New findings explain how it promotes weight loss

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A new study in mice and humans points to a mechanism by which keto diets protect against weight gain. Image: Alba Vitta/Stocksy.
  • Ketogenic diets support short-term weight loss, but the precise mechanisms behind metabolic changes remain unknown.
  • New research in mice and humans suggests that the ketogenic diet may protect against obesity by increasing specific bile acids and decreasing calorie absorption in the gut.
  • The long-term health effects of the ketogenic diet are unclear. Experts recommend plant-based diets, such as the Mediterranean diet, which promote a more favorable diversity of gut microbiomes.

The ketogenic diet is a low-carb eating pattern that has been extensively tested as a weight loss aid. However, 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 are still poorly understood.

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

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

To distinguish their work from typical animal studies, the researchers took additional steps to investigate whether these findings could also apply to humans.

They documented similar associations between bile acids and metabolic properties in two human studies, further increasing the potential significance of their findings.

This multi-method study highlights a specific interaction between the host and the gut microbiome that may explain how the ketogenic diet reduces body weight and fasting blood sugar in both rodents and humans.

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

They found that following a ketogenic diet significantly altered these metabolites, and body weight and fasting blood sugar levels decreased significantly.

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

When the researchers tested another 7-week dietary intervention using supplements of an amino acid, methionine, it reversed the decreases in body weight and fasting caused by the ketogenic diet. It also reduced six specific bile acids that are linked to weight and glucose changes.

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

Other bile acids detected were not affected by dietary changes and showed no association with body weight or fasting blood glucose levels.

Through a series of additional experiments, the researchers showed that following 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 current study wanted to determine whether their findings in mice could also be applied to humans.

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

They also examined data from a previously published low-carb diet ketogenic diet intervention study in which 25 adult women with overweight or obesity participated.

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 that are linked to human BMI and fasting blood sugar. The low-carb diet intervention appeared to significantly reduce these genes, and these changes were linked to BMI, fasting glucose and bile acid levels.

In this study, it was shown that increases in the levels of certain bile acids — taurodeoxycholic acid and tauroursodeoxycholic acid — resulted in reduced body weight and fasting glucose levels in mice. Similar associations were observed in humans.

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

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

These increased bile acids in turn decrease calorie absorption by disrupting the expression of a gene that codes for proteins, carbonic anhydrase 1, in the intestines. This gene may be linked to obesity.

According to the study, reduced calorie intake results in weight loss and lower fasting blood sugar levels.

The researchers propose this mechanism of regulation for bile acids because it matches their findings in animals and humans. However, they acknowledge that other possible explanations cannot be ruled out due to the limited evidence.

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

She noted that the research suggests there is a novel, possible ketogenic diet mechanism for weight loss that also involves calorie absorption, influenced by changes in bile acids.

However, she generally does not recommend patients to follow the ketogenic diet. She doubts whether the diet is sustainable in the long term and what consequences it has for health, due to its restrictive nature.

Simpson explained that:

“Although effective for [short-term] Weight loss, the ketogenic diet raises concerns because of its impact on the gut microbiome, resulting in reduced diversity and altered bile acids, potentially having implications for long-term health.”

She pointed out that previous research has shown that high-fat, low-carb diets reduce microbiome diversity in ways that may reduce the production of beneficial antioxidants and short chain fatty acids.

“This study confirms the impact of the ketogenic diet on reduced microbial diversity, highlighting selective changes,” she confirmed.

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 noted limitations of the study, such as the fact that only male mice were included, despite known variations in the bile acid profiles of males and females in humans.

Whitaker specifically emphasized that “the findings differ from previous studies that have suggested that higher-fat diets may affect the gut microbiome in ways that contribute to obesity.”

Both Simpson and Whitaker recommend more frequent diets that lead to better health in the long term, including the Mediterranean diet and the DASH diet.

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

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