A study of mice found that dietary sugar alters the gut microbiome, setting off a chain of events that leads to metabolic disease, pre-diabetes, and weight gain.

The findings, published today in Cell(link is external and opens in a new window), suggest that diet matters, but an optimal microbiome is equally important for the prevention of metabolic syndrome, diabetes, and obesity. 

Diet alters microbiome

A Western-style high-fat, high-sugar diet can lead to obesity, metabolic syndrome, and diabetes, but how the diet kickstarts unhealthy changes in the body is unknown.

The gut microbiome is indispensable for an animal’s nutrition, so Ivalyo Ivanov, PhD, associate professor of microbiology & immunology at Columbia University Vagelos College of Physicians and Surgeons, and his colleagues investigated the initial effects of the Western-style diet on the microbiome of mice.

After four weeks on the diet, the animals showed characteristics of metabolic syndrome, such as weight gain, insulin resistance, and glucose intolerance. And their microbiomes had changed dramatically, with the amount of segmented filamentous bacteria—common in the gut microbiota of rodents, fish, and chickens—falling sharply and other bacteria increasing in abundance.

Microbiome changes alter Th17 cells

The reduction in filamentous bacteria, the researchers found, was critical to the animals’ health through its effect on Th17 immune cells. The drop in filamentous bacteria reduced the number of Th17 cells in the gut, and further experiments revealed that it’s the Th17 cells that are necessary to prevent metabolic disease, diabetes, and weight gain.

“These immune cells produce molecules that slow down the absorption of ‘bad’ lipids from the intestines and they decrease intestinal inflammation,” Ivanov says. “In other words, they keep the gut healthy and protect the body from absorbing pathogenic lipids.”

Sugar vs. fat

What component of the high-fat, high-sugar diet led to these changes? Ivanov’s team found that sugar was to blame.

“Sugar eliminates the filamentous bacteria, and the protective Th17 cells disappear as a consequence,” says Ivanov. “When we fed mice a sugar-free, high-fat diet, they retain the intestinal Th17 cells and were completely protected from developing obesity and pre-diabetes, even though they ate the same number of calories.”

But eliminating sugar did not help all mice. Among those lacking any filamentous bacteria to begin with, elimination of sugar did not have a beneficial effect, and the animals became obese and developed diabetes.

“This suggests that some popular dietary interventions, such as minimizing sugars, may only work in people who have certain bacterial populations within their microbiota,” Ivanov says.

In those cases, certain probiotics might be helpful. In Ivanov’s mice, supplements of filamentous bacteria led to the recovery of Th17 cells and protection against metabolic syndrome, despite the animals’ consumption of a high-fat diet.

Though people do not have the same filamentous bacteria as mice, Ivanov thinks that other bacteria in people may have the same protective effects.

Providing Th17 cells to the mice also provided protection and may also be therapeutic for people. “Microbiota are important, but the real protection comes from the Th17 cells induced by the bacteria,” Ivanov says.

“Our study emphasizes that a complex interaction between diet, microbiota, and the immune system plays a key role in the development of obesity, metabolic syndrome, type 2 diabetes, and other conditions,” Ivanov says. “It suggests that for optimal health it is important not only to modify your diet but also improve your microbiome or intestinal immune system, for example, by increasing Th17 cell-inducing bacteria.”

University of Virginia School of Medicine researchers have identified a potential way to battle the health effects of obesity and type 2 diabetes in women after discovering an important factor that could determine how their bodies use and store fat.

Based on their new discovery, the researchers, led by Associate Professor of Biomedical Engineering Mete Civelek, PhD, were able to change whether female lab mice’s bodies stored fat subcutaneously (under the skin) or viscerally (wrapped around the organs). While visceral fat goes unseen, hidden deep inside the body, it can be particularly harmful to good health.

The researchers say their results in mice suggest that a similar approach could help treat the effects of obesity and battle metabolic diseases, such as diabetes, in women.

“There is a strong need for targeted therapies against metabolic abnormalities caused by obesity and diabetes,” said the study’s first author, Qianyi Yang, PhD, of UVA’s Center for Public Health Genomics. “We hope that increasing KLF14 abundance in fat cells of females with obesity and diabetes may provide a novel treatment option to alleviate these metabolic abnormalities.”

How We Store Fat

Men and women naturally store fat differently. Men tend to be more apple-shaped, meaning they store fat around the waist, while women tend to be more pear-shaped. This is because women store more subcutaneous fat and less visceral fat in their lower body. Civelek’s new findings help explain why.

Civelek and his team were investigating a particular gene, KLF14, that has been linked to many different metabolic problems, including type 2 diabetes and coronary artery disease. These health associations are more pronounced in women than men, but scientists haven’t understood the reason.

Civelek and his collaborators found that the KLF14 gene is a key regulator of how the female body uses lipids (fats). The gene makes a protein that plays a critical in how fat cells form, what type of fat they turn into and where they are stored. When Civelek’s team blocked the production of this protein in lab mice, they noticed very different effects in males and females: Females gained fat, while males lost it. The females also stored fat differently than normal, gaining more visceral fat and less subcutaneous fat. 

There were other sex-specific changes as well: The female mice suffered slower metabolic rates and faster breathing, suggesting they were relying more on carbohydrates for fuel. And their bodies became less efficient at managing triglycerides, a type of fat in the blood.

Interestingly, when the researchers amped up production of the KLF14 protein in in female mice, the mice lost weight. But male mice did not. 

Based on what they’ve found, the researchers believe that increasing production of the KLF14 protein in fat cells in women may offer a way to treat the harmful effects of obesity and type 2 diabetes. More research will be needed, but the researchers say it is promising that their mouse findings align closely with what we see in humans.

“We are now working to create a drug delivery system that will target fat cells and deliver a small molecule to increase KLF14 abundance,” Civelek said. “We hope to translate our laboratory’s findings to the clinic to help women fight the effects of obesity and diabetes.”