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Wednesday, June 30, 2021

Gastrointestinal tract

From Wikipedia, the free encyclopedia

Gastrointestinal tract
Stomach colon rectum diagram-en.svg
Diagram of stomach, intestines and rectum in the average human
Details
SystemDigestive system
Identifiers
LatinTractus digestorius (mouth to anus),
canalis alimentarius (esophagus to large intestine),
canalis gastrointestinales stomach to large intestine)
MeSHD041981

The gastrointestinal tract (GI tract, GIT, digestive tract, digestion tract, alimentary canal) is the tract from the mouth to the anus which includes all the organs of the digestive system in humans and other animals. Food taken in through the mouth is digested to extract nutrients and absorb energy, and the waste expelled as feces. The mouth, esophagus, stomach and intestines are all part of the gastrointestinal tract. Gastrointestinal is an adjective meaning of or pertaining to the stomach and intestines. A tract is a collection of related anatomic structures or a series of connected body organs.

All vertebrates and most invertebrates have a digestive tract. The sponges, cnidarians, and ctenophores are the early invertebrates with an incomplete digestive tract having just one opening instead of two, where food is taken in and waste expelled.

The human gastrointestinal tract consists of the esophagus, stomach, and intestines, and is divided into the upper and lower gastrointestinal tracts. The GI tract includes all structures between the mouth and the anus, forming a continuous passageway that includes the main organs of digestion, namely, the stomach, small intestine, and large intestine. However, the complete human digestive system is made up of the gastrointestinal tract plus the accessory organs of digestion (the tongue, salivary glands, pancreas, liver and gallbladder). The tract may also be divided into foregut, midgut, and hindgut, reflecting the embryological origin of each segment. The whole human GI tract is about nine metres (30 feet) long at autopsy. It is considerably shorter in the living body because the intestines, which are tubes of smooth muscle tissue, maintain constant muscle tone in a halfway-tense state but can relax in spots to allow for local distention and peristalsis.

The gastrointestinal tract contains trillions of microbes, with some 4,000 different strains of bacteria having diverse roles in maintenance of immune health and metabolism. Cells of the GI tract release hormones to help regulate the digestive process. These digestive hormones, including gastrin, secretin, cholecystokinin, and ghrelin, are mediated through either intracrine or autocrine mechanisms, indicating that the cells releasing these hormones are conserved structures throughout evolution.

Human gastrointestinal tract

Structure

Salivary glandsParotid glandSubmandibular glandSublingual glandpharynxTongueEsophagusPancreasStomachPancreatic ductIleumAnusRectumVermiform appendixCecumDescending colonAscending colonTransverse colonColon (anatomy)Bile ductDuodenumGallbladderLiveroral cavity
Upper and lower human gastrointestinal tract
 
Illustration of human gastrointestinal tract

The structure and function can be described both as gross anatomy and as microscopic anatomy or histology. The tract itself is divided into upper and lower tracts, and the intestines small and large parts.

Upper gastrointestinal tract

The upper gastrointestinal tract consists of the mouth, pharynx, esophagus, stomach, and duodenum. The exact demarcation between the upper and lower tracts is the suspensory muscle of the duodenum. This differentiates the embryonic borders between the foregut and midgut, and is also the division commonly used by clinicians to describe gastrointestinal bleeding as being of either "upper" or "lower" origin. Upon dissection, the duodenum may appear to be a unified organ, but it is divided into four segments based upon function, location, and internal anatomy. The four segments of the duodenum are as follows (starting at the stomach, and moving toward the jejunum): bulb, descending, horizontal, and ascending. The suspensory muscle attaches the superior border of the ascending duodenum to the diaphragm.

The suspensory muscle is an important anatomical landmark which shows the formal division between the duodenum and the jejunum, the first and second parts of the small intestine, respectively. This is a thin muscle which is derived from the embryonic mesoderm.

Lower gastrointestinal tract

The lower gastrointestinal tract includes most of the small intestine and all of the large intestine. In human anatomy, the intestine (bowel, or gut. Greek: éntera) is the segment of the gastrointestinal tract extending from the pyloric sphincter of the stomach to the anus and as in other mammals, consists of two segments, the small intestine and the large intestine. In humans, the small intestine is further subdivided into the duodenum, jejunum and ileum while the large intestine is subdivided into the cecum, ascending, transverse, descending and sigmoid colon, rectum, and anal canal.

Small intestine

The small intestine begins at the duodenum and is a tubular structure, usually between 6 and 7 m long. Its mucosal area in an adult human is about 30 m2 (320 sq ft). The combination of the circular folds, the villi, and the microvilli increases the absorptive area of the mucosa about 600-fold, making a total area of about 250 m2 (2,700 sq ft) for the entire small intestine. Its main function is to absorb the products of digestion (including carbohydrates, proteins, lipids, and vitamins) into the bloodstream. There are three major divisions:

  1. Duodenum: A short structure (about 20–25 cm long) which receives chyme from the stomach, together with pancreatic juice containing digestive enzymes and bile from the gall bladder. The digestive enzymes break down proteins, and bile emulsifies fats into micelles. The duodenum contains Brunner's glands which produce a mucus-rich alkaline secretion containing bicarbonate. These secretions, in combination with bicarbonate from the pancreas, neutralize the stomach acids contained in the chyme.
  2. Jejunum: This is the midsection of the small intestine, connecting the duodenum to the ileum. It is about 2.5 m (8.2 ft) long and contains the circular folds also known as plicae circulares and villi that increase its surface area. Products of digestion (sugars, amino acids, and fatty acids) are absorbed into the bloodstream here.
  3. Ileum: The final section of the small intestine. It is about 3 m long, and contains villi similar to the jejunum. It absorbs mainly vitamin B12 and bile acids, as well as any other remaining nutrients.
Large intestine

The large intestine also called the colon, consists of the cecum, rectum, and anal canal. It also includes the appendix, which is attached to the cecum. The colon is further divided into:

  1. Cecum (first portion of the colon) and appendix
  2. Ascending colon (ascending in the back wall of the abdomen)
  3. Right colic flexure (flexed portion of the ascending and transverse colon apparent to the liver)
  4. Transverse colon (passing below the diaphragm)
  5. Left colic flexure (flexed portion of the transverse and descending colon apparent to the spleen)
  6. Descending colon (descending down the left side of the abdomen)
  7. Sigmoid colon (a loop of the colon closest to the rectum)
  8. Rectum
  9. Anus

The main function of the large intestine is to absorb water. The area of the large intestinal mucosa of an adult human is about 2 m2 (22 sq ft).

Development

The gut is an endoderm-derived structure. At approximately the sixteenth day of human development, the embryo begins to fold ventrally (with the embryo's ventral surface becoming concave) in two directions: the sides of the embryo fold in on each other and the head and tail fold toward one another. The result is that a piece of the yolk sac, an endoderm-lined structure in contact with the ventral aspect of the embryo, begins to be pinched off to become the primitive gut. The yolk sac remains connected to the gut tube via the vitelline duct. Usually, this structure regresses during development; in cases where it does not, it is known as Meckel's diverticulum.

During fetal life, the primitive gut is gradually patterned into three segments: foregut, midgut, and hindgut. Although these terms are often used in reference to segments of the primitive gut, they are also used regularly to describe regions of the definitive gut as well.

Each segment of the gut is further specified and gives rise to specific gut and gut-related structures in later development. Components derived from the gut proper, including the stomach and colon, develop as swellings or dilatations in the cells of the primitive gut. In contrast, gut-related derivatives — that is, those structures that derive from the primitive gut but are not part of the gut proper, in general, develop as out-pouchings of the primitive gut. The blood vessels supplying these structures remain constant throughout development.

Part Part in adult Gives rise to Arterial supply
Foregut esophagus to first 2 sections of the duodenum Esophagus, stomach, duodenum (1st and 2nd parts), liver, gallbladder, pancreas, superior portion of pancreas
(Note that though the spleen is supplied by the celiac trunk, it is derived from dorsal mesentery and therefore not a foregut derivative)
celiac trunk
Midgut lower duodenum, to the first two-thirds of the transverse colon lower duodenum, jejunum, ileum, cecum, appendix, ascending colon, and first two-thirds of the transverse colon branches of the superior mesenteric artery
Hindgut last third of the transverse colon, to the upper part of the anal canal last third of the transverse colon, descending colon, rectum, and upper part of the anal canal branches of the inferior mesenteric artery

Histology

General structure of the gut wall
  • 1: Mucosa: Epithelium
  • 2: Mucosa: Lamina propria
  • 3: Mucosa: Muscularis mucosae
  • 4: Lumen
  • 5: Lymphatic tissue
  • 6: Duct of gland outside tract
  • 7: Gland in mucosa
  • 8: Submucosa
  • 9: Glands in submucosa
  • 10: Meissner's submucosal plexus
  • 11: Vein
  • 12: Muscularis: Circular muscle
  • 13: Muscularis: Longitudinal muscle
  • 14: Serosa: Areolar connective tissue
  • 15: Serosa: Epithelium
  • 16: Auerbach's myenteric plexus
  • 17: Nerve
  • 18: Artery
  • 19: Mesentery

The gastrointestinal tract has a form of general histology with some differences that reflect the specialization in functional anatomy. The GI tract can be divided into four concentric layers in the following order:

Mucosa

The mucosa is the innermost layer of the gastrointestinal tract. The mucosa surrounds the lumen, or open space within the tube. This layer comes in direct contact with digested food (chyme). The mucosa is made up of:

  • Epithelium – innermost layer. Responsible for most digestive, absorptive and secretory processes.
  • Lamina propria – a layer of connective tissue. Unusually cellular compared to most connective tissue
  • Muscularis mucosae – a thin layer of smooth muscle that aids the passing of material and enhances the interaction between the epithelial layer and the contents of the lumen by agitation and peristalsis

The mucosae are highly specialized in each organ of the gastrointestinal tract to deal with the different conditions. The most variation is seen in the epithelium.

Submucosa

The submucosa consists of a dense irregular layer of connective tissue with large blood vessels, lymphatics, and nerves branching into the mucosa and muscularis externa. It contains the submucosal plexus, an enteric nervous plexus, situated on the inner surface of the muscularis externa.

Muscular layer

The muscular layer consists of an inner circular layer and a longitudinal outer layer. The circular layer prevents food from traveling backward and the longitudinal layer shortens the tract. The layers are not truly longitudinal or circular, rather the layers of muscle are helical with different pitches. The inner circular is helical with a steep pitch and the outer longitudinal is helical with a much shallower pitch. Whilst the muscularis externa is similar throughout the entire gastrointestinal tract, an exception is the stomach which has an additional inner oblique muscular layer to aid with grinding and mixing of food. The muscularis externa of the stomach is composed of the inner oblique layer, middle circular layer, and outer longitudinal layer.

Between the circular and longitudinal muscle layers is the myenteric plexus. This controls peristalsis. Activity is initiated by the pacemaker cells, (myenteric interstitial cells of Cajal). The gut has intrinsic peristaltic activity (basal electrical rhythm) due to its self-contained enteric nervous system. The rate can be modulated by the rest of the autonomic nervous system.

The coordinated contractions of these layers is called peristalsis and propels the food through the tract. Food in the GI tract is called a bolus (ball of food) from the mouth down to the stomach. After the stomach, the food is partially digested and semi-liquid, and is referred to as chyme. In the large intestine the remaining semi-solid substance is referred to as faeces.

Adventitia and serosa

The outermost layer of the gastrointestinal tract consists of several layers of connective tissue.

Intraperitoneal parts of the GI tract are covered with serosa. These include most of the stomach, first part of the duodenum, all of the small intestine, caecum and appendix, transverse colon, sigmoid colon and rectum. In these sections of the gut, there is a clear boundary between the gut and the surrounding tissue. These parts of the tract have a mesentery.

Retroperitoneal parts are covered with adventitia. They blend into the surrounding tissue and are fixed in position. For example, the retroperitoneal section of the duodenum usually passes through the transpyloric plane. These include the esophagus, pylorus of the stomach, distal duodenum, ascending colon, descending colon and anal canal. In addition, the oral cavity has adventitia.

Gene and protein expression

Approximately 20,000 protein coding genes are expressed in human cells and 75% of these genes are expressed in at least one of the different parts of the digestive organ system. Over 600 of these genes are more specifically expressed in one or more parts of the GI tract and the corresponding proteins have functions related to digestion of food and uptake of nutrients. Examples of specific proteins with such functions are pepsinogen PGC and the lipase LIPF, expressed in chief cells, and gastric ATPase ATP4A and gastric intrinsic factor GIF, expressed in parietal cells of the stomach mucosa. Specific proteins expressed in the stomach and duodenum involved in defence include mucin proteins, such as mucin 6 and intelectin-1.

Time taken

The time taken for food to transit through the gastrointestinal tract varies on multiple factors, including age, ethnicity, and gender. Several techniques have been used to measure transit time, including radiography following a barium-labeled meal, breath hydrogen analysis, and scintigraphic analysis following a radiolabeled meal. It takes 2.5 to 3 hours for 50% of the contents to leave the stomach. The rate of digestion is also dependent of the material being digested, as food composition from the same meal may leave the stomach at different rates. Total emptying of the stomach takes around 4–5 hours, and transit through the colon takes 30 to 50 hours.

Immune function

The gastrointestinal tract forms an important part of the immune system.

Immune barrier

The surface area of the digestive tract is estimated to be about 32 square meters, or about half a badminton court. With such a large exposure (more than three times larger than the exposed surface of the skin), these immune components function to prevent pathogens from entering the blood and lymph circulatory systems. Fundamental components of this protection are provided by the intestinal mucosal barrier, which is composed of physical, biochemical, and immune elements elaborated by the intestinal mucosa. Microorganisms also are kept at bay by an extensive immune system comprising the gut-associated lymphoid tissue (GALT)

There are additional factors contributing to protection from pathogen invasion. For example, low pH (ranging from 1 to 4) of the stomach is fatal for many microorganisms that enter it. Similarly, mucus (containing IgA antibodies) neutralizes many pathogenic microorganisms. Other factors in the GI tract contribution to immune function include enzymes secreted in the saliva and bile.

Immune system homeostasis

Beneficial bacteria also can contribute to the homeostasis of the gastrointestinal immune system. For example, Clostridia, one of the most predominant bacterial groups in the GI tract, play an important role in influencing the dynamics of the gut's immune system. It has been demonstrated that the intake of a high fiber diet could be responsible for the induction of T-regulatory cells (Tregs). This is due to the production of short-chain fatty acids during the fermentation of plant-derived nutrients such as butyrate and propionate. Basically, the butyrate induces the differentiation of Treg cells by enhancing histone H3 acetylation in the promoter and conserved non-coding sequence regions of the FOXP3 locus, thus regulating the T cells, resulting in the reduction of the inflammatory response and allergies.

Intestinal microbiota

The large intestine hosts several kinds of bacteria that can deal with molecules that the human body cannot otherwise break down. This is an example of symbiosis. These bacteria also account for the production of gases at host-pathogen interface, inside our intestine (this gas is released as flatulence when eliminated through the anus). However the large intestine is mainly concerned with the absorption of water from digested material (which is regulated by the hypothalamus) and the re absorption of sodium, as well as any nutrients that may have escaped primary digestion in the ileum.

Health-enhancing intestinal bacteria of the gut flora serve to prevent the overgrowth of potentially harmful bacteria in the gut. These two types of bacteria compete for space and "food", as there are limited resources within the intestinal tract. A ratio of 80-85% beneficial to 15–20% potentially harmful bacteria generally is considered normal within the intestines.

Detoxification and drug metabolism

Enzymes such as CYP3A4, along with the antiporter activities, are also instrumental in the intestine's role of drug metabolism in the detoxification of antigens and xenobiotics.

Clinical significance

Diseases

There are many diseases and conditions that can affect the gastrointestinal system, including infections, inflammation and cancer.

Various pathogens, such as bacteria that cause foodborne illnesses, can induce gastroenteritis which results from inflammation of the stomach and small intestine. Antibiotics to treat such bacterial infections can decrease the microbiome diversity of the gastrointestinal tract, and further enable inflammatory mediators. Gastroenteritis is the most common disease of the GI tract.

Diverticular disease is a condition that is very common in older people in industrialized countries. It usually affects the large intestine but has been known to affect the small intestine as well. Diverticulosis occurs when pouches form on the intestinal wall. Once the pouches become inflamed it is known as diverticulitis.

Inflammatory bowel disease is an inflammatory condition affecting the bowel walls, and includes the subtypes Crohn's disease and ulcerative colitis. While Crohn's can affect the entire gastrointestinal tract, ulcerative colitis is limited to the large intestine. Crohn's disease is widely regarded as an autoimmune disease. Although ulcerative colitis is often treated as though it were an autoimmune disease, there is no consensus that it actually is such.

Functional gastrointestinal disorders the most common of which is irritable bowel syndrome. Functional constipation and chronic functional abdominal pain are other functional disorders of the intestine that have physiological causes but do not have identifiable structural, chemical, or infectious pathologies.

Symptoms

Several symptoms are used to indicate problems with the gastrointestinal tract:

Treatment

Gastrointestinal surgery can often be performed in the outpatient setting. In the United States in 2012, operations on the digestive system accounted for 3 of the 25 most common ambulatory surgery procedures and constituted 9.1 percent of all outpatient ambulatory surgeries.

Imaging

Various methods of imaging the gastrointestinal tract include the upper and lower gastrointestinal series:

Other related diseases

  • Cholera
  • Enteric duplication cyst
  • Giardiasis
  • Pancreatitis
  • Peptic ulcer disease
  • Yellow fever
  • Helicobacter pylori is a gram-negative spiral bacterium. Over half the world's population is infected with it, mainly during childhood; it is not certain how the disease is transmitted. It colonizes the gastrointestinal system, predominantly the stomach. The bacterium has specific survival conditions that our gastric microenvironment: it is both capnophilic and microaerophilic. Helicobacter also exhibits a tropism for gastric epithelial lining and the gastric mucosal layer about it. Gastric colonization of this bacterium triggers a robust immune response leading to moderate to severe inflammation, known as gastritis. Signs and symptoms of infection are gastritis, burning abdominal pain, weight loss, loss of appetite, bloating, burping, nausea, bloody vomit, and black tarry stools. Infection can be detected in a number of ways: GI X-rays, endoscopy, blood tests for anti-Helicobacter antibodies, a stool test, and a urease breath test (which is a by-product of the bacteria). If caught soon enough, it can be treated with three doses of different proton pump inhibitors as well as two antibiotics, taking about a week to cure. If not caught soon enough, surgery may be required.
  • Intestinal pseudo-obstruction is a syndrome caused by a malformation of the digestive system, characterized by a severe impairment in the ability of the intestines to push and assimilate. Symptoms include daily abdominal and stomach pain, nausea, severe distension, vomiting, heartburn, dysphagia, diarrhea, constipation, dehydration and malnutrition. There is no cure for intestinal pseudo-obstruction. Different types of surgery and treatment managing life-threatening complications such as ileus and volvulus, intestinal stasis which lead to bacterial overgrowth, and resection of affected or dead parts of the gut may be needed. Many patients require parenteral nutrition.
  • Ileus is a blockage of the intestines.
  • Coeliac disease is a common form of malabsorption, affecting up to 1% of people of northern European descent. An autoimmune response is triggered in intestinal cells by digestion of gluten proteins. Ingestion of proteins found in wheat, barley and rye, causes villous atrophy in the small intestine. Lifelong dietary avoidance of these foodstuffs in a gluten-free diet is the only treatment.
  • Enteroviruses are named by their transmission-route through the intestine (enteric meaning intestinal), but their symptoms aren't mainly associated with the intestine.
  • Endometriosis can affect the intestines, with similar symptoms to IBS.
  • Bowel twist (or similarly, bowel strangulation) is a comparatively rare event (usually developing sometime after major bowel surgery). It is, however, hard to diagnose correctly, and if left uncorrected can lead to bowel infarction and death. (The singer Maurice Gibb is understood to have died from this.)
  • Angiodysplasia of the colon
  • Constipation
  • Diarrhea
  • Hirschsprung's disease (aganglionosis)
  • Intussusception
  • Polyp (medicine) (see also colorectal polyp)
  • Pseudomembranous colitis
  • Toxic megacolon usually a complication of ulcerative colitis

Uses of animal guts

Intestines from animals other than humans are used in a number of ways. From each species of livestock that is a source of milk, a corresponding rennet is obtained from the intestines of milk-fed calves. Pig and calf intestines are eaten, and pig intestines are used as sausage casings. Calf intestines supply calf-intestinal alkaline phosphatase (CIP), and are used to make goldbeater's skin. Other uses are:

  • The use of animal gut strings by musicians can be traced back to the third dynasty of Egypt. In the recent past, strings were made out of lamb gut. With the advent of the modern era, musicians have tended to use strings made of silk, or synthetic materials such as nylon or steel. Some instrumentalists, however, still use gut strings in order to evoke the older tone quality. Although such strings were commonly referred to as "catgut" strings, cats were never used as a source for gut strings.
  • Sheep gut was the original source for natural gut string used in racquets, such as for tennis. Today, synthetic strings are much more common, but the best gut strings are now made out of cow gut.
  • Gut cord has also been used to produce strings for the snares that provide a snare drum's characteristic buzzing timbre. While the modern snare drum almost always uses metal wire rather than gut cord, the North African bendir frame drum still uses gut for this purpose.
  • "Natural" sausage hulls, or casings, are made of animal gut, especially hog, beef, and lamb.
  • The wrapping of kokoretsi, gardoubakia, and torcinello is made of lamb (or goat) gut.
  • Haggis is traditionally boiled in, and served in, a sheep stomach.
  • Chitterlings, a kind of food, consist of thoroughly washed pig's gut.
  • Animal gut was used to make the cord lines in longcase clocks and for fusee movements in bracket clocks, but may be replaced by metal wire.
  • The oldest known condoms, from 1640 AD, were made from animal intestine.

Other animals

Many birds and other animals have a specialised stomach in the digestive tract called a gizzard used for grinding up food.

Another feature not found in the human but found in a range of other animals is the crop. In birds this is found as a pouch alongside the esophagus.

Other animals including amphibians, birds, reptiles, and egg-laying mammals have a major difference in their GI tract in that it ends in a cloaca and not an anus.

In 2020, the oldest known fossil digestive tract, of an extinct wormlike organism in the Cloudinidae was discovered; it lived during the late Ediacaran period about 550 million years ago.

 

Bile acid

From Wikipedia, the free encyclopedia
 

Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.

Primary bile acids are those synthesized by the liver. Secondary bile acids result from bacterial actions in the colon. In humans, taurocholic acid and glycocholic acid (derivatives of cholic acid) and taurochenodeoxycholic acid and glycochenodeoxycholic acid (derivatives of chenodeoxycholic acid) are the major bile salts. They are roughly equal in concentration. The salts of their 7-alpha-dehydroxylated derivatives, deoxycholic acid and lithocholic acid, are also found, with derivatives of cholic, chenodeoxycholic and deoxycholic acids accounting for over 90% of human biliary bile acids.

Bile acids comprise about 80% of the organic compounds in bile (others are phospholipids and cholesterol). An increased secretion of bile acids produces an increase in bile flow. Bile acids facilitate digestion of dietary fats and oils. They serve as micelle-forming surfactants, which encapsulate nutrients, facilitating their absorption. These micelles are suspended in the chyme before further processing. Bile acids also have hormonal actions throughout the body, particularly through the farnesoid X receptor and GPBAR1 (also known as TGR5).

Structure of cholic acid showing relationship to other bile acids

Production

Bile acid synthesis occurs in liver cells, which synthesize primary bile acids (cholic acid and chenodeoxycholic acid in humans) via cytochrome P450-mediated oxidation of cholesterol in a multi-step process. Approximately 600 mg of bile salts are synthesized daily to replace bile acids lost in the feces, although, as described below, much larger amounts are secreted, reabsorbed in the gut and recycled. The rate-limiting step in synthesis is the addition of a hydroxyl group of the 7th position of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase. This enzyme is down-regulated by cholic acid, up-regulated by cholesterol and is inhibited by the actions of the ileal hormone FGF15/19.

Prior to secreting any of the bile acids (primary or secondary, see below), liver cells conjugate them with either glycine or taurine, to form a total of 8 possible conjugated bile acids. These conjugated bile acids are often referred to as bile salts. The pKa of the unconjugated bile acids are between 5 and 6.5, and the pH of the duodenum ranges between 3 and 5, so when unconjugated bile acids are in the duodenum, they are almost always protonated (HA form), which makes them relatively insoluble in water. Conjugating bile acids with amino acids lowers the pKa of the bile-acid/amino-acid conjugate to between 1 and 4. Thus conjugated bile acids are almost always in their deprotonated (A-) form in the duodenum, which makes them much more water-soluble and much more able to fulfil their physiologic function of emulsifying fats.

Once secreted into the lumen of the intestine, bile salts are modified by gut bacteria. They are partially dehydroxylated. Their glycine and taurine groups are removed to give the secondary bile acids, deoxycholic acid and lithocholic acid. Cholic acid is converted into deoxycholic acid and chenodeoxycholic acid into lithocholic acid. All four of these bile acids recycled, in a process known as enterohepatic circulation.

Functions

As amphipathic molecules with hydrophobic and hydrophilic regions, conjugated bile salts sit at the lipid/water interface and, above the right concentration, form micelles. The added solubility of conjugated bile salts aids in their function by preventing passive re-absorption in the small intestine. As a result, the concentration of bile acids/salts in the small intestine is high enough to form micelles and solubilize lipids. "Critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles. Bile acid-containing micelles aid lipases to digest lipids and bring them near the intestinal brush border membrane, which results in fat absorption.

Synthesis of bile acids is a major route of cholesterol metabolism in most species other than humans. The body produces about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis producing 400–600 mg daily. Human adults secrete between 12-18 g of bile acids into the intestine each day, mostly after meals. The bile acid pool size is between 4–6 g, which means that bile acids are recycled several times each day. About 95% of bile acids are reabsorbed by active transport in the ileum and recycled back to the liver for further secretion into the biliary system and gallbladder. This enterohepatic circulation of bile acids allows a low rate of synthesis, only about 0.3g/day, but with large amounts being secreted into the intestine.

Bile acids have other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate certain catabolites (including bilirubin), emulsifying fat-soluble vitamins to enable their absorption, and aiding in motility and the reduction of the bacteria flora found in the small intestine and biliary tract.

Bile acids have metabolic actions in the body resembling those of hormones, acting through two specific receptors, the farnesoid X receptor and G protein-coupled bile acid receptor/TGR5. They bind less specifically to some other receptors and have been reported to regulate the activity of certain enzymes  and ion channels  and the synthesis of diverse substances including endogenous fatty acid ethanolamides.

Structure and synthesis

Bile salts constitute a large family of molecules, composed of a steroid structure with four rings, a five- or eight-carbon side-chain terminating in a carboxylic acid, and several hydroxyl groups, the number and orientation of which is different among the specific bile salts. The four rings are labeled A, B, C, and D, from the farthest to the closest to the side chain with the carboxyl group. The D-ring is smaller by one carbon than the other three. The structure is commonly drawn with A at the left and D at the right. The hydroxyl groups can be in either of two configurations: either up (or out), termed beta (β; often drawn by convention as a solid line), or down, termed alpha (α; displayed as a dashed line). All bile acids have a 3-hydroxyl group, derived from the parent molecule, cholesterol, in which the 3-hydroxyl is beta.

IUPAC recommended ring lettering (left) and atom numbering (right) of the steroid skeleton. The four rings A-D form a sterane core.

The initial step in the classical pathway of hepatic synthesis of bile acids is the enzymatic addition of a 7α hydroxyl group by cholesterol 7α-hydroxylase (CYP7A1) forming 7α-hydroxycholesterol. This is then metabolised to 7α-hydroxy-4-cholesten-3-one. There are multiple steps in bile acid synthesis requiring 14 enzymes in all. These result in the junction between the first two steroid rings (A and B) being altered, making the molecule bent; in this process, the 3-hydroxyl is converted to the α orientation. The simplest 24-carbon bile acid has two hydroxyl groups at positions 3α and 7α. This is 3α,7α-dihydroxy-5β-cholan-24-oic acid, or, as more usually known, chenodeoxycholic acid. This bile acid was first isolated from the domestic goose, from which the "cheno" portion of the name was derived (Greek: χήν = goose). The 5β in the name denotes the orientation of the junction between rings A and B of the steroid nucleus (in this case, they are bent). The term "cholan" denotes a particular steroid structure of 24 carbons, and the "24-oic acid" indicates that the carboxylic acid is found at position 24, at the end of the side-chain. Chenodeoxycholic acid is made by many species, and is the prototypic functional bile acid.

An alternative (acidic) pathway of bile acid synthesis is initiated by mitochondrial sterol 27-hydroxylase (CYP27A1), expressed in liver, and also in macrophages and other tissues. CYP27A1 contributes significantly to total bile acid synthesis by catalyzing sterol side chain oxidation, after which cleavage of a three-carbon unit in the peroxisomes leads to formation of a C24 bile acid. Minor pathways initiated by 25-hydroxylase in the liver and 24-hydroxylase in the brain also may contribute to bile acid synthesis. 7α-hydroxylase (CYP7B1) generates oxysterols, which may be further converted in the liver to CDCA.

Cholic acid, 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid, the most abundant bile acid in humans and many other species, was discovered before chenodeoxycholic acid. It is a tri-hydroxy-bile acid with 3 hydroxyl groups (3α, 7α and 12α). In its synthesis in the liver, 12α hydroxylation is performed by the additional action of CYP8B1. As this had already been described, the discovery of chenodeoxcholic acid (with 2 hydroxyl groups) made this new bile acid a "deoxycholic acid" in that it had one fewer hydroxyl group than cholic acid.

Deoxycholic acid is formed from cholic acid by 7-dehydroxylation, resulting in 2 hydroxyl groups (3α and 12α). This process with chenodeoxycholic acid results in a bile acid with only a 3α hydroxyl group, termed lithocholic acid (litho = stone) having been identified first in a gallstone from a calf. It is poorly water-soluble and rather toxic to cells.

Different vertebrate families have evolved to use modifications of most positions on the steroid nucleus and side-chain of the bile acid structure. To avoid the problems associated with the production of lithocholic acid, most species add a third hydroxyl group to chenodeoxycholic acid. The subsequent removal of the 7α hydroxyl group by intestinal bacteria will then result in a less toxic but still-functional dihydroxy bile acid. Over the course of vertebrate evolution, a number of positions have been chosen for placement of the third hydroxyl group. Initially, the 16α position was favored, in particular in birds. Later, this position was superseded in a large number of species selecting the 12α position. Primates (including humans) utilize 12α for their third hydroxyl group position, producing cholic acid. In mice and other rodents, 6β hydroxylation forms muricholic acids (α or β depending on the 7 hydroxyl position). Pigs have 6α hydroxylation in hyocholic acid (3α,6α,7α-trihydroxy-5β-cholanoic acid), and other species have a hydroxyl group on position 23 of the side-chain.

Ursodeoxycholic acid was first isolated from bear bile, which has been used medicinally for centuries. Its structure resembles chenodeoxycholic acid but with the 7-hydroxyl group in the β position.

Obeticholic acid, 6α-ethyl-chenodeoxycholic acid, is a semi-synthetic bile acid with greater activity as FXR agonist which is undergoing investigation as a pharmaceutical agent.

Hormonal actions

Bile acids also act as steroid hormones, secreted from the liver, absorbed from the intestine and having various direct metabolic actions in the body through the nuclear receptor Farnesoid X receptor (FXR), also known by its gene name NR1H4. Another bile acid receptor is the cell membrane receptor known as G protein-coupled bile acid receptor 1 or TGR5. Many of their functions as signaling molecules in the liver and the intestines are by activating FXR, whereas TGR5 may be involved in metabolic, endocrine and neurological functions.

Regulation of synthesis

As surfactants or detergents, bile acids are potentially toxic to cells, and so their concentrations are tightly regulated. Activation of FXR in the liver inhibits synthesis of bile acids, and is one mechanism of feedback control when bile acid levels are too high. Secondly, FXR activation by bile acids during absorption in the intestine increases transcription and synthesis of FGF19, which then inhibits bile acid synthesis in the liver.

Metabolic functions

Emerging evidence associates FXR activation with alterations in triglyceride metabolism, glucose metabolism, and liver growth.

Other interactions

Bile acids bind to some other proteins in addition to their hormone receptors (FXR and TGR5) and their transporters. Among these protein targets, the enzyme N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) generates bioactive lipid amides (e.g. the endogenous cannabinoid anandamide) that play important roles in several physiological pathways including stress and pain responses, appetite, and lifespan. NAPE-PLD orchestrates a direct cross-talk between lipid amide signals and bile acid physiology.

Clinical significance

Hyperlipidemia

As bile acids are made from endogenous cholesterol, disruption of the enterohepatic circulation of bile acids will lower cholesterol. Bile acid sequestrants bind bile acids in the gut, preventing reabsorption. In so doing, more endogenous cholesterol is shunted into the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are then excreted in the feces.

Cholestasis

Tests for bile acids are useful in both human and veterinary medicine, as they aid in the diagnosis of a number of conditions, including types of cholestasis such as intrahepatic cholestasis of pregnancy, portosystemic shunt, and hepatic microvascular dysplasia in dogs. Structural or functional abnormalities of the biliary system result in an increase in bilirubin (jaundice) and in bile acids in the blood. Bile acids are related to the itching (pruritus) which is common in cholestatic conditions such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis or intrahepatic cholestasis of pregnancy. Treatment with ursodeoxycholic acid has been used for many years in these cholestatic disorders.

Gallstones

The relationship of bile acids to cholesterol saturation in bile and cholesterol precipitation to produce gallstones has been studied extensively. Gallstones may result from increased saturation of cholesterol or bilirubin, or from bile stasis. Lower concentrations of bile acids or phospholipids in bile reduce cholesterol solubility and lead to microcrystal formation. Oral therapy with chenodeoxycholic acid and/or ursodeoxycholic acid has been used to dissolve cholesterol gallstones. Stones may recur when treatment is stopped. Bile acid therapy may be of value to prevent stones in certain circumstances such as following bariatric surgery.

Bile acid diarrhea

Excess concentrations of bile acids in the colon are a cause of chronic diarrhea. It is commonly found when the ileum is abnormal or has been surgically removed, as in Crohn's disease, or cause a condition that resembles diarrhea-predominant irritable bowel syndrome (IBS-D). This condition of bile acid diarrhea/bile acid malabsorption can be diagnosed by the SeHCAT test and treated with bile acid sequestrants.

Bile acids and colon cancer

Bile acids may have some importance in the development of colorectal cancer. Deoxycholic acid (DCA) is increased in the colonic contents of humans in response to a high fat diet. In populations with a high incidence of colorectal cancer, fecal concentrations of bile acids are higher, and this association suggests that increased colonic exposure to bile acids could play a role in the development of cancer. In one particular comparison, the fecal DCA concentrations in Native Africans in South Africa (who eat a low fat diet) compared to African Americans (who eat a higher fat diet) was 7.30 vs. 37.51 nmol/g wet weight stool. Native Africans in South Africa have a low incidence rate of colon cancer of less than 1:100,000, compared to the high incidence rate for male African Americans of 72:100,000.

Experimental studies also suggest mechanisms for bile acids in colon cancer. Exposure of colonic cells to high DCA concentrations increase formation of reactive oxygen species, causing oxidative stress, and also increase DNA damage. Mice fed a diet with added DCA mimicking colonic DCA levels in humans on a high fat diet developed colonic neoplasia, including adenomas and adenocarcinomas (cancers), unlike mice fed a control diet producing one-tenth the level of colonic DCA who had no colonic neoplasia.

The effects of ursodeoxycholic acid (UDCA) in modifying the risk of colorectal cancer has been looked at in several studies, particularly in primary sclerosing cholangitis and inflammatory bowel disease, with varying results partly related to dosage. Genetic variation in the key bile acid synthesis enzyme, CYP7A1, influenced the effectiveness of UDCA in colorectal adenoma prevention in a large trial.

Dermatology

Bile acids may be used in subcutaneous injections to remove unwanted fat (see Mesotherapy). Deoxycholic acid as an injectable has received FDA approval to dissolve submental fat. Phase III trials showed significant responses although many subjects had mild adverse reactions of bruising, swelling, pain, numbness, erythema, and firmness around the treated area.

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