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Sequencing Study Highlights Intestinal Microbe, Immune Shifts on Ketogenic Diet

NEW YORK – A team led by University of California at San Francisco scientists has identified an apparent link between high-fat, low-carbohydrate ketogenic diet and gut microbial community composition in mice and humans — an interaction that appears to correspond with a decline in representation by inflammation-promoting Th17 immune cells in the intestine.

"Together, our results emphasize the importance of considering the chemical dialogs between host and microbial cells to gain a more comprehensive view of the mechanistic links between diet and host physiology," senior author Peter Turnbaugh, a microbiology and immunology researcher affiliated with UCSF and the Chan Zuckerberg Biohub, and his colleagues wrote.

As they reported in Cell on Wednesday, the researchers did targeted 16S ribosomal RNA gene sequencing on stool samples collected over time from 17 overweight or obese, non-diabetic men between the ages of 18 and 50 years old who were treated at an in-patient metabolic ward. In addition to having their exercise tracked over time, the participants received a standard diet for four weeks, followed by a ketogenic diet for the remaining four weeks.

"[O]ur prior research showed that high-fat diets induce shifts in the gut microbiome that promote metabolic and other diseases in mice, yet ketogenic diets, which are even higher in fat content, have been proposed as a way to prevent or even treat disease," Turnbaugh said. "We decided to explore that puzzling dichotomy."

Based on 16S sequence data generated with five fecal samples collected each day over the last week of each diet, the team identified 19 bacterial genera that were found at distinct gut levels when individuals switched to or from a standard diet — made up of 50 percent carbohydrate, 35 percent fat, and 15 percent protein fare — to a ketogenic diet that was just 5 percent carbohydrate and 80 percent fat.

In particular, Bifidobacterium species tended to be less common in the gut microbiomes of participants partaking of the ketogenic diet, the researchers reported, and additional metagenomic sequence data and proton nuclear magnetic resonance-based metabolomic profiles suggested that ketone bodies such as beta-hydroxybutyrate that are produced on the ketogenic diet can dial down bifidobacteria levels in the gut.

The team saw similar bifidobacterial declines in mice fed a ketogenic-like diet — gut microbial community effects that were distinct from those found in animals that were fed a high-fat, but non-ketogenic, diet.

When the researchers delved into the broader consequences of these gut microbiome changes in mouse models, they uncovered declining pro-inflammatory Th17 immune cell representation in intestinal cells after exposure to the ketogenic diet, after exposure to ketone bodies or specific bacterial representatives, or in germ-free mice that received gut microbe transplants from individuals with the ketogenic diet microbiome.

Along with other studies published in the past, the human and mouse findings suggested that the gut microbiome "appears to play a causal role in mediating host immune responses to diet," the authors wrote.

"Given the links between obesity and chronic low-grade inflammation, decreased levels of pro-inflammatory Th17 cells in both gut and adipose tissues on a [keto diet] may be a potential mechanism contributing to the greater efficacy of [keto diet] in improving some aspects of metabolic syndrome such as glycemic control and reductions in body fat," they suggested.