Heart disease is the number one cause of death in the United States, owing to a constellation of risk factors including a sedentary lifestyle, disrupted sleep patterns, stress, and poor diet. The average American adult consumes 29 grams of saturated fat per day (the amount in about four tablespoons of butter, four slices of pepperoni pizza, or 1.5 cups of ice cream), possibly contributing to heart disease risk through interactions with the gut microbiota. Findings of a new report link high saturated-fat diets to increased heart disease biomarkers among mice with high levels of E. coli bacteria.

The gut microbiota, the community of bacteria, archaea, fungi, and viruses that lives in the human intestine, is highly influenced by changes in diet. Dietary fats that are not absorbed in the small intestine travel to the large intestine where microbes metabolize them. The same is true for other nutrients not absorbed by the gut, including choline, an essential nutrient found in high amounts in organ meats, egg yolks, and legumes. Choline is an important component of cellular membranes, a precursor for the production of neurotransmitters, and is incorporated into bile acids needed for the digestion of fats; however, some gut microbes convert choline into trimethylamine (TMA), which is absorbed by the intestine and converted to trimethylamine N-oxide (TMAO) in the liver. High serum levels of TMAO have been shown to increase the risk of major cardiovascular events such as heart attack and stroke by increasing the deposition of cholesterol in arterial walls (i.e., atherosclerosis).

Clostridia and Enterobacteriaceae are the only two bacterial families common to the human gut microbiota that are known to produce TMAO, but only Enterobacteriaceae abundance is substantially increased on a high-fat diet. Oxygen content in the gastrointestinal tract decreases through the small and large intestines so that bacteria in the colon are mostly anaerobic (meaning they do not use oxygen for metabolism). This low oxygen environment is needed to promote the growth of more beneficial bacteria such as Clostridia and suppress the growth of more detrimental bacteria such as Enterobacteriaceae. In order to maintain this low oxygen environment, the mitochondria of colon cells must consume high levels of oxygen; however, a diet high in saturated fat may impair mitochondrial function, facilitating the growth of TMAO-producing bacteria and increasing heart disease risk.

The investigators performed their experiments using two mouse strains with altered gut microbiota: mice that do not carry Enterobacteriaceae in their gut microbiota (E. negative) and germ-free mice, which are raised in a sterile environment and do not have a microbiota. They fed mice either a high-fat (60 percent of calories from fat) or low-fat (10 percent of calories from fat) diet for 10 weeks. The main source of fat in the high-fat diet was lard with casein protein, sugar, and micronutrients added. The researchers added a choline supplement to both the high-fat and low-fat diets one week before administering a single dose of a probiotic containing E. coli, a member of the Enterobacteriaceae family, to both E. negative and germ-free mice. All mice consumed their assigned diet for a total of 14 weeks. The researchers measured changes to epithelial cells in the colon including mitochondrial metabolism, inflammation, and cancer signatures.

Both E. negative and germ-free mice that gained weight on the high-fat diet had increased inflammation and cancer signatures, suggesting some of the detrimental diet effects were independent of the microbiota. Germ-free mice on a low-fat diet had colon epithelial cells with appropriately low levels of oxygen; however, germ-free mice on a high-fat diet had colon epithelial cells with increased oxygen levels and reduced mitochondrial metabolism. Following E. Coli exposure, E. negative mice fed a high-fat diet supplemented with choline gained more weight and had higher levels of oxygen, inflammation, and signatures of cancer in their colons than E. negative mice fed a low-fat diet. These changes were associated with an increased concentration of fecal E. coli. In germ-free mice exposed to E. coli, a high-fat diet supplemented with choline significantly increased serum TMAO levels compared to all other groups.

These results elucidate the mechanisms by which diets high in saturated fat may contribute to heart disease through interactions with choline metabolism by the gut microbiota. However, there are several important factors to consider in translating these results into relevant information for humans. Mouse diets often contain just one or two sources of fat such as lard and soybean oil, as was used in this study. Human diets contain a wider variety of fats, including various saturated and unsaturated fats. These diets also often contain high amounts of simple sugars, such as the sucrose and maltodextrin used in this study. The diet used in this study is also not representative of a standard human diet and limits the ability to distinguish between the effects of saturated fat and sugar. So, while animal studies are a vital foundation for human research, they should not be the basis for individual health recommendations. To hear Dr. Rhonda Patrick review the evidence on saturated fat and heart disease, listen to this episode of the FoundMyFitness podcast.

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• To learn even more about the effects of saturated fat and cholesterol on human health, watch this episode featuring expert Dr. Ronald Krauss, MD.