A ketogenic diet can raise LDL cholesterol, and a synbiotic supplement—a combination of prebiotic fibre and live bacteria—might stop that from happening. This matters because ketogenic diets are used for epilepsy, neurological conditions, and type 2 diabetes, and are popular among healthy adults. But the rise in LDL cholesterol that often accompanies them increases cardiovascular disease risk. The problem may stem from the diet’s low fibre content, which reduces gut microbial diversity and depletes beneficial bacteria like *Bifidobacterium*. Animal studies and human trials on non-ketogenic diets suggest that synbiotics can lower cholesterol, but no one has tested whether they work specifically during nutritional ketosis. If the trial shows that synbiotic supplementation prevents the LDL cholesterol increase, it could make ketogenic diets safer for long-term use. That would directly affect people who rely on the diet for medical reasons, as well as healthy individuals who choose it. The research also explores the underlying mechanisms—how gut microbes, bile acids, and short-chain fatty acids interact—which could inform future products or dietary strategies. This is applied, translational science with a clear practical endpoint.
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Ketogenic diets, which limit digestible carbohydrate intake to less than 50g per day, induce ketosis by producing ketone bodies from the breakdown of fatty acids and amino acids. While recognised as a therapy for epilepsy and increasingly used for various neurological disorders and conditions like type 2 diabetes, ketogenic diets have also gained popularity among healthy adults. However, one of the negative consequences from consuming a ketogenic diet is an increase in circulating LDL cholesterol (LDL-C) concentrations, which increases the risk of cardiovascular disease. One potential explanation for the rise in LDL-C during nutritional ketosis is changes to the gut microbiome. Our preliminary data indicate that ketogenic diets, which are typically low in fibre, reduce the diversity of gut microorganisms and decrease the abundance of specific genera, such as Bifidobacterium. Animal studies have demonstrated the crucial role of gut microbiota in host cholesterol metabolism, and thus changes in gut microbial composition and activity could explain the increase in LDL-C in humans consuming a ketogenic diet. Dietary supplementation with prebiotics and probiotics can modulate gut microbial composition and activity. Prebiotics are substrates that selectively support the growth of beneficial microorganisms, whereas probiotics are live microorganisms. When pre- and probiotics are consumed in combination, these are referred to as synbiotics. In mice fed a high fat diet, treatment with prebiotic fibre and probiotics maintains gut microbial composition and reduces cholesterol concentrations. In humans with chronically elevated cholesterol on a non-ketogenic diet, treatment with a synbiotic reduced LDL-C. Thus, we hypothesise that synbiotic supplementation will maintain gut microbial composition and mitigate against the negative effects of a ketogenic diet on LDL-C. To investigate this hypothesis, we will conduct a 12-week randomised controlled trial (RCT) in men and women (Synbiotic versus Placebo, N=64). We will examine the effect of synbiotic treatment (Polydextrose & Bifidobacterium animalis subsp. lactis B420) on LDL-C concentrations and lipoprotein profile using NMR spectroscopy. Gut microbial composition will be characterised using metagenomic analysis. We will use validated biomarkers to assess cholesterol and bile acid synthesis, and stable isotope techniques to examine cholesterol absorption. To examine dynamic changes, including metabolic handling of the prebiotic (polydextrose), we will examine postprandial fermentation (expired H2/CH4) and circulating concentrations of short chain fatty acids (SCFAs) and bile acids, including interconversion of 13C-labelled polydextrose into systemic SCFAs. We will examine distal effects of synbiotic treatment in adipose tissue biopsies taken in basal conditions and 6h after meal ingestion, and we will use in vitro approaches to interrogate key pathways, including experiments using media conditioned with ex vivo serum from our human RCT (e.g., fasted/fed). This collaboration is an Industrial Partnership Award (IPA) that arose from activities coordinated by the BBSRC-funded ORIC hub INFORM. The industrial partner (IFF) has agreed to make a £107,000 cash contribution. They will also make a substantial £120,000 in-kind contribution through (i) the provision of pre- and probiotic supplements, (ii) the manufacture of isotopically-labelled polydextrose, and (iii) access to their laboratories and technical platforms to measure short chain fatty acids and bile acids. This project will establish whether synbiotic treatment prevents a ketogenic diet from increasing LDL-C. In addition to characterising key mechanisms and distal effects on host metabolism, this research will lay the foundation for new strategies and products to help people to get the benefits of ketogenic diets more safely.
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