Liver, Bile Ducts and Bile Acids

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exponentialclinicaloutcomes

Liver, Bile Ducts and Bile AcidsDr. Jay Davidson, D.C., PSc.D.Dr. Todd Watts, D.C., PSc.D.

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The Roadmap to Health

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Amazing Healing Ability of the Liver

o Researchers report that when disease or injury causes a shortage in one type of liver cell, the organ can instruct another type of liver cell to change identities to provide replacement supplies.

o Previous research has detected adaptive reprogramming in other organs, but it typically involves only a few cells at a time. Our study shows that cells switch their identity at a massive rate in the liver.Nature. 2018 May;557(7704):247-251.https://www.nature.com/articles/s41586-018-0075-5https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597492/https://www.sciencedaily.com/releases/2018/05/180502132119.htm

https://www.nature.com/articles/s41586-018-0075-5

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597492/

https://www.sciencedaily.com/releases/2018/05/180502132119.htm

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Summary

o Cover anatomy and physiology

o 3 Phases of Liver, we are focusing on Phase 3 and Bile acid production

o Different types of bile acids

o Blood Bile Barrier

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Phase 1 & 2 Liver Detoxification

INTERMEDIARY METABOLISM

FAT-SOLUBLE

TOXINSWATER-SOLUBLE

WASTEPHASE 1 PHASE 2

(Cytochrome P450 Enzymes)

OxidationReductionHydrolysisHydration

Dehalogenation

(Conjugation Pathways)Sulfation

GlucoronidationGlutathione Conjugation

AcetylationAmino Acid Conjugation

Methylation

Eliminated via:UrineBileStool

Nutrients Needed:•Vitamins B2, B3, B6, B12•Folic Acid•Glutathione•Flavonoids

•Methionine•Cysteine•Magnesium•Glutathione•Vitamins B5, B12

•Vitamin C•Glycine•Taurine•Glutamine•Folic Acid•Choline

Nutrients Needed:

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Anatomy & Physiology

Image source: https://quizlet.com/485338047/liver-flash-cards/

o Liver produces bile salts and bile acids

o Gallbladder stores and concentrates bile from the liver between meals

o Pancreas produces sodium bicarbonate and digestive enzymes

o Stomach releases acidic chyme into small intestine

https://quizlet.com/485338047/liver-flash-cards/

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Pancreaso 95% consists of exocrine tissue that

produces pancreatic enzymes for digestion.

o 5% consists of endocrine cells called islets of Langerhans that produce hormones.o Insulin

o Glucagon

o Somatostatin

o Ghrelin

o Pancreatic polypeptidehttps://columbiasurgery.org/pancreas/pancreas-and-its-functionshttps://www.nature.com/subjects/islets-of-langerhans

https://columbiasurgery.org/pancreas/pancreas-and-its-functions

https://www.nature.com/subjects/islets-of-langerhans

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o The total bile flow in a day is approximately 600 ml, of which 75% is derived from the hepatocyte, and 25% is from the cholangiocytes.1

o Cholaniocytes are highly specialized cells that secrete and modify bile, facilitate bile transport through the biliary system, and create an important barrier between bile and surrounding tissue.2

1) https://www.ncbi.nlm.nih.gov/books/NBK470209/2) https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/cholangiocyteImage: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831353/

https://www.ncbi.nlm.nih.gov/books/NBK470209/

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/cholangiocyte


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Ancient Greece and Rome

o Ancient physicians believed the body was made up of 4 humors:o Yellow Bile

o Black Bile

o Blood

o Phlegm

Science Daily April 14, 2006https://www.sciencedaily.com/releases/2006/04/060414013606.htm


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Key Takeaway

o Bile is released to assist in digestion of fats and neutralize acidity

o If there is not enough bile released into the small intestine, the body decreases stomach acid

o Low stomach acid means low bile flow (cholestasis)

o Low stomach acid means:o Poor digestion

o Gateway for microorganisms

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Bile is Not Just a Detergent Molecule

o They are not mere detergent molecules that play a key role in fat digestion and the intestinal absorption of hydrophobic compounds present in the intestinal lumen after meals, including fat soluble vitamins.

o They are now known to be involved in the regulation of multiple functions in liver cells, mainly hepatocytes and cholangiocytes, and also in extrahepatic tissues.

Curr Drug Metab. 2015;17(1):4-29.https://pubmed.ncbi.nlm.nih.gov/26526836/

https://pubmed.ncbi.nlm.nih.gov/26526836/

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Bile is Not Just a Detergent Molecule

o The identification of nuclear receptors and plasma membrane receptors can trigger specific and complex responses upon activation by different bile acid molecular species and synthetic agonists, has opened a new and promising field of research whose implications extend to physiology, pathology and pharmacology.

o From 2005-2015, more than four thousand papers addressing (both directly and indirectly) bile acids and their involvement in physiology, pathology and pharmacology have been published.



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o 95% water

o 5% organic compounds

o Bile salts (conjugated acids) (51%)o Electrolytes

o Phospholipids such as lecithin (phosphatidylcholine) (25%)

o Bilirubin

o Fatty Acids

o Cholesterol in unmodified form

o Xenobiotics

o Glutathione

Bile

Compr Physiol. 2013 Jul; 3(3): 1035–1078. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091928/


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Bile Ductso Bile is also the major route of excretion of trace metals,

particularly arsenic, copper, manganese, lead, mercury, selenium, silver, and zinc.

o Bile also delivers vitamins to the intestine. Folic acid, pyridoxine, and transcobalamin also enter the intestine via the bile.

o Cholesterol, Steroid hormones, estrogens, prolactin, and insulin are other important substances excreted in bile.

o High cholesterol and melatonin hangover can indicate bile issues.

Compr Physiol. 2013 Jul; 3(3): 1035–1078.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091928/


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Bile is Recycledo The overall volume of bile salts in humans is

roughly 3g-4go Mainly maintained by recycling of bile salts via

enterohepatic circulation

o Cycles 6 to 8 times between the liver and the small intestine daily

o 95% of the bile salts in the intestine are absorbed and transported back to the liver, where hepatocytes take up the bile salts again

Journal of Virology. 2014 Mar; 88(6): 3273–3284https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957944/Curr Drug Metab. 2015;17(1):4-29.https://pubmed.ncbi.nlm.nih.gov/26526836/



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PPAR Res. 2009; 2009: 501739.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712638/

Cholesterol is an important precursor to our steroid hormones and bile acids.


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Cholesterol & Bile Acids

o 70-80% of cholesterol is used for bile acid production

PPAR Res. 2009; 2009: 501739.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712638/


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Bile Acids Important In Constipation

1) Dig. Dis. Sci., 1979, 24(7), 545-550. https://link.springer.com/article/10.1007/BF014893242) Hepatology, 1993, 18(5), 1182-92. https://pubmed.ncbi.nlm.nih.gov/8225225/3) Am. J. Physiol. Gastrointest. Liver Physiol., 1995, 268(6), G1051- G1059. https://journals.physiology.org/doi/abs/10.1152/ajpgi.1995.268.6.G10514) Mol. Cancer. Res., 2014, 12(1), 91-100. https://mcr.aacrjournals.org/content/12/1/91

o Bile acids promote the secretion of water and electrolytes by the human colon.1

o Bile acids as signaling molecules to affect liver cell proliferation, which may affect liver regeneration, and carcinogenesis. 2,3,4

https://link.springer.com/article/10.1007/BF01489324


https://journals.physiology.org/doi/abs/10.1152/ajpgi.1995.268.6.G1051

https://mcr.aacrjournals.org/content/12/1/91

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Different Types of Bile Acids

o Some bile acids are particularly aggressive, causing oxidative stress and apoptosis, such as deoxycholic acid (DCA), while other, e.g., UDCA & TUDCA, have hepatoprotective properties.



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Not All Bile Acids are the Same

o A major cause of liver damage in cholestatic diseases is the accumulation of hydrophobic bile acids, such as CDCA and DCA, in hepatocytes.

o In contrast, UDCA and the taurine-conjugated TUDCA, which are more hydrophilic, have been shown to efficiently modulate bile acid-induced injury in hepatocytes, and also in organs such as brain, kidney and placenta.

Hepatology, 2002, 36(3), 525-531. https://pubmed.ncbi.nlm.nih.gov/12198643/


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Making UDCA

J Biotechnol. 2014 Dec 10;191:11-21.https://pubmed.ncbi.nlm.nih.gov/25131646/


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Bacteria Make UDCA Conversion

J Biotechnol. 2014 Dec 10;191:11-21.https://pubmed.ncbi.nlm.nih.gov/25131646/


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Bile Acids Responsible For Flow

o Bile acids are the main driving force of bile that generates the bile flow toward the canalicular lumen.

o Once in the duodenum, bile acids are involved in the regulation of cholecystokinin release, which plays a role in gallbladder contraction and enzyme secretion by the pancreas.



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Tinea Pedis

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https://www.ncbi.nlm.nih.gov/pubmed/23933920


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Thyroid and Bile Flowo The Sphincter of Oddi

o Muscular valve that surrounds the exit of the bile duct and pancreatic duct into the small bowel

o Controls the release of bile into the small intestine

o Contains receptor sites for thyroid hormones

o Relaxes in response to the thyroxine, allowing bile release into the duodenum (the first part of the small intestine)

o When thyroxine is lacking (hypothyroid) the sphincter of Oddi may remain contractedo Without an open sphincter and free-flowing bile, the bile

can sit and stagnate

o Creates conditions where common bile duct stones can form from stagnated bile in the ducts

Laukkarinen, J et al. “Mechanism of the Prorelaxing Effect of Thyroxine on the Sphincter of Oddi.” Scand J Gastroenterol, vol. 37, no. 6, Jun 2002.

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Thyroid –Gall Bladder Connection


Low levels of thyroxine (or low thyroid function) correlate to poor gallbladder functioning and reduced bile flow, which can induce the formation of gallstones.World journal of gastroenterology, vol. 11, no. 35, 21 Sept 2005


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Compr Physiol. 2013 Jul; 3(3): 1035–1078. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091928/


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Drainage Funnel

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Drainage Funnel Overflow

o Accumulation of bile acids in the systemic circulation leads to pruritus (itchy skin), and may contribute to endothelial injury in the lungs and kidney.1

o It is thought that bile acids reach the lungs from the systemic circulation.2

o Under cholestatic conditions the formation of sulfate derivatives is increased, and renal elimination is the main route for bile acid detoxification. 3

1) Liver. 2002;22 Suppl 2:14-9.https://www.ncbi.nlm.nih.gov/pubmed/122202972) J Mol Med (Berl) . 2014 Apr;92(4):359-72. https://pubmed.ncbi.nlm.nih.gov/24317353/3) Curr Drug Metab. 2015;17(1):4-29.https://pubmed.ncbi.nlm.nih.gov/26526836/




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J Hepatol. 2017 Sep;67(3):619-631.https://pubmed.ncbi.nlm.nih.gov/28712691/

In cholestasis, when less bile constituents reach the duodenum, BAs accumulate in serum and liver.


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The Results of Bile Duct Dysfunction

o Intestinal inflammation

o Changed gene expression in the gut

o Leaky gut

o Altered gut microbiome

o Increased insulin resistance

o Damage and loss of microvilli

Br J Pharmacol. 2018 Feb;175(3):469-484https://www.ncbi.nlm.nih.gov/pubmed/29139555Transpl Int. 2008 Aug;21(8):792-800.https://www.ncbi.nlm.nih.gov/pubmed/18435680



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Increased Cancer Risk

o Bile duct obstruction is correlated with ductal cancer.

Science Daily May 1, 2007https://www.sciencedaily.com/releases/2007/04/070429113500.htm


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ATP & Bile Flow Connectedo The correlation between the bile flow rate and the

cellular ATP level was confirmed in a liver perfusion system.

o On anoxic perfusion, the ATP level and bile flow rate changed in the same manner as in ischemia.

o The concentrations of main bile components, such as phospholipids, cholesterol, and taurocholate increased, but their total outputs decreased with decrease in the ATP level, and returned to the normal range with recovery of the ATP level.

Transplantation. 1985 Jan;39(1):50-5.https://pubmed.ncbi.nlm.nih.gov/3966273/


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ATP & Bile Flow Connected

o Thus, it was shown experimentally that the extent of hepatic injury can be assessed simply by monitoring the bile flow rate, which reflects the cellular level of ATP.

Transplantation. 1985 Jan;39(1):50-5.https://pubmed.ncbi.nlm.nih.gov/3966273/


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750,000 Gallbladders Removed Annually

o There are several variations and etiologies of gallbladder disease.

o Chronic and acute cholecystitis are the two ways this condition can present.o Calculous and acalculous (with or without gallstones or

cholelithiasis) are also variants of this disease.

o The most common form of gallbladder disease is chronic cholecystitis with cholelithiasis.

Jones MW, Kashyap S, Ferguson T. Gallbladder Imaging. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.https://pubmed.ncbi.nlm.nih.gov/29262051/


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750,000 Gallbladders Removed Annually

o Up to 15% of the population of the United States has asymptomatic gallstones.

o 20-25 million Americans have gallstones.

o Annually, more the 750,000 individuals undergo cholecystectomy in the United States.



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Factors Linked to Gallbladder Disease

o Female gender

o Obesity

o Hormone exposure

o Diabetes

o Liver disease

o Age older than 40 years

o Drastic weight loss



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Intrahepatic Cholestasis of Pregnancy

o Intrahepatic cholestasis of pregnancy affects nearly 0.4-1.5% of pregnancies and is characterized by otherwise unexplained itching (pruritus) with elevated serum bile acids and/or liver enzymes in the late second and third trimester of pregnancy.

o The condition is associated with risks for the unborn child, in particular preterm delivery, and less frequently stillbirth.

J Hepatol . 2015 Aug;63(2):456-61.https://pubmed.ncbi.nlm.nih.gov/25772037/


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Hepatology. 2017 Feb;65(2):722-738. https://pubmed.ncbi.nlm.nih.gov/27981592/


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Downstream Firsto The first and early lesions are in ’downstream’ bile

ducts.

o This eventually leads to cholestasis and this causes bile salt-mediated toxic injury of the ‘upstream’ liver parenchyma.

o Bile salts are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts and gallbladder.

o Leakage of bile from this network and ducts could be an important driver of toxicity.



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New View on Cholestatic Liver Disease

o We propose a new view on the stratification of cholestatic liver diseases as we develop the argument that the pathophysiology in a number of these diseases follows an ‘ascending’ pattern.

o Usually the lesions start ‘downstream’ in the large or small bile ducts. As the disease follows its course in time the ‘upstream’ canalicular network and liver parenchyma become involved.o The terms ‘downstream’ and ‘upstream’ refer to the

direction of bile flow and ‘ascending’ refers to lesions spreading from the downstream (bile ducts) to the upstream area (canaliculi and parenchyma) in the liver.



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Cholestasis Induced from Drugs

o Drugs may cause several overlapping syndromes of cholestasis, the pathophysiological syndrome resulting from impaired bile flow.

o There are currently no pretreatment tests to predict drug safety.

Expert Opin Drug Saf. 2003 May;2(3):287-304.https://pubmed.ncbi.nlm.nih.gov/12904107/


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2019 Drug-Induced Liver Injury

o Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as it represents the leading cause of drug failure and attrition.

o Historically, there have been over 1000 drugs linked to DILI, including antibiotics, central nervous system agents, antineoplastics, immunomodulatory agents and herbal medicines.

Curr Drug Metab. 2019; 20(8): 621–632.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833946/


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2019 Drug-Induced Liver Injury

o There are five main classes of DILI, as reported by the drug-induced liver injury network, including necrosis, cholestasis, steatosis, vascular injury patterns, and cytoplasmic alterations.

o The most prevalent and severe forms of DILI involves the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC).

Curr Drug Metab. 2019; 20(8): 621–632.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833946/


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SIBOo The continuous flow of bile acids through the bile

duct constitutes a strong antimicrobial barrier, preventing both ascending bacterial invasion of the biliary tree and over-growth in the small bowel.1

o By contrast, reduced bile acid levels in the gut are associated with bacterial overgrowth and inflammation.2

1) FEMS Microbiol. Rev., 2005, 29(4), 625-651.


Gut Microbes, 2013, 4(5), 382-387.

2) https://pubmed.ncbi.nlm.nih.gov/23851335/



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Bile Acids Inhibit C. Diff

o Bile acids, which are altered by bacteria normally living in the large intestine, inhibit the growth of Clostridium difficile, new research indicates.

o The work sheds light on the ways in which some commonly used antibiotics can promote C. diff infections by killing off the bile acid-altering microbes.

mSphere. 2016 Jan-Feb; 1(1): e00045-15.

https://msphere.asm.org/content/1/1/e00045-15


https://msphere.asm.org/content/1/1/e00045-15


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Microbiome Makes Bileo Much of our knowledge about bile hasn’t changed in

many decades. It’s produced in the liver, stored in our gallbladder and injected into our intestine when we eat, where it breaks down fats in our gut.

o In fact, the first bile acid was discovered in 1848, and the scientists who revealed the structure of bile acids in 1928 won the Nobel Prize.

o “Since then, our understanding of the chemistry of bile production in the liver was that the cholesterol backbone of the bile acid structure is linked to the amino acids glycine or taurine to produce our primary bile acids.”

Nature volume 579, pages 123–129(2020)https://www.nature.com/articles/s41586-020-2047-9




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Microbiome Makes Bileo These new bile acids are not produced by our

enzymes; they’re made by microbes in our gut.

o Researchers showed that microbes in the gut, members of the microbiome, produce unique bile acids by conjugating the cholesterol backbone with myriad other amino acids.

o The represents a fifth mechanism of bile acid metabolism by the microbiome that greatly expands our understanding of mammalian bile.

o They’re particularly abundant in the guts of people suffering with gastrointestinal diseases, such as Crohn’s disease and cystic fibrosis.

Nature volume 579, pages 123–129 (2020)https://www.nature.com/articles/s41586-020-2047-9https://www.sciencedaily.com/releases/2020/02/200226131321.htm



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Recent Research

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Research From 2006o The small intestine communicates with the liver to

control the production of bile acids

o For this study, UT Southwestern researchers looked at a protein in mice called fibroblast growth factor 15 (FGF15), which is part of a cascade of chemical reactions that also dialed down production of CYP7A1 and reduced the production of bile acids in the liver.

o Surprisingly, they found that FGF15 was made in the small intestine, not in the liver, suggesting a new role for the small intestine in regulating bile acid levels.

Nature Medicine volume 12, pages 1253–1255 (2006)https://www.nature.com/articles/nm1501Cell Metab. 2006 Dec;4(6):423-4https://www.cell.com/cell-metabolism/fulltext/S1550-4131(06)00368-8https://www.sciencedaily.com/releases/2005/11/051108084101.htm

https://www.nature.com/articles/nm1501

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(06)00368-8


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Research From 2011o Cortisol is responsible for the recycling of bile acids

from the blood, according to new research.

o When we are hungry, our body releases a hormone called cortisol, which is a glucocorticoid. Hepatic cells receive this hormone signal through their cortisol receptors (glucocorticoid receptors) and respond by filling the gallbladder with bile in preparation of the imminent food intake. Directly upon eating a meal, bile is secreted into the intestine.

Molecular Control of Systemic Bile Acid Homeostasis by the Liver Glucocorticoid Receptor. Cell Metabolism, 2011; 14 (1): 123https://www.cell.com/cell-metabolism/fulltext/S1550-4131(11)00210-5https://www.sciencedaily.com/releases/2011/07/110707102001.htm



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Research From 2011

o Our body recovers 95 percent of bile acids from the bowel contents. They are reabsorbed by cells of the intestinal mucosa and transported back to the liver via the blood.

o “We have now found out that this recycling process is controlled by the cortisol hormone,”

Molecular Control of Systemic Bile Acid Homeostasis by the Liver Glucocorticoid Receptor. Cell Metabolism, 2011; 14 (1): 123https://www.cell.com/cell-metabolism/fulltext/S1550-4131(11)00210-5https://www.sciencedaily.com/releases/2011/07/110707102001.htm



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Research From 2020o Growing evidence suggests that the cross-talk

between the gut microbiome and metabolome (ie, gut-liver axis) are related to the development of hepatic inflammation, and ultimately, HCC.

o Bile acids are metabolites, derived from cholesterol and synthesized in the liver, which may have a critical role in regulation of the gut-liver axis.

Int J Cancer. 2020 May 13.https://pubmed.ncbi.nlm.nih.gov/32406072/


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Bile Acids Turn Fat-Storing Cells to Fat-Burning

o Scientists discovered that bile acids can turn fat-storing cells into fat-burning ones. This process is called thermogenesis (literally, ”heat production”) and it helps maintain body temperature in cold environments.

o There are three different types of fat cells: white fat cells, which store energy; brown fat cells, which expend energy; and the so-called ”beige” fat cells, which are functionally related to brown cells while being located in typically white-fat deposits.

Nat Commun. 2018 Jan 16;9(1):245.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770450/https://www.nature.com/articles/s41467-017-02068-0



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o What can turn a white cell into a beige one – a process called “beiging” – and shift the balance from fat-storing to fat-burning?




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o This research suggests that this process can be coordinated by secondary bile acids, metabolites that are generated by our liver and gut bacteria.

o This is more than a mere change of color, as the researchers also found that these bile acids increase the number of mitochondria in the new fat cells. This indicates higher energy consumption in the new, beige fat cells.




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o The bile-acid mimetics also triggered lipolysis, the first step in fat degradation, allowing the fat cells to use fatty acids as their main fuel source.

o "Moreover, this study highlights mitochondrial fission -- or the splitting of mitochondria -- as a pivotal mechanism by which bile acids turn white fat into beige fat,"




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Bile Acids in Immunity and Inflammation

o Two separate Harvard Medical School studies published in Nature.

o The findings of the two studies, both conducted in mice, show that bile acids promote the differentiation and activity of several types of T cells involved in regulating inflammation and linked to intestinal inflammatory conditions.

o They also reveal that gut microbes are critical for converting bile acids into immune-signaling molecules.

Science Daily January 3, 2020https://www.sciencedaily.com/releases/2020/01/200103141047.htm


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First Studyo The first study reveals bile acids exert their

immune-modulating effect by interacting with immune cells in the gut. Once bile acids leave the gallbladder and complete their fat-dissolving duties, they make their way down the digestive tract where they are modified into immune-regulatory molecules by gut bacteria.

o The modified bile acids then activate two classes of immune cells: regulatory T cells (Tregs) and effector helper T cells, specifically Th17, each responsible for modulating immune response by either curbing or promoting inflammation.

Nature. 2019 Dec;576(7785):143-148.https://www.nature.com/articles/s41586-019-1785-zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949019/

https://www.nature.com/articles/s41586-019-1785-z


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First Studyo Under normal conditions, the levels of

proinflammatory Th17 cells and anti-inflammatory Treg cells balance each other, maintaining a degree of protection against pathogens without causing too much tissue-damaging inflammation.

o "Our findings identify an important regulatory mechanism in gut immunity, showing that microbes in our intestines can modify bile acids and turn them into regulators of inflammation."

Nature. 2019 Dec;576(7785):143-148.https://www.nature.com/articles/s41586-019-1785-zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949019/

https://www.nature.com/articles/s41586-019-1785-z


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Second Studyo The second study focused on a subset of

inflammation-taming regulatory T cells, or Tregs, that arise in the colon as a result of exposure to gut microbes. In contrast, most other immune cells originate in the thymus.

o Low levels of colonic regulatory T cells (colonic Tregs) have been linked to the development of autoimmune conditions such as IBD and Crohn's disease.

o They also show that low levels of Treg cells induced by lack of bile acids or deficiency in bile acid sensors makes animals prone to developing inflammatory colitis -- a condition that mimics human IBD.

Nature. 2020 Jan;577(7790):410-415.https://www.nature.com/articles/s41586-019-1865-0https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274525/



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Second Studyo In a final step, the researchers gave three groups of mice

a compound that induces colitis. One group was fed a minimal diet, another group received nutrient-rich meals and a third group received minimal food and drank water supplemented with bile acid molecules.

o As expected, only mice fed minimal diets not supplemented by bile acid molecules developed colitis.

o The experiment confirmed that bile acids play a critical role in Treg regulation, intestinal inflammation and colitis risk.

o "Our results demonstrate an elegant three-way interaction between gut microbes, bile acids and the immune system." Nature. 2020 Jan;577(7790):410-415.

https://www.nature.com/articles/s41586-019-1865-0https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274525/



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Cholestasis = Bacterial Translocation

o Intestinal microbiome composition is an important factor for the maintenance of a general state of health.

o During cholestasis, a dysbiotic state in the gut and the mesenteric lymph nodes, is established; in this state bacteria of the Proteobacteria phylum predominate.

o This, combined with an imbalance in the immune response, can be an important trigger for bacterial translocation and the perpetuation of liver damage.

Iran J Basic Med Sci. 2020 Feb;23(2):178-185.https://pubmed.ncbi.nlm.nih.gov/32405360/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211354 /


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211354

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Gut Inflammation Affects Liver Cells

o This study strongly suggests that gut inflammation affects hepatic cells by altering BA receptor levels as well as increasing the production of pro-inflammatory cytokines and oxidative stress.

o Hence, reducing gut inflammation is needed not only to improve the intestinal disease but also to protect the liver.

J Pediatr Gastroenterol Nutr. 2020 May 11.

https://pubmed.ncbi.nlm.nih.gov/32404746 /

https://pubmed.ncbi.nlm.nih.gov/32404746

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Cirrhotic Liver

o The metabolic and functional cirrhotic liver is characterized by cytolysis and cholestasis activation, inhibition of detoxication, prooxidant-antioxidant, including nitrooxidative, disbalance.

Wiad Lek. 2020;73(5):947-952.



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Blood-Bile Barrier (BBlB)Gastroenterology Volume 155, Issue 4, October 2018, Pages 1218-1232.e24


https://www.sciencedirect.com/science/article/abs/pii/S0016508518346900


https://www.sciencedirect.com/science/article/abs/pii/S0016508518346900

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Blood-Bile Barrier (BBlB)o The term blood–bile barrier (BBlB) refers to the

physical structure within a hepatic lobule

o Compartmentalizes and hence segregates sinusoidal blood from canalicular bile.

o Provides physiological protection in the liver, shielding the hepatocytes from bile toxicity and restricting the mixing of blood and bile.

o BBlB is primarily composed of tight junctions.o Adherens junction, desmosomes, gap junctions, and

hepatocyte bile transporters also contribute to the barrier function of the BBlB.

Gene Expr. 2019; 19(2): 69–87.



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Blood-Bile Barrier (BBlB)o Recent findings also suggest that disruption of BBlB is

associated with major hepatic diseases characterized by cholestasis and aberrations in BBlB thus may be a hallmark of many chronic liver diseases.

o Common examples of epithelial barriers in addition to the blood–brain barrier include the blood–placenta barrier, the blood–retina barrier, the blood–mucosal barrier, the blood–air barrier, and the blood–testis barrier. Another important and relatively less well-understood barrier is the blood–bile barrier (BBlB).

o Loss of BBlB function has been shown to be the primary pathophysiology of cholestasis in children as well as adults.

Gene Expr. 2019; 19(2): 69–87.



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Nonalcoholic Fatty Liver Disease

o A few studies have linked BBlB with Nonalcoholic Fatty Liver Disease (NAFLD).

o Taken together, these studies suggest that tight junctions play an essential role in maintaining the barrier function of the liver and provide protection from chronic liver injury such as NAFLD.

Gene Expr. 2019; 19(2): 69–87.



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Cirrhosiso Liver cirrhosis is a chronic liver injury leading to

scarring of liver tissue. A plethora of causes can lead to cirrhosis including alcoholic liver disease, NAFLD, and hepatitis C. Accumulation of bacterial endotoxin present in the outer leaflet of a Gram-negative bacterial membrane is primarily associated with liver cirrhosis. Interestingly, increase in endotoxin levels led to hepatic TJ disruption and breach in the BBlB.

o Due to a leakage in the BBlB and leaky gut, bacterial translocation increases causing a rise in lipopolysaccharide level leading to steatohepatitis, increased injury, inflammation, and cirrhosis.

Gene Expr. 2019; 19(2): 69–87.



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Barrier Permeabilityo Primary bile acids—cholic acid (CA) and

chenodeoxycholic acid (CDCA)—are synthesized in the liver, whereas secondary bile acids—lithocholic acid (LCA), deoxyxholic acid (DCA), and ursodeoxyxholicacid (UDCA)—are produced due to bacterial action in the colon.

o A few studies have explored how bile acid components can affect the BBlB. Experiments have shown that selective bile acids, namely, CA, DCA, and CDCA, but not UDCA, can increase intestinal permeability.

Gene Expr. 2019; 19(2): 69–87.



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Aging

o Compromised BBlB function has been associated with aging.

Gene Expr. 2019; 19(2): 69–87.



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Disruption of Barrierso Pesticides are known individually to induce toxicity at

the cellular level throughout oxidant-mediated responses such as apoptotic or necrotic cells death, membrane lipids peroxidation, metabolic perturbation, deregulation of several signaling pathways or alteration of tight junctions.

o Oxidative stress is also known to disturb intestinal and renal epithelium or blood brain barrier integrity by altering tight junction molecules.

o Is it too far of stretch to say these affect the blood-bile barrier too?

Toxicol Rep. 2014; 1: 474–489.



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TUDCA

o See Additional Handout for Research

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Where Does TUDCA Come From

o Human bile contains 2% TUDCA

o Bear bile contains 50% TUDCA

o Bull bile contains 40% TUDCA

o CellCore Biosciences TUDCA is synthesized, not animal- or human-sourcedo Higher purity

o Consistent

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Kinesiology Testing

o Another TUDCA brando Phase 1: --

o Phase 2: --

o Phase 3: 50-60%

o Advanced TUDCAo Phase 1: 93%

o Phase 2: 92%

o Phase 3: 92%

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Advanced TUDCA

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Advanced TUDCA Dosing

o Standard: 1 capsule, 2x daily

o Aggressive: 2 capsules, 2x daily

o Sensitive: 1 capsule, 1x daily

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Side Effects?

o Potentially too effective for those really struggling

o Opens up deep pathways that haven’t been opened before

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750,000+ Gallbladders Removed Annually

o The gallstone (cholelithiasis) is a common digestive disease, affecting 10-20% of the global adult population.

o More than 90% of gallstones are gallbladder cholesterol stones.

o At present, the primary treatments for symptomatic gallbladder cholesterol stones are cholecystectomy, extracorporeal shockwave lithotripsy, and medical dissolution.

Gastroenterol Res Pract. 2020; Apr 21;2020:1343969.


Jones MW, Kashyap S, Ferguson T. Gallbladder Imaging. In: StatPearls.

Treasure Island (FL): StatPearls Publishing; 2020.




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Liver Gallbladder Flush

o Originally made famous by Dr. Hulda RegehrClark in her book, The Cure for All Diseases.

o 6:00 pm Epsom salt

o 8:00 pm Epsom salt

o 10:00 pm Olive oil & grapefruit mixture

o 6:00 am Epsom salt

o 8:00 am Epsom salt

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TUDCA Breakthrough

o 6 caps of TUDCA 30-60 minutes before a coffee enema

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4-4-4 Protocol

o 4 capsules of TUDCA Plus

o 4 capsules of Lymphatic Support

o 4 capsules of Kidney & Liver Support

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exponentialclinicaloutcomes

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Liver, Bile Ducts and Bile Acids