It has been known for a long time that a lack of vitamin D increases your risk of overweight. Now, an Italian study gives a whole new view on low vitamin D and how it is linked to elevated levels of TMAO (Trimethylamine N-oxide), a metabolite that increases the risk of non-alcoholic fatty liver and accompanying complications such as insulin resistance, diabetes, and cardiovascular disease. The scientists also looked at the gut flora’s and the liver’s roles in TMAO production and the fact that low vitamin D levels and overweight are a vicious cycle. It appears that overweight people need more vitamin D than the recommended level. In terms of non-alcoholic fatty liver, we will also be looking at the controversial delicacy, foie gras, and the fact that carbohydrate overconsumption burdens your liver.
Sun awareness campaigns and the official low-fat dietary guidelines do not work as planned, on the contrary. Lack of vitamin D and overweight are two related problems that have grown worse over the past decades. Researchers from University Medical School of Naples in Italy have now become aware that lack of vitamin D affects the liver, the gut flora, and gut-related metabolites such as TMAO (Trimethylamine N-oxide). Earlier studies have revealed a link between high levels of TMAO and non-alcoholic liver disease, which increases the risk of insulin resistance, overweight, diabetes, and cardiovascular disease. But it is the first time that scientists take a closer look at the relation between vitamin D and TMAO.
Higher blood levels of vitamin D mean lower levels of TMAO – and that is a problem
The study was carried out with 104 overweight adults – 50 men and 54 women. Their average age was 35 years. The participants’ fatty liver index (FLI) was used to diagnose non-alcoholic fatty liver disease, which is the most common liver ailment. The prevalence of non-alcoholic fatty liver disease is associated with metabolic syndrome, which is characterized by insulin resistance, overweight (apple-shaped body and enlarged waist circumference), high blood pressure, and elevated blood lipid levels. Metabolic syndrome is also an early stage of type 2 diabetes, which is spreading like a bushfire. The scientists measured the participants’ BMI, waist circumference, blood pressure, cholesterol and triglyceride levels, and liver function. Changes in these measures are linked to non-alcoholic fatty disease. The participants’ BMI was classified in accordance with WHO’s criteria, which are as follows:
Underweight: Below 18.5
Normal weight: 18.5 – 24.9
Overweight: 25 – 29.9
Class I obesity: 30 - 34.9
Class II obesity: 35 – 39.9
Class III obesity: Above 40
Vitamin D levels were defined as being adequate if they were higher than 30 ng/ml. TMAO concentrations were measured by using a special method.
Most of the participants (27.9%) were very obese and had a BMI count that corresponded with class III obesity. Also, most of the participants (62.5%) lacked vitamin D, and more than half (59.6%) had fatty liver/non-alcoholic fatty liver disease.
The study showed that the more vitamin D the participants had in their blood, the lower TMAO levels they had. There is a natural limit to how much vitamin D a person should have in the blood, but none of the participants exceeded 35 ng/ml. Just for the record, in Denmark, the minimum level is 50 ng/ml, while optimal levels should ideally be in the range 75-100 ng/ml. Even though there is more sunshine in Italy, none of the participants had optimal values. This may be due to a sedentary lifestyle with too much time spent indoors and overweight, which impairs the body’s ability to utilize the vitamin.
Vitamin D protects against overweight and cardiovascular disease in many ways
Over the past decades, epidemiological studies have shown a relation between lack of vitamin D and an increased risk of cardiovascular disease. A meta-analysis has demonstrated that population groups with low vitamin D levels in their blood have a 57% higher risk of developing cardiovascular disease compared with those with optimal levels of the nutrient. It is already known that overweight increases your risk of cardiovascular disease and that the visceral fat in between the abdominal organs is particularly harmful. This is because this type of fat triggers inflammatory processes that can damage cholesterol and embed the damaged cholesterol in the vessel walls.
It also appears that the combination of lacking vitamin D and being overweight or obese steps up the cardiovascular risk massively. This is because several vitamin D-dependent mechanisms are affected by the deficiency, for instance the regulation of inflammation, insulin sensitivity, and the renin-angiotensin-aldosterone-system that controls blood pressure and fluid balance.
The inverse relation between vitamin D and blood levels of TMAO could be another possible mechanism, where low vitamin D levels increase the risk of cardiovascular disease in connection with overweight and obesity.
An earlier meta-analysis has indicated that high TMAO levels increase the risk of cardiovascular disease by 23% and the risk of premature all-cause mortality by 55%. However, there are divided opinions as to whether different foods increase levels of TMAO.
The liver and gut flora and their impact on vitamin D and TMAO
We humans synthesize a vitamin D precursor in our skin by means of cholesterol and UVB rays from the sun. This precursor, which is named cholecalciferol and is the form of vitamin D that is also sold in supplements, is not yet biologically active. Helped by certain enzymes, the liver converts cholecalciferol into 25-hydroxyvitamin D3, the form of vitamin D that is measured in blood tests. When the body needs vitamin D for various purposes, the kidneys convert 25-hydroxyvitamin D3 to its active form using other enzymes.
The liver and kidneys therefore play a great role in the activation and utilization of vitamin D, but many overweight people have problems with this activation because of impaired liver and kidney function.
Vitamin D is involved in lipogenesis, which turns the liver into a virtual fat factory. As explained, lack of vitamin D contributes to disturbances in the body’s sugar and lipid metabolism, including insulin resistance, where cellular glucose uptake is reduced. The liver also plays a role for the enzymes that convert TMAO, and levels of this compound go up if the liver lacks vitamin D.
The gut flora also plays a role in TMAO production. Our comprehensive intestinal flora consists of around 1,000 different species that keep each other in check in a delicate balance. A healthy gut flora benefits us in many ways by displacing harmful microorganisms, improving digestion, producing lactic acid, forming certain vitamins and enzymes and numerous signaling substances that affect the metabolism, the immune system, the nervous system, and the hormone balance.
The gut flora is affected by what we eat and drink. For instance, it is commonly known that dietary fiber has a positive impact, and that gut bacteria like Clostridium and Ruminococcus increase levels of TMAO, while other gut bacteria such as certain types of Bacteroides lower them. There is a highly complex interplay that involves vitamin D, the liver, the gut flora, and TMAO.
Many – especially overweight people – do not get enough vitamin D
The sun during the summer period is our main source of vitamin D. However, many people become vitamin D-deficient due to things like spending too much time indoors, not getting enough sun during the winter, and being overweight. Also, ageing decreases vitamin D levels. The reference intake (RI) level for adults in Denmark is 5 micrograms, but many scientists believe that the actual need for vitamin D is much higher, perhaps as much as 30-100 micrograms daily. We also need magnesium to activate vitamin D. Many people lack this mineral
Vitamin D supplements, absorption, and utilization
Vitamin D is lipid-soluble. For that reason, we benefit the most from taking the vitamin in capsules where it is mixed with oil. It is perfectly safe to take vitamin D in doses between 20-80 micrograms daily. People who are overweight or have diabetes often benefit from increasing their magnesium intake from food or bioavailable supplements, as this helps them activate vitamin D.
New dietary guidelines for non-alcoholic fatty liver disease and type 2 diabetes
Since the 1970s, the general population as well as diabetics have been recommended to eat a low-fat diet with bread, potatoes, fruit, and other sources of carbohydrate. However, the abundance of carbohydrates burdens the liver, and it is especially fructose from sugar, fruit, juice, and commonly used sweeteners such as corn syrup and high-fructose corn syrup (HFCS) that is the problem. When the liver is flooded with fructose, the sugar compound is converted into cholesterol and triglycerides in a process known as lipogenesis, which was detailed earlier.
According to a new Danish study from Bispebjerg Hospital, diabetics benefit from eating a diet with a limited amount of carbohydrates, and this supports several international studies. People with diabetes or non-alcoholic fatty liver disease and sensitive blood sugar should try to eat a healthier diet with fewer carbohydrates and more protein and healthy fats.
Foie gras is an example of non-alcoholic fatty liver
This somewhat controversial delicacy is a result of corn (that contains a lot of fructose) being force-fed into ducks and geese in a process known as gavage.
Luigi Barres et al. E New Light on Vitamin D in Obesity: A Novel Association with Trimethylamine- N-Oxide (TMAO). Nutrients 2019
Anne Marie Uwitonze, Mohammed S Razzaque. Role of magnesium in Vitamin D Activation and Function. The Journal of the American Osteopathic Association. 2018
Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease. Nutrients 2017
Bispebjerg Hospital. Færre kulhydrater forbedrer type-2 diabetikeres evne til at regulere blodsukkeret. Nyhedsbrev 10. august 2019
Mads J Skytte et al. A Carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomized trial. Diabetologica. First online July 23 2019
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