduced omega-3 fatty acids in the diet. These fatty acids are ‘essential’, meaning that they are only obtained through the diet. An ideal ratio of these fatty acids would be 1-2:1. The WSD has a ratio of 15-20:1.
Not only does omega-6 have a byproduct with pro-inflammatory effects, it may also be a contributor to the altered gut microbiome seen in the animals who consume a WSD. The resulting altered gut microbiome with an increased Firmicutes:Bacteroidetes ratio, classically seen in obesity, can also drive the pro-inflammatory status. Furthermore, these immune system alterations are also seen in pups born to mothers who consume the WSD during pregnancy, even if the pups consume a normal diet after weaning. The liver of the animals born to an obese mother on a WSD also tends to store fat, a condition called “steatosis” which is a precursor to non-alcoholic fatty liver disease.
Can you describe your experiment?
Our hypothesis is that we can reverse the harmful effects of the western style diet during pregnancy and lactation on the microbiome of the offspring by re-balancing the omega-6:omega-3 fatty acids ratio back to 1:1 during pregnancy, without changing total calories.
To test this hypothesis we used a transgenic mouse that has been engineered with a novel gene termed fat-1 that makes an enzyme that will convert the harmful omega-6 fatty acids into healthier anti-inflammatory omega-3 within the body, even when consuming a WSD. The benefit of this model is that we can isolate the impact of correcting the maternal omega-6 fatty acids on the negative outcomes seen in her offspring. We are also able to produce offspring who have the transgene even though its mother does not, to determine the ability of the offspring to prevent the negative impacts of WSD by restoring healthy omega-6:omega-3 levels.
In our preliminary results we have found that both maternal and pup fat-1 transgene prevents the negative shifts in microbiota abundances on a phylum and family level. The microbiome populations from these pups are similar to those in healthy mice. The fat-1 gene in both the mother and the offspring may also increase the production of beneficial short chain fatty acid microbial metabolites, further supporting the idea that the shift in the microbiome is beneficial for both the developing immune system and possibly the early-onset obesity in offspring born to obese mothers.
Did anything surprise you about your results?
I was pleasantly surprised about the power of the fat-1 transgene to correct many of the effects of the obesogenic WSD on the pup microbiome, inflammatory signature, and fatty liver. However, I was not expecting that a double dose of the gene (in both mother and fetus) would over-correct the problem. I had hypothesized that dual exposure to the transgene would have a synergistically beneficial anti-inflammatory effect. Surprisingly, we actually found increased pro-inflammatory markers in pups that had the dual exposure from both the mother’s fat-1 transgene and from their own fat-1 transgene expression. Excessive omega-3 supplementation has been associated with an adverse immune response, which could be the case in our study.
How do you think this finding might apply to humans in the future? What needs to be done next?
Obesity and gestational diabetes continue to increase world-wide and span the spectrum of age, race, ethnicity, and socioeconomic status. Alarmingly, 1 in 10 infants and toddlers are obese, and 1 in 5 youths are both obese and at risk for metabolic syndrome prior to puberty.
The mechanisms underlying how poor maternal health imparts risk for future metabolic disease in the offspring may have to do with early changes in the microbiome. Maternal diet and obesity may impact the development of the infant microbiome, with negative consequences for future health. That some of these changes are persistent suggests that early life exposures have chronic effects across the lifespan. These results, if extended to humans, suggest that gestational and lactational dietary exposures are driving health risks in the next generation. Whether alterations of maternal diet like what we accomplish with our fat-1 model can prevent changes in the microbiome and alter infant life-course disease risk is still unknown.
As a MD/PhD student I am always thinking of how my research could apply to the women I see during my clinical training in obstetrics. The long-term outcome for my research would be to develop recommendations about dosage and timing of omega-3 supplementation in pregnancy and maternal obesity, or perhaps contribute to the development of a probiotic based on the microbiome changes seen in the restoration of a healthy metabolic state. As is highlighted by my surprising results with excessive omega-6 conversion to omega-3, we cannot make clinical recommendations until the mechanisms behind our interventions are fully understood. Cross-fostering studies will help us to determine the role of pre- verses post-natal environment on the offspring microbiome and inflammatory state. Furthermore, fecal transplants from babies born to obese mothers into germ-free mice will allow us to study the effect of various microbiome compositions on metabolic outcomes. These studies will help to bridge our findings from the bench to the bedside.