Atherosclerosis, fatty liver and type 2 diabetes
CardioHeparMetabolic recognizes gut-associated risks
When the composition of the intestinal microbiota changes, the amount and thus the effect of the microbially formed metabolites also changes.
The new CardioHeparMetabolic Diagnostics (CHM) detects changes in the intestinal microbiota and selected metabolic products that pose a risk for the development of atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.1,2,3,4
The diagnostics make it possible to intervene early and effectively and to minimize the risk of disease. This is particularly important when there are first indications of the onset of metabolic disorders, the onset of arteriosclerosis or signs of liver stress.
If a disease has already manifested itself, the targeted modulation of the microbial metabolic products can effectively support the therapy and improve the success of the treatment.
Indications for CHM diagnostics
- Pathologic Glucose Tolerance (Pre-Diabetes)
- Metabolic syndrome
- Presence of risk factors for atherosclerosis
- High blood pressure
- Type 2 diabetes mellitus
- Hyperlipidemia (cholesterol, triglycerides)
- Silent Inflammation
- Elevated lipoprotein(a)
- Nicotine abuse
- Increased intima-media thickness in duplex sonografy (first stage of vessel wall changes before plaques become visible)
- Unclear increase in liver values
- Chronic liver diseases (in the sense of relief)
CHM identifies three separate risks
CHM diagnostics separately identifies microbiota-related risks for the development of arteriosclerosis, NAFLD and type 2 diabetes: the cardio risk, the hepatic risk and the metabolic risk.
The diagnostics are an extension of the KyberBiom® diagnostics: In addition to the new CHM parameters, functional groups from the KyberBiom® diagnostics are included in the risk assessment.
In addition to the detailed measurement results, the finding contains an overview of the results with traffic lights for the identified risks. The clear presentation of the findings facilitates the discussion with the patient.
Cardio risk – specific parameters
Bacterial TMA producers promote arteriosclerosis
Some intestinal bacteria convert choline, carnitine and lecithin into trimethylamine (TMA). Choline, carnitine and lecithin are found, for example, in meat or eggs, but also in dietary supplements for muscle building. The TMA formed is a gas that is well absorbed and rapidly oxidized by liver enzymes to trimethylamine N-oxide (TMAO).
Elevated TMAO levels are associated with a higher risk of cardiovascular disease – especially heart attack and stroke. TMAO increases the concentration of macrophage-specific cholesterol and the formation of foam cells in the vessel wall. It also promotes inflammation of the vascular wall and increases platelet activity.5
TMAO: more cholesterol and foam cells
Studies on mice have uncovered the causal relationship between TMA, TMAO and arteriosclerosis:
If mice were given TMAO, it promoted the formation of foam cells in the arterial wall. The same effect could be achieved if the mice were only given choline as a starting material for bacterial TMA production.
A diet high in TMAO, choline, or L-carnitine increased levels of scavenger receptors, too, which are involved in cholesterol accumulation and foam cell formation. Diet also altered sterol metabolism in the arterial wall, liver and intestines.
TMAO can also drive inflammation by activating pro-inflammatory proteins such as IL-6.
Human studies confirm: TMAO has an atherogenic effect
A clinical study examined the relationship between TMAO levels and cardiovascular events in more than 2,000 patients from two cohorts - in Switzerland and the USA.6 The subjects presented with suspected acute coronary syndrome. The result: In both cohorts, TMAO levels were able to predict short- and long-term risks for major cardiac complications. Overall, the TMAO levels in the American patients were higher than in the patients from Switzerland, so complications were more frequent in the Americans.
In previous studies, physicians had already shown an association between high plasma TMAO levels and cardiovascular events within the next three years.7 For example, in patients with heart failure, high TMAO levels were associated with significantly higher mortality.8
Affect TMA formation
The detection of TMA-formers in the stool provides information about the vascular load in a diet rich in meat and eggs. Athletes should also know and consider their gut-associated cardio risk if they take carnitine-containing dietary supplements to build muscle. If the concentration of TMA-formers is increased, the patient should reduce meat and egg consumption. In addition, bacterial TMA production can be reduced, for example, using phytotherapeutics such as allicin from garlic.9
Hepar risk – specific parameters
Bilophila wadsworthia and hepatotoxins from the intestine put a strain on the liver
For the hepar risk, the CardioHeparMetabolic records two parameters that drive the development of NAFLD:
- The intestinal bacterium Bilophila wadsworthia promotes intestinal inflammation and increases fatty liver in a high-fat diet.
- The iso-fatty acids show how strongly the intestinal bacteria form hepatotoxins and thus burden the liver.
In the case of an unclear increase in liver values, but also in the case of chronic liver diseases and manifest NAFLD, it is therefore expedient to determine the intestinal-associated hepatic risk. This enables targeted therapeutic intervention to reduce the load on the liver from the intestine.
Bilophila wadsworthia promotes fatty liver
Bilophila wadsworthia amplifies the adverse effects of a diet high in saturated fat. The intestinal bacterium reacts to a corresponding overnutrition with increased growth, as a recent study with overweight and obese adults has shown.10
Unsaturated fatty acids, on the other hand, increased cell counts in butyrate producers.
If Bilophila wadsworthia had increased numbers of cells in the intestine, the subjects' fatty liver would be fueled even more if they consumed a lot of saturated fatty acids.
The mouse model showed how exactly the intestinal bacterium affects the body.4 Bilophila wadsworthia:
- increases inflammation,
- increases mucosal permeability and
- dysregulates bile acid metabolism.
Bile acids are increasingly recognized as important regulators of metabolism. This is where Bilophila wadsworthia comes in: The bacterium modulates a number of genes that influence bile acid homeostasis.4 Altered bile acid metabolism in turn destabilizes blood sugar regulation and promotes the development of fatty liver.
The process is independent of the pro-inflammatory properties of Bilophila wadsworthia: The intestinal bacterium produces the gas hydrogen sulfide, which promotes chronic inflammatory diseases and cancer when produced in large quantities. In low concentrations, however, it has an anti-inflammatory effect on the intestinal mucosa, which also produces the gas itself.11
Iso fatty acids as markers for hepatotoxin formation
Other intestinal bacteria can also burden the liver with their metabolic products. The concentration of iso fatty acids indicates how strongly the intestinal bacteria form hepatotoxins such as ammonia, indole12, skatole and phenol. The substances are formed during protein breakdown - together with the branched-chain fatty acids isobutyric acid and isovaleric acid, which can be excreted and detected in the stool. Increased bacterial protein breakdown can be caused by high cell counts of proteolytic bacteria in the intestine and a diet rich in animal protein.
Targeted countermeasures against endogenous liver stress
From the hepar risk of CHM it can be deduced whether there is an endogenous liver burden and whether the composition of the intestinal microbiota favors fatty degeneration of the liver. If this is the case, hepatotoxins can be bound and eliminated before tissue damage occurs. A change in diet and preparations with lactic acid-forming bacteria can limit the growth of proteolytic bacteria and Bilophila wadsworthia4 and thus counteract the risk of fatty liver.
Metabolic risk – specific parameters
Short-chain fatty acids and branched-chain amino acids as signal transmitters
The short-chain fatty acids acetic acid and propionic acid and the branched-chain amino acids (BCAA) formed by Prevotella copri play an important role in the pathogenesis of obesity and type 2 diabetes:
- The bacterially formed acetic acid increases the feeling of hunger and stimulates gluconeogenesis and liponeogenesis.13
- The bacterially produced propionic acid, on the other hand, increases the feeling of satiety, lowers cholesterol levels and improves insulin sensitivity.14
- BCAA promote insulin resistance and serve as a source of nutrients and energy for differentiated adipocytes.
The measurement of the parameters is therefore useful in the case of obesity, pre-diabetes and metabolic syndrome. Subsequent therapy aimed at the microbiota and its metabolic products makes it possible to counteract the metabolic imbalances.
Prevotella copri is the most important BCAA producer
BCAAs enter the bloodstream via animal foods and the metabolism of the intestinal bacteria. The human metabolism cannot form the BCAA.
Prevotella copri is the intestinal bacterium that plays the most important role in the production of BCAAs - and thus also in the overall development of insulin resistance, as a Danish cohort of non-diabetic men revealed.15 In another study, Prevotella copri cell counts and LPS levels were elevated in patients with type 2 diabetes.2
BCAA as a signal transmitter
BCAAs are unique among amino acids in that they cannot be metabolized in the gut or liver. Their circulating concentrations therefore serve as a signal for nutrient supply to many target tissues.2 Leucine in particular provides the body's own sensor system - the mTOR complex - with information about the availability of amino acids. If the supply situation is good, the mTOR complex stimulates the production of new proteins, but also the storage of fat in metabolically active tissues. If, on the other hand, there is no nutrient supply, mTOR switches from anabolic to catabolic metabolism. Instead of producing new proteins from amino acids, for example, cleaning processes are set in motion and defective proteins that can be harmful to the cell or organ are disposed of.
BCAA promote insulin resistance and fatten adipocytes
When the mTOR complex is activated via leucine, downstream mechanisms decrease insulin-dependent glucose uptake into cells.2 The result is hyperglycemia. If Prevotella copri constantly activates the mTOR complex via leucine production, this can lead to insulin resistance16 and subsequently to type 2 diabetes.
The diabetes drug metformin aims to repress the mTor complex, and intermittent fasting also works by inactivating it.17,18
BCAAs also fatten the differentiated adipocytes: leucine and isoleucine contribute about one-third to lipogenesis in the adipocytes.19 Pre-adipocytes, on the other hand, use glucose and glutamine for fatty acid synthesis.
Biomarkers for emerging type 2 diabetes
Due to their signaling function, BCAAs are excellently suited as biomarkers. An increase is associated with a five-fold increased risk of type 2 diabetes3 and predicts diabetes up to twelve years before its onset.20
As a cross-sectional analysis in the Women's Health Study with 19,472 participants showed, women with high plasma BCAA levels also have21:
- higher inflammatory markers
- lower high-density lipoprotein cholesterol (HDL-C)
- higher triglycerides and higher low-density lipoprotein cholesterol (LDL-C)
Acetic acid signals hunger and promotes fat storage
The acetic acid formed by the intestinal microbiota also promotes fat storage in a high-fat diet and at the same time increases the feeling of hunger.
Studies on rats have shown that if the animals ate food with a high fat content, the intestinal microbiota produced more acetic acid. This activated the parasympathetic nervous system13; glucose-stimulated insulin secretion and ghrelin secretion increased. The rats ate significantly more due to the increased ghrelin secretion and the increased glucose-stimulated insulin secretion promoted energy storage in the form of fat. The rats stored fat in their skeletal muscles and liver.
But a high-sugar diet can also increase the acetic acid concentration in the intestine, since some intestinal bacteria convert simple carbohydrates into acetic acid.
Counterpart propionic acid: saturates and improves insulin sensitivity
Elevated levels of propionic acid in the colon, on the other hand, can prevent weight gain - especially in overweight adults. This has been shown in human studies with overweight and obese test subjects.14 The cause was increased release of hormones such as PYY and GLP-1, which reduce calorie intake. In addition, administration of propionic acid improved insulin sensitivity and reduced the concentration of the pro-inflammatory cytokine IL-8.
Studies on rats were able to uncover further mechanisms of action of propionic acid: Propionic acid seems to reverse fat-induced lipid accumulation, decrease hepatic triglyceride concentrations, and improve insulin sensitivity.14 Accordingly, propionic acid administration reduced body weight, fat mass, and white adipose tissue volume in rats despite a high-fat diet.
Targeted dietary change
A targeted change in diet based on the CHM findings and the administration of phytotherapeutics can lower the concentration of BCAAs2 and influence the ratio of propionic acid to acetic acid. This alters the signals that the gut microbiota sends to the human metabolism, increasing satiety, improving insulin sensitivity and reducing the caloric yield of food.
Basic parameters of CHM risks
The cell counts of the LPS-bearing microbiota and the butyric acid determination are included in all three CHM risks.
LPS-bearing microbiota and butyric acid
Increased LPS entry from the gut microbiota in a hyperpermeable gut mucosa is closely linked to the development of obesity and insulin resistance. Both are among the leading causes of cardiovascular disease, NAFLD and type 2 diabetes.3
Influencing factor nutrition
Diet strongly influences the composition of the intestinal microbiota and thus also LPS input and butyric acid production. A diet rich in simple carbohydrates, proteins or saturated fatty acids is particularly problematic.
A rich supply of protein promotes the growth of the LPS-bearing microbiota. The lipopolysaccharides (LPS) in the outer cell membrane of Gram-negative bacteria act as endotoxins. Under certain conditions, they can pass through the intestinal barrier and develop their toxic effect.
This is exactly what happens after a meal that contains a lot of saturated fatty acids: the bacterial lipopolysaccharides diffuse into the intestinal mucosa cells together with the dietary fats. There they are packed with triglycerides, phospholipids and cholesterol into chylomicrons and transported to the blood via the lymph.3
As a recent publication has shown, the type of fatty acids is crucial for a postprandial increase in LPS concentrations.22 According to this, only the consumption of saturated fatty acids increases the LPS concentration in the blood, whereas unsaturated fatty acids protect against elevated LPS concentrations.
Metabolic endotoxemia and silent inflammation
If the diet is high in saturated fatty acids and low in fiber over a longer period of time, the composition of the intestinal microbiota changes and the mucous membrane becomes more permeable overall. The bacteria produce less butyric acid and the intestinal mucosa lacks the nutrient it needs to maintain the functionality of the selective mucosal barrier.
If the intestinal mucosa is hyperpermeable, bacteria23, bacterial LPS and excess hepatotoxins constantly enter the lamina propria and the bloodstream.1 Scientists speak of metabolic endotoxemia: the endotoxin concentration is subclinically elevated over a longer period of time and the body continuously produces pro -Inflammatory cytokines released. This triggers an underlying inflammation - the silent inflammation - that can fuel insulin resistance and contribute to the development of atherosclerosis and high blood pressure.24,3 Scientists have even identified bacterial LPS as the triggering inflammatory factor responsible for obesity and diabetes.25
Persistent endotoxemia can also have a lasting impact on liver function and lead to fatty liver. Fatty liver, in turn, can progress to liver cancer without the intermediate stage of liver cirrhosis.26
LPS affects body fat and blood pressure
It is likely that invading LPS can also directly amplify the increase in body fat mass. Studies in mice suggest this3: If the mice received continuous LPS infusions for four weeks, their glucose and insulin levels increased and they gained weight - at a rate that is otherwise observed after a four-week high-fat diet.24, 25
In a small human study with eight volunteers and in studies on rats, scientists uncovered further mechanisms of the LPS effect.24 The bacterial LPS:
- increased heart rate and norepinephrine levels,
- increased neuroinflammation and
- decreased baroreflex sensitivity.
The baroreflex counteracts blood pressure fluctuations and thus maintains blood pressure.
The proven activation of the sympathetic nervous system is considered a cause of hypertension, which can already be observed in the early stages.24
Stabilize intestinal mucosa and reduce LPS concentration
If the permeability of the intestinal mucosa is increased, natural therapies to stabilize the intestinal mucosa make sense. In order to suppress unwanted intestinal bacteria and lower the LPS concentration in the intestine, an individual, diagnosis-based therapy with preparations containing bacteria is suitable, for example. This means that fewer harmful metabolic products are produced and fewer pro-inflammatory substances get into the body. Researchers believe that lowering plasma LPS concentrations is a powerful strategy to control metabolic diseases.25
Range of natural therapy options
The CHM finding enables you to specifically minimize microbiota-related stress on the liver and blood vessels. They can also counteract the mechanisms of the intestinal microbiota that are responsible for an increased feeling of hunger and the development of insulin resistance.
If arteriosclerosis, NAFLD or type 2 diabetes have already manifested themselves, a targeted modulation of the microbial metabolites can effectively support the therapy and improve the success of the treatment.1
A wide range of natural forms of therapy are available for this purpose:
- Probiotic Therapy
- dietary change
- Orthomolecular Therapy
- Adsorbents (healing earth)
- complex homeopathy
You can request individual nutritional and therapy recommendations for your patients with the CHM report.
If you have any questions, our medical hotline, made up of experienced doctors and non-medical practitioners, is at your side.
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