US researchers who transplanted human intestinal microbes into germ-free mice and then switched their diet from a low-fat plant-based one to a more Westernized diet, high in fat and sugars, found that within one day obesity-linked microbes were thriving in the gut and the mice eventually became obese.
The study was the work of Dr Jeffrey I Gordon and colleagues and was published on 11 November in the journal Science Translational Medicine. Gordon, the senior author of the study, is director of the Center for Genome Sciences at Washington University School of Medicine in St. Louis, Missouri.
Gordon and colleagues wrote how over time, compared with mice kept on a low-fat, plant-based diet, the “humanized” mice fed the Westernized high-fat, high-sugar diet diet became obese, and that their weight gain patterns followed shifts in the types of bacteria present in their gut.
Using DNA sequencing technology the researchers also discovered that the guts of the mice on the high-fat, high-sugar diet had more obesity-related gut microbes and genes devoted to extracting calories from food and that these were “switched on” when the researchers started feeding the mice on the Westernized diet.
The researchers said that the study is useful not only because it documents the intimate relationship between diet and the dynamism of intenstinal microbe communities, but it also paves the way for using humanized mouse models to study the complexity of this relationship in humans, and how it contributes to obesity and its converse, malnutrition.
Gordon told the press that trying to study individual triggers for malnutrition and obesity in humans is hard because there are so many genetic, cultural and environmental variables to take into account.
“Recreating the human gut ecosystem in mice gives us a way to control these variables. The information gained from these studies allows us to develop hypotheses that we can test in humans,” he explained.
Humanized mouse models could help scientists discover which gut microbes thrive on which diets, and determine new classes of probiotics to help digest certain foods and nutrients, said Gordon.
Gordon and colleagues had already established that nutrient and caloric value of foods is not just determined by the food itself but also by how it is digested in the gut, and that this depends on the mix of gut bacteria present.
For this study, which was funded by the National Institutes of Health and the Crohn’s and Colitis Foundation of America, Gordon and his team created the humanized mouse model by extracting human gut bacteria from a stool sample and then transplanting them into the guts of germ-free mice that had been fed on low-fat, plant-rich diets for several weeks.
They kept the mice on the low-fat, plant-based diet for another month while they collected and DNA tested their stool samples after one day, one week and then one month after the transplants. The DNA tests showed that the transplants had been remarkably successful and the guts of the mice had microbe colonies like those of the human donor.
After the mice had been fed for one month on the low-fat, plant-based diet, the researchers switched half of them to a high-fat, high-sugar “Westernized” diet, and continued to collect and analyze stool samples from both groups of mice: 24 hours after the diet switch, and then weekly for another two months.
Co-author Peter Turnbaugh, a graduate student in Gordon’s lab, said:
“We were surprised to see the rapid shift in the microbial communities of mice on the high-fat, high-sugar diets.”
“Assuming it takes four to six hours for microbes to move through the intestine, this means that the initial shift in the microbial community occurred 18 to 20 hours after exposure to a western diet,” he explained.
Compared to the mice that stayed on the low-fat, plant-based diet, the mice on the Westernized diet had a significantly greater proportion of two types of gut bacteria: Erysipielotrichi and Bacilli, both of which belong to a family of bacteria known as the Firmicutes, and a reduced proportion of bacteria belonging to the family Bacteroidetes.
Earlier studies from Gordon and colleagues have also revealed that changes in balance between Firmicutes and Bacteroidetes is linked to obesity in mice and humans.
With further DNA sequencing, Gordon and colleagues found that the guts of the mice on the high-fat, high-sugar diet had more microbial genes devoted to breaking down and processing simple sugars and other components of a Western diet and that these genes were activated after they switched to the unhealthy diet.
Also when they transplanted gut microbes from the mice that had been on the Westernized diet into germ-free mice fed on a low-fat, plant-based diet, those mice also gained weight and fat.
The authors concluded that:
“Humanized mice fed the Western diet have increased adiposity; this trait is transmissible via microbiota transplantation. Humanized gnotobiotic mice will be useful for conducting proof-of-principle ‘clinical trials’ that test the effects of environmental and genetic factors on the gut microbiota and host physiology.”
Gordon and colleagues also found that the microbial colonies passed down from mother to offspring.
The team is now using the new mouse model to study malnutrition in children.
“The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice.”
Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI.
DOI: 10.1126/scitranslmed.3000322
Source: Washington University in St Louis.
Written by: Catharine Paddock, PhD