The  lips  come together to close the opening of the mouth, forming a line between the upper and lower lip. In  facial expression , this  mouth line  is iconically shaped like an up-open  parabola  in a  smile , and like a down-open parabola in a  frown . A  down-turned mouth  means a mouth line forming a down-turned parabola, and when permanent can be normal. Also, a  down-turned mouth  can be part of the presentation of  Prader–Willi syndrome . [ 4 ]


The teeth and the  periodontium  (the  tissues  that support the teeth) are innervated by the  maxillary  and  mandibular nerves  – divisions of the  trigeminal nerve . Maxillary (upper) teeth and their associated  periodontal ligament  are innervated by the superior alveolar nerves, branches of the maxillary division, termed the  posterior superior alveolar nerve ,  anterior superior alveolar nerve , and the variably present  middle superior alveolar nerve . These nerves form the  superior dental plexus  above the maxillary teeth. The mandibular (lower) teeth and their associated periodontal ligament are innervated by the  inferior alveolar nerve , a branch of the mandibular division. This nerve runs inside the mandible, within the  inferior alveolar canal  below the mandibular teeth, giving off branches to all the lower teeth ( inferior dental plexus ). [ 5 ] [ 6 ]  The  oral mucosa  of the gingiva (gums) on the  facial  (labial) aspect of the maxillary  incisors ,  canines  and  premolar  teeth is innervated by the superior labial branches of the  infraorbital nerve . The posterior superior alveolar nerve supplies the gingiva on the facial aspect of the maxillary  molar  teeth. The gingiva on the  palatal  aspect of the maxillary teeth is innervated by the  greater palatine nerve  apart from in the incisor region, where it is the  nasopalatine nerve  (long sphenopalatine nerve). The gingiva of the  lingual  aspect of the mandibular teeth is innervated by the sublingual nerve, a branch of the  lingual nerve . The gingiva on the facial aspect of the mandibular incisors and canines is innervated by the  mental nerve , the continuation of the inferior alveolar nerve emerging from the  mental foramen . The gingiva of the buccal (cheek) aspect of the mandibular molar teeth is innervated by the  buccal nerve  (long buccal nerve). [ 7 ]


The  philtrum  is the vertical depression formed between the  philtral ridges  between the upper lip and the nasal septum, formed where the  nasomedial  and  maxillary  processes meet during  embryo development . When these processes fail to fuse fully, a  cleft lip ,  cleft palate , or both can result.


The  nasolabial folds  are the deep creases of tissue that extend from the nose to the sides of the mouth. One of the first signs of age on the human face is the increase in prominence of the nasolabial folds.


The mouth plays an important role in  eating ,  drinking , and speaking.  Mouth breathing  refers to the act of breathing through the mouth (as a temporary backup system) if there is an obstruction to  breathing through the nose , which is the designated breathing organ for the human body. [ 8 ]


Infants  are born with a  sucking reflex , by which they  instinctively  know to suck for nourishment using their lips and  jaw .
The mouth also helps in  chewing  and  biting  food.


For some disabled people, especially many disabled artists, who through illness, accident or congenital disability have lost dexterity, their mouths take the place of their hands, when typing, texting, writing, making  drawings ,  paintings  and other works of art by maneuvering brushes and other tools, in addition to the basic oral functions.  Mouth painters  hold the brush in their mouth or between their teeth and maneuver it with their tongue and cheek muscles, but mouth painting can be strenuous for neck and jaw muscles since the head has to perform the same back and forth movement as a hand does when painting. [ 9 ] [ 10 ]


A  male  mouth can hold, on average, 71.2 ml (2.51 imp fl oz; 2.41 US fl oz), while a  female  mouth holds 55.4 ml (1.95 imp fl oz; 1.87 US fl oz). [ 11 ]


Gastric  hydrogen potassium ATPase , also known as  H + /K +  ATPase , is an  enzyme  which functions to acidify the stomach. [ 1 ]  It is a member of the  P-type ATPases , also known as E 1 -E 2  ATPases due to its two states. [ 2 ]


The gastric hydrogen potassium  ATPase  or H + /K +  ATPase is the  proton pump  of the  stomach . It exchanges potassium from the intestinal  lumen  with  cytoplasmic   hydronium [ 2 ]  and is the enzyme primarily responsible for the acidification of the stomach contents and the activation of the digestive enzyme  pepsin [ 3 ]  (see  gastric acid ).


The H + /K +  ATPase is found in  parietal cells , which are highly specialized  epithelial  cells located in the inner cell lining of the stomach called the gastric  mucosa . Parietal cells possess an extensive secretory membrane system and the H + /K +  ATPase is the major protein constituent of these membranes. A small amount of H + /K +  ATPase is also found in the  renal medulla . [ 2 ]


The H + /K +  ATPase is a heterodimeric  protein , the product of 2 genes. The gene  ATP4A [ 4 ]  encodes the H + /K +  ATPase α subunit, and is a ~1000-amino acid protein that contains the catalytic sites of the enzyme and forms the pore through the cell membrane that allows the transport of ions. Hydronium ions bind to two active sites present in the α subunit. [ 5 ]  The α subunit also has a phosphorylation site (Asp 385 ). [ 6 ]  The gene  ATP4B [ 7 ]  encodes the β subunit of the H + /K +  ATPase, which is a ~300-amino acid protein with a 36-amino acid N-terminal cytoplasmic domain, a single transmembrane domain, and a highly glycosylated extracellular domain.


The H + /K +  ATPase β subunit stabilizes the H + /K +  ATPase α subunit and is required for function of the enzyme. The β subunit prevents the pump from running in reverse, [ 8 ]  and it also appears to contain signals that direct the heterodimer to membrane destinations within the cell, although some of these signals are subordinate to signals found in H + /K +  ATPase α subunit.


The structure of H + /K +  ATPase has been determined for humans, dogs, hogs, rats, and rabbits and is 98% homologous across all species. [ 2 ]


H + /K +  ATPase is a P 2 -type ATPase, a member of the eukaryotic class of  P-type ATPases . [ 9 ]  Like the Ca 2+  and the Na + /K +  ATPases, the H + /K +  ATPase functions as an α, β protomer. [ 10 ]  Unlike other eukaryotic ATPases, the H + /K +  ATPase is electroneutral, transporting one proton into the stomach lumen per potassium ion retrieved from the gastric lumen. [ 9 ]  As an ion pump the H + /K +  ATPase is able to transport ions against a concentration gradient using energy derived from the hydrolysis of ATP. Like all P-type ATPases, a phosphate group is transferred from  adenosine triphosphate  (ATP) to the H + /K +  ATPase during the transport cycle. This phosphate transfer powers a conformational change in the enzyme that helps drive ion transport. [ citation needed ]


The hydrogen potassium ATPase is activated indirectly by  gastrin  that causes  ECL cells  to release  histamine . [ 11 ]  The histamine binds to H2 receptors on the parietal cell, activating a  cAMP-dependent pathway  which causes the enzyme to move from the cytoplasmic tubular membranes to deeply folded canaliculi of the stimulated parietal cell. [ 2 ]  Once localized, the enzyme alternates between two conformations, E1 and E2, to transport ions across the membrane.


The E1 conformation binds a phosphate from ATP and hydronium ion on the cytoplasmic side. The enzyme then changes to the E2 conformation, allowing hydronium to be released in the lumen. The E2 conformation binds potassium, and reverts to the E1 conformation to release phosphate and K +  into the cytoplasm where another ATP can be hydrolyzed to repeat the cycle. [ 2 ]  The β subunit prevents the E2-P conformation from reverting to the E1-P conformation, making proton pumping unidirectional. [ 8 ]  The number of ions transported per ATP varies from 2H + /2K +  to 1H + /1K + depending on the pH of the stomach. [ 12 ]


Inhibiting the hydrogen potassium pump to decrease stomach acidity has been the most common method of treating diseases including  gastroesophageal reflux disease  (GERD/GORD) and  peptic ulcer  disease (PUD). [ 13 ]  Reducing acidity alleviates disease symptoms but does not treat the actual cause of GERD (abnormal relaxation of the esophageal sphincter) or PUD ( Helicobacter pylori  and  NSAIDs ). [ 14 ]


Three drug classes have been used to inhibit H + /K + -ATPases.  H 2 -receptor antagonists , like  cimetidine  (Tagamet), inhibit the signaling pathway that leads to activation of the ATPase. This type of inhibitor is effective in treating ulcers but does not prevent them from forming, and patients develop tolerance to them after about one week, leading to a 50% reduction in efficacy. [ 15 ]   Proton pump inhibitors  (PPIs) were later developed, starting with Timoprazole in 1975. [ 15 ]  PPIs are acid-activated  prodrugs  that inhibit the hydrogen-potassium ATPase by binding covalently to active pumps. [ 16 ]  Current PPIs like  Omeprazole  have a short half-life of approximately 90 minutes. [ 17 ]  Acid pump antagonists (APAs) or potassium-competitive acid blockers (PCABs) are a third type of inhibitor that blocks acid secretion by binding to the K +  active site. [ 15 ]  APAs provide faster inhibition than PPIs since they do not require acid activation.  Revaprazan  was the first APA used clinically in east Asia, and other APAs are being developed since they appear to provide better acid control in clinical trials. [ 17 ]


Inactivation of the proton pump can also lead to health problems. A study in mice by Krieg et al. [ 18 ]  found that a mutation of the pump's α-subunit led to  achlorhydria , resulting in problems with iron absorption, leading to iron deficiency and  anemia . The use of PPIs has not been correlated with an elevated risk of anemia, so the H + /K + -ATPase is thought to aid iron absorption but is not necessarily required. [ 18 ]


Current association of dementia and PPIs have been documented in Germany and in research articles denoting how Benzimidazole derivatives,  Astemizole  (AST) and  Lansoprazole  (LNS) interact with anomalous aggregates of tau protein ( neurofibrillary tangles ). [ 19 ] [ 20 ] [ 21 ]  Current theories include the non-selective blockade of sodium-potassium pumps in the brain causing osmotic imbalances or swelling in the cells. [auth opinion]
Interaction of PPIs with other drug affecting the sodium-potassium pump, e.g., digoxin, warfarin etc., has been well documented. [ 22 ]
Memory has been associated with astrocytes and the alpha3 subunit of adenosine receptor found in hydrogen/Sodium-potassium pumps may be a focal point in dementia. [ 23 ] [ 24 ] [ 25 ]
Chronic use of PPIs may cause down regulation of alpha3 subunit increasing damage to astrocytes. [ 26 ]
Osteopetrosis via TCIRG1 gene has a strong association with pre-senile dementia. [ 27 ] [ 28 ]


The  ileocecal fold  (or  ileocaecal fold ) is an  anatomical  structure of the human abdomen formed by a layer of  peritoneum  between the  ileum  and   cecum . The upper border of the ileocecal fold is fixed to the ileum opposite its  mesenteric  attachment, and the lower border passes over the  ileocecal junction  to join the  mesentery of the appendix  (and sometimes the  appendix  itself as well). Behind the ileocecal fold is the inferior ileocecal fossa. [ 1 ]


The ileocecal fold is also called a  ligament ,  veil , or  bloodless fold of Treves  (after English surgeon  Sir Frederick Treves ). [ 1 ]  Despite the latter name, the ileocecal fold in fact often contains a vessel. [ 2 ]


This article incorporates text in the  public domain  from  page 1160  of the 20th edition of   Gray's Anatomy   (1918)


Ileus  is a disruption of the normal  propulsive  ability of the  intestine . It can be caused by lack of  peristalsis  or by  mechanical obstruction . [ 1 ]
The word 'ileus' derives from  Ancient Greek     εἰλεός  (eileós)  'intestinal obstruction'. The term 'subileus' refers to a partial obstruction. [ 2 ]


Symptoms of ileus include, but are not limited to: [ citation needed ]


Decreased propulsive ability may be broadly classified as caused either by bowel obstruction or by intestinal  atony  or paralysis. However, instances with symptoms and signs of a bowel obstruction occur, but with the absence of a mechanical obstruction, mainly in acute colonic  pseudo-obstruction ,  Ogilvie's syndrome . [ 3 ]  In 2023 the US  FDA  reported gastrointestinal ileus as an  adverse effect  of the medication  semaglutide , with frequency and causal relationship unknown. [ 4 ]


A bowel obstruction is generally a mechanical obstruction of the gastrointestinal tract and can occur anywhere from the Ligament of Treitz to the anus. When the obstruction affects only the small intestine, it is generally referred to as a small bowel obstruction to distinguish it from a colonic obstruction, which may or may not affect the small intestine. The distinction helps to narrow the possible causes and treatment.


Common causes of small bowel obstruction include post-operative adhesions, hernias, intussusception, and intraabdominal tumors. Common causes of colonic obstruction include primary colon cancer,  volvulus  and post-operative adhesions. When the ileocecal valve is competent, colonic obstruction may manifest as gaseous distention of the colon, but not the small intestine; when the ileocecal valve is incompetent, it does not prevent retrograde passage of air and stool and a colonic obstruction will cause dilation of both large and small bowel.


Bowel obstructions can be partial or complete. They can be differentiated on imaging by the intestinal gas pattern. Partial obstructions will have gas distal to the obstruction, whereas a complete obstruction will not. Sounds of "rushes and tinkles" are associated with partial obstructions [ 5 ]  and represent brief passages of fluid and gas (respectively) through the partial obstruction. Complete obstructions do not make these sounds.


Paralytic ileus is paralysis of the intestine, whether or not complete, sufficient to prohibit the passage of food through the intestine and lead to intestinal blockage.  It causes constipation and bloating. On listening to the abdomen with a stethoscope, no bowel sounds are heard because the bowel is inactive. [ citation needed ]   It is a common side effect of some types of surgery, termed postsurgical ileus. It can also result from certain drugs and from various injuries and illnesses, such as  acute pancreatitis .


A temporary paralysis of a portion of the intestines occurs typically after abdominal surgery. Since the intestinal content of this portion is unable to move forward, food or drink should be avoided until  peristaltic  sound is heard, by  auscultation  (use of a stethoscope) of the area where this portion lies. Intestinal atony or paralysis may be caused by inhibitory neural reflexes, inflammation or other implication of neurohumoral peptides. [ citation needed ]


Traditionally,  nothing by mouth  was considered to be mandatory in all cases, but gentle feeding by enteral  feeding tube  may help to restore motility by triggering the gut's normal feedback signals, so this is the recommended management initially. [ 7 ]  When the patient has severe, persistent signs that motility is completely disrupted,  nasogastric suction  and  parenteral nutrition  may be required until passage is restored. In such cases, continuing aggressive enteral feeding causes a risk of perforating the gut.


Several options are available in the case of paralytic ileus. Most treatment is supportive. If caused by medication, the offending agent is discontinued or reduced. Bowel movements may be stimulated by prescribing  lactulose ,  erythromycin  or, in severe cases that are thought to have a neurological component (such as  Ogilvie's syndrome ),  neostigmine . There is also evidence from a systematic review of  randomized controlled trials  that chewing gum, as a form of ' sham feeding ', may stimulate gastrointestinal motility in the post-operative period and reduce the duration of postoperative ileus. [ 8 ]


If possible the underlying cause is corrected (e.g. replace electrolytes).


Ileus is a cause of  colic  in horses due to functional obstruction of the intestines. It is most commonly seen in horses postoperatively, especially following colic surgery. [ 9 ]  Horses experiencing ileus are at risk for gastric rupture due to rapid reflux build-up, and require intense medical management with frequent nasogastric intubation. [ 9 ]  Ileus may increase  adhesion  formation, because intestinal segments have more prolonged contact and intestinal distention causes serosal injury and  ischemia . It is usually treated with aggressive fluid support,  prokinetics , and anti-inflammatories. [ 9 ]


ICD-10  coding reflects both impaired-peristalsis senses and mechanical-obstruction senses of the term as modified by various adjectives. [ 1 ]  Some authors have argued for trying to reserve the term for the impaired-peristalsis senses, [ 10 ] [ 11 ]  under which  prescription  certain older terms such as " gallstone  ileus" and " meconium  ileus", although now technically  misnomers , are still accepted as correct owing to their long-established usage. [ 12 ]


Ingestion   is the consumption of a substance by an  organism . In  animals , it normally is accomplished by taking in a substance through the  mouth  into the  gastrointestinal tract , such as through  eating  or  drinking . In  single-celled organisms , ingestion takes place by absorbing a substance through the  cell membrane .


Besides  nutritional  items, substances that may be ingested include  medication  (where ingestion is termed  oral administration ),  recreational drugs , and substances considered inedible, such as  foreign bodies  or  excrement . Ingestion is a common route taken by  pathogenic   organisms  and  poisons  entering the body.


Ingestion can also refer to a mechanism picking up something and making it enter an internal hollow of that mechanism, e.g. " a  grille  was fitted to prevent the pump from ingesting  driftwood ".


Some  pathogens  are  transmitted  via ingestion, including  viruses ,  bacteria , and  parasites . Most commonly, this takes place via the  faecal-oral route . An intermediate step is often involved, such as  drinking water  contaminated by  faeces  or  food  prepared by workers who fail to practice adequate  hand-washing , and is more common in regions where  untreated   sewage  is common.  Diseases  transmitted via the fecal-oral route include  hepatitis A ,  polio , and  cholera .


Some pathogenic organisms are typically ingested by other routes.


Disk batteries , also called button cells, are often mistakenly ingested, particularly by  children  and the  elderly . They may be mistaken for a  medication   pill  because of their size and shape, or they may be swallowed after being held in the mouth while the battery is being changed. Battery ingestion can cause medical problems including blocked  airway ,  vomiting ,  irritability , persistent  drooling , and  rash  (due to  nickel  metal  allergy ). [ 4 ]


Pica  is an abnormal appetite for non- nutritive  objects or for food items in a form not normally eaten, such as  flour .  Coprophagia  is the consumption of  feces , an  abnormal ingestive behavior  common in some animals.


Interstitial cells of Cajal  (ICC) are  interstitial cells  found in the  gastrointestinal tract . There are different types of ICC with different functions. ICC and another type of interstitial cell, known as  platelet-derived growth factor receptor alpha  (PDGFRα) cells, are electrically coupled to  smooth muscle cells  via  gap junctions , that work together as an  SIP functional syncytium . [ 2 ]   Myenteric  interstitial cells of Cajal (ICC-MY) serve as pacemaker cells that generate the bioelectrical events known as  slow waves . [ 3 ]  Slow waves conduct to smooth muscle cells and cause phasic contractions. [ 4 ] [ 5 ]


The picture to the right shows an isolated Interstitial cell of Cajal from the Myenteric plexus of the mouse small intestine grown in a primary cell culture. This cell type can be characterized morphologically as having a small cell body often triangular or stellate-shaped with several long processes branching out into secondary and tertiary extensions - these processes often contact smooth muscle cells. They have contractile behaviour in both the cell body and the extended processes.


These cells are derived from  mesoderm , [ 6 ]  unlike the  enteric neurons  that arise from neural crest cells.


Intramuscular Interstitial cells of Cajal (ICC-IM) are involved in mediating responses to neurotransmission. [ 7 ]   All ICC in the gastrointestinal tract express calcium-activated chloride channels encoded by the gene  ANO1 .  These channels are activated by release of calcium in ICC and are important for both the pacemaker activity of ICC and their responses to neurotransmitters.  A recent review noted that  carbachol  increases ICC activity through this channel. [ 8 ] [ 9 ]   ANO1-knockout mice fail to produce slow waves and ANO1 channel inhibitors block slow waves. [ 8 ]


ICC are also thought to be present in other types of smooth muscle tissues. But with few exceptions the function of these cells is not well understood and currently an area of active  research .


ICC serve as  electrical  pacemakers and generate spontaneous electrical  slow waves  in the gastrointestinal (GI) tract.  Electrical slow waves spread from ICC to  smooth muscle cells  and the resulting depolarization initiates  calcium ion  entry and contraction.  Slow waves organize gut contractions into phasic contractions that are the basis for  peristalsis  and  segmentation . [ medical citation needed ]


The frequency of ICC pacemaker activity differs in different regions of the GI tract: [ 10 ]


ICC also mediate neural input from  enteric   motor neurons . Animals lacking ICC have greatly reduced responses to the  neurotransmitter   acetylcholine , released from excitatory motor neurons, and to the  transmitter   nitric oxide , released from  inhibitory motor neurons . Loss of ICC in  disease , therefore, may interrupt normal neural control of gastrointestinal (GI) contractions and lead to  functional GI disorders , such as  irritable bowel syndrome . [ medical citation needed ]


ICC also express mechano-sensitive mechanisms that cause these cells to respond to stretch. Stretching GI muscles can affect the  resting potentials  of ICC and affect the frequency of pacemaker activity.   Carbachol  increases ICC activity through  ANO1  activation. [ 8 ] [ 9 ]


ICC are also critical in the propagation of electrical slow waves.  ICC form a network through which slow wave activity can propagate. If this network is broken, then 2 regions of muscle will function independently. [ medical citation needed ]


ICCs are thought to be the cells from which  gastrointestinal stromal tumours  (GISTs) arise. [ 11 ]  Also, abnormalities in the ICC network is one cause of  chronic intestinal pseudo-obstruction . [ 12 ]


The interstitial cells of Cajal are named after  Santiago Ramón y Cajal , [ 13 ]  a  Spanish   pathologist  and  Nobel laureate .


In  histology , an  intestinal gland  (also  crypt of  Lieberkühn  and  intestinal crypt ) is a  gland  found in between  villi  in the  intestinal epithelial  lining of the  small intestine  and  large intestine  (or colon). The glands and intestinal villi are covered by  epithelium , which contains multiple types of  cells :  enterocytes  (absorbing water and electrolytes),  goblet cells  (secreting mucus),  enteroendocrine cells  (secreting hormones), cup cells,  myofibroblast ,  tuft cells , and at the base of the gland,  Paneth cells  (secreting anti-microbial peptides) and  stem cells .


Intestinal glands are found in the  epithelia  of the  small intestine , namely the  duodenum ,  jejunum , and  ileum , and in the  large intestine  (colon), where they are sometimes called  colonic crypts . Intestinal glands of the small intestine contain a base of replicating  stem cells ,  Paneth cells  of the  innate immune system , and  goblet cells , which produce mucus. [ 1 ]  In the colon, crypts do not have Paneth cells. [ 2 ]


The  enterocytes  in the small intestinal  mucosa  contain  digestive enzymes  that digest specific foods while they are being absorbed through the epithelium. These enzymes include  peptidase ,  sucrase ,  maltase ,  lactase  and intestinal  lipase . This is in contrast to the  gastric glands  of the  stomach  where  chief cells  secrete  pepsinogen .


Also, new epithelium is formed here, which is important because the cells at this site are continuously worn away by the passing food. The basal (further from the  intestinal lumen ) portion of the crypt contains multipotent  stem cells . During each  mitosis , one of the two daughter cells remains in the crypt as a stem cell, while the other differentiates and migrates up the side of the crypt and eventually into the  villus . These stem cells can differentiate into either an absorptive ( enterocytes ) or secretory ( Goblet cells ,  Paneth cells ,  enteroendocrine cells ) lineages. [ 3 ]  Both  Wnt  and  Notch  signaling pathways play a large role in regulating cell proliferation and in intestinal  morphogenesis  and  homeostasis . [ 4 ]


Loss of proliferation control in the crypts is thought to lead to  colorectal cancer .


Intestinal juice ( also called  succus entericus [ 5 ] ) refers to the clear to pale yellow watery secretions from the glands lining the  small intestine  walls. The  Brunner's glands  secrete large amounts of alkaline mucus in response to (1) tactile or irritating stimuli on the duodenal mucosa; (2) vagal stimulation, which increases Brunner's glands secretion concurrently with increase in stomach secretion; and (3) gastrointestinal hormones, especially  secretin . [ 6 ]


Its function is to complete the process begun by  pancreatic juice ; the  enzyme   trypsin  exists in pancreatic juice in the inactive form  trypsinogen , it is activated by the intestinal  enterokinase  in intestinal juice. Trypsin can then activate other protease enzymes and catalyze the reaction pro-colipase → colipase.   Colipase  is necessary, along with  bile salts , to enable  lipase  function.  [ citation needed ]


Intestinal juice also contains  hormones ,  digestive enzymes ,  mucus , substances to neutralize  hydrochloric acid  coming from the  stomach . Various  exopeptidase  which further digests  polypeptides  into  amino acids  complete the digestion of  proteins . [ citation needed ]


The intestinal glands in the colon are often referred to as colonic crypts. The  epithelial  inner surface of the colon is punctuated by invaginations, the colonic crypts. The colon crypts are shaped like microscopic thick-walled test tubes with a central hole down the length of the tube (the crypt  lumen ). Four tissue sections are shown here, two (A and B) cut across the long axes of the crypts and two (C and D) cut parallel to the long axes.


In these images the cells have been  stained  to show a brown-orange color if the cells produce a  mitochondrial  protein called  cytochrome c oxidase subunit I  (CCOI or COX-1).  The  nuclei  of the cells (located at the outer edges of the cells lining the walls of the crypts) are stained blue-gray with  haematoxylin . As seen in panels C and D, crypts are about 75 to about 110 cells long. The average crypt circumference is 23 cells. [ 8 ]  From the images, an average is shown to be about 1,725 to 2530 cells per colonic crypt. Another measure was attained giving a range of 1500 to 4900 cells per colonic crypt. [ 9 ]  Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic  lumen  days later. [ 8 ]   There are 5 to 6 stem cells at the bases of the crypts. [ 8 ]


As estimated from the image in panel A, there are about 100 colonic crypts per square millimeter of the colonic epithelium. [ 10 ]   The length of the human colon is, on average 160.5 cm (measured from the bottom of the cecum to the colorectal junction) with a range of 80 cm to 313 cm. [ 11 ]  The average inner circumference of the colon is 6.2 cm. [ 10 ]  Thus, the inner surface epithelial area of the human colon has an area, on average, of about 995 cm 2 , which includes 9,950,000 (close to 10 million) crypts.


In the four tissue sections shown here, many of the intestinal glands have cells with a  mitochondrial DNA  mutation in the CCOI gene and appear mostly white, with their main color being the blue-gray staining of the nuclei.  As seen in panel B, a portion of the stem cells of three crypts appear to have a mutation in CCOI, so that 40% to 50% of the cells arising from those stem cells form a white segment in the cross cut area.


Overall, the percentage of crypts deficient for CCOI is less than 1% before age 40, but then increases linearly with age. [ 7 ]  Colonic crypts deficient for CCOI reaches, on average, 18% in women and 23% in men, by 80–84 years of age. [ 7 ]


Crypts of the colon can reproduce by fission, as seen in panel C, where a crypt is dividing to form two crypts, and in panel B where at least one crypt appears to be fissioning.  Most crypts deficient in CCOI are in clusters of crypts (clones of crypts) with two or more CCOI-deficient crypts adjacent to each other (see panel D). [ 7 ]


Crypt  inflammation  is known as  cryptitis  and characterized by the presence of  neutrophils  between the  enterocytes .  A severe cryptitis may lead to a crypt  abscess .


Pathologic processes that lead to Crohn's disease, i.e. progressive intestinal crypt destruction, are associated with branching of the crypts.


Causes of crypt branching include:


Intestinal glands contain adult stem cells referred to as  intestinal stem cells . [ 12 ]  These cells have been used in the field of stem biology to further understand  stem cell niches , [ 13 ]  and to generate intestinal  organoids . [ 12 ]


The crypts of Lieberkühn are named after the eighteenth-century German anatomist  Johann Nathanael Lieberkühn .


The  intestinal mucosal barrier , also referred to as  intestinal barrier , refers to the property of the  intestinal mucosa  that ensures adequate containment of undesirable  luminal  contents within the intestine while preserving the ability to absorb  nutrients . The separation it provides between the body and the gut prevents the uncontrolled translocation of luminal contents into the body proper. Its role in protecting the mucosal tissues and  circulatory system  from exposure to  pro-inflammatory molecules , such as  microorganisms ,  toxins , and  antigens  is vital for the maintenance of health and well-being. [ 1 ] [ 2 ] [ 3 ]  Intestinal mucosal barrier dysfunction has been implicated in numerous health conditions such as:  food allergies ,  microbial infections ,  irritable bowel syndrome ,  inflammatory bowel disease ,  celiac disease ,  metabolic syndrome ,  non-alcoholic fatty liver disease ,  diabetes , and  septic shock . [ 3 ] [ 4 ] [ 5 ]


The intestinal mucosal barrier is a  heterogeneous  entity composed of physical, biochemical, and immune elements elaborated by the intestinal mucosa. The central component is the  intestinal epithelial layer , which provides physical separation between the lumen and the body. The secretion of various molecules into the lumen reinforces the barrier function on the extra-epithelial side, while a variety of immune cells provide additional protection below the epithelial layer. [ 3 ] [ 5 ] [ 6 ]


Mucus  forms a layer (or layers, in the case of the  colon ) that separates the bulk of the luminal contents from the intestinal epithelium. The mucus consists of a highly  glycosylated   hydrated gel  formed by  mucin molecules  that are secreted by  goblet cells . The mucus prevents large particles from contacting the epithelial cell layer while allowing small molecules to pass. The mucus also facilitates passage of the luminal contents along the length of the intestines, protects the epithelial cells from  digestive enzymes , and prevents the direct contact of microorganisms with the epithelial layer. [ 1 ] [ 5 ] [ 6 ] [ 7 ]


The  intestinal epithelium  is the foremost component of the intestinal mucosal barrier. It consists of the layer of epithelial cells lining the intestine. Crucial for forming an effective barrier is the precise control of the  paracellular pathway  (a route for translocation of molecules between cells). Sealing of the space between adjacent cells is mediated by  junctional complexes  formed by protein connections elaborated by each individual cell. [ 1 ]  In addition to its protective function, the intestinal epithelium controls the selective uptake of beneficial ions, nutrients, and other substances from the lumen into the body. [ 3 ]


The  commensal microbial species  that inhabit the gut are considered by some to be part of the intestinal mucosal barrier. The  gut microbiota  can influence barrier function both directly, by stimulating epithelial cell proliferation and secretion of  IL-8 , and indirectly by producing  short-chain fatty acids , which are an important energy source for colonic epithelial cells (colonocytes). [ 3 ]


The  bile  produced by the  liver  to aid in the digestion of  lipids  has  bactericidal  properties. [ 7 ]  The  gastric acid  produced by the stomach can also kill microorganisms. [ 8 ]  Both contribute to intestinal barrier function although they are not produced by the intestinal mucosa.


Specialised secretory epithelial cells called  Paneth cells  secrete abundant quantities  human α-defensins  into the intestinal lumen of healthy individuals. [ 9 ]


Lysozyme  is another defensive molecule secreted by Paneth cells into the lumen. [ 10 ]


Reg3γ  is an antibacterial  lectin  secreted by Paneth cells that serves to prevent microorganisms from coming into contact with the epithelial layer. [ 3 ] [ 10 ]


Antimicrobial peptides (AMPs) , which are a diverse array of molecules that kill bacteria and fungi, are secreted by Paneth cells into the lumen. [ 6 ] [ 7 ]


Secretory immunoglobulin A (sIgA)  is produced by  plasma cells  in the lamina propria and transported into the lumen by intestinal epithelial cells. [ 7 ]  SIgA blocks epithelial-specific  receptors  on pathogens, thereby preventing their attachment to epithelial cells.


A variety of immune cells reside in the  lamina propria  which underlies the intestinal epithelium. These include  dendritic cells (DCs) ,  macrophages ,  intraepithelial lymphocytes  (IEL),  T regulatory cells (T Regs) ,  TCD4+ lymphocytes ,  B lymphocytes , and  plasma cells . [ 6 ]  This population provides immune protection that is characterised by the rapid detection and killing of microorganisms that penetrate the intestinal epithelium. [ 7 ]


Intestinal barrier integrity is malleable and multiple mechanisms have been shown to be capable of modulating intestinal permeability (a measure of intestinal barrier function). [ 4 ]  Modulating factors include  cytokines ,  immune cells , and exogenous factors. [ 4 ]


Intestinal permeability  is a measurement of intestinal mucosal barrier function and is defined as "the facility with which intestinal epithelium allows molecules to pass through by non-mediated  passive diffusion ." [ 11 ]  Permeability in this respect is mostly related to the measurable passage of ions and small inert molecules. Standard methods for measurement include tissue electrical resistance for in vitro testing and passage of ingested inert molecules of specific molecular weights into the urine for in vivo testing. [ 12 ] [ 13 ]  For example, in vivo testing using  lactulose  /  mannitol  consists of ingesting 5 g lactulose and 2 g mannitol followed by determination of urinary concentrations of lactulose and mannitol 5 hours after ingestion. The percentage lactulose excretion and the lactulose mannitol ratio in the urine are calculated and used as a measure of intestinal permeability. [ 14 ]


A disrupted intestinal mucosal barrier can allow passage of microbes, microbial products, and  foreign antigens  into the mucosa and the body proper. This can result in activation of the  immune system  and secretion of  inflammatory mediators . Certain immune responses might, in turn, cause cellular damage that could result in further barrier dysfunction. [ 7 ]  Defects in intestinal mucosal barrier function with the accompanying translocation of microbes and their products have been linked with a variety of conditions, [ 3 ]  some of which are thought to additionally require a  genetic predisposition . [ 15 ]  Both intestinal and extra-intestinal autoimmune disorders can result. [ 15 ]  Intestinal barrier dysfunction is thought to be precondition for and  exacerbating factor  of numerous autoimmune and inflammatory conditions, including  food allergies ,  inflammatory bowel diseases ,  celiac disease  and  diabetes . [ 4 ]


Intestinal barrier dysfunction may be a critical factor for antigen sensitisations and the  IgE / mast cell -mediated  anaphylactic  effector phase of food allergies. The development of food allergies depend on the antigen coming into contact with components of the mucosal immune system. This leads to antigen sensitisation and dietary antigen-specific CD4+  Th2 cell  and IgE production. The hypothesis is that intestinal barrier dysfunction allows dietary antigens to cross the intestinal barrier, come into contact with the mucosal immune system, and trigger an antigen-specific immune response. [ 4 ]


Reduced intestinal barrier function correlates with the severity of symptoms experienced by food allergy sufferers. Oral challenge with the implicated allergen results in an increased lactulose/mannitol ratio in the urine (a measure of intestinal permeability). [ 4 ]


An emerging model of inflammatory bowel disease (IBD)  pathogenesis  postulates three prerequisite factors: 1) degradation of intestinal barrier function, 2) translocation of luminal contents into the lamina propria and subsequent exposure to immune cells, and 3) an inappropriate immune response. Although intestinal barrier dysfunction is clearly implicated in the development of inflammatory bowel disease, it is unclear what initiates the self-perpetuating cycle that leads to disease exacerbation. Nevertheless, there is a growing body of evidence that implicates increased intestinal permeability as a primary  etiologic factor  of inflammatory bowel disease pathogenesis. [ 4 ]


Altered intestinal barrier function may play a role in the development of celiac disease. By allowing  gliadin , the causative agent of celiac disease, to cross the intestinal barrier, inappropriate activation of the immune system can occur. Celiac disease sufferers have been shown to have elevated intestinal permeability and altered tight junctions. Moreover, these disruptions persist in patients who successfully maintain a  gluten-free diet . Data also exist demonstrating that increased intestinal permeability is present prior to onset of celiac disease. [ 4 ]


A combination of genetics, dysregulated intestinal barrier function, and inappropriate immune responses has been hypothesised to play a role in  type 1 diabetes . Elevated intestinal permeability has been reported observed in patients at disease onset. The resulting increase in exposure to antigens can trigger  autoimmune  destruction of  beta cells  in the  pancreas . [ 4 ]


Defects in intestinal mucosal barrier function have also been implicated in  irritable bowel syndrome ,  metabolic syndrome ,  non-alcoholic fatty liver disease , and  septic shock . [ 3 ] [ 13 ]


Psychological  and  physical stress  can induce a variety of alterations in intestinal function. These include changes in  gut motility ,  intestinal permeability , ion flux,  fluid balance  and mucus secretion. Furthermore, acute and chronic stress in  animal models  has shown that stress can cause degradation of intestinal barrier function. [ 4 ]  Psychological stress can influence the clinical outcome of  inflammatory bowel disease  and  irritable bowel syndrome . Long-term stress has been shown to be positively associated with an increased propensity for relapse of  ulcerative colitis . [ 4 ]


Cummings adopted the term mucosal barrier in 2004 to describe the "complex structure that separates the internal milieu from the luminal environment." [ 16 ]  More recently, intestinal barrier has been used by gastroenterologists, immunologists and microbiologists to emphasise the component of the intestine that protects the body from microorganisms and their toxins. [ 6 ]


Intestinal permeability  is a term describing the control of material passing from inside the  gastrointestinal tract  through the  cells  lining the  gut wall , into the rest of the body. The intestine normally exhibits some permeability, which allows nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances (such as  antigens ) from leaving the intestine and migrating to the body more widely. [ 1 ]  In a healthy human intestine, small particles (< 4  Å  in radius) can migrate through  tight junction   claudin  pore pathways, [ 2 ]  and particles up to 10–15 Å (3.5  kDa ) can transit through the paracellular space uptake route. [ 3 ]  There is some evidence abnormally increased intestinal permeability may play a role in some chronic diseases and inflammatory conditions. [ 4 ]  The most well understood condition with observed increased intestinal permeability is  celiac disease . [ 5 ]


The barrier formed by the  intestinal epithelium  separates the external environment (the contents of the intestinal  lumen ) from the body [ 6 ]  and is the most extensive and important  mucosal surface  of the body. [ 7 ]  However, the intestinal mucin can also be barriers for the host antimicrobial peptides, thus plays a bidirectional barrier for host-microbial interaction. [ 8 ]  The intestinal epithelium is composed of a single layer of cells and serves two crucial functions. First, it acts as a barrier, preventing the entry of harmful substances such as foreign  antigens ,  toxins  and  microorganisms . [ 6 ] [ 9 ]  Second, it acts as a selective filter which facilitates the uptake of dietary  nutrients ,  electrolytes , water and various other beneficial substances from the intestinal lumen. [ 6 ]  Selective permeability is mediated via two major routes: [ 6 ]


One way in which intestinal permeability is modulated is via  CXCR3  receptors in cells in the  intestinal epithelium , which respond to  zonulin . [ 4 ]


Gliadin  (a glycoprotein present in wheat) activates zonulin signaling in all people who eat  gluten , irrespective of the genetic expression of  autoimmunity . This leads to increased intestinal permeability to macromolecules. [ 4 ] [ 12 ] [ 5 ]  Bacterial infections such as  cholera , select enteric viruses, parasites, and stress can all modulate intestinal tight junction structure and function, and these effects may contribute to the development of chronic intestinal disorders. [ 4 ] [ 13 ] [ 12 ]  So called absorption modifying excipients, investigated for the possibility of increasing intestinal drug absorption, can increase the gut permeability. [ 14 ]


Most people do not experience adverse symptoms, but the opening of intercellular tight junctions (increased intestinal permeability) can act as a trigger for diseases that can affect any organ or tissue depending on genetic predisposition. [ 4 ] [ 5 ] [ 15 ]


Increased intestinal permeability is a factor in several diseases, such as  celiac disease , [ 16 ]   irritable bowel syndrome ,  [ 17 ]   type 1 diabetes , [ 18 ]   type 2 diabetes , [ 16 ]   rheumatoid arthritis ,  spondyloarthropathies , [ 19 ]   inflammatory bowel disease , [ 4 ] [ 20 ]   schizophrenia , [ 21 ] [ 22 ]  certain types of  cancer , [ 4 ]   obesity , [ 23 ]   fatty liver , [ 24 ]   atopy  and  allergic  diseases, [ 18 ]  among others. In the majority of cases, increased permeability develops prior to disease, [ 4 ]  but the cause–effect relationship between increased intestinal permeability in most of these diseases is not clear. [ 20 ] [ 25 ]


A well studied model is celiac disease, in which increased intestinal permeability appears secondary to the abnormal immune reaction induced by gluten and allows fragments of gliadin protein to get past the intestinal epithelium, triggering an immune response at the intestinal submucosa level that leads to diverse gastrointestinal or extra-gastrointestinal symptoms. [ 26 ] [ 27 ]   Other environmental triggers may contribute to alter permeability in celiac disease, including intestinal infections and iron deficiency. [ 26 ]  Once established, this increase of permeability might self-sustain the inflammatory immune responses and perpetuate a vicious cycle. [ 26 ]  Eliminating gluten from the diet leads to normalization of intestinal permeability and the autoimmune process shuts off. [ 28 ]


In normal physiology,  glutamine  plays a key role in signalling in  enterocytes  that are part of the intestinal barrier, but it is not clear if  supplementing the diet  with glutamine is helpful in conditions where there is increased intestinal permeability. [ 29 ]


Prebiotics  and certain  probiotics  such as  E. coli  strain Nissle 1917  have been found to reduce increased intestinal permeability. [ 12 ]   Lactobacillus rhamnosus , [ 30 ]   Lactobacillus reuteri , [ 30 ]  and  Faecalibacterium prausnitzii [ 31 ]  have also been shown to significantly reduce increased intestinal permeability.


Larazotide acetate  (previously known as AT-1001) is a zonulin receptor antagonist that has been probed in clinical trials. It seems to be a drug candidate for use in conjunction with a  gluten-free diet  in people with celiac disease, with the aim to reduce the intestinal permeability caused by gluten and its passage through the epithelium, and therefore mitigating  the resulting cascade of immune reactions. [ 27 ] [ 32 ]


Genetic disruption of arginase-2 in mouse attenuates the onset of senescence and extends lifespan. [ 33 ] [ 34 ]
Arginase inhibitors have been developed to reduce the effect of NO on intestinal permeability. [ 34 ]


" Leaky gut syndrome " is a hypothetical, medically unrecognized condition. [ 20 ]  It has been popularized by some  nutritionists  and practitioners of  alternative medicine  who claim that  restoring normal functioning  of the  gut wall  can cure many systemic health conditions. However, reliable source evidence to support this claim has not been published. Nor has there been published any reliable evidence that the treatments promoted for so-called "leaky gut syndrome"—including nutritional supplements,  probiotics , [ 12 ]  herbal remedies, (or low- FODMAP  diets; low-sugar, antifungal, or  gluten-free  diets)—have any beneficial effect for most of the conditions they are claimed to help. [ 20 ]


Exercise-induced stress can diminish intestinal barrier function. [ 35 ] [ 36 ] [ 37 ]  In humans, the level of physical activity modulates the gastrointestinal  microbiota , an increased intensity and volume of exercise may lead to gut  dysbiosis , and supplementation may keep  gut microbiota  in  biodiversity , especially with intense exercise. [ 38 ]  In mice, exercise reduced the richness of the microbial community, but increased the distribution of bacterial communities. [ 39 ]


Intraepithelial lymphocytes  ( IEL ) are  lymphocytes  found in the  epithelial  layer of mammalian  mucosal linings , such as the  gastrointestinal (GI) tract  and  reproductive tract . [ 1 ]  However, unlike other  T cells , IELs do not need priming. Upon encountering antigens, they immediately release  cytokines  and cause killing of infected target cells. In the GI tract, they are components of  gut-associated lymphoid tissue  (GALT). [ 2 ]


Intestinal IELs are long-lived resistant effector cells spread along the entire length of intestine, where they patrol the space between intestinal  epithelial cells  (IEC) and the  basement membrane  (the intraepithelial space). Epithelium of  small intestine  contains approximately 1 IEL per 10  enterocytes . [ 3 ]  Due to their constant exposure to of antigens at mucosal barrier, they have unique antigen-experienced activated phenotypes and they constantly express  CD103  (αE integrin), that is distinct from the conventional T cells in the intestine. [ 3 ]  IELs are mainly T cells with mixture of subsets. They are divided into two groups – conventional and unconventional IELs. [ 4 ]


In mice both groups are retained in almost equal proportions. [ 5 ]  In humans, the majority of IELs are alpha beta T cells. 15% of IELs are gamma delta T cells and thus represent a minor component of human IELs. However, IELs significantly increase under certain conditions, such as  celiac disease . [ 1 ]


The majority of IELs (80%) are  CD3+ , and over 75% of these also express  CD8 . IELs can be divided into two major subsets based on their CD8 coreceptor expression. [ 5 ]  One subset of IELs typically express activation marker CD8αα and some IELs express CD8αβ +  marker (CD8αβ promotes  TCR  activation, whereas CD8αα suppresses TCR signals).


In both humans and mice IELs express higher levels of  CD103 , activation marker  CD69 ,  granzyme B  and  perforin  cytolytic granules.  CD25  expression is lower in comparison with effector memory T cells. [ 6 ] [ 7 ]


Expression of CD8αα is an important phenotypic marker of IELs, but not all IELs subpopulations express this molecule. CD8αα  homodimer  is an alternative isoform to classical  CD8 αβ heterodimer, which is expressed on conventional  CD8 T-cells . CD8αα is mainly expressed by effector or mature antigen-experienced cells in the gut. This molecule can bind  MHC I , but, opposed to the function of CD8αβ, CD8αα reduces sensitivity of  TCR  towards antigens. Thus, when recognizing MHC I, CD8αα functions as a repressor of activation. [ 8 ]


CD8αα can also recognize thymus leukemia (TL) antigen, which is a  non-classical MHC I  molecule that is expressed in  thymus  and in intestinal epithelium. Interaction between TL and CD8αα does not serve for migration of IELs into the epithelium, but it is important for modulating immune response of IELs. [ 9 ]  It has been suggested that cross-talk between TL and CD8αα might regulate IELs survival and proliferation. [ 8 ]  More accurately, TL prevents proliferation of IELs, when there is co-occurrence of weak TCR stimulation. [ 9 ]


Induced IELs (TCRαβ+ CD8αβ + ) are generated from  naive T cells  during an  immune response . TCRαβ +  CD8αα (natural IELs) cells differentiate in the  thymus . [ 6 ] [ 10 ]


Development and cytolytic activation are independent of live micro-organisms but they become cytolytic in response to the exogenous antigenic substances other than live micro-organisms in the gut. IEL T cells acquire their activated memory phenotype post-thymically, in response to  antigens  encountered in the periphery. [ 11 ]


Their role in immune system is crucial because IELs provide a first line of defense at this extensive barrier with the outside world. All IEL T cells are antigen-experienced T cells, which typically display a cytotoxic functional phenotype. IELs mediate antigen-specific delayed-type hypersensitivity (DTH) responses, exhibit virus-specific CTL function, to express  natural killer  (NK)-like activity and produce a local  graft-versus-host reaction (GVHR)  when transferred to semiallogeneic hosts. IELs are also able to produce a variety of  cytokines  which are characteristically produced by T h 1- and T h 2-type cells and can also provide help for  B cell  responses. [ 6 ] [ 10 ] [ 11 ]


An elevated IEL population, as determined by biopsy, typically indicates ongoing inflammation within the mucosa.  In diseases such as  celiac sprue , IEL elevation throughout the small intestine is one of many specific markers. [ 1 ]  IELs have heightened activated status that can lead to inflammatory disease such as IBD, promote cancer development and progression, [ 12 ]  or become the malignant cells in  enteropathy-associated T-cell lymphoma , a lymphoma that is a complication of celiac sprue. [ 13 ] [ 14 ]


Alternatively, elevated IEL populations can be a marker for developing neoplasia in the tissue such as found in  cervical  and  prostate  cancers, as well as some  colorectal cancers , particularly those associated with  Lynch syndrome  (hereditary non-polyposis colon cancer <HNPCC>). [ 15 ]  IELs themselves can, when chronically activated, undergo mutation that can lead to  lymphoma . [ 16 ]


IELs can be divided into different subpopulations based on molecular markers expression, mainly by expression of TCR and CD8αα, and by origin.


Also termed conventional IELs, express TCRαβ together with CD4 or CD8αβ and are derived from antigen-experienced T cells that home to intraepithelial space. Contrary to natural IELs, induced IELs are the progeny of  MHCI -restricted CD8αβ or  MHCII -restricted CD4 naïve T cells that further undergo a post-thymic differentiation. These cells express activation markers ( CD44 ,  CD69 ) and unlike natural TCR + IELs express  CD2 ,  CD5 ,  CD28 ,  LFA-1 , and  Thy1 . Upon the entry into the intestinal epithelium, these cells can start express also CD8αα. [ 4 ] [ 3 ]


TCRαβ + CD4 +  IELs arise from conventional peripheral  CD4 +  T-cells . These cells migrate into the intestinal epithelium as effector or tissue-resident memory T cells.


In mice, up to 50% of these IELs can express CD8αα homodimer, which they acquire in the intestinal epithelium after external stimuli such as  TGF-β ,  IFN-γ ,  IL-27  and  retinoic acid . Function of TCRαβ +  CD4 +  CD8αα +  IELs is unclear. Even though they express granzymes and have cytolytic properties, it has been suggested that they can also have regulatory properties in the context of chronic intestinal inflammation. [ 3 ] [ 17 ]


These IELs emerge from peripherally activated conventional CD8 +  T-cells and home to the intestinal epithelium, where they function as effector or memory cells. They continuously express  integrin β7 ,  granzyme B ,  CD103  and  CD69  and produce lower amounts of  TNF-α  and  IFN-γ  as opposed to the conventional  CD8 +  T-cells . [ 4 ]


Some of these cells also express CD8αα homodimer and can be pathogenic during  coeliac disease  in humans. [ 3 ]


These DP IELs are subset of induced IELs, which are CD4 +  IELs with some functions of CD8 +  IELs and under physiological condition their number in the intestine is very small. During the intestinal inflammation, levels of DP IELs significantly increase. [ 18 ]


DP IELs develop independently of the  thymus  and contrary to natural IELs, these cells increase with age, especially when they are exposed to  exogenous antigens . Their migration into the intestinal epithelium depends mainly on the luminal bacteria and the dietary antigens. [ 18 ]


DP IELs induction is directed by the transcriptional regulation. During the development of IELs, CD4 +  T cells downregulate ThPOK and instead start to express  Runx3  transcription factor, because CD4 + CD8aa +  IELs have low levels of ThPOK expression while the expression of Runx3 is very high. T-bet inducing environment is also required for the Runx3 upregulation, most likely containing  IFN-y ,  IL-27 ,  IL-15  and  Retionic acid  (RA). [ 19 ]  RA have the ability to induce an expression of the intetsine-homing receptors, such as  α4β7-integrin  and CC-chemokine receptor 9 ( CCR9 ). [ 20 ]  Another transcription factor responsible for DP IELs induction is the  Aryl hydrocarbon receptor  (AhR). AhR is ligand-dependent transcription factor, and its activation is responsible for ThPOK downregulation. AhR is activated by  indole  metabolites of  tryptophan  induced by microbiota, such as  Lactobacillus reuteri . [ 21 ]  Therefore, the DP IELs induction is dependent on the microbiota composition and the diet.


The function of CD4CD8aa IELs is due to their CD8 phenotype and  granzyme B  expression to prevent pathogens from invading and to maintain integrity of the intestinal epithelial barrier. Their CD4 phenotype is responsible for  IL-10  and  TGF-β  secretion that prevents Th1-induced inflammation in the intestine, therefore their role can be complementary to T regulatory cells. [ 18 ] [ 22 ]


DP IELs probably play role in intestinal homeostasis because of their immunosuppressive function. But for their cytotoxic responses they may play an important role in the pathological process of  IBD . [ 18 ]


Also termed unconventional IELs, express either TCRαβ or TCRγδ and do not express either CD4 or CD8αβ, but express CD8αα homodimers. In contrast to induced TCR +  IELs lack expression of CD2, CD5, CD28, LFA-1, and Thy1. [ 4 ]


In mice, these IELs are the most abundant at birth and with age their numbers decrease. In humans, these cells are present during gestation but are very rare in adulthood. TCRαβ +  IELs develop in thymus where they undergo agonist positive selection and thereby are self-reactive. Nevertheless, they have regulatory properties and protect against  colitis  in animal experiments. These cells are influenced by normal intestinal  microbiota  and  vitamin D .  NOD2  receptor expressed by  antigen presenting cells  and epithelial cells in the intestine recognizes microbes and triggers the production of  IL-15  cytokine, which promotes TCRαβ + CD8αα +  IELs. [ 3 ]


TCRγδ +  IELs develop outside of thymus and their maintenance and function in the intestinal epithelium is influenced by a cross-talk with enterocytes. Moreover, they can migrate through the epithelium with the help of interactions with epithelial cells. [ 23 ]  Most of these cells express Vγ7 in mice and Vγ4 in humans. Their function resides in the protection of the intestinal barrier against pathogens early in the infection and later they quench the inflammation and protect the barrier from tissue damage. The mechanism is not clear, but TCRγδ +  IELs have cytotoxic properties and can produce cytokines  TGF-β ,  TNF-α ,  IFN-γ ,  IL-13  and  IL-10  and  antimicrobial peptides , all of which can contribute to the diverse functions. [ 3 ]


Similar functions have been found in the context of  colitis , where these cells seem to have pathogenic role at the beginning, whereas later they protect the epithelium against tissue damage. [ 17 ]


IELs that do not express TCR.


These cells show properties of  NK cells . In humans, they are elevated during  Crohn´s disease  and in mice, they are pathogenic during colitis. [ 4 ]


These innate lymphocytes express homodimer CD8αα and CD3 and develop outside of thymus. They have cytotoxic and phagocytic properties, express  MHC II  and thereby can present antigens to conventional CD4 +  T-cells. iCD8α protect against bacterial infections and promotes experimental colitis. [ 3 ]


These cells are very similar to iCD8α population and it is unclear if this is a different subset of cells or only precursors of iCD8α. [ 3 ]


IEL of the GI tract


A  Kock pouch  is a continent pouch formed by the terminal  ileum  after  colectomy .  The procedure was detailed and first performed in 1969 by Dr.  Nils Kock .  [ citation needed ]


Kock pouch ileostomy is indicated for patients who are unfit for  ileal pouch anal anastomosis  (IPAA) because the anus and anal sphincter will be removed during the operation; and patients who develop severe  incontinence  after IPAA. [ 1 ]


A Kock pouch need not be created during the initial colectomy surgery. [ citation needed ]


The pouch has a volume of 500ml to 1000ml so that  feces  can be stored temporarily and the patient need not carry a  stoma bag . This improves the patient's quality of life. A valve is constructed by  intussusception  of the terminal ileum, [ 2 ]  thereby containing the stored feces. [ 1 ]


Lactase persistence  or  lactose tolerance  is the continued activity of the  lactase   enzyme  in adulthood, allowing the  digestion  of  lactose  in  milk . In most  mammals , the activity of the enzyme is dramatically reduced after  weaning . [ 1 ]  In some human populations though, lactase persistence has recently  evolved [ 2 ]  as an  adaptation  to the consumption of nonhuman milk and dairy products beyond infancy. Lactase persistence is very high among northern Europeans, especially  Irish people . Worldwide, most people are lactase  non -persistent, [ 1 ]  and are affected by varying degrees of  lactose intolerance  as adults. However, lactase persistence and lactose intolerance can overlap.


The distribution of the lactase persistence (LP)  phenotype , or the ability to digest lactose into adulthood, is not homogeneous in the world. Lactase persistence frequencies are highly variable. In Europe, the distribution of the lactase persistence phenotype is  clinal , with frequencies ranging from 15–54% in the south-east to 89–96% in the north-west. [ 3 ]  For example, only 17% of  Greeks  and 14% of  Sardinians  are predicted to possess this phenotype, while around 80% of  Finns   and  Hungarians  and 100% of  Irish people  are predicted to be lactase persistent. [ 4 ]  Similarly, the frequency of lactase-persistence is clinal in India, a 2011 study of 2,284 individuals identifying a prevalence of LP in the  Ror  community, of  Haryana , in the North West, of 48.95%, declining to 1.5% in the  Andamanese , of the South East, and 0.8% in the Tibeto-Burman communities, of the North East. [ 5 ] [ 6 ]


High frequencies of lactase persistence are also found in some places in Sub-Saharan Africa [ 7 ] [ 8 ]
and in the Middle East. [ 9 ] [ 10 ]
But the most common situation is intermediate to low lactase persistence: intermediate (11 to 32%) in Central Asia, [ 11 ]  low (<=5%) in  Native Americans , East Asians, most Chinese populations [ 2 ]  and some African populations. [ 3 ] [ 4 ] [ 11 ]


In Africa, the distribution of lactase persistence is "patchy": [ 12 ] [ 13 ] [ 3 ]  high variations of frequency are observed in neighbouring populations, for example between  Beja  and  Nilotes  from Sudan. [ 14 ]  This makes the study of lactase persistence distribution more difficult. [ 4 ]  High percentages of lactase persistence phenotype are found in traditionally  pastoralist  populations like  Fulani  and  Bedouins . [ 3 ] [ 15 ]


Lactase persistence is prevalent in  Nguni  and certain other pastoralist populations of South Africa as a result of the dairy they consume in their diet. Lactase persistence amongst Nguni people is, however, less common than in Northern European populations because traditionally, their consumption of dairy came primarily in the form of  amasi  (known as Maas in Afrikaans), which is lower in lactose than fresh, raw milk as a result of the fermentation process it goes through. [ 16 ] [ 17 ] [ 15 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ excessive citations ]


Multiple studies indicate that the presence of the two  phenotypes  "lactase persistent" (derived phenotype) and "lactase nonpersistent" ( hypolactasia ) is genetically programmed, and that lactase persistence is not necessarily conditioned by the consumption of lactose after the suckling period. [ 24 ] [ 25 ]


The lactase persistent phenotype involves high  mRNA  expression, high lactase activity, and thus the ability to digest lactose, while the lactase nonpersistent phenotype involves low mRNA expression and low lactase activity. [ 26 ]  The enzyme lactase is encoded by the gene  LCT . [ 24 ]


Hypolactasia is known to be recessively and autosomally inherited, which means that individuals with the nonpersistent phenotype are  homozygous  and received the two copies of a low lactase-activity  allele  (the ancestral allele) from their parents, who may be homozygous or at least  heterozygous  for the allele. [ 24 ]  Only one high-activity allele is required to be lactase persistent. [ 24 ] [ 25 ]  Lactase persistence behaves as a dominant trait because half levels of lactase activity are sufficient to show significant digestion of lactose. [ 1 ]   Cis-acting  transcriptional silence of the lactase gene is responsible for the hypolactasia phenotype. [ 24 ] [ 25 ]  Furthermore, studies show that only eight cases were found where the parents of a child with lactase persistence were both hypolactasic. [ 1 ]  While a variety of genetic, as well as nutritional, factors determine lactase expression, no evidence has been found for adaptive alteration of lactase expression within an individual in response to changes in lactose consumption levels. [ 1 ]  The two distinct phenotypes of hypolactasia are: Phenotype I, characterized by reduced synthesis of precursor LPH, and phenotype II, associated with ample precursor synthesis, but reduced conversion of the protein to its mature molecular form. [ 27 ]
The lactase enzyme has two active sites which break down lactose. The first is at Glu1273 and the second is at Glu1749, which separately break down lactose into two separate kinds of molecules. [ 1 ]


At least six mutations ( single-nucleotide polymorphisms  – SNPs) have been associated with lactase expression. [ 28 ]  They are all located in a region of the gene  MCM6  upstream of  LCT . This region is considered as an enhancer region for the transcription of  LCT . [ 29 ] [ 30 ] [ 31 ]  The first identified genetic variant associated with lactase persistence is C/T*−13910. [ 32 ]  The ancestral allele is C and the derived allele – associated with lactase persistence – is T. In the same study, another variant was found to also correlate with the phenotype in most of the cases: G*/A-22018. [ citation needed ]


Other alleles associated with lactase persistence have been identified: G/C*-14010, [ 15 ]  C/G*-13907, [ 15 ] [ 13 ] [ 33 ]  and T/G*-13915. [ 34 ]  This variant is described as part of a compound allele with T/C*3712 in. [ 31 ]  These three variants are widespread in some populations. Rare variants were reported in a few studies, like the G/A*14107 in the Xhosa [ 35 ]  and the Fulani (from Mali); [ 28 ]  the C/T*13906 in the Fulani (from Mali). [ 28 ]


Lactase-persistence alleles vary in their geographic distributions. Within European and populations of European ancestry, they are almost entirely correlated with the presence of the −13,910 C/T mutation in the enhancer region of the lactase gene ( LCT ). [ citation needed ]


This differs from lactase persistence allelic distributions in the rest of the world, particularly in Africa and in the Middle East, where several alleles coexist. [ citation needed ]


The T/G*-13915 allele is found mostly in populations from East and North Africa and the Middle East. The allele G/C*-14010 was identified in East Africa. [ 36 ]  The C/G*13907 allele was described in Sudan and Ethiopia. [ 15 ] [ 33 ] [ 37 ]  The "European" allele T*13910 allele is also found in some populations from Africa, including the Fulani (from Mali, [ 28 ]  Sudan, [ 38 ]  and Cameroon [ 33 ] ) and the Khoe from South Africa. [ 20 ] [ 22 ]  This allele has also been found in Central Asia. [ 11 ]


It is not known how exactly the different variants described above regulate  LCT  expression. None of the mutations so far identified have been shown to be exclusively causal for lactase persistence, and it is possible that there are more alleles to be discovered. [ 39 ]  If we focus on the "European variant", the position −13910 has an enhancer function on the lactase promoter (the promoter facilitates the transcription of the  LCT  gene). T−13910 is a greater enhancer than C−13910, so this mutation is thought to be responsible for the differences in lactase expression, [ 40 ]  although not enough evidence is found to prove that lactase persistence is only caused by C−13910→T−13910. [ 24 ]


In addition, it was shown in one study involving a Finnish population that the lactase gene has a higher expression when G−22018 is combined with T-13910. [ 24 ]


Lactase persistence is a textbook example of  natural selection  in humans: it has been reported to present stronger selection pressure than any other known human gene. [ 24 ]  However, the specific reasons as to why lactase persistence confers a selective advantage "remain open to speculation". [ 41 ]


Several pieces of evidence for positive selection acting at the T*-13910 allele were given: it is located in a stretch of homozygosity of c. 1 Mb; [ 42 ]  the strength of selection is similar to that estimated for the resistance to malaria. [ 2 ]  Haplotype inferences were performed on data from Central Asia populations; selection was detected there as well – though less strong than in European populations. [ 11 ]  Thus, even if T*13910 may not be causative for lactase persistence, it was selected during human evolutionary history.


The other variants were also proved to be under selection. The C*-14010 allele is located on a particularly long stretch of homozygosity (> 2 Mb). [ 15 ]


The compound allele G*-13915 & C*-3712 was proved to be located on a long stretch of homozygosity (1.1 Mb [ 15 ]  to 1.3 Mb [ 31 ] ).


The ability to digest lactose is not an evolutionary novelty in human populations. Nearly all mammals begin life with the ability to digest lactose. This trait is advantageous during the infant stage, because milk serves as the primary source for nutrition. As weaning occurs, and other foods enter the diet, milk is no longer consumed. As a result, the ability to digest lactose no longer provides a distinct fitness advantage. [ 43 ]   This is evident in examining the mammalian lactase gene ( LCT ), whose expression decreases after the weaning stage, resulting in a lowered production of lactase enzymes. [ 43 ]  When these enzymes are produced in low quantities, lactase non-persistence (LNP) results. [ 38 ]


The ability to digest fresh milk through adulthood is genetically coded for by different variants which are located upstream of the  LCT  gene and which differ among populations. Those variants are found at very high frequencies in some populations and show signatures of selection. There are two notable hypotheses with dissimilar theories which try to explain why lactase persistence phenotype has been positively selected. [ 3 ]  The first one, known as the cultural-historical hypothesis, states that the main reason for LP is the introduction of dairy-based food products into the diet, [ 3 ]  while the reverse-cause hypothesis argues that dairy consumption was embraced by the societies which were already high in LP frequency. [ 3 ]


The  gene–culture coevolution  hypothesis of the positive selection of the lactase persistence phenotype is based on the observation that pastoralist populations often present high levels of lactase persistence. According to this hypothesis, the reason of selection is the nutritional advantage of being lactase persistent. [ 2 ] [ 15 ]


Individuals who expressed lactase-persistent phenotypes would have had a significant advantage in nutritional acquisition. [ 38 ]  This is especially true for societies in which the domestication of milk-producing animals and pastoralism became a main way of life. [ citation needed ]


The combination of pastoralism and lactase persistence genes would have allowed individuals the advantage of niche construction, meaning they would have had less competition for resources by deriving a secondary food source, milk. [ 44 ]  Milk as a nutrition source may have been more advantageous than meat, as its rate of renewal is significantly faster. Rather than having to raise and slaughter animals, one cow or goat could repeatedly serve as a resource with fewer time and energy constraints. The competitive advantage conferred on lactose-tolerant individuals would have given rise to strong selective pressures for this genotype, especially in times of starvation and famine, which in turn gave rise to higher frequencies in lactase persistence within the populations. Milk is also generally less contaminated than water, which decreases exposure to pathogens or parasites. [ 45 ]


By contrast, for societies which did not engage in pastoral behaviors, no selective advantage exists for lactase persistence. Mutations which may have developed allelic variations which code for lactase production into adulthood are simply neutral mutations. They seemingly confer no fitness benefit to individuals. As a result, no selection has perpetuated the spread of these allelic variants, and the lactase persistence genotype and phenotype remains rare. [ 1 ]  For example, in East Asia, historical sources also attest that the  Chinese  did not consume milk, whereas the nomads who lived on the borders did. This reflects modern distributions of intolerance. China is particularly notable as a place of poor tolerance, whereas in  Mongolia  and the  Asian steppes , milk and dairy products are a main nutrition source. The nomads also make an alcoholic beverage, called  airag  or  kumis , from mare's milk, although the  fermentation  process reduces the amount of lactose present. [ citation needed ]


Two scenarios have been proposed for the gene–culture coevolution hypothesis: either lactase persistence developed and was selected after the onset of pastoralist practices (culture-historical hypothesis); or pastoralism spread only in populations where lactase persistence was already at high frequencies (reverse-cause hypothesis). There are exceptions to the hypothesis like the hunter-gatherers  Hadza  (Tanzania) with a prevalence of lactase persistence phenotype of 50%. [ 15 ]


The evolution of lactase persistence in response to pastoral behavior can be seen as an example of the  Baldwin effect , by which animals' behavior affects the selection pressure they are under. [ 46 ]


The consumption of  lactose  has been shown to benefit humans with lactase persistence through adulthood. For example, the 2009 British Women's Heart and Health Study [ 47 ]  investigated the effects on women's health of the alleles that coded for lactase persistence.  Where the C  allele  indicated lactase nonpersistence and the T allele indicated lactase persistence, the study found that women who were homozygous for the C allele exhibited worse health than women with a C and a T allele and women with two T alleles.  Women who were CC reported more hip and wrist fractures, more  osteoporosis , and more  cataracts  than the other groups. [ 48 ]  They also were on average 4–6 mm shorter than the other women, as well as slightly lighter in weight. [ 48 ]   In addition, factors such as metabolic traits, socioeconomic status, lifestyle, and fertility were found to be unrelated to the findings, indicating that health improvements for these women were due to dairy products consumption and exhibited lactase persistence. [ citation needed ]


Another possibility is the calcium absorption hypothesis. [ 13 ] [ 48 ]  Lactose favors the intestinal absorption of calcium; it helps maintaining it in a soluble form. This can be advantageous in regions of low sunlight exposure where Vitamin D, necessary for the transport of calcium, is a limiting factor. The lactase persistence gene has been shown to correlate with higher levels of Vitamin D. [ 49 ]


The correlation between lactase persistence frequencies and latitude in 33 populations in Europe was found to be positive and significant, while the correlation between lactase persistence and longitude was not, suggesting that high levels of lactose assimilation were indeed useful in areas of low sunlight in northern Europe. [ 50 ]


Increased calcium absorption helps to prevent  rickets  and  osteomalacia . [ 1 ]


A hypothesis specific to arid climate was proposed: [ 51 ]  here, milk is not only a source of nutrients, but also a source of fluid, which could be particularly advantageous during epidemics of gastrointestinal diseases like cholera (where water is contaminated).
Human populations differ in the prevalence of genotypic lactase persistence, phenotypic lactose tolerance, and habitual milk consumptions. (Vliert, et al, 2018). An individual's capacity to absorb milk is widespread under three conditions. [ citation needed ]


One study suggested that lactase persistence was selected for parallel to malaria resistance in the Fulani from Mali. [ 28 ]  Proposed mechanisms are: nutritional advantage of milk; low content of  p -aminobenzoic acid compared to non-milk diets; intake of immunomodulators contained in milk.


Although the selective advantages of lactase persistence have been discussed, there have been studies of ethnic groups whose populations, despite relying heavily on milk consumption, currently have a low frequency of lactase persistence. [ 13 ]  A study of 303 individuals from the Beja tribe and 282 individuals from various Nilotic tribes in Sudan discovered a sharp difference between the distribution of lactase phenotypes of the two populations. Lactase persistence was determined with  hydrogen breath tests . The frequency of lactose malabsorbers was 18.4% in members of Beja tribes over the age of 30, and 73.3% in members of Nilotic tribes over the age of 30. [ 14 ]


According to the gene-culture coevolution hypothesis, the ability to digest lactose into adulthood (lactase persistence)  became advantageous to humans after the invention of  animal husbandry  and the domestication of animal species that could provide a consistent source of milk.  Hunter-gatherer  populations before the  Neolithic Revolution  were overwhelmingly lactose intolerant, [ 53 ] [ 54 ]  as are modern hunter-gatherers. Genetic studies suggest that the oldest mutations associated with lactase persistence only reached appreciable levels in human populations in the last 10,000 years. [ 55 ] [ 2 ]  This correlates with the beginning of animal domestication, which occurred during the Neolithic transition. Therefore, lactase persistence is often cited as an example of both  recent human evolution [ 15 ]  and, as lactase persistence is a genetic trait but animal husbandry a cultural trait,  gene-culture coevolution  in the mutual human-animal  symbiosis  initiated with the advent of  agriculture . [ 56 ]


Depending on the populations, one or the other hypothesis for the selective advantage of lactase persistence is more relevant: In Northern Europe, the calcium absorption hypothesis might be one of the factors leading to the strong selection coefficients, [ 57 ]  whereas in African populations, where vitamin D deficiency is not as much of an issue, the spread of the allele is most closely correlated with the added calories and nutrition from pastoralism. [ 2 ]


Several  genetic markers  for lactase persistence have been identified, and these show that lactase persistence has multiple origins in different parts of the world (i.e. it is an example of  convergent evolution ). In particular, it has been hypothesized [ 58 ]  that the T*13910 variant appeared at least twice independently. Indeed, it is observed on two different haplotypes: H98, the more common (among others in the Finnish and in the Fulani); and H8 H12, related to geographically restricted populations. The common version is relatively older. The H98 variant – most common among Europeans – is estimated to have risen to significant frequencies about 7,500 years ago in the central  Balkans  and  Central Europe , a place and time roughly corresponding to the archaeological  Linear Pottery culture  and  Starčevo cultures . [ citation needed ]


The T*13910 variant is also found in North Africans. Thus it probably originated earlier than 7500 ya, in the  Near East , but the earliest farmers did not have high levels of lactase persistence and did not consume significant amounts of unprocessed milk. [ 59 ]


Some hypotheses regarding the evolutionary history of lactase persistence in given regions of the world are described below.


Concerning Europe, the model proposed for the spread of lactase persistence combines selection and demographic processes. [ 47 ] [ 36 ] [ 3 ] [ 13 ]  Some studies used modelling approaches to investigate the role of genetic drift. [ 3 ]  According to some models, the spread of lactase persistence in Europe can be attributed primarily to a form of  genetic drift . [ 47 ]  Evidence can also come from other fields, for example written historical records: Roman authors recorded that the people of northern Europe, particularly  Britain  and  Germany , drank unprocessed milk. This corresponds very closely with modern European distributions of lactose intolerance, where the people of Britain, Germany, and Scandinavia have a high tolerance, and those of southern Europe, especially Italy, have a lower tolerance. [ 41 ]  The lower tolerance in southern Europe can be explained by genetic drift alone but the higher tolerance in northern Europe may be a result of positive selection. [ 3 ]  2017 reports, by 23AndMe, indicated 40.4% of its customers, who self identified as European, carried a single copy of the mutated 13910C/T allele and a further 42% carried two copies of the Lactase persistence mutation. [ 60 ]


A 2015 genome-wide scan for selection using DNA gathered from 230 ancient West Eurasians who lived between 6500 and 300 BCE found that the earliest appearance of the allele responsible for lactase persistence occurred in an individual who lived in central Europe between 2450 and 2140 BCE. [ 61 ]


A 2021  archaeogenetics  study found that lactase persistence rose swiftly in early  Iron Age Britain , a thousand years before it became widespread in mainland Europe, which suggests that milk became a very important foodstuff in Britain at this time. [ 62 ]


In Central Asia, the causal polymorphism for lactase persistence is the same as in Europe (T*13910, rs4988235), suggesting genetic diffusion between the two geographical regions. [ 11 ]


It is indicated that the allele responsible for lactase persistence (T*13910) may have arisen in  Central Asia , based on the higher frequency of lactase persistence among Kazakhs who have the lowest proportion of "western" gene pool inferred from admixture analysis from autosomal microsatellite data. [ 11 ]  This, in turn, could also be an indirect genetic proof of early domestication of horses for milk products as recently attested from archaeological remains. [ 11 ] [ 63 ]  In Kazakhs, traditionally herders, lactase persistence frequency is estimated to 25–32%, of which only 40.2% have symptoms and 85–92% of the individuals are carriers of the T*13910 allele. [ 11 ]


In South Asia, the dominant causal polymorphism for lactase persistence is the same as in Europe (T*13910, rs4988235), suggesting genetic diffusion between the two geographical regions. A 2012 study, of 2284 individual across the region, identified an average frequency of 10.3% for the mutation, though varying in prevalence from 0.8% among the Tibeto-Burman speakers to 18.4% among Indo-European speakers; the west of India hosting the highest incidents of the derived allele. Additionally approximately 3.4% of the population possessed one of the other known mutations. [ 64 ]


The situation is more complex in  Africa , where all five main lactase persistence variants are found. [ 65 ] [ 15 ] [ 19 ] [ 20 ]


The presence of T*13910 alleles among the Khoe pastoralists is ascribed to gene flow from Europe. However, the presence of other alleles signals gene flow from East Africa. [ 19 ]


It has been hypothesized that the G*13915 variant dispersed from the Middle East, [ 65 ]  in association with the domestication of the  Arabian camel . [ 31 ]


The G-14009 mutation is based in Ethiopia. [ 66 ]


The G*13907 variant is concentrated among  Afroasiatic  speakers in  Northeast Africa . [ 65 ]


The C*14010 allele is today most common among pastoralist groups inhabiting eastern Africa, from where it is thought to have spread along with pastoralism into parts of southern Africa. [ 65 ] [ 19 ] [ 20 ] [ 67 ]  Ultimately, the C*14010 lactase persistence variant is believed to have arrived from the Sahara in areas that were previously inhabited by Afroasiatic-speaking populations. This was deduced from the existence of animal husbandry- and milking-related loanwords of Afroasiatic origin in various  Nilo-Saharan  and  Niger-Congo  languages, as well as from the earliest appearance of processed milk lipids on ceramics which were found at the  Tadrart Acacus  archaeological site in  Libya  (radiocarbon-dated to c. 7,500 BP, close to the estimated age of the C*14010 mutation). [ 68 ]


The evolutionary processes driving the rapid spread of lactase persistence in some populations are not known. [ 1 ]  Among some populations inhabiting East Africa, lactase persistence has gone from negligible to near-ubiquitous frequencies in just 3000 years, suggesting a very strong  selective pressure . [ 15 ]  Some studies also proposed that selection for lactase persistence is not as strong as supposed ( soft selective sweep ), and that its strength varies a lot depending on particular environmental conditions. [ 13 ]
Post animal domestication, individuals gained the ability to tolerate lactose after weaning from infancy. This offered a crucial advantage to humans through natural selection by creating genetic variances. [ 69 ]


Neolithic   agriculturalists , who may have resided in  Northeast Africa  and the  Near East , may have been the source population for lactase persistence variants, including –13910*T, and may have been subsequently supplanted by later migrations of peoples. [ 70 ]  The  Sub-Saharan   West African  Fulani, the  North African   Tuareg , and  European agriculturalists , who are descendants of these Neolithic agriculturalists, share the lactase persistence variant –13910*T. [ 70 ]  While shared by Fulani and Tuareg herders, compared to the Tuareg variant, the Fulani variant of –13910*T has undergone a longer period of haplotype differentiation. [ 70 ]  The  Fulani  lactase persistence variant –13910*T may have spread, along with cattle  pastoralism , between 9686 BP and 7534 BP, possibly around 8500 BP; corroborating this timeframe for the Fulani, by at least 7500 BP, there is evidence of herders engaging in the act of  milking  in the Central  Sahara . [ 70 ]


Lactose  malabsorption  is typical for adult mammals, and lactase persistence is a phenomenon likely linked to human interactions in the form of dairying.
Most mammals lose the ability to digest lactose once they are old enough to find their own source of nourishment away from their mothers. [ 71 ]  After  weaning , or the transition from being milk-fed to consuming other types of food, their ability to produce lactase naturally diminishes as it is no longer needed. For example, in the time a piglet in one study aged from five to 18 days, it lost 67% of its lactose absorption ability. [ 72 ]  While nearly all humans can normally digest lactose for the first 5 to 7 years of their lives, [ 71 ]  most mammals stop producing lactase much earlier. Cattle can be  weaned  from their mothers' milk at 6 months to a year of age. [ 73 ]  Lambs are regularly weaned around 16 weeks old. [ 74 ]  Such examples suggest that lactase persistence is a uniquely human phenomenon. [ citation needed ]


Some examples exist of factors that can cause the lactase persistence phenotype in the absence of any genetic variant associated with LP. Individuals may lack the alleles for lactase persistence, but still tolerate dairy products in which lactose is broken down by the fermentation process (e.g. cheese, yogurt). [ 75 ]  Also, healthy colonic gut bacteria may also aid in the breakdown of lactose, allowing those without the genetics for lactase persistence to gain the benefits from milk consumption. [ 75 ] [ 76 ]


A lactose tolerance test may be conducted by asking test subjects to fast overnight, then sampling blood to establish a baseline glucose level. Lactose solution is then given to the subjects to drink, and blood glucose levels are checked at 20 minute intervals for an hour. The subjects who show a substantial rise in their blood glucose level are considered lactose tolerant. [ 22 ]


A  hydrogen breath test  is often used to detect lactose intolerance. [ citation needed ]


A  lacteal  is a  lymphatic capillary  that absorbs dietary  fats  in the  villi  of the  small intestine .


Triglycerides are emulsified by  bile  and  hydrolyzed  by the enzyme  lipase , resulting in a mixture of  fatty acids , di- and  monoglycerides . [ 1 ]  These then pass from the intestinal lumen into the  enterocyte , where they are re-esterified to form  triglyceride . The triglyceride is then combined with  phospholipids ,  cholesterol   ester , and  apolipoprotein B 48 to form  chylomicrons . These chylomicrons then pass into the lacteals, forming a milky substance known as  chyle . The lacteals merge to form larger lymphatic vessels that transport the chyle to the  thoracic duct  where it is emptied into the bloodstream at the  subclavian vein . [ 2 ] [ 3 ]


At this point, the fats are in the bloodstream in the form of chylomicrons. Once in the blood, chylomicrons are subject to delipidation by  lipoprotein lipase . Eventually, enough lipid has been lost and additional apolipoproteins gained, that the resulting particle (now referred to as a chylomicron remnant) can be taken up by the  liver . From the liver, the fat released from chylomicron remnants can be re-exported to the blood as the triglyceride component of  very low-density lipoproteins . Very low-density lipoproteins are also subject to delipidation by vascular lipoprotein lipase, and deliver fats to tissues throughout the body.  In particular, the released fatty acids can be stored in  adipose  cells as triglycerides. As triglycerides are lost from very low-density lipoproteins, the lipoprotein particles become smaller and denser (since protein is denser than lipid) and ultimately become  low-density lipoproteins . LDL particles are highly  atherogenic . [ 4 ]


In contrast to any other route of absorption from the small intestine, the lymphatic system avoids  first pass metabolism .


Lacticaseibacillus casei  is an organism that belongs to the largest genus in the family  Lactobacillaceae , a  lactic acid bacteria  (LAB), that was previously classified as  Lactobacillus casei . [ 1 ]  This bacteria has been identified as  facultatively anaerobic  or microaerophilic, acid-tolerant, non-spore-forming bacteria.


This species is a non-sporing, rod-shaped, gram positive microorganism that can be found within the reproductive and digestive tract of the human body. [ 2 ]  Since  L. casei  can survive in a variety of environmental habitats, it has and continues to be extensively studied by health scientists. Commercially,  L. casei  is used in fermenting dairy products and its application as a  probiotic . [ 3 ]


In bacteraemia, it is regarded to be similar in pathogenicity to Lactobacillus and associated with  infective endocarditis . [ 4 ]


The taxonomy of the  L. casei  group  has been debated for several years because researchers struggled to differentiate between the strains of  L. casei  and  L. paracasei  using methods of traditional bacteriology, i.e. phenotypic, physiological, and biochemical similarities. In the 1990s, researchers began to realize that the  type strain  for  L. casei , ATCC 393, does not quite match most other strains classified as "L. casei" by then. To solve this discrapency, Dellaglio  et al.  argued to simply replace the type with ATCC 334, which is closer to these "other strains", and to bury the name "L. paracasei". This argument was not accepted by the  ICSP , which ruled in 1994 [ 5 ]  and 2008 that the type strain should not be changed. ICSP also mentions that ATCC 334 is a strain of  L. paracasei , meaning that it's the aforementioned "other strains" that need to be moved to  paracasei . [ 6 ]


The next major event in taxonomic revision came with Zheng  et al.  2020, which split  Lactobacillus  into several genera on phylogenomic grounds.  L. casei  was made the  type species  of  Lacticaseibacillus , containing more than 20 species. [ 2 ]


As of December 2023, the accepted taxonomy under the  species complex  is as follows: [ 7 ] [ 8 ]


The most common application of  L. casei  is industrial, specifically for  dairy  production. [ citation needed ]


Lacticaseibacillus casei  is typically the dominant species of nonstarter lactic acid bacteria (i.e. contaminant bacteria [ 10 ] ) present in ripening  cheddar cheese , and, recently, the complete genome sequence of  L. casei   ATCC  334 has become available. [ dubious  –  discuss ]   L. casei  is also the dominant species in naturally fermented Sicilian  green olives . [ 11 ]


A commercial beverage containing  L. casei  strain Shirota has been shown to inhibit the  in vivo  growth of  Helicobacter pylori , but when the same beverage was consumed by humans in a small trial,  H. pylori  colonization decreased only slightly, and the trend was not statistically significant. [ 12 ]  Some  L. casei  strains are considered to be  probiotic , and may be effective in alleviation of gastrointestinal pathogenic bacterial diseases. According to  World Health Organization , those properties have to be demonstrated on each specific strain—including human clinical studies—to be valid. [ 13 ]   L. casei  has been combined with other probiotic strains of bacteria in randomized trials studying its effects in preventing  antibiotic-associated diarrhea  (AAD) and  Clostridioides difficile  infections (CDI), and patients in the trials who were not given the placebo had significantly lower rates of AAD or CDI (depending on the trial) with no adverse effects reported. [ 14 ]  Additionally, trials have shown significantly shorter recovery times in children suffering from acute diarrhea (primarily caused by rotavirus) when given different  L. casei  treatments when compared to placebo. [ 15 ]  Studies suggest that  lactobacilli  are a safe and effective treatment for acute and infectious diarrhea. [ 16 ]


In the preparation of food,  L. casei  bacteria can be used in the natural  fermentation  of beans to lower levels of the compounds causing flatulence upon digestion. [ 17 ]


Another strain that has been studied is "01", also known as "Lc-01" or  Lacticaseibacillus casei -01. [ 18 ]


Among the best-documented probiotic strains of  L. casei ,  L. casei  DN-114001 ( Actimel/DanActive ) and  L. casei  Shirota ( Yakult ) have been extensively studied [ 19 ]  and are widely available as  functional foods .


The genomes of these two strains have been sequenced from commercial yogurt, re-designated "LcA" and "LcY" respectively. They were found to be extremely closely related. [ 20 ]


In the past few years, many studies have been conducted in the decolorization of  azo dyes  by lactic acid bacteria such as  L. casei  TISTR 1500,  L. paracasei ,  Oenococcus oeni , etc. With the  azoreductase  activity, mono- and diazo bonds are degraded completely, and generate other aromatic compounds as intermediates. [ 21 ]


The following table includes the colony, morphological, physiological, and biochemical characteristics of  L. casei . [ 22 ] [ 23 ] [ 24 ]


Lactic acid bacteria (LAB) is widely exploited for its probiotic and fermenting properties, so understanding how its genetic material is exchanged was crucial for researchers. A wide variety of comparative analyses were used to determine that  horizontal gene transfer  (HGT) influenced the evolution of the  Lactobacillus  genus. [ 25 ]  HGT in  L. casei  includes  transformation ,  conjugation , and  transduction . The mobile genetic elements found within the genome, known as  mobilomes , play an important role in  Lactobacillaceae  transfer. This includes  insertion sequences ,  bacteriophages ,  integrons ,  plasmids ,  genomic islands , and  transposons . [ 26 ]  Within LAB, they are responsible for metabolizing different molecules, hydrolyzing proteins, resisting antibiotics, DNA, and phages, and modifying genetic elements. [ 27 ]


The first form of gene transfer used by  Lactobacillus  is transformation. This includes the uptake of naked DNA by a recipient bacterial cell to gain the genetic information of a donor cell. [ 28 ]  This occurs after a donor bacterium has undergone  autolysis  and its DNA fragments are left within the free extracellular fluid. [ 29 ]  The recipient bacterium will then ingest the DNA fragments and will result in either a bacterial cell with a plasmid or recombination of the recipient DNA will transpire within the chromosome.


The next form of transfer is conjugation, a process that involves the transfer of DNA from a  Lactobacillus  donor to a recipient via cell-to-cell contact or direct cytoplasmic contact. [ 30 ]  In this process, the recipient cell is known as the  transconjugant . [ 31 ]  Once the cells come together, fragments of DNA are directly transferred from the donor to the transconjugant. This is mediated by pheromone-induced cell aggregation and mobilization proteins since many of the plasmids are unable to transfer on their own. [ 25 ]  Afterward, the mating cells will separate and a recombinant cell will be produced after homologous recombination. [ citation needed ]


Finally, transduction in  Lactobacillus  cells is a bacteriophage-mediated transfer of plasmid or chromosomal genetic information. [ 32 ]  To initiate this process, a bacteriophage must first infect the donor cell so that  lysis  of the cell will occur. At this point, the cell lysate will be filled with phages that carry donated genome fragments and the recipient cell will be injected with abnormal phage. This will result in a recombination cell whether the cell is infected after homologous recombination or after the infection occurs by bacteriophage integrase. [ 25 ]