Switching from a low-fat, plant-based diet to one high in fat and sugar alters the collection of microbes living in the gut in less than a day, with obesity-linked microbes suddenly thriving, according to new School of Medicine research.
The study was based on transplants of human intestinal microbes into germ-free mice.
Over time, mice that received the transplants, or humanized mice, on the junk-food diet became obese. Their weight gain was in lock step with dramatic shifts in the types of intestinal bacteria present compared to mice on a low-fat diet.
Using the latest DNA sequencing technology, the researchers found that mice on the high-fat, high-sugar diet had more microbes and microbial genes devoted to extracting calories from their “western” diet. These microbial genes were turned on when the mice were switched to the diet high in fat and sugar.
The study, published in Science Translational Medicine, documents the intimate relationship between diet and the dynamic variations in the community of intestinal microbes that can influence metabolism and weight.
The research also paves the way for using humanized mouse models to tease apart the contributions of human intestinal microbes and human diets to obesity and its converse, malnutrition.
“Pinpointing triggers of obesity or malnutrition in humans is hard because there’s a host of factors — genetic, cultural and environmental, such as diet — that are extremely difficult to control,” said senior author Jeffrey I. Gordon, M.D., director of the Center for Genome Sciences.
“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,” Gordon said.
Researchers can use these humanized mice to discover the types of microbes that bloom in response to particular diets, with the goal of identifying a new class of probiotics that aid in the digestion of certain foods and nutrients, he said.
Gordon’s pioneering research first established a possible link between obesity and the trillions of friendly microbes that live in the intestine and help to digest food. His group’s studies have suggested that the nutrient and caloric value of foods is not absolute but depends, in part, on the mix of microbes that inhabit our intestines.
In the new research, Gordon and Peter Turnbaugh, postdoctoral research associate, along with lab members Vanessa Ridaura, graduate research assistant, and Jeremiah Faith, Ph.D., postdoctoral research scholar, created an animal model of the human gut ecosystem by transplanting an adult’s gut microbial community (obtained from a stool sample) into the guts of germ-free mice. The mice ate low-fat, plant-rich diets in the weeks leading up to the transplants.
The mice continued to eat a low-fat, plant-based diet for one month, and their stool samples were analyzed one day, one week and one month after the microbe transplants. Using DNA sequencing tools that allowed the researchers to take a census of the gut bacteria, the researchers found that the microbe transplants were remarkably successful: The mice carried a collection of bacteria that mimicked the human donor’s.
After one month on the low-fat, plant-based diet, half the mice were switched to a high-fat, high-sugar “Western” diet. Stool samples from all the mice were analyzed 24 hours after the diet change and then again weekly for two months.
“We were surprised to see the rapid shift in the microbial communities of mice on the high-fat, high-sugar diets,” Turnbaugh said. “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 18-20 hours after exposure to a Western diet.”
Compared with mice on the low-fat, plant-based diet, mice on the Western diet had a greater proportion of a main type of intestinal microbes called the Firmicutes, and fewer members of another type, known as the Bateroidetes, changes that Gordon’s earlier studies linked to obesity in mice and humans.
Interestingly, when the researchers transplanted the gut microbes from humanized obese mice into germ-free mice, the recipients gained more fat even when fed low-fat diets, compared with mice that got human microbes from mice fed low-fat diets. The researchers also showed that gut microbes and their genes can be passed down from generation to generation, suggesting that it is possible for mothers to pass their microbial communities to their children.
Gordon and members of his group already are using the humanized mouse model to understand how communities of human gut microbes may be altered in malnourished children in work funded by the Bill & Melinda Gates Foundation.
The researchers also noted that microbial communities could be transplanted successfully into the mice using either fresh or frozen stool samples from a human donor. The ability to use frozen stool samples has broad implications because it means that humans around the world could have their stool samples stored and analyzed.