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A new study in mice and humans pinpoints a mechanism through which keto diets protect against weight gain. Image credit: Alba Vitta/Stocksy.
  • Ketogenic diets support short-term weight loss, but the precise mechanisms behind metabolic changes are still unknown.
  • New research in mice and humans suggests the ketogenic diet may protect against obesity by increasing specific bile acids and decreasing calorie absorption in the intestines.
  • The long-term health effects of the ketogenic diet are not clear, and experts recommend plant-based diets, such as the Mediterranean diet, that promote more favorable gut microbiome diversity.

The ketogenic diet is a low-carbohydrate eating pattern that has been widely tested as a tool for weight loss. Yet exactly how it works to reduce body weight remains unclear.

Some propose that gut bacteria and their byproducts may play a role in the beneficial metabolic effects of a ketogenic diet. However, the specific bacteria or byproducts involved have yet to be well understood.

Now, a new study published in Nature Metabolism suggests that following a ketogenic diet results in changes to the gut microbiome that increase the blood levels of specific bile acids in mice.

These bile acids, namely taurodeoxycholic acid and tauroursodeoxycholic acid, may protect against obesity by decreasing calorie absorption in the intestines. This might lead to a decrease in body weight and fasting blood sugar levels.

Distinguishing their work from typical animal studies, the researchers took additional steps to investigate whether these findings might apply to humans.

They documented similar associations between the bile acids and metabolic traits in two human studies, adding to the potential significance of their findings.

This multimethod research highlights a specific interaction between the host and the gut microbiome that might explain how the ketogenic diet reduces body weight and fasting blood sugar levels in both rodents and humans.

Researchers investigated the effects of a ketogenic diet on blood levels of bioactive metabolites by feeding mice either a ketogenic diet or a regular diet for seven weeks.

They found that consuming a ketogenic diet significantly changed these metabolites, along with notably reduced body weight and fasting blood sugar levels.

Further analysis showed that 22 specific metabolites increased, while 18 decreased on the ketogenic diet.

When the researchers tested another 7-week diet intervention involving supplementation with an amino acid, methionine, it reversed the decreases in body weight and fasting caused by the ketogenic diet. It also reduced six particular bile acids linked to weight and glucose changes.

Treating mice with four of these bile acids revealed that two — taurodeoxycholic acid and tauroursodeoxycholic acid — significantly lowered body weight and blood sugar levels and improved glucose tolerance. This was regardless of whether they were on a regular diet or a ketogenic diet supplemented with methionine.

Other detected bile acids were unaffected by diet changes and showed no link to body weight or fasting blood sugar levels.

Through a series of additional experiments, the researchers showed that consuming a ketogenic diet increased blood levels of taurodeoxycholic acid and tauroursodeoxycholic acid in mice while decreasing their body weight and fasting glucose levels.

The researchers who conducted the present study sought to determine whether their findings in mice were potentially applicable to humans.

They conducted an observational study, measuring bile acids in blood and stool samples from 416 healthy participants aged 20 to 60.

They also examined data from a previously published low-carbohydrate ketogenic diet intervention study involving 25 adult women with overweight or obesity.

Consistent with their findings in mice, lower blood levels of specific bile acids in humans were significantly associated with higher body mass index (BMI) and fasting blood sugar levels.

They also found specific gut bacteria genes linked to human BMI and fasting blood sugar. The low-carb diet intervention appeared to reduce these genes significantly, and these changes were connected to BMI, fasting glucose, and bile acid levels.

In this study, increases in the levels of certain bile acids — taurodeoxycholic acid and tauroursodeoxycholic acid — were shown to result in decreased body weight and fasting glucose levels in mice. Similar associations were observed in humans.

The study authors explain that the ketogenic diet reduces the levels of a specific gut bacterium called Lactobacillus murinus ASF361, which produces an enzyme called bile salt hydrolase.

Lower levels of this bacteria or reductions in bile salt hydrolase increase the levels of the two mentioned bile acids, taurodeoxycholic and tauroursodeoxycholic acid.

These increased bile acids, in turn, reduce calorie absorption by interfering with the expression of a protein-coding gene called carbonic anhydrase 1 in the intestines, which may be linked to obesity.

The reduced calorie absorption results in weight loss and decreased fasting blood sugar levels, according to the study.

The researchers propose this regulatory mechanism for bile acids, as it aligns with their findings in animals and humans. However, they acknowledge that, due to limited evidence, other potential explanations cannot be ruled out.

Medical News Today spoke with Alyssa Simpson, RDN, CGN, CLT, a registered dietitian, certified gastrointestinal nutritionist, and owner of Nutrition Resolution in Phoenix, AZ, who was not involved in the study.

She commented that the research suggests a new potential ketogenic diet mechanism of weight loss that extends to include calorie absorption, influenced by changes in bile acids.

Still, she does not generally recommend the ketogenic diet to patients, questioning its long-term sustainability and health implications because of its restrictive nature.

Simpson explained that:

“Although effective for [short-term] weight loss, the ketogenic diet raises concerns due to its impact on the gut microbiome, resulting in reduced diversity and altered bile acids, potentially impacting long-term health.”

She pointed out that previous research suggests that high-fat, no-carb diets reduce microbiome diversity in ways that may decrease the production of beneficial antioxidants and short-chain fatty acids.

“This study confirms the ketogenic diet’s impact on reduced microbial diversity, highlighting selective changes,” she affirmed.

Eliza Whitaker, MS, RDN, a registered dietitian and medical nutrition advisor at Dietitian Insights, who was also not involved in the study, agreed that the results should be interpreted with caution.

She mentioned study limitations, such as only including male mice, despite known variations in the bile acid profiles of males and females in humans.

Notably, Whitaker highlighted that “the findings differ from previous studies that have suggested higher fat diets may impact the gut microbiome in ways that could contribute to obesity.”

Both Simpson and Whitaker recommend diets more consistently associated with improved long-term health, including Mediterranean and DASH diets.

Compared to a ketogenic diet, these diets more reliably “promote microbiome diversity through a variety of plant foods and provide essential nutrients, [which] may better support overall well-being,” Simpson concluded.