Gallbladder, Methylation and Bile Function

Choline, methylation and liver functions

• Choline is an essential nutrient needed for structural integrity and signalling

functions of cell membranes, methyl group metabolism, and neurotransmitter

synthesis

• Diets deficient in choline result in fatty liver, liver damage, and muscle

damage

• Maternal dietary choline deficiency during pregnancy is associated with a 4-

fold increased risk of having a baby with neural tube defect

• Pregnant rodents diets deficient in choline may have perturbed brain

development in their foetuses

• Choline requirement is modified by dietary availability of other methyl

donors; and by endogenous biosynthesis of choline moiety

• Individuals carrying different gene SNPs require more choline (especially in

their diet) ideal dose 550mg choline (70Kg person)What is gallbladder?

It is a small, thin-walled, pear-shaped pouch organ. It is about 7 to 10 centimetres

long, up to 5 centimetres across at its widest point, located in the upper right

abdomen, between the chest and hips, and below the liver.

The gallbladder and biliary tract

• The biliary tract consists of the gallbladder and the bile ducts

• The gallbladder stores bile

• The bile ducts carry bile and other digestive enzymes from the

liver and pancreas to the duodenum

• Bile is reddish-yellow, and consists of cholesterol, bile salts,

bilirubin, and other toxins and waste products

Gallbladder Functions

• The liver produces 0. 8 to 1 litre of bile, and passes the bile on through small

canals to the bile duct, a small duct leading to the gallbladder branches off of

the larger bile duct, before it connects to the intestine

• The bile flows into the small intestine during a meal. Between meals, when no

fat needs to be digested, the bile flows into the gallbladder instead, where it is

concentrated and stored.

Functions

• Break up fats in the diet into smaller pieces

• Rinse bacteria off the lining of the small intestine

• Affect detoxification functions of the liver

• Since the bile is stored in the gallbladder, toxins either degraded or non-degraded

will be stored in the bile; these toxins can be chemicals, pesticides, heavy metals,

herbicides like glyphosate, and hormones like oestrogen

Factors affecting & damaging bile functions:

• Stressful lifestyles

• Unbalanced hormones,

• Lower stomach acid

• Higher toxins such as herbicides and pesticides

The Consequences of a damaged gallbladder:

• Reduce or stop the release of bile

• Change the composition of bile

• Reduced or changed bile damages the gallbladder itself, the intestine, and the

body

Methylation and bile functions

• Bile is involved in detoxification, which is related to methylation because

methylation is the key way we rid our body of toxins and hormones .

• Genetic variants and epigenetics affect the detoxification of hormones and

environmental toxins in the bile of gallbladder

• When hormones and environmental toxins cannot be detoxified, they cause

gallbladder stones and cancer

• MTHFR often induces SIBO (small intestinal bacterial overgrowth ), because

MTHFR reduces methylation functions resulting in less bile, leading to

insufficient intestine clean-up, and accumulation of toxins and bacteria, which

may cause gallbladder issues

What are gallbladder related diseases?

Diseases of the gallbladder are common and costly. Many risk factors for

gallbladder diseases are not modifiable such as ethnic background, increasing age,

female gender and family history or genetics.

Related diseases:

• Gallstone diseases

• Gallbladder cancer

• Congenital biliary abnormalities

• Gallbladder polyps

Gallstone prevalence

• A trend for increasing gallstone prevalence is identified in Europe and the US

• 15% (20 million) of the U. S. population has gallstones

• 9 - 21% (0.63/100) of European population has gallstone

• 10-15% of gallstone patients has simultaneous gallbladder and common bile

duct stones

• 85% of gallstones is cholesterol stone

Gallbladder cancer prevalence

• 7-22/100,000 of the Asian population has gallbladder cancer

• < 2/100,000 in the rest of the world populations including the U. S.

Asymptomatic gallbladder diseases

• Most of them are clinically silent, an incidental finding often uncovered

during abdominal ultrasound

• Up to 80% will never experience biliary pain or complications

• 2% to 3% per year, and 10% by 5 years may develop symptoms; 1% to 2%

per year may develop major complications

Symptomatic gallbladder diseases

• Biliary pain: episodic, steady, or severe pain located in the upper abdomen and

lasting more than 30 minutes

• Complications and nonspecific abdominal complaints including dyspepsia

Gall Stone Diseases

Risk factors for developing gall stone diseases:

• Ethnicity: Asian, North American Indians, and Eastern European;

• Gender: women especially during the fertile years are twice as likely as men,

because female sex hormones reduce bile secretion & function

• Age: older than 40 years

• Genetics: 5 times elevated risk in patient relatives. These rate are even higher

in monozygotic twins at 12% and dizygotic twins at 6%

• Obesity: 25% of morbidly obese individuals have gallstones

• Rapid weight loss: 30% to 71% increased risk

• Dyslipidemia: diabetes and the metabolic syndrome

• Diet: high in cholesterol, fatty acids, sugars, legumes, and carbohydrates

Taurine, bile and gallstone formation

• Taurine is an organic osmolyte involved in cell volume regulation, and

provides a substrate for the formation of bile salts

• One of the few amino acids not incorporated into proteins

• Its cellular and biochemical mechanisms mediating the actions of taurine are

not fully known

• It increases bile acid pool size and reduces bile saturation through increasing

bile flow as well as in the rate of excretion of bile acids, and decreasing the

secretion rate of cholesterol in bile

• Most bile acids are conjugated with taurine in the liver, and taurine-

conjugated bile acids increase membrane mobility and fluidity of hepatocytes

• It suppresses triglyceride secretion from the liver, and thus reduces cholesterol

gallstone formation

How MTHFR Affects Gallbladder Function

MTHFR affects methylation in the liver

• MTHFR affects biliary excretion

• Oestrogen & gallbladder disease is connected

• Taurine, bile and gallstone formation

• MTHFR, SIBO and bile functions

SAMe (S-adenosylmethionine) & its importance in the liver

• SAMe is converted by the liver from methionine, and the liver is where the

bulk of SAMe produced

• SAMe is needed mainly for liver methylation of a large variety of substances:

DNA, proteins, lipids and many others

• Betaine & choline are the only two nutrients that can supply the methyl group

for methionine and 5-MTHF synthesis

• SAMe activates CBS and inhibits MTHFR, and consequently the synthesis of

5-MTHF

• If SAMe levels drop then normal methylation of DNA, proteins, PE,

guanidinoacetate and many other molecules are not able to continue.

• If SAMe levels rise too much, hyper methylation may affect the normal

function of the liver.

MTHFR affects biliary excretion

• Common phospholipids in foods are PC, others such as PE, PS and PI are

present in much smaller amounts

• PC is synthesized in hepatocytes by three sequential methylations of PE,

catalysed by PEMT, using SAMe as methyl donor

• PE is methyl dependent and affects biliary excretion of phospholipids and

cholesterol

• Increasing cholesterol amount leads to a significant decrease in PE:PC ratio

Total plasma PC is affected by dietary choline supplementation

Hormones and the Gall bladder (Oestrogen)

• Dietary intake of methyl donors like choline influences methylation of DNA

and histones in the liver

• Choline is required for SAMe production catalyzed by PEMT, which is

induced by oestrogen

• Eating low-choline diets develop fatty liver and liver damage. Gallstones,

fatty liver, and hepatic fibrosis, and hepatocarcinomas are epigenetically

regulated

• Choline is a source of phospholipids which is critical for enterohepatic

circulation of bile, bile salts and cholesterol

• Dietary choline requirement varies depending on an individual's genotype and

oestrogen status

• Postmenopausal women are more susceptible to the risk of organ dysfunction

requiring higher choline diet

MTHFR, SIBO and bile functions

• SIBO is an increase of the bacteria in the small intestine. SIBO can interfere

the MTHFR pathways by increasing blood folate, decreasing the absorption

of vitamin B12, A, D, E, and K resulting in poor methylation and chronic

diseases, such as diarrhoea, diabetes, and malnutrition

• MTHFR often develops SIBO because MTHFR reduces methylation

functions resulting in less bile

• Bile acids are potent antimicrobial agents that prevent bacterial over-growth

in the small bowel

• Bile in the bowel interacts with the gut microbes/flora to complete the

enterohepatic circulation, which includes the liver, the biliary tree, the

intestine and the portal vein

• Normal levels of the gut flora are required by the enterohepatic circulation to

process and deliver bile acids back to the liver

Key SNPs Affecting Gallbladder Functions

PEMT,

BHMT

MTHFR

These genes and how they affect bile functions are newly emerging

concepts

• Current research finds that the three genes are related to methylation, toxin

and hormone detoxification functions of the liver; and affective bile function.

• Bile stored and concentrated in the gallbladder has unique functions in the

intestine, not just for food digestion, but also for keeping the gallbladder and

intestine healthy

• The three genes are working together to regulate bile formation and excretion

from the liver to the gallbladder

• Changes in each of the three genes, particularly MTHFR, may affect the

gallbladder and bile function; mostly reduce their functions

BHMT SNPs and bile functions: (Affecting Homocysteine)

BHMT (betaine homocysteine methyltransferase) catalyzes homocysteine re-

methylation in the liver, which depends on SAMe

When a SNP is associated with both gene activity and protein, it indicates the SNP

has possible genotype-phenotype correlations

• BHMT SNPs: rs41272270, rs16876512, and rs6875201), located 28kb upstream of the

5'-UTR and in intron 1 of BHMT, are significantly correlated with both BHMT

activity and protein levels. Their AAG haplotype increases but GGA haplotype

decreases protein levels and enzyme activity

• BHMT SNP: rs7700790, is also highly associated with hepatic BHMT enzyme activity

and protein

BHMT c.716G>A AA genotype is associated with lower plasma dimethylglycine

in pregnancy, compared to GG genotype

BHMT -742G>A is protective in uterine cervical cancer

BHMT SNP rs3733890 is up-regulated & associated with nHcy concentration

PEMT SNPs and bile functions: (Affecting Choline)

https://www.mdpi.com/2072-6643/11/10/2265/htm

PEMT (phosphatidylethanolamine N-methyltransferase) affects nutrient

requirement of choline

• Premenopausal women may be resistant to choline deficiency-induced organ

dysfunction, because oestrogen induces PEMT

• PEMT -744 G-->C rs12325817 develops organ dysfunction when fed a low

choline diet, particularly in women

• PEMT SNP rs12325817 is linked to choline deficiency syndrome

PEMT SNP V175M (rs 7946), a loss of function mutation, is associated with

diminished activity and may confer susceptibility to non-alcoholic fatty liver

disease TT (AA) allele

PEMT SNPs and bile functions: (Affecting Choline)

• CHKA (Choline Kinase) rs6591331 – commits choline molecules to a pathway

for phosphatidylcholine synthesis rather than be used as a methyl group donor.

Post menopausal women who were carriers of the T allele CHKA rs6591331

were more likely to develop organ dysfunction when fed a low choline diet.

• CHDH – choline dehydrogenase – converts choline to betaine (an important

methyl donor). This alters the dietary choline requirement.

• Rs9001/ rs7634578 affected choline levels.

• MTHFD1 rs2236225 – lower choline in the diet affects choline status

• MTHFR rs1801133 – altered dietary choline requirements.

SLC

• SLC44A1 – required fro transport of choline into muscle mitochondria

• These people develop muscle damage when given a low choline diet

• G allele of SLC44A1 rs7873937

• G allele of SLC44A1 rs2771040

• This is down regulated by choline deficiency – limited capacity to

transport choline into muscle cells to maintain integrity and fluidity,

leaving those cells to leak CPK and therefore are especially sensitive to

diets low in choline.

https://pubmed.ncbi.nlm.nih.gov/24671709/

https://pubmed.ncbi.nlm.nih.gov/24671709/

Improving Bile Function

MTHFR reduces methylation and liver detoxification leading to accumulated

toxins and hormones, which are excreted into the bile, leading to sticky bile with

cholesterol crystal formation. These may cause higher risks of gallbladder stones

and cancer.

We need methylation for Gall bladder function and bile synthesis

• Folate, a key nutritional factor in one-carbon metabolism, supplies the methyl

units for DNA methylation

• Polyphenols and flavonoids in green tea, phytoestrogen, and lycopene may

also affect methylation by providing methyl donors

• Physical activity and energy balance influences methylation and obesity

changes DNA methylation and makes people more susceptible to Gall bladder

and bile issues.

• Genetic variants and environmental impacts play a role in susceptibility

• Oestrogen promotes PEMT production of phosphatidylcholine so a low

oestrogen environment will affect choline production.

Taurine, a potential supplement for liver:

• Taurine supplementation protects the liver against histological damage,

fibrosis, and significant reductions in oxidative stress

• It increases bile flow and excretion rate of bile acids, and decreases secretion

rate of cholesterol in bile

• Taurine-conjugated bile acids increase membrane mobility and fluidity of

hepatocytes

• It suppresses triglyceride secretion from the liver, and thus reduces cholesterol

gallstone formation

• It has potential beneficial actions in congestive heart failure, hypertension,

ischemic heart disease, atherosclerosis and diabetic cardiomyopathy

Remember CBS pathway is crucial for Taurine synthesis Athough taurine is helpful in healing gallbladder issues, don’t automatically assume that your taurine is low. Taurine is actually usually very high with those with CBS SNPs.

Choline, methylation and liver functions:

• Choline is an essential nutrient needed for structural integrity and signalling

functions of cell membranes, methyl group metabolism, and neurotransmitter

synthesis

• Diets deficient in choline result in fatty liver, liver damage, and muscle

damage

• Maternal dietary choline deficiency during pregnancy is associated with a 4-

fold increased risk of having a baby with neural tube defect

• Pregnant rodents diets deficient in choline may have perturbed brain

development in their foetuses

• Choline requirement is modified by dietary availability of other methyl

donors; and by endogenous biosynthesis of choline moiety

• Individuals carrying different gene SNPs require more choline (especially in

their diet) ideal dose 550mg choline (70Kg person)

Symptoms of Gall Bladder / Bile Issues:

>5 fold increase of serum creatine phosphokinase (CPK) activity

• >1.5 fold increase in aspartate aminotransferase (AST) (over 30)

• Elevated GGT (over 30)

• Increase in liver fat via ultrasound

• People who experience nausea after eating

• People with floating stools

• Everyone that has constipation

• Anyone that has SIBO

• Anyone with traditional GB signs/symptoms – upper quadrant pain etc.

• Women or men with low oestrogen

• Genetic polymorphisms (as listed above)

Other symptoms Include:

- Brain function, memory

- Constipation

- Nausea after eating

- Gall Bladder Pain

- SIBO

- Low Oestrogen

- Poor Methylation

- Low B12

- Low Folate

- Low Betaine

- Muscle Breakdown, Dystrophy.

- Weight gain, lack of exercise

Be sure to get at least of 550mg of Choline in your diet per day, if not you need to be taking an high quality organic Phosphatidylcholine supplement. . An insufficient amount of phosphatidylcholine in the diet, then their mitochondrial cell wall will extremely fragile. A liposomal form of the nutrient would be better and you can take a little more than recommended suggestion to help get relief, if taking the normal amount hasn't been enough.

If your low in oestrogen you can increase dose further. Don’t be afraid to give

them much more than the recommended dose. HOWEVER, if you specifically have a mast cell problem then you want to avoid adding more estrogens to your body, as this will increase mast cell degranulation issues.

There does seem to be a similar quality of choline in sunflower and soy., but remember there may be allergies to soy and ALWAYS consider if its GMO. If it is, you'll want to avoid it. In the United States, pretty much all soy is GMO unless specifically noted to be organic.

Ox Bile may be required to help support bile synthesis and help with fat

absorption and breakdown. It "can" make a big difference initially, but you MUST GO SLOW with it. Too much will be just as detrimental.

Athough taurine is helpful in healing gallbladder issues, don’t automatically assume that your taurine is low. Taurine is actually usually very high with those with CBS SNPs. So go slowly and ease into it.

Key genetic SNP’s to consider

We can’t see them all on the variant report but key SNP’s are:

PEMT SNPs:

• Rs12325817 – C allele not on 23andme

• Rs7946 – PEMTV175M ++ TT/AA = same (on variant report)

• Rs4646343 A allele – not on 23andme

• Rs3760188 A allele – not on 23andme

• Rs1531100 A allele – Post menopausal (not on 23)

• Rs4646365 A allele – post menopausal (not on 23)

CHKB rs1557502 – not on 23and me

MTHFD1 rs2236225 – on 23and me and variant report. Low

choline

MTHFR rs1801133 – MTHFR C677T on variant report and

23andme

BHMT rs3733890 – on 23andme and variant report

Love and Light,

Happy Healing