Lacticaseibacillus rhamnosus  (previously  Lactobacillus rhamnosus [ 1 ] ) is a  bacterium  that originally was considered to be a subspecies of  L. casei , but genetic research found it to be a separate species in the  L. casei  clade, which also includes  L. paracasei  and  L. zeae . [ 2 ] [ 3 ]  It is a short  Gram-positive  homofermentative  facultative anaerobic  non-spore-forming rod that often appears in chains. Some strains of  L. rhamnosus  bacteria are being used as  probiotics , and are particularly useful in treating infections of the female urogenital tract, most particularly very difficult to treat cases of  bacterial vaginosis  (or "BV"). [ 4 ]  The species  Lacticaseibacillus rhamnosus  and  Limosilactobacillus reuteri   are commonly found in the healthy female genito-urinary tract and are helpful to regain control of dysbiotic bacterial overgrowth during an active infection.  L. rhamnosus  sometimes is used in  dairy products  such as fermented milk and as non-starter-lactic acid bacterium (NSLAB) in long-ripened cheese. [ 5 ]  While frequently considered a beneficial organism,  L. rhamnosus  may not be as beneficial to certain subsets of the population; in rare circumstances, especially those primarily involving  weakened immune system  or infants, it may cause  endocarditis . [ 6 ]  Despite the rare infections caused by  L. rhamnosus , the species is included in the list of bacterial species with qualified presumed safety (QPS) status of the  European Food Safety Agency . [ 7 ]


Lacticaseibacillus rhamnosus  is considered a nomadic organism [ 8 ]  and strains have been isolated from many different environments including the vagina and the gastrointestinal tract.  L. rhamnosus  strains have the capacity for strain-specific gene functions that are required to adapt to a large range of environments. [ 9 ]  Its core  genome  contains 2,164 genes, out of 4,711 genes in total (the  pan-genome ). [ 9 ]  The accessory genome is overtaken by genes encoding carbohydrate transport and metabolism,  extracellular polysaccharides ,  biosynthesis ,  bacteriocin  production,  pili  production, the  CRISPR-Cas system , the clustered regularly interspaced short palindromic repeat ( CRISPR ) loci, and more than 100 transporter functions and mobile genetic elements such as  phages ,  plasmid  genes, and  transposons . [ 9 ]


The genome of the specific strain  L. rhamnosus  LRB, in this case, taken from a human baby tooth, consists of a circular chromosome of 2,934,954 bp with 46.78% GC content. [ 10 ]  This genome contains 2,749 total genes with 2,672 that are total protein-coding sequences. [ 10 ]  This sample did not contain any plasmids. [ 10 ]  The most extensively studied strain,  L. rhamnosus  GG, a gut isolate, consists of a genome of 3,010,111 bp. Therefore, the LRB genome is shorter than GG’s genome. LRB lacks the spaCBA gene cluster of GG and is not expected to produce functional pili (6). [ 10 ]  This difference may help explain why each strain lives in a different habitat.


Lacticaseibacillus rhamnosus  GG (ATCC 53103) is a  strain  of  L. rhamnosus  that was isolated in 1983 from the intestinal tract of a healthy human being; filed for a patent on 17 April 1985, by  Sherwood Gorbach  and Barry Goldin, [ 11 ]  the 'GG' derives from the first letters of their surnames. [ 12 ]  The patent refers to a strain of " L. acidophilus  GG" with  American Type Culture Collection  (ATCC) accession number 53103; later reclassified as a strain of  L. rhamnosus . The patent claims the  L. rhamnosus  GG (ATCC 53103) strain is acid- and bile-stable, has a great  avidity  for human intestinal mucosal cells, and produces  lactic acid . Since the discovery of the  L. rhamnosus  GG (ATCC 53103) strain, it has been studied extensively on its various health benefits and currently  L. rhamnosus  GG (ATCC 53103) strain is the world's most studied probiotic bacterium with more than 800 scientific studies.


The genome sequence of  Lactobacillus rhamnosus  GG (ATCC 53103) has been decoded in 2009. [ 13 ] [ 14 ]


In 1983,  L. rhamnosus  GG was isolated from the intestinal tract of a healthy human by Sherwood Gorbach and Barry Goldin.


While  L. rhamnosus  GG (ATCC 53103) is able to survive the acid and bile of the stomach and intestine, [ 15 ]  is claimed to colonize the digestive tract, and to balance intestinal microbiota, evidence suggests that  L. rhamnosus , comparable to virtually all probiotic lactobacilli, is only a transient inhabitant and not  autochthonous . [ 16 ]   Lactobacillus rhamnosus  GG binds to the gut mucosa. [ 17 ]  These features make it a favorable organism for the investigation of probiotic supplementation as a potential treatment for a variety of disease states.


Lacticaseibacillus rhamnosus  GG is beneficial in the prevention of  rotavirus   diarrhea  in children. Prevention and treatment of various types of  diarrhea  have been shown in children and in adults. [ 18 ] [ 19 ]   L. rhamnosus  GG can be beneficial in the prevention of antibiotic-associated diarrhea and nosocomial diarrhea and this has been recently supported by European guidelines. [ 20 ] [ 21 ] [ 22 ]   Lactobacillus rhamnosus  GG may reduce the risk of traveler's diarrhea. [ 23 ]


A position paper published by ESPGHAN Working Group for Probiotics and Prebiotics based on a systematic review and  randomized controlled trials  (RCTs) suggested that  L. rhamnosus  GG (low quality of evidence, strong recommendation) may be considered in the management of children with acute  gastroenteritis  in addition to  rehydration therapy . [ 24 ]


Lacticaseibacillus rhamnosus  GG has been found to be ineffective for treating eczema. [ 25 ]  However in one non-randomized clinical observation [ 26 ]  dealing with resistant childhood atopic eczema, a substantial improvement in quality of life was reported in pediatric patients given Lactobacillus rhamnosus as a supplement.


The use of  L. rhamnosus  GG for  probiotic  therapy has been linked with rare cases of  sepsis  in certain risk groups, primarily those with a  weakened immune system  and infants. [ 27 ]  Ingestion of GG is considered to be safe and data show a significant growth in the consumption of  L. rhamnosus  GG at the population level did not lead to an increase in  Lactobacillus   bacteraemia  cases. [ 28 ]


Lacticaseibacillus rhamnosus  GR-1 was originally found in the urethra of a healthy female and is nowadays a model strain for vaginal probiotics. A genome comparison between  L. rhamnosus  GG and  L. rhamnosus  GR-1 shows that GR-1 lacks  spaCBA -encoded pili, an important adhesin in  L. rhamnosus  GG adhesion to the intestinal epithelial cells. [ 29 ]  In contrast,  L. rhamnosus  GR-1 utilises  lectin -like proteins to attach to carbohydrates on the surface of the target cell. Lectin-like proteins preferentially bind to nonkeratinized stratified squamous cells which are found in the urethra and vagina. The lectin-like protein 1 purified from  L. rhamnosus  GR-1 is found to prevent infection by the uropathogenic  E. coli  UTI89 by inhibiting its adhesion to epithelial cells and by disrupting its  biofilm  formation. [ 30 ]  Additionally, it can increase biofilm formation in other beneficial lactobacilli that inhabit the vagina.


Salminen MK, Rautelin H, Tynkkynen S, Poussa T, Saxelin M, Valtonen V, Järvinen A (January 2004). "Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG".  Clinical Infectious Diseases .  38  (1):  62– 9.  doi : 10.1086/380455 .  PMID   14679449 .


Lactiplantibacillus plantarum  (formerly  Lactobacillus arabinosus  and  Lactobacillus plantarum ) [ 3 ]  is a widespread member of the genus  Lactiplantibacillus  and commonly found in many fermented food products as well as anaerobic plant matter. [ 4 ]   L. plantarum  was first isolated from  saliva . Based on its ability to temporarily persist in plants, the insect intestine and in the intestinal tract of vertebrate animals, it was designated as a nomadic organism. [ 5 ] [ 6 ]   L. plantarum  is Gram positive, bacilli shaped bacterium.  L. plantarum  cells are rods with rounded ends, straight, generally 0.9–1.2 μm wide and 3–8 μm long, occurring singly, in pairs or in short chains. [ 7 ]   L. plantarum  has one of the largest  genomes  known among the  lactic acid bacteria  and is a very flexible and versatile species. It is estimated to grow between pH 3.4 and 8.8. [ 8 ]   Lactiplantibacillus plantarum  can grow in the temperature range 12 °C to 40 °C. [ 9 ]  The viable counts of the "L. plantarum" stored at refrigerated condition (4 °C) remained high, while a considerable reduction in the counts was observed stored at room temperature (25 ± 1 °C). [ 10 ]


Lactiplantibacillus plantarum  are homofermentative,  aerotolerant   Gram-positive bacteria  that grow at 15 °C (59 °F), but not at 45 °C (113 °F), and produce both isomers of  lactic acid  ( D and L ).  Many lactobacilli including  L. plantarum  are unusual in that they can respire oxygen and express  cytochromes  if heme and menaquinone are present in the growth medium. [ 11 ] [ 12 ]  In the absence of heme and menaquinone, oxygen is consumed by NADH-peroxidase with  hydrogen peroxide  as intermediate and water as end product. [ 11 ] [ 12 ]   The peroxide, it is presumed, acts as a weapon to exclude competing bacteria from the food source. In place of the protective enzyme  superoxide dismutase  present in almost all other oxygen-tolerant cells, this organism accumulates millimolar quantities of  manganese   polyphosphate . Manganese is also used by  L. plantarum  in a  pseudo-catalase  to lower reactive oxygen levels. Because the chemistry by which manganese complexes protect the cells from oxygen damage is subverted by  iron , these cells contain virtually no iron atoms; in contrast, a cell of  Escherichia coli  of comparable volume contains over one-million iron atoms. Because of this,  L. plantarum  cannot be used to create active enzymes that require a  heme  complex, such as true catalases. [ 13 ]


L. plantarum  can also reduce insoluble terminal electron acceptors, such as iron oxides or solid electrodes through extracellular electron transfer when riboflavin and quinone (such as 1 4-dihydroxy-2-naphthoic acid, DHNA) are present. [ 14 ] [ 15 ]   L. plantarum  uses extracellular electron transfer to increase the NAD + /NADH ratio, accelerate fermentation, generate more ATP through the substrate-level phosphorylation, and accumulate more biomass. [ 14 ]


Lactiplantibacillus plantarum , like many lactobacilli, can be cultured using  MRS  media. [ 16 ]


The genome sequencing of the lactic acid bacterium  L. plantarum  WCFS1 shows more molecular details. The chromosome contains 3,308,274 base pairs. [ 17 ]  The GC content of  L. plantarum  is 44.45% with the average protein count 3063. According to the experiment from Wageningen Centre for Food Sciences, the rRNA number of  L. plantarum  WCFS1 is 15, and the number or tRNA is 70. [ 7 ]


Lactiplantibacillus plantarum  is the most common bacterium used in  silage   inoculants . During the anaerobic conditions of ensilage, these organisms quickly dominate the microbial population, and, within 48 hours, they begin to produce lactic and acetic acids via the  Embden-Meyerhof Pathway , further diminishing their competition. Under these conditions,  L. plantarum  strains producing high levels of  heterologous  proteins have been found to remain highly competitive. This quality could allow this species to be utilized as an effective biological pretreatment for  lignocellulosic biomass . [ 18 ]


Lactiplantibacillus plantarum  is commonly found in milk products, meat and a lot of vegetable fermentations including  sauerkraut , pickles, brined  olives , Korean  kimchi , Nigerian  Ogi ,  sourdough , and other fermented plant material, and also some  cheeses ,  fermented sausages , and  stockfish .  The high levels of this organism in food also makes it an ideal candidate for the development of  probiotics . In a 2008 study by Juana Frias et al.,  L. plantarum  was applied to reduce the allergenicity of  soy flour . The result showed that, compared to other microbes,  L. plantarum -fermented soy flour showed the highest reduction in  IgE   immunoreactivity  (96–99%), depending upon the sensitivity of the plasma used.  L. plantarum   is also found in  dadiah , a traditional fermented  buffalo  milk of the  Minangkabau people , native to  Sumatra ,  Indonesia . [ 19 ]


Lactobacillus plantarum  strain K21 is a  gram-positive   bacteria  isolated from  fermented  vegetables. It has the ability to hydrolyze  bile salt  when it is provided as a supplement. In fat mice, K21 also reduces the levels of  cholesterol  and  triglyceride , and inhibits the accumulation of lipid in 3T3-L1  preadipocytes .
Furthermore, it reduces the level of plasma  leptin , mitigates liver damage and alleviates  glucose intolerance . Finally K21 inhibits body weight gain and fat mass accumulation. [ 20 ]


Because it is abundant, of human origin, and easy to grow,  L. plantarum  has been tested for health effects. It has been identified as a probiotic, which suggests its value for further research and application. [ 21 ]   L. plantarum  has significant antioxidant activities and also helps to maintain  intestinal permeability . [ 22 ]  It is able to suppress the growth of gas-producing bacteria in the intestines and may benefit some patients who suffer from  IBS . [ 23 ]  It helps to create microbe balance and stabilize digestive enzyme patterns. [ 17 ]   Lactiplantibacillus plantarum  has been found in experiments to increase  hippocampal   brain derived neurotrophic factor , which means  L. plantarum  may have a beneficial role in the treatment of depression. [ 24 ]  The ability of  L. plantarum  to survive in the  human gastro-intestinal tract  makes it a possible  in vivo  delivery vehicle for therapeutic compounds or proteins.


Lactiplantibacillus plantarum  is a constituent in  VSL#3 . This proprietary, standardized formulation of live bacteria may be used in combination with conventional therapies to treat  ulcerative colitis  and requires a prescription. [ 25 ]


The ability of  L. plantarum  to produce antimicrobial substances helps them survive in the  gastrointestinal tract  of humans. The antimicrobial substances produced have shown significant effect on  Gram-positive  and  Gram-negative bacteria . [ citation needed ]


As a result of initial  HIV  infection, the gut has been found to be a prime center of immune activity. [ 26 ]   The immune systems'  Paneth cells  of the gut attack HIV by producing  interleukin 1 beta  (IL-1β), which results in extensive collateral damage—sloughing of tight intestinal lining, witnessed as severe  diarrhea . This destruction of the gut lining allows fungal pathogens to invade, e.g.,  Cryptococcus  species, resulting in an  AIDS-defining illness  such as  cryptococcosis , representing 60% to 70% of all AIDS-defining cases, [ 27 ]  but not necessarily only the gut. In  rhesus macaques ,  L. plantarum  is able to reduce (destroy) IL-1β, resolving inflammation, and accelerating gut repair within hours. [ 26 ]


The entire  genome  has recently been sequenced, and  promoter  libraries have been developed for both conditional and constitutive gene expression, adding to the utility of  L. plantarum . It is also commonly employed as the indicative organism in  niacin   bioassay  experiments, in particular,  AOAC International  Official Method 944.13, as it is a niacin  auxotroph . [ 28 ] [ 29 ]


Lactose intolerance  is caused by a lessened ability or a complete inability to digest  lactose , a sugar found in  dairy products . [ 1 ]  Humans vary in the amount of lactose they can tolerate before symptoms develop. [ 1 ]  Symptoms may include  abdominal pain ,  bloating ,  diarrhea ,  flatulence , and  nausea . [ 1 ]  These symptoms typically start thirty minutes to two hours after eating or drinking something containing lactose, [ 1 ]  with the severity typically depending on the amount consumed. [ 1 ]  Lactose intolerance does not cause damage to the  gastrointestinal tract . [ 2 ]


Lactose intolerance is due to the lack of the  enzyme   lactase  in the  small intestines  to break lactose down into  glucose  and  galactose . [ 3 ]  There are four types: primary, secondary, developmental, and congenital. [ 1 ]  Primary lactose intolerance occurs as the amount of lactase declines as people grow up. [ 1 ]  Secondary lactose intolerance is due to injury to the small intestine. Such injury could be the result of infection,  celiac disease ,  inflammatory bowel disease , or other diseases. [ 1 ] [ 4 ]  Developmental lactose intolerance may occur in  premature babies  and usually improves over a short period of time. [ 1 ]  Congenital lactose intolerance is an extremely rare  genetic disorder  in which little or no lactase is made from birth. [ 1 ]  The reduction of lactase production starts typically in late childhood or early adulthood, [ 1 ]  but prevalence increases with age. [ 5 ]


Diagnosis may be confirmed if symptoms resolve following eliminating lactose from the diet. [ 1 ]  Other supporting tests include a  hydrogen breath test  and a  stool acidity test . [ 1 ]  Other conditions that may produce similar symptoms include  irritable bowel syndrome ,  celiac disease , and  inflammatory bowel disease . [ 1 ]  Lactose intolerance is different from a  milk allergy . [ 1 ]  Management is typically by decreasing the amount of lactose in the diet, taking  lactase supplements , or treating the underlying disease. [ 1 ] [ 6 ]  People are typically able to drink at least one cup of milk without developing symptoms, with greater amounts tolerated if drunk with a meal or throughout the day. [ 1 ] [ 7 ]


Worldwide, around 65% of adults are affected by lactose malabsorption. [ 5 ] [ 8 ]  Other  mammals  usually lose the ability to digest lactose after  weaning . Lactose intolerance is the  ancestral state  of all humans before the  recent evolution  of  lactase persistence  in some cultures, which extends lactose tolerance into adulthood. [ 9 ]  Lactase persistence evolved in several populations independently, probably as an adaptation to the  domestication  of  dairy animals  around 10,000 years ago. [ 10 ] [ 11 ]  Today the prevalence of lactose tolerance varies widely between regions and ethnic groups. [ 5 ]  The ability to digest lactose is most common in people of Northern European descent, and to a lesser extent in some parts of the Middle East and Africa. [ 5 ] [ 8 ]  Lactose intolerance is most common among people of East Asian descent, with 90% lactose intolerance, people of Jewish descent, in many  African countries  and  Arab countries , and among people of Southern European descent (notably amongst Greeks and Italians).  Traditional food  cultures reflect local variations in tolerance [ 5 ]  and historically many societies have adapted to low levels of tolerance by making  dairy products  that contain less lactose than fresh milk. [ 12 ]  The  medicalization  of lactose intolerance as a disorder has been attributed to biases in research history, since most early studies were conducted amongst populations which are normally tolerant, [ 9 ]  as well as the cultural and economic importance and impact of milk in countries such as the United States. [ 13 ]


Lactose intolerance  primarily refers to a syndrome with one or more symptoms upon the consumption of food substances containing  lactose sugar . Individuals may be lactose intolerant to varying degrees, depending on the severity of these symptoms.


Hypolactasia  is the term specifically for the  small intestine  producing little or no  lactase enzyme . [ 14 ]  If a person with hypolactasia consumes lactose sugar, it results in  lactose malabsorption . [ 2 ]  The digestive system is unable to process the lactose sugar, and the unprocessed sugars in the gut produce the symptoms of  lactose intolerance .


Lactose intolerance is not an  allergy , because it is not an immune response, but rather a sensitivity to dairy caused by a deficiency of lactase enzyme.  Milk allergy , occurring in about 2% of the population, is a separate condition, with distinct symptoms that occur when the presence of milk proteins trigger an immune reaction. [ 15 ]


The principal manifestation of lactose intolerance is an adverse reaction to products containing lactose (primarily milk), including abdominal  bloating  and  cramps ,  flatulence ,  diarrhea ,  nausea ,  borborygmi , and  vomiting  (particularly in  adolescents ). These appear one-half to two hours after consumption. [ 1 ]  The severity of these signs and symptoms typically increases with the amount of lactose consumed; most lactose-intolerant people can tolerate a certain level of lactose in their diets without ill effects. [ 16 ] [ 17 ]


Because lactose intolerance is not an allergy, it does not produce  allergy symptoms  (such as itching,  hives , or  anaphylaxis ).


Lactose intolerance is a consequence of  lactase  deficiency, which may be genetic ( primary hypolactasia  and  primary congenital alactasia ) or environmentally induced ( secondary or acquired hypolactasia ). In either case, symptoms are caused by insufficient levels of lactase in the lining of the  duodenum . Lactose, a  disaccharide  molecule found in milk and dairy products, cannot be directly absorbed through the wall of the small intestine into the bloodstream, so, in the absence of lactase, passes intact into the  colon . [ citation needed ]   Bacteria  in the colon can metabolise lactose, and the resulting  fermentation  produces copious amounts of gas (a mixture of  hydrogen ,  carbon dioxide , and  methane ) that causes the various abdominal symptoms. The unabsorbed sugars and fermentation products also raise the  osmotic pressure  of the colon, causing an increased flow of water into the bowels (diarrhea). [ 18 ] [ 9 ]


Lactose intolerance in infants (congenital lactase deficiency) is caused by mutations in the  LCT  gene. The  LCT  gene provides the instructions for making lactase. Mutations are believed to interfere with the function of lactase, causing affected infants to have a severely impaired ability to digest lactose in breast milk or formula. [ 19 ]  Lactose intolerance in adulthood is a result of gradually decreasing activity (expression) of the  LCT  gene after infancy, which occurs in most humans. The specific DNA sequence in the  MCM6  gene helps control whether the  LCT  gene is turned on or off. [ 20 ]  At least several thousand years ago, some humans developed a mutation in the  MCM6  gene that keeps the  LCT  gene turned on even after breast feeding is stopped. [ 21 ]  Populations that are lactose intolerant lack this mutation.  The  LCT  and  MCM6  genes are both located on the long arm (q) of chromosome 2 in region 21. The locus can be expressed as 2q21. [ 21 ]  The lactase deficiency also could be linked to certain heritages and varies widely. A 2016 study of over 60,000 participants from 89 countries found regional prevalence of lactose malabsorption was "64% (54–74) in Asia (except Middle East), 47% (33–61) in eastern Europe, Russia, and former Soviet Republics, 38% (CI 18–57) in Latin America, 70% (57–83) in the Middle East, 66% (45–88) in northern Africa, 42% (13–71) in northern America, 45% (19–71) in Oceania, 63% (54–72) in sub-Saharan Africa, and 28% (19–37) in northern, southern and western Europe." [ 5 ]  According to Johns Hopkins Medicine, lactose intolerance is more common in Asian Americans, African Americans, Mexican Americans, and Native Americans. [ 22 ]  Analysis of the DNA of 94 ancient skeletons in Europe and Russia concluded that the mutation for lactose tolerance appeared about 4,300 years ago and spread throughout the European population. [ 23 ]


Some human populations have developed  lactase persistence , in which lactase production continues into adulthood probably as a response to the benefits of being able to digest milk from farm animals. Some have argued that this links intolerance to  natural selection  favoring lactase-persistent individuals, but it is also consistent with a physiological response to decrease lactase production when it is not needed in cultures in which dairy products are not an available food source. [ 24 ]  Although populations in Europe, India, Arabia, and Africa were first thought to have high rates of lactase persistence because of a single mutation, lactase persistence has been traced to a number of mutations that occurred independently. [ 11 ]  Different alleles for lactase persistence have developed at least three times in East African populations, with persistence extending from 26% in  Tanzania  to 88% in the  Beja  pastoralist population in  Sudan . [ 25 ]


The accumulation of  epigenetic  factors, primarily  DNA methylation , in the extended LCT region, including the gene  enhancer  located in the  MCM6  gene near C/T-13910 SNP, may also contribute to the onset of lactose intolerance in adults. [ 26 ] [ 27 ]  Age-dependent expression of  LCT  in mice intestinal epithelium has been linked to DNA methylation in the gene enhancer. [ 27 ]


Lactose intolerance is classified according to its causes as:


In order to assess lactose intolerance, intestinal function is challenged by ingesting more dairy products than can be readily digested.  Clinical symptoms typically appear within 30 minutes, but may take up to two hours, depending on other foods and activities. [ 35 ]   Substantial variability in response (symptoms of nausea, cramping, bloating, diarrhea, and flatulence) is to be expected, as the extent and severity of lactose intolerance varies among individuals. [ 36 ]


The next step is to determine whether it is due to primary lactase deficiency or an underlying disease that causes secondary lactase deficiency. [ 2 ]  Physicians should investigate the presence of undiagnosed  coeliac disease ,  Crohn's disease , or other  enteropathies  when secondary lactase deficiency is suspected and infectious gastroenteritis has been ruled out. [ 2 ]


Lactose intolerance is distinct from  milk allergy , an immune response to cow's milk proteins. They may be distinguished in diagnosis by giving lactose-free milk, producing no symptoms in the case of lactose intolerance, but the same reaction as to normal milk in the presence of a milk allergy. A person can have both conditions. If positive confirmation is necessary, four tests are available. [ 37 ]


In a  hydrogen breath test , the most accurate lactose intolerance test, after an overnight fast, 25 grams of lactose (in a solution with water) are swallowed. If the lactose cannot be digested, enteric bacteria metabolize it and produce hydrogen, which, along with methane, if produced, can be detected on the patient's breath by a clinical gas chromatograph or compact solid-state detector. The test takes about 2.5 hours to complete. If the hydrogen levels in the patient's breath are high, they may have lactose intolerance. This test is not usually done on babies and very young children, because it can cause severe diarrhea. [ 38 ]


In conjunction, measuring blood glucose level every 10 to 15 minutes after ingestion will show a "flat curve" in individuals with lactose malabsorption, while the lactase persistent will have a significant "top", with a typical elevation of 50% to 100%, within one to two hours. However, due to the need for frequent blood sampling, this approach has been largely replaced by breath testing. [ 39 ]


After an overnight fast, blood is drawn and then 50 grams of lactose (in aqueous solution) are swallowed. Blood is then drawn again at the 30-minute, 1-hour, 2-hour, and 3-hour marks.  If the lactose cannot be digested, blood glucose levels will rise by less than 20 mg/dl. [ 40 ]


This test can be used to diagnose lactose intolerance in infants, for whom other forms of testing are risky or impractical. [ 41 ]  The infant is given lactose to drink. If the individual is tolerant, the lactose is digested and absorbed in the small intestine; otherwise, it is not digested and absorbed, and it reaches the colon. The bacteria in the colon, mixed with the lactose, cause acidity in stools. Stools passed after the ingestion of the lactose are tested for level of acidity. If the stools are acidic, the infant is intolerant to lactose. [ 42 ]
Stool pH in lactose intolerance is less than 5.5.


An intestinal biopsy must confirm lactase deficiency following discovery of elevated hydrogen in the hydrogen breath test. [ 43 ]   Modern techniques have enabled a bedside test, identifying presence of lactase enzyme on upper gastrointestinal endoscopy instruments. [ 44 ]   However, for research applications such as  mRNA  measurements, a specialist laboratory is required.


Chromatography can be used to separate and identify undigested sugars present in faeces. Although lactose may be detected in the faeces of people with lactose intolerance, this test is not considered reliable enough to conclusively diagnose or exclude lactose intolerance. [ citation needed ]


Genetic tests may be useful in assessing whether a person has primary lactose intolerance. Lactase activity persistence in adults is associated with two  polymorphisms : C/T 13910 and G/A 22018 located in the  MCM6  gene. [ 28 ]  These polymorphisms may be detected by  molecular biology  techniques at the  DNA  extracted from blood or saliva samples; genetic kits specific for this diagnosis are available. The procedure consists of extracting and amplifying DNA from the sample, following with a hybridation protocol in a strip. Colored bands are obtained as result, and depending on the different combinations, it would be possible to determine whether the patient is lactose intolerant. This test allows a noninvasive definitive diagnostic. [ citation needed ]


When lactose intolerance is due to secondary lactase deficiency, treatment of the underlying disease may allow lactase activity to return to normal levels. [ 6 ]  In people with celiac disease, lactose intolerance normally reverts or improves several months after starting a  gluten-free diet , but temporary dietary restriction of lactose may be needed. [ 4 ] [ 45 ]


People with primary lactase deficiency cannot modify their body's ability to produce lactase. [ 1 ]  In societies where lactose intolerance is the norm, it is not considered a condition that requires treatment. However, where dairy is a larger component of the normal diet, a number of efforts may be useful. There are four general principles in dealing with lactose intolerance: avoidance of dietary lactose, substitution to maintain nutrient intake, regulation of calcium intake, and use of enzyme substitute. [ 43 ]  Regular consumption of dairy food by lactase deficient individuals may also reduce symptoms of intolerance by promoting colonic bacteria adaptation. [ 46 ]


The primary way of managing the symptoms of lactose intolerance is to limit the intake of lactose to a level that can be tolerated. [ 47 ]  Lactase deficient individuals vary in the amount of lactose they can tolerate, [ 1 ]  and some report that their tolerance varies over time, depending on health status and pregnancy. [ 48 ] [ 49 ]  However, as a rule of thumb, people with primary lactase deficiency and no small intestine injury are usually able to consume at least 12 grams of lactose per sitting without symptoms, or with only mild symptoms, with greater amounts tolerated if consumed with a meal or throughout the day. [ 1 ] [ 49 ] [ 46 ]


Lactose is found primarily in  dairy products , which vary in the amount of lactose they contain:


There used to be [ 59 ]  a lack of standardization on how lactose is measured and reported in food. The different molecular weights of anhydrous lactose or lactose monohydrate result in up to 5% difference. [ 60 ]  One source recommends using the "carbohydrates" or "sugars" part of the nutritional label as surrogate for lactose content, [ 57 ]  but such "lactose by difference" values are not assured to correspond to real lactose content. [ 59 ]  The stated dairy content of a product also varies according to manufacturing processes and labelling practices, and commercial terminology varies between languages and regions. [ 43 ]  As a result, absolute figures for the amount of lactose consumed (by weight) may not be very reliable.


Kosher  products labeled  pareve  or  fleishig  are free of milk. However, if a "D" (for "dairy") is present next to the circled "K", "U", or other  hechsher , the food product likely contains milk solids, [ 61 ]  although it may also simply indicate the product was produced on equipment shared with other products containing milk derivatives.


Lactose is also a commercial  food additive  used for its texture, flavor, and adhesive qualities. It is found in additives labelled as  casein ,  caseinate ,  whey ,  lactoserum ,  milk solids ,  modified milk ingredients , etc. [ citation needed ]  As such, lactose is found in foods such as processed meats ( sausages / hot dogs , sliced meats,  pâtés ), [ 61 ]  gravy stock powder,  margarines , [ 62 ]  sliced  breads , [ 63 ] [ 64 ]  breakfast cereals,  potato chips , [ 65 ]   processed foods ,  medications , prepared meals, meal replacements (powders and bars), protein supplements (powders and bars), and even  beers  in the  milk stout  style. Some barbecue sauces and liquid cheeses used in fast-food restaurants may also contain lactose. When dining out, carrying lactose intolerance cards that explain dietary restrictions in the local language can help communicate needs to restaurant staff. [ 66 ]  Lactose is often used as the primary filler (main ingredient) in most prescription and non-prescription solid pill form medications, though product labeling seldom mentions the presence of 'lactose' or 'milk', and neither do product monograms provided to pharmacists, and most pharmacists are unaware of the very wide scale yet common use of lactose in such medications until they contact the supplier or manufacturer for verification. [ citation needed ]


Plant-based milks  and derivatives such as  soy milk ,  rice milk ,  almond milk ,  coconut milk ,  hazelnut  milk,  oat milk ,  hemp milk , macadamia nut milk, and  peanut milk  are inherently lactose-free.  Low-lactose and lactose-free versions of foods are often available to replace dairy-based foods for those with lactose intolerance. [ 67 ]


When lactose avoidance is not possible, or on occasions when a person chooses to consume such items, then enzymatic lactase supplements may be used. [ 68 ] [ 69 ]


Lactase enzymes similar to those produced in the small intestines of humans are produced industrially by  fungi  of the  genus   Aspergillus . The enzyme,  β-galactosidase , is available in tablet form in a variety of doses, in many countries without a prescription. It functions well only in high-acid environments, such as that found in the human gut due to the addition of gastric juices from the stomach. Unfortunately, too much acid can denature it, [ 70 ]  so it should not be taken on an empty stomach. Also, the enzyme is ineffective if it does not reach the small intestine by the time the problematic food does. Lactose-sensitive individuals can experiment with both timing and dosage to fit their particular needs.


While essentially the same process as normal intestinal lactose digestion, direct treatment of milk employs a different variety of industrially produced lactase. This enzyme, produced by  yeast  from the genus  Kluyveromyces , takes much longer to act, must be thoroughly mixed throughout the product, and is destroyed by even mildly acidic environments. Its main use is in producing the lactose-free or lactose-reduced dairy products sold in supermarkets. [ 71 ]


Regular consumption of dairy foods containing lactose can promote a colonic bacteria adaptation, enhancing a favorable microbiome, which allows people with primary lactase deficiency to diminish their intolerance and to consume more dairy foods. [ 46 ] [ 49 ] [ 72 ]  The way to induce tolerance is based on progressive exposure, consuming smaller amounts frequently, distributed throughout the day. [ 73 ]  Lactose intolerance can also be managed by ingesting live yogurt cultures containing  lactobacilli  that are able to digest the lactose in other dairy products. [ 74 ]


Worldwide, about 65% of people experience some form of lactose intolerance as they age past infancy, but there are significant differences between populations and regions. As few as 5% of northern Europeans are lactose intolerant, while as many as 90% of adults in parts of Asia are lactose intolerant. [ 76 ]


In northern European countries, early adoption of dairy farming conferred a selective evolutionary advantage to individuals that could tolerate lactose. This led to higher frequencies of lactose tolerance in these countries. For example, almost 100% of  Irish people  are predicted to be lactose tolerant. [ 77 ]  Conversely, regions of the south, such as Africa, did not adopt dairy farming as early and tolerance from milk consumption did not occur the same way as in northern Europe. [ 46 ]  Lactose intolerance is common among people of Jewish descent, as well as from West Africa, the Arab countries, Greece, and Italy. [ 76 ]  Different populations will present certain gene constructs depending on the evolutionary and cultural pre-settings of the geographical region. [ 46 ]


Greater lactose tolerance has come about in two ways. [ 78 ]  Some populations have developed genetic changes to allow the digestion of lactose:  lactase persistence . [ 78 ]  Other populations developed cooking methods like milk fermentation. [ 78 ]


Lactase persistence in humans evolved relatively recently (in the last 10,000 years) among some populations. Around 8,000 years ago in modern-day Turkey, humans became reliant on newly-domesticated animals that could be milked; such as cows, sheep, and goats. This resulted in higher frequency of lactase persistence. [ 79 ]  Lactase persistence became high in regions such as Europe, Scandinavia, the Middle East and Northwestern India. However, most people worldwide remain lactase  non -persistent. [ 9 ]  Populations that raised animals not used for milk tend to have 90–100 percent of a lactose intolerant rate. [ 80 ]  For this reason, lactase persistence is of some interest to the fields of  anthropology ,  human genetics , and  archaeology , which typically use the genetically derived persistence/non-persistence terminology. [ 81 ]


The rise of dairy and producing dairy related products from cow milk alone, varies across different regions of the world, aside from genetic predisposition. [ 46 ]  The process of turning milk into cheese dates back earlier than 5200 BC. [ 82 ]


DNA analysis in February 2012 revealed that  Ötzi  was lactose intolerant, supporting the theory that lactose intolerance was still common at that time, despite the increasing spread of agriculture and dairying. [ 83 ]


Genetic analysis shows lactase persistence has developed several times in different places independently in an example of  convergent evolution . [ 25 ]


It was not until relatively recently that  medicine  recognised the worldwide prevalence of lactose intolerance and its genetic causes. Its symptoms were described as early as  Hippocrates  (460–370 BC), [ 84 ]  but until the 1960s, the prevailing assumption was that tolerance was the norm. Intolerance was explained as the result of a milk allergy, intestinal pathogens, or as being  psychosomatic  – it being recognised that some cultures did not practice dairying, and people from those cultures often reacted badly to consuming milk. [ 85 ] [ 86 ]  Two reasons have been given for this misconception. One was that early research was conducted solely on European-descended populations, which have an unusually low incidence of lactose intolerance [ 87 ]  and an extensive cultural history of dairying. As a result, researchers wrongly concluded that tolerance was the global norm. Another reason is that lactose intolerance tends to be under-reported: lactose intolerant individuals can tolerate at least some lactose before they show symptoms, and their symptoms differ in severity. The large majority of people are able to digest some quantity of milk, for example in tea or coffee, without developing any adverse effects. [ 16 ]   Fermented dairy products , such as cheese, also contain significantly less lactose than plain milk. Therefore, in societies where tolerance is the norm, many lactose intolerant people who consume only small amounts of dairy, or have only mild symptoms, may be unaware that they cannot digest lactose.


Eventually, in the 1960s, it was recognised that lactose intolerance was correlated with  race  in the United States. [ 88 ] [ 89 ] [ 90 ]  Subsequent research revealed that lactose intolerance was more common globally than tolerance, [ 91 ] [ 92 ] [ 93 ] [ 94 ] [ 95 ]  and that the variation was due to genetic differences, not an adaptation to cultural practices. [ 86 ] [ 96 ]


Most  mammals  normally cease to produce lactase and become lactose intolerant after  weaning . [ 9 ]  The downregulation of lactase expression in  mice  could be attributed to the accumulation of  DNA methylation  in the  Lct  gene and the adjacent  Mcm6  gene. [ 97 ]


The  large intestine , also known as the  large bowel , is the last part of the  gastrointestinal tract  and of the  digestive system  in  tetrapods . Water is absorbed here and the remaining waste material is stored in the  rectum  as  feces  before being removed by  defecation . [ 1 ]  The  colon  (progressing from the  ascending colon  to the  transverse , the  descending  and finally the  sigmoid colon ) is the longest portion of the large intestine, and the terms "large intestine" and "colon" are often used interchangeably, but most sources define the large intestine as the combination of the  cecum , colon,  rectum , and  anal canal . [ 1 ] [ 2 ] [ 3 ]  Some other sources exclude the anal canal. [ 4 ] [ 5 ] [ 6 ]


In humans, the large intestine begins in the right  iliac region  of the  pelvis , just at or below the  waist , where it is joined to the end of the  small intestine  at the cecum, via the  ileocecal valve . It then continues as the colon  ascending  the  abdomen , across the width of the  abdominal cavity  as the  transverse colon , and then  descending  to the rectum and its endpoint at the   anal canal . [ 7 ]  Overall, in humans, the large intestine is about 1.5 metres (5 ft) long, which is about one-fifth of the whole length of the human gastrointestinal tract. [ 8 ]


The  colon  of the large intestine is the last part of the  digestive system . It has a segmented appearance due to a series of saccules called  haustra . [ 9 ]  It extracts  water  and  salt  from  solid wastes  before they are  eliminated  from the body and is the site in which the  fermentation  of unabsorbed material by the  gut microbiota  occurs. Unlike the  small intestine , the colon does not play a major role in absorption of foods and nutrients. About 1.5 litres or 45 ounces of water arrives in the colon each day. [ 10 ]


The colon is the longest part of the large intestine and its average length in the adult human is 65 inches or 166 cm (range of 80 to 313 cm) for males, and 61 inches or 155 cm (range of 80 to 214 cm) for females. [ 11 ]


In  mammals , the large intestine consists of the  cecum  (including the  appendix ), colon (the longest part),  rectum , and  anal canal . [ 1 ]


The four sections of the colon are: the  ascending colon ,  transverse colon ,  descending colon , and  sigmoid colon . These sections turn at the  colic flexures .


The parts of the colon are either intraperitoneal or behind it in the  retroperitoneum . Retroperitoneal organs, in general, do not have a complete covering of  peritoneum , so they are fixed in location. Intraperitoneal organs are completely surrounded by peritoneum and are therefore mobile. [ 12 ]  Of the colon, the ascending colon, descending colon and rectum are retroperitoneal, while the cecum, appendix, transverse colon and sigmoid colon are intraperitoneal. [ 13 ]  This is important as it affects which organs can be easily accessed during surgery, such as a  laparotomy .


In terms of diameter, the cecum is the widest, averaging slightly less than 9 cm in healthy individuals, and the transverse colon averages less than 6 cm in diameter. [ 14 ]  The descending and sigmoid colon are slightly smaller, with the sigmoid colon averaging 4–5 cm (1.6–2.0 in) in diameter. [ 14 ] [ 15 ]  Diameters larger than certain thresholds for each colonic section can be diagnostic for  megacolon .


The  cecum  is the first section of the large intestine and is involved in digestion, while the  appendix  which develops embryologically from it, is not involved in digestion and is considered to be part of the  gut-associated lymphoid tissue . The function of the appendix is uncertain, but some sources believe that it has a role in housing a sample of the  gut microbiota , and is able to help to repopulate the colon with microbiota if depleted during the course of an immune reaction. The appendix has also been shown to have a high concentration of lymphatic cells.


The ascending colon is the first of four main sections of the large intestine. It is connected to the small intestine by a section of bowel called the cecum. The ascending colon runs upwards through the abdominal cavity toward the transverse colon for approximately eight inches (20 cm).


One of the main functions of the colon is to remove the water and other key nutrients from waste material and recycle it. As the waste material exits the small intestine through the  ileocecal valve , it will move into the cecum and then to the ascending colon where this process of extraction starts. The waste material is pumped upwards toward the transverse colon by  peristalsis . The ascending colon is sometimes attached to the  appendix  via  Gerlach's valve . In  ruminants , the ascending colon is known as the  spiral colon . [ 16 ] [ 17 ] [ 18 ]
Taking into account all ages and sexes, colon cancer occurs here most often (41%). [ 19 ]


The transverse colon is the part of the colon from the  hepatic flexure , also known as the right colic, (the turn of the colon by the  liver ) to the  splenic flexure  also known as the left colic, (the turn of the colon by the  spleen ). The transverse colon hangs off the  stomach , attached to it by a large fold of  peritoneum   called the  greater omentum . On the posterior side, the transverse colon is connected to the posterior abdominal wall by a  mesentery  known as the  transverse mesocolon .


The transverse colon is encased in  peritoneum , and is therefore mobile (unlike the parts of the colon immediately before and after it).


The proximal two-thirds of the transverse colon is perfused by the  middle colic artery , a branch of the  superior mesenteric artery  (SMA), while the latter third is supplied by branches of the  inferior mesenteric artery  (IMA). The "watershed" area between these two blood supplies, which represents the embryologic division between the  midgut  and  hindgut , is an area sensitive to  ischemia .


The descending colon is the part of the colon from the splenic flexure to the beginning of the sigmoid colon. One function of the descending colon in the digestive system is to store feces that will be emptied into the rectum. It is  retroperitoneal  in two-thirds of humans. In the other third, it has a (usually short) mesentery. [ 20 ]  The arterial supply comes via the  left colic artery . The descending colon is also called the  distal gut , as it is further along the gastrointestinal tract than the proximal gut. Gut flora are very dense in this region.


The sigmoid colon is the part of the large intestine after the descending colon and before the rectum. The name  sigmoid  means S-shaped (see  sigmoid ; cf.  sigmoid sinus ). The walls of the sigmoid colon are muscular and contract to increase the pressure inside the colon, causing the  stool  to move into the rectum.


The sigmoid colon is supplied with blood from several branches (usually between 2 and 6) of the  sigmoid arteries , a branch of the IMA. The IMA terminates as the  superior rectal artery .


Sigmoidoscopy  is a common diagnostic technique used to examine the sigmoid colon.


The  rectum  is the last section of the large intestine. It holds the formed feces awaiting elimination via defecation.
It is about 12 cm long. [ 21 ]


The  cecum  – the first part of the large intestine


The  taenia coli  run the length of the large intestine.  Because the taenia coli are shorter than the large bowel itself, the colon becomes  sacculated , forming the  haustra  of the colon which are the shelf-like intraluminal projections. [ 22 ]


Arterial  supply to the colon comes from branches of the  superior mesenteric artery  (SMA) and  inferior mesenteric artery  (IMA). Flow between these two systems communicates via the  marginal artery of the colon  that runs parallel to the colon for its entire length. Historically, a structure variously identified as the arc of Riolan or meandering mesenteric artery (of Moskowitz) was thought to connect the  proximal  SMA to the proximal IMA. This variably present structure would be important if either vessel were occluded. However, at least one review of the literature questions the existence of this vessel, with some experts calling for the abolition of these terms from future medical literature. [ 23 ]


Venous  drainage usually mirrors colonic arterial supply, with the  inferior mesenteric vein  draining into the  splenic vein , and the  superior mesenteric vein  joining the splenic vein to form the  hepatic portal vein  that then enters the  liver .  Middle rectal veins  are an exception, delivering blood to  inferior vena cava  and bypassing the liver. [ 24 ]


Lymphatic drainage  from the ascending colon and proximal two-thirds of the  transverse colon  is to the  ileocolic lymph nodes  and the  superior mesenteric lymph nodes , which drain into the  cisterna chyli . [ 25 ]  The lymph from the distal one-third of the  transverse colon , the  descending colon , the sigmoid colon, and the upper  rectum  drain into the inferior mesenteric and colic lymph nodes. [ 25 ]  The lower rectum to the anal canal above the pectinate line drain to the internal ileocolic nodes. [ 26 ]  The anal canal below the pectinate line drains into the superficial  inguinal  nodes. [ 26 ]  The  pectinate line  only roughly marks this transition.


Sympathetic supply: superior & inferior mesenteric ganglia;
parasympathetic supply: vagus & sacral plexus (S2-S4) [ citation needed ]


The endoderm, mesoderm and ectoderm are germ layers that develop in a process called gastrulation. Gastrulation occurs early in human development. The gastrointestinal tract is derived from these layers. [ 27 ]


One variation on the normal anatomy of the colon occurs when extra loops form, resulting in a colon that is up to five metres longer than normal. This condition, referred to as  redundant colon , typically has no direct major health consequences, though rarely  volvulus  occurs, resulting in obstruction and requiring immediate medical attention. [ 28 ] [ 29 ]  A significant indirect health consequence is that use of a standard adult  colonoscope  is difficult and in some cases impossible when a redundant colon is present, though specialized variants on the instrument (including the pediatric variant) are useful in overcoming this problem. [ 30 ]


The wall of the large intestine is lined with simple columnar  epithelium  with  invaginations .  The invaginations are called the  intestinal glands  or 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 cut across the long axes of the crypts and two cut parallel to the long axes.  In these images the cells have been stained by  immunohistochemistry  to show a brown-orange color if the cells produce a  mitochondrial  protein called  cytochrome c oxidase subunit I  (CCOI).  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.  Baker et al. [ 32 ]  found that the average crypt circumference is 23 cells.  Thus, by the images shown here, there are an average of about 1,725 to 2,530 cells per colonic crypt.  Nooteboom et al. [ 33 ]  measuring the number of cells in a small number of crypts reported a range of 1,500 to 4,900 cells per colonic crypt.  Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic  lumen  days later. [ 32 ]   There are 5 to 6 stem cells at the bases of the crypts. [ 32 ]


As estimated from the image in panel A, there are about 100 colonic crypts per square millimeter of the colonic epithelium. [ 34 ]   Since the average length of the human colon is 160.5 cm [ 11 ]  and the average inner circumference of the colon is 6.2 cm, [ 34 ]  the inner surface epithelial area of the human colon has an average area 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 percent of crypts deficient for CCOI is less than 1% before age 40, but then increases linearly with age. [ 31 ]  Colonic crypts deficient for CCOI in women reaches, on average, 18% in women and 23% in men by 80–84 years of age. [ 31 ]


Crypts of the colon can reproduce by fission, as seen in panel C, where a crypt is fissioning 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). [ 31 ]


About 150 of the many thousands of  protein coding genes  expressed in the large intestine, some are specific to the mucous membrane in different regions and include  CEACAM7 . [ 35 ]


The large intestine absorbs water and any remaining absorbable nutrients from the food before sending the indigestible matter to the rectum. The colon absorbs vitamins that are created by the colonic bacteria, such as  thiamine ,  riboflavin , and  vitamin K  (especially important as the daily ingestion of vitamin K is not normally enough to maintain adequate  blood coagulation ). [ 36 ] [ citation needed ] [ 37 ]  It also compacts feces, and stores fecal matter in the rectum until it can be discharged via the  anus  in  defecation .


The large intestine also secretes K+ and Cl-. Chloride secretion increases in cystic fibrosis.
Recycling of various nutrients takes place in the colon. Examples include fermentation of carbohydrates, short chain fatty acids, and urea cycling. [ 38 ] [ citation needed ]


The  appendix  contains a small amount of  mucosa-associated lymphoid tissue  which gives the appendix an undetermined role in immunity. However, the appendix is known to be important in fetal life as it contains  endocrine  cells that release biogenic amines and peptide hormones important for  homeostasis  during early growth and development. [ 39 ]


By the time the  chyme  has reached this tube, most  nutrients  and 90% of the water have been absorbed by the body. Indeed, as demonstrated by the commonality of  ileostomy  procedures, it is possible for many people to live without large portions of their large intestine, or even without it completely. At this point only some  electrolytes  like  sodium ,  magnesium , and  chloride  are left as well as indigestible parts of ingested food (e.g., a large part of ingested  amylose , starch which has been shielded from digestion heretofore, and  dietary fiber , which is largely indigestible  carbohydrate  in either soluble or insoluble form). As the chyme moves through the large intestine, most of the remaining  water  is removed, while the chyme is mixed with  mucus  and  bacteria  (known as  gut flora ), and becomes feces. The  ascending colon  receives fecal material as a liquid. The muscles of the colon then move the watery waste material forward and slowly absorb all the excess water, causing the stools to gradually solidify as they move along into the  descending colon . [ 40 ]


The bacteria break down some of the  fiber  for their own nourishment and create  acetate ,  propionate , and  butyrate  as waste products, which in turn are used by the cell lining of the colon for nourishment. [ 41 ]  No protein is made available. In humans, perhaps 10% of the undigested carbohydrate thus becomes available, though this may vary with diet; [ 42 ]  in other animals, including other apes and primates, who have proportionally larger colons, more is made available, thus permitting a higher portion of plant material in the diet.  The large intestine [ 43 ]  produces no digestive  enzymes  —  chemical digestion  is completed in the  small intestine  before the chyme reaches the large intestine. The  pH  in the colon varies between 5.5 and 7 (slightly  acidic  to neutral). [ 44 ]


Water absorption at the colon typically proceeds against a  transmucosal   osmotic pressure   gradient . The  standing gradient osmosis  is the reabsorption of water against the osmotic gradient in the intestines. Cells occupying the intestinal lining pump sodium ions into the intercellular space, raising the osmolarity of the intercellular fluid. This  hypertonic  fluid creates an osmotic pressure that drives water into the lateral intercellular spaces by osmosis via  tight junctions  and adjacent cells, which then in turn moves across the  basement membrane  and into the  capillaries , while more sodium ions are pumped again into the intercellular fluid. [ 45 ]  Although water travels down an osmotic gradient in each individual step, overall, water usually travels against the osmotic gradient due to the pumping of sodium ions into the intercellular fluid. This allows the large intestine to absorb water despite the blood in capillaries being  hypotonic  compared to the fluid within the intestinal lumen.


The large intestine houses over 700 species of  bacteria  that perform a variety of functions, as well as  fungi ,  protozoa , and  archaea . Species diversity varies by geography and diet. [ 46 ]  The microbes in a human distal gut often number in the vicinity of 100 trillion, and can weigh around 200 grams (0.44 pounds). This mass of mostly symbiotic microbes has recently been called the latest human organ to be "discovered" or in other words, the "forgotten organ". [ 47 ]


The large intestine absorbs some of the products formed by the bacteria inhabiting this region. Undigested  polysaccharides  (fiber) are metabolized to short-chain fatty acids by bacteria in the large intestine and absorbed by  passive diffusion . The bicarbonate that the large intestine secretes helps to neutralize the increased acidity resulting from the formation of these fatty acids. [ 48 ]


These bacteria also produce large amounts of  vitamins , especially  vitamin K  and  biotin  (a  B vitamin ), for absorption into the blood. Although this source of vitamins, in general, provides only a small part of the daily requirement, it makes a significant contribution when dietary vitamin intake is low. An individual who depends on absorption of vitamins formed by bacteria in the large intestine may become vitamin-deficient if treated with  antibiotics  that inhibit the vitamin producing species of bacteria as well as the intended disease-causing bacteria. [ 49 ]


Other bacterial products include gas ( flatus ), which is a mixture of  nitrogen  and  carbon dioxide , with small amounts of the gases  hydrogen ,  methane , and  hydrogen sulfide . Bacterial  fermentation  of undigested  polysaccharides  produces these. Some of the fecal odor is due to  indoles , metabolized from the amino acid tryptophan. The normal flora is also essential in the development of certain tissues, including the cecum and  lymphatics . [ citation needed ]


They are also involved in the production of cross-reactive antibodies. These are antibodies produced by the immune system against the normal flora, that are also effective against related pathogens, thereby preventing infection or invasion.


The two most prevalent phyla of the colon are  Bacillota  and  Bacteroidota . The ratio between the two seems to vary widely as reported by the Human Microbiome Project. [ 50 ]   Bacteroides  are implicated in the initiation of  colitis  and  colon cancer .  Bifidobacteria  are also abundant, and are often described as 'friendly bacteria'. [ 51 ] [ 52 ]


A  mucus  layer protects the large intestine from attacks from colonic  commensal bacteria . [ 53 ]


Following are the most common diseases or disorders of the colon:


Colonoscopy  is the  endoscopic  examination of the large intestine and the  distal  part of the  small bowel  with a  CCD camera  or a  fiber optic  camera on a flexible tube passed through the  anus . It can provide a visual diagnosis (e.g.  ulceration ,  polyps ) and grants the opportunity for  biopsy  or removal of suspected  colorectal cancer  lesions. Colonoscopy can remove polyps as small as one millimetre or less. Once polyps are removed, they can be studied with the aid of a microscope to determine if they are precancerous or not. It takes 15 years or fewer for a polyp to turn cancerous.


Colonoscopy is similar to  sigmoidoscopy —the difference being related to which parts of the colon each can examine. A colonoscopy allows an examination of the entire colon (1200–1500 mm in length). A sigmoidoscopy allows an examination of the distal portion (about 600 mm) of the colon, which may be sufficient because benefits to cancer survival of colonoscopy have been limited to the detection of lesions in the distal portion of the colon. [ 54 ] [ 55 ] [ 56 ]


A sigmoidoscopy is often used as a screening procedure for a full colonoscopy, often done in conjunction with a stool-based test such as a fecal occult blood test (FOBT), fecal immunochemical test (FIT), or multi-target stool DNA test (Cologuard) or blood-based test, SEPT9 DNA methylation test (Epi proColon). [ 57 ]  About 5% of these screened patients are referred to colonoscopy. [ 58 ]


Virtual colonoscopy , which uses 2D and 3D imagery reconstructed from  computed tomography  (CT) scans or from  nuclear magnetic resonance  (MR) scans, is also possible, as a totally  non-invasive  medical test, although it is not standard and still under investigation regarding its diagnostic abilities. Furthermore, virtual colonoscopy does not allow for therapeutic maneuvers such as polyp/tumour removal or biopsy nor visualization of lesions smaller than 5 millimeters.  If a growth or polyp is detected using CT colonography, a standard colonoscopy would still need to be performed. Additionally, surgeons have lately been using the term  pouchoscopy  to refer to a colonoscopy of the  ileo-anal pouch .


The large intestine is truly distinct only in  tetrapods , in which it is almost always separated from the small intestine by an  ileocaecal valve . In most vertebrates, however, it is a relatively short structure running directly to the anus, although noticeably wider than the small intestine. Although the caecum is present in most  amniotes , only in mammals does the remainder of the large intestine develop into a true colon. [ 59 ]


In some small mammals, the colon is straight, as it is in other tetrapods, but, in the majority of mammalian species, it is divided into ascending and descending portions; a distinct transverse colon is typically present only in  primates . However, the taeniae coli and accompanying haustra are not found in either  carnivorans  or  ruminants . The rectum of mammals (other than  monotremes ) is derived from the  cloaca  of other vertebrates, and is, therefore, not truly  homologous  with the "rectum" found in these species. [ 59 ]


In some fish, there is no true large intestine, but simply a short rectum connecting the end of the digestive part of the gut to the cloaca. In  sharks , this includes a  rectal gland  that secretes salt to help the animal maintain  osmotic  balance with the seawater. The gland somewhat resembles a caecum in structure but is not a homologous structure. [ 59 ]


This article incorporates text in the  public domain  from  page 1177  of the 20th edition of   Gray's Anatomy   (1918)


Limosilactobacillus reuteri  is a  lactic acid bacterium  found in a variety of natural environments, including the  gastrointestinal tract  of humans and other animals. It does not appear to be pathogenic and may have health effects.


At the turn of the 20th century,  L. reuteri  was recorded in scientific classifications of  lactic acid bacteria , [ 1 ]  though at this time it was mistakenly grouped as a member of  Lactobacillus fermentum . In the 1960s, further work by  microbiologist   Gerhard Reuter , for whom the species eventually was named, reclassified the species as  L. fermentum  biotype II. [ 2 ]


Significant differences were found between biotype II and other biotypes of  L. fermentum , to the point that in 1980 it was identified as a distinct species and the formal species identity,  L. reuteri , was proposed. [ 3 ]  In April 2020,  L. reuteri  was reassigned to the genus  Limosilactobacillus . [ 4 ]


Limosilactobacillus reuteri  is found in a variety of natural environments. It has been isolated from many foods, especially meats and dairy products. [ 2 ] [ 5 ] [ 6 ]  It appears to be essentially ubiquitous in the animal kingdom, having been found in the  gastrointestinal tracts  and feces of healthy humans, [ 7 ]   sheep ,  chickens , [ 8 ]   pigs , [ 9 ]  and  rodents . [ 10 ]  It is the only species to constitute a "major component" of the  Lactobacillus  species present in the gut of each of the tested host animals, [ 11 ]  and each host seems to harbor its own specific strain of  L. reuteri . [ 10 ] [ 12 ]  It is possible that  L. reuteri  contributes to the health of its host organism in some manner. [ 13 ]


Limosilactobacillus reuteri  is present as a dominant member of  fermenting  organisms in type II  sourdoughs ; several metabolic traits of  L. reuteri , including  exopolysaccharide  formation and conversion of  glutamine  to  glutamate , improve bread quality.  [ 14 ]


Limosilactobacillus reuteri  is known to produce  reuterin , [ 15 ]  reutericin 6 [ 16 ]  and  reutericyclin . [ 17 ] [ 18 ]


In the late 1980s,  Walter Dobrogosz , Ivan Casas and colleagues discovered that  L. reuteri  produced a novel broad-spectrum  antibiotic  substance via the organism's  fermentation  of  glycerol . They named this substance reuterin, after Reuter. [ 15 ]  Reuterin is a multiple-compound  dynamic equilibrium  (HPA system, HPA) consisting of 3-hydroxypropionaldehyde, its  hydrate , and its  dimer . [ 19 ] [ 20 ]  At concentrations above 1.4  M , the HPA dimer was predominant. However, at concentrations relevant for biological systems, HPA hydrate was the most abundant, followed by the  aldehyde  form. [ 21 ]


Reuterin inhibits the growth of some harmful  Gram-negative  and  Gram-positive  bacteria, along with  yeasts ,  fungi  and  protozoa . [ 22 ]  Researchers found that  L. reuteri  can secrete sufficient amounts of reuterin to achieve the desired antimicrobial effects. Furthermore, since about four to five times the amount of reuterin is needed to kill "good" gut bacteria (i.e.  L. reuteri  and other  Lactobacillus  species) as "bad", this would allow  L. reuteri  to remove gut invaders without harming other gut microbiota. [ 13 ]


Some studies questioned whether reuterin production is essential for  L. reuteri ' s health-promoting activity. The discovery that it produces an antibiotic substance led to a great deal of further research. In early 2008,  L. reuteri  was confirmed to be capable of producing reuterin in the  gastrointestinal tract , improving its ability to inhibit the growth of  E. coli . [ 23 ]


The gene cluster controlling the biosynthesis of reuterin and  cobalamin  in the  L. reuteri  genome is a  genomic island  acquired from an anomalous source. [ 24 ]


Although  L. reuteri  occurs naturally in humans, it is not found in all individuals. Dietary supplementation can sustain high levels of it in those with deficiencies. Oral intake of  L. reuteri  has been shown to effectively colonize the  intestines  of healthy individuals. Colonization begins within days of  ingestion , although levels drop months later if intake is stopped. [ 25 ]   L. reuteri  is found in  breast milk . [ 26 ]  Oral intake on the mother's part increases the amount of  L. reuteri  present in her milk, and the likelihood that it will be transferred to the child. [ 27 ]


Manipulation of gut microbiota is a complex process that may cause bacteria-host interactions. [ 28 ]  Although  probiotics  in general are considered safe, concerns exist about their use in certain cases. [ 28 ] [ 29 ]  Some people, such as those with  compromised immune systems ,  short bowel syndrome ,  central venous catheters ,  heart valve disease , and  premature infants , may be at higher risk for adverse events. [ 30 ]  Rarely, consumption of probiotics may cause  bacteremia ,  fungemia  and  sepsis , potentially fatal infections, in children with compromised immune systems or who are already critically ill. [ 31 ]


One of the better documented effects of  L. reuteri  is a significant reduction of symptom duration in pediatric  diarrheal  disease. [ 32 ] [ 33 ] [ 34 ]   L. reuteri  is effective as a  prophylactic  for this illness; children fed it while healthy are less likely to fall ill with diarrhea. [ 35 ]  With regard to prevention of gut infections, comparative research found  L. reuteri  to be more potent than other probiotics. [ 36 ] [ 37 ]  Animal research found it to reduce motor complexes and thus  intestinal motility . [ 38 ]


Limosilactobacillus reuteri  may be effective treating  necrotizing enterocolitis  in preterm infants. Meta-analysis of randomized studies suggests that  L. reuteri  can reduce the incidence of  sepsis  and shorten the required duration of hospital treatment in this population. [ 39 ]


Limosilactobacillus reuteri  is an effective treatment against infant  colic . [ 40 ] [ 41 ] [ 42 ]  Studies suggest that colicky infants treated with  L. reuteri  experience a reduction in time spent crying compared to those treated with  simethicone [ 43 ]  or placebo. [ 44 ]  However, colic is still poorly understood, and it is not clear why or how  L. reuteri  ameliorates its symptoms. One theory holds that affected infants cry because of gastrointestinal discomfort; if this is the case, it is plausible that  L. reuteri  somehow acts to lessen this discomfort, since its primary residence is inside the gut.


Limosilactobacillus reuteri  have a pronounced anti-helicobacter activity and its use as adjuvant therapy of  H. pylori  in children appears to be very promising, especially in the case of detection of infection with  H. pylori  with no absolute indication of eradication. [ 45 ]


Growing evidence indicates  L. reuteri  is capable of fighting the gut  pathogen   Helicobacter pylori , which causes  peptic ulcers  and is endemic in parts of the developing world. One study showed dietary supplementation of  L. reuteri  alone reduces, but does not eradicate,  H. pylori  in the gut. [ 46 ]  Another study found the addition of  L. reuteri  to  omeprazole  therapy dramatically increased (from 0% to 60%) the cure rate of  H. pylori -infected patients compared to the drug alone. [ 47 ]  Yet another study showed that  L. reuteri  effectively suppressed  H. pylori  infection and decreased the occurrence of dyspeptic symptoms, although it did not improve the outcome of antibiotic therapy. [ 48 ]


Llimosilactobacillus reuteri  has the potential to suppress  H. Pylori  infection and may lead to an improvement of H. Pylori-associated gastrointestinal symptoms, [ 49 ]  reducing specific symptoms such as diarrhea and frequent abdominal distention. [ 50 ]  In the future,  L. reuteri  can become a central part of a strategy to avoid using antibiotics and fighting antibiotic resistance in  H. pylori  infections [ 51 ]  and besides fighting  antibiotics resistance ,  L. reuteri  may be a great alternative treatment for  H. pylori  causing fewer side effects than antibiotics. [ 52 ]


Limosilactobacillus reuteri  may be capable of promoting dental health, as it has been proven to kill  Streptococcus mutans , a bacterium responsible for  tooth decay . A screen of several probiotic bacteria found  L. reuteri  was the only tested species able to block  S. mutans . Before testing in humans began, another study showed  L. reuteri  had no harmful effects on  teeth .  Clinical trials  proved that people whose  mouths  are colonized with  L. reuteri  (via dietary supplementation) have significantly less  S. mutans . [ 53 ]  Since these studies were short-term, it is not known whether  L. reuteri  prevents tooth decay. However, since it is able to reduce the numbers of an important decay-causing bacterium, this would be expected.


Gingivitis  may be ameliorated by consumption of  L. reuteri . Patients afflicted with severe gingivitis showed decreased  gum  bleeding,  plaque  formation and other gingivitis-associated symptoms compared with placebo after chewing  gum  containing  L. reuteri . [ 54 ]


Lactobacillus reuteri  and other probiotics may influence the  gut microbiome  in ways that protect against  bone loss , common in post-menopausal women.
 [ 55 ] [ 56 ] [ 57 ] [ 58 ] [ 59 ]


By protecting against many common infections,  L. reuteri  promotes overall wellness in both children and adults.  Double-blind ,  randomized  studies in  child care  centers have found  L. reuteri -fed infants fall sick less often, require fewer doctor visits and are absent fewer days from the center compared to placebo and to the competing probiotic  Bifidobacterium lactis . [ 60 ]


Similar results have been found in adults; those consuming  L. reuteri  daily end up falling ill 50% less often, as measured by their decrease use of sick leave. [ 61 ]


Scientific studies that require harming the subjects (for example, exposing them to a dangerous  virus ) cannot be conducted in  humans . Therefore, many of  L. reuteri's  benefits have been studied only in different animal species, such as pigs and  mice .


In general, animal studies on  L. reuteri  are done using the species-specific strain of the bacterium.


Limosilactobacillus reuteri  confers a high level of resistance to the  pathogen   Salmonella typhimurium , halving  mortality rates  in mice. [ 62 ]  The same is true for chickens [ 63 ]  and turkeys;  L. reuteri  greatly moderates the morbidity and mortality caused by this dangerous food-borne pathogen.


Limosilactobacillus reuteri  is effective in stopping harmful strains of  E. coli  from affecting their hosts. A study performed in chickens showed  L. reuteri  was as potent as the antibiotic  gentamicin  in preventing  E. coli -related deaths. [ 64 ]


The  protozoic   parasite   Cryptosporidium parvum  causes severe watery diarrhea, which can become life-threatening in  immunocompromised  (as in individuals infected with  HIV ) patients.  L. reuteri  is known to lessen the symptoms of  C. parvum  infection in mice [ 65 ]  and pigs. [ 13 ]


Some protective effect against the yeast  Candida albicans  has been found in mice, but in this case,  L. reuteri  did not work as well as other probiotic organisms, such as  L. acidophilus  and  L. casei . [ 66 ]


In juvenile commercial  livestock , such as turkey poults and piglets,  body weight  and growth rate are good health indicators. Animals raised in the dirty, crowded environments of  commercial farms  are generally less healthy (and therefore weigh less) than their counterparts born and bred in cleaner spaces. In turkeys, for example, this phenomenon is known as "poult growth depression", or PGD. [ 67 ]


Supplementing the diets of these young animals with  L. reuteri  helps them to largely overcome the stresses imposed by unhealthy environs. Commercial turkeys fed  L. reuteri  from birth had nearly a 10% higher adult body weight than their peers raised in the same conditions. [ 68 ]  A similar study on piglets showed  L. reuteri  is at least as effective as synthetic  antibiotics  in improving body weight under crowded conditions. [ 69 ]


The mechanism by which  L. reuteri  is able to support healthy growth is not entirely understood. It possibly serves to protect against illness caused by  S. typhimurium  and other pathogens (see above), which are much more common in crowded commercial farms. However, other studies found that it can help when the growth depression is caused entirely by a lack of  dietary protein , and not by contagious disease. [ 70 ]  This raises the possibility that  L. reuteri  somehow improves the intestines' ability to absorb and process  nutrients . [ 13 ]


Treating  colonic  tissue from rats with  acetic acid  causes an injury similar to the human condition  ulcerative colitis . Treating the injured tissue with  L. reuteri  immediately after removing the acid almost completely reverses any ill effects, [ 71 ]  leading to the possibility that  L. reuteri  may be beneficial in the treatment of human colitis patients.


In addition to its role in  digestion , the intestinal wall is also vital in preventing harmful bacteria, endotoxins, [ 72 ]  etc., from "leaking" into the bloodstream. This leaking, known as  bacterial "translocation" , can lead to lethal conditions such as  sepsis . In humans, translocation is more likely to occur following such events as  liver  injury and ingestion of some  poisons . In  rodent studies ,  L. reuteri  was found to greatly reduce the amount of bacterial translocation following either the surgical removal of the liver [ 73 ]  or injection with  D-galactosamine , [ 74 ]  a chemical which causes liver damage.


The  anticancer  drug  methotrexate  causes severe  enterocolitis  in high doses.  L. reuteri  greatly mitigates the symptoms of methotrexate-induced enterocolitis in rats, one of which is bacterial translocation. [ 75 ]


In mice, the absence of  L. reuteri  has been causally linked to maternal diet. [ 72 ]  A gut microbial imbalance, lacking in  L. reuteri , was linked to behavioral abnormalities consistent with  autism  in humans. [ 72 ]  These symptoms were reversible by supplementing  L. reuteri . [ 72 ]


The  lips  are a horizontal pair of  soft   appendages  attached to the  jaws  and are the most visible part of the  mouth  of many  animals , including  humans . [ 1 ]   Vertebrate  lips are soft, movable and serve to facilitate the  ingestion  of  food  (e.g.  suckling  and  gulping ) and the  articulation  of sound and  speech . Human lips are also a  somatosensory  organ, and can be an  erogenous zone  when used in  kissing  and other acts of  intimacy .


The upper and lower lips are referred to as the  labium superius oris  and  labium inferius oris , respectively. [ 2 ] [ 3 ]   The juncture where the lips meet the surrounding skin of the mouth area is the  vermilion border , [ 4 ]  and the typically reddish area within the borders is called the vermilion zone. [ 5 ]   The vermilion border of the upper lip is known as the  Cupid's bow . [ 6 ]   The fleshy protuberance located in the center of the upper lip is a  tubercle  known by various terms including the procheilon (also spelled  prochilon ), the "tuberculum labii superioris", and the "labial tubercle". [ 7 ]   The vertical groove extending from the procheilon to the  nasal septum  is called the  philtrum . [ 8 ]


The skin of the lip, with three to five cellular layers, is very thin compared to typical face skin, which has up to 16 layers. With light skin color, the lip skin contains fewer  melanocytes  (cells which produce melanin  pigment , which give skin its color). Because of this, the  blood vessels  appear through the skin of the lips, which leads to their notable red coloring. With darker skin color this effect is less prominent, as in this case the skin of the lips contains more melanin and thus is visually darker.  The skin of the lip forms the border between the exterior skin of the face, and the interior  mucous membrane  of the inside of the mouth.


The lip skin is not hairy and does not have  sweat glands . Therefore, it does not have the usual protection layer of sweat and body oils which keep the skin smooth, inhibit pathogens, and regulate warmth. For these reasons, the lips dry out faster and become  chapped  more easily.


The lower lip is formed from the  mandibular prominence , a branch of the  first pharyngeal arch . The lower lip covers the anterior  body of the mandible . It is lowered by the  depressor labii inferioris muscle  and the  orbicularis oris  borders it inferiorly.


The upper lip covers the  anterior surface of the body of the maxilla . Its upper half is of usual skin color and has a depression at its center, directly under the nasal septum, called the  philtrum , which is Latin for "lower nose", while its lower half is a markedly different, red-colored skin tone more similar to the color of the inside of the mouth, and the term  vermillion  refers to the colored portion of either the upper or lower lip.


It is raised by the  levator labii superioris  and is connected to the  lower lip  by the thin lining of the lip itself.


Thinning of the vermilion of the upper lip and flattening of the  philtrum  are two of the facial characteristics of  fetal alcohol syndrome , a lifelong  disability  caused by the mother's consumption of alcohol during pregnancy.


The skin of the lips is  stratified squamous epithelium . The mucous membrane is represented by a large area in the  sensory cortex , and is therefore highly sensitive. The  frenulum labii inferioris  is the  frenulum  of the lower lip. The  frenulum labii superioris  is the frenulum of the upper lip.


The  facial artery  is one of the six non-terminal branches of the  external carotid artery .


This artery supplies both lips by its superior and inferior labial branches. Each of the two branches  bifurcate  and  anastomose  with their companion branch from the other terminal.


The muscles acting on the lips are considered part of the muscles of  facial expression .  All muscles of facial expression are derived from the  mesoderm  of the second  pharyngeal arch  and are therefore supplied (motor supply) by the nerve of the second pharyngeal arch, the  facial nerve  (7th  cranial nerve ). The muscles of facial expression are all specialized members of the  panniculus carnosus , which attach to the  dermis  and so wrinkle or dimple the overlying skin. Functionally, the muscles of facial expression are arranged in groups around the  orbits , nose, and mouth.


The muscles acting on the lips:


Because they have their own muscles and bordering muscles, the lips are easily movable. Lips are used for eating functions, like holding food or to get it in the mouth. In addition, lips serve to close the mouth airtight shut, to hold food and drink inside, and to keep out unwanted objects. Through making a narrow  funnel  with the lips, the suction of the mouth is increased. This suction is essential for babies to  breast feed . Lips can also be used to suck in other contexts, such as sucking on a straw to drink liquids.


The lips serve for creating different sounds—mainly  labial ,  bilabial , and  labiodental  consonant sounds as well as  vowel rounding —and thus are an important part of the speech apparatus.  The lips enable  whistling  and the performing of wind instruments such as the trumpet,  clarinet , flute, and saxophone. People who have  hearing loss  may unconsciously or consciously  lip read  to understand speech without needing to perceive the actual sounds, and visual cues from the lips affect the perception of what sounds have been heard, for example the  McGurk effect .


The lip has many  nerve endings   and reacts as part of the  tactile  (touch) senses.  Lips are very sensitive to touch, warmth, and cold.  It is therefore an important aid for exploring unknown objects for babies and toddlers.


Because of their high number of nerve endings, the lips are an  erogenous zone . The lips therefore play a crucial role in  kissing  and other acts of intimacy.


A woman's lips are also a visible expression of her fertility. In studies performed on the science of human attraction, psychologists have concluded that a woman's facial and sexual attractiveness is closely linked to the makeup of her hormones during puberty and development.  Contrary to the effects of  testosterone  on a man's facial structure, the effects of a woman's  oestrogen  levels serve to maintain a relatively "childlike" and youthful facial structure during puberty and during final maturation.  It has been shown that the more oestrogen a woman has, the larger her eyes and the fuller her lips, characteristics which are perceived as more feminine. [ 9 ]   Surveys performed by sexual psychologists [ who? ]  have also found that universally, men find a woman's full lips to be more sexually attractive than lips that are less so. [ citation needed ]   A woman's lips are therefore sexually attractive to males because they serve as a biological indicator of a woman's health and fertility.  A woman's lipstick (or  collagen   lip enhancement ) attempts to take advantage of this fact by creating the illusion that a woman has more oestrogen than she actually has and thus that she is more fertile and attractive. [ 10 ]


Lip size is linked to sexual attraction in both men and women. Women are attracted to men with masculine lips that are more middle size and not too big or too small; they are to be rugged and sensual. In general, the researchers found that a small nose, big eyes and voluptuous lips are sexually attractive both in men and women. [ 11 ]  The lips may temporarily swell during sexual arousal due to engorgement with blood. [ medical citation needed ]


The lips contribute substantially to  facial expressions . The lips visibly express emotions such as a  smile  or frown, iconically by the curve of the lips forming an up-open or down-open arc, respectively. Lips can also be made pouty when whining or perky to be provocative.


The function of the abrupt change in skin structure between the lips and surrounding face (in particular, the function of the less keratinized  vermillion  and the  white roll ) is not completely understood. [ 12 ]  Possible reasons for the difference may include advantages to somatosensory function, better communication of facial expressions, and/or emphasis of the lips' slight  sexual dimorphism  as a  secondary sex characteristic .


As an organ of the body, the lip can be a focus of disease or show symptoms of a disease:


Lips are often viewed as a symbol of sensuality and sexuality. This has many origins; above all, the lips are a very sensitive erogenous and tactile organ. Furthermore, in many cultures of the world, a woman's mouth and lips are veiled because of their representative association with the vulva, and because of their role as a woman's secondary sexual organ. [ 19 ]


As part of the mouth, the lips are also associated with the symbolism associated with the mouth as orifice by which food is taken in.  The lips are also linked symbolically to neonatal psychology (see for example  oral stage  of the psychology according to  Sigmund Freud ).


Lip piercing  or  lip augmentation  is sometimes carried out for cosmetic reasons. Products designed for use on the lips include lipstick,  lip gloss  and  lip balm .


In most vertebrates, the lips are relatively unimportant folds of tissue lying just outside the jaws. However, in  mammals , they become much more prominent, being separated from the jaws by a deep cleft [ citation needed ]  (a notable exception being the  naked mole-rat , whose lips close behind the front teeth). [ 20 ]  They are also more mobile in mammals than in other groups since it is only in this group that they have any attached muscles. In some  teleost  fish, the lips may be modified to carry sensitive  barbels . In birds and turtles, the lips are hard and  keratinous , forming a solid  beak . [ 21 ]   Clevosaurids  like  Clevosaurus  are notable for the presence of bone "lips"; in these species the tooth-like jaw projections common to all  sphenodontians  form a beak-like edge around the jaws, protecting the teeth within. [ 22 ]


The following is a  list of intestinal stem cell marker genes,  including their name and known function.


In the adult  intestine , the  crypts of Lieberkühn  are the niche for  epithelial   stem cells  and contain all proliferative stem and progenitor cells. Differentiating cells exit the cell cycle and migrate out of the crypts and onto the surface epithelium of the intestine, where they perform their physiological role (e.g., nutrient absorption by enterocytes; mucous secretion by goblet cells) and are eventually shed into the lumen. [ 1 ]  Intestinal stem cells were first identified as such in the 1970s. Cheng and Leblond used autoradiography of phagosomes to track the fate of cells at the base of the crypts, and determined that slender cells interspersed among Paneth cells at the crypt base could give rise to all of the other cell types that constituted the intestinal epithelium. [ 2 ]   Due to their narrow shape and location, these cells were called crypt base columnar cells (CBCs). Potten and colleagues used a combination of DNA labeling and assessment of the response of the epithelium to high-dose radiation to identify label-retaining cells (LRCs) as putative stem cells, which were typically located around four cell positions above the bottom of the crypt, and were therefore also called "+4 cells". [ 3 ] [ 4 ]  Later work suggested that these "+4 cells" may function as reserve or back-up stem cells, and further suggested that they divide slowly relative to the other progenitor cells in the crypt. Thus, these cells are also called quiescent stem cells. [ 5 ]


The stem cell zone model states that the CBC stem cells reside in a stem-cell-permissive environment. These cycling stem cells regularly generate progeny, which subsequently exit the niche and pass through the “common origin of differentiation” around position +5, where they commit toward the various individual lineages. Progenitors mature as they migrate upward onto the villus. Maturing Paneth cell progenitors migrate downward, with the oldest Paneth cells residing at the very base of the crypt. [ 6 ]  In accordance with the stem cell zone model proposing that, during their upward migration, CBC stem cells would only gradually lose their self-renewal capacity, it was shown in vivo that transient amplifying cells can revert to Lgr5+ CBC stem cells after damage, presumably by direct contact with Paneth cells. [ 6 ]


More recently modern genetics techniques, primarily using transgenic mice, have been used to identify genes that are specifically expressed or highly enriched in the intestinal stem cells. Below, a table of intestinal stem cell  "marker" genes  is given, along with a notation if this marks active of CBC stem cells, or quiescent/reserve/+4 stem cells.


Additional possible markers:
CD24
CD44v6
Active beta-catenin
Pcdh8  21419747


The  major duodenal papilla  (papilla of Vater) is a rounded projection in the  duodenum  into which the  common bile duct  and  pancreatic duct  drain. The major duodenal papilla is, in most people, the primary mechanism for the secretion of  bile  and other enzymes that facilitate  digestion .


The major duodenal papilla is situated in the second part of the  duodenum , 7–10 cm from the  pylorus , at the level of the second or third  lumbar vertebrae . It is surrounded by the  sphincter of Oddi , a circular muscle, and receives a mixture of pancreatic enzymes and  bile  from the  Ampulla of Vater , which drains both the  pancreatic duct  and  biliary system . [ 2 ]   The junction between the  foregut  and  midgut  occurs directly below the major duodenal papilla. [ 3 ]   : 274   The major duodenal papilla projects less than a centimetre into the  lumen  of the duodenum. [ 4 ]  It appears rounded and is often covered by a fold on the uppermost side of the papilla; that is, the side which receives contents from the stomach. [ 4 ]


The major duodenal papilla is seen from the duodenum as lying within a  mucosal  fold. The  minor duodenal papilla  is situated 2 cm proximal. [ 2 ]


The major duodenal papilla is occasionally found in the junction between the descending and horizontal parts of the duodenum, or in the horizontal part of the duodenum; a case study of 1000 people demonstrated this in 12 and 8% respectively. [ 4 ]  in the third part of the duodenum, the level of the vertebrae may be L2-3, and in about 10% of people, it may not receive  bile . Additionally, in a small number of people, the primary papilla for draining the pancreas may in fact be the  accessory pancreatic duct . [ 2 ]


Pancreatic enzymes and bile drain into the duodenum from both the  pancreatic duct  and  biliary system . [ 4 ]  This facilitates the digestion of food; particularly proteins (pancreatic enzymes), and fat-soluble vitamins (bile).


The minor papilla drains the duct of Santorini, superior in position to the major papilla. In pancreatic divisum, in which the minor papilla drains the bulk of pancreatic secretions and major drains a minority of secretions (opposite of normal), a Santorinicele may develop leading to obstructed secretions/reflux resulting in pancreatitis.


The major duodenal papilla was first illustrated by  Gottfreid Bidloo  in 1685, although is sometimes called the  papilla of Vater , after  German   anatomist   Abraham Vater . [ 2 ]


The  mesenteric arteries  take blood from the aorta and distribute it to a large portion of the  gastrointestinal tract .


Both the  superior  and  inferior  mesenteric arteries arise from the  abdominal aorta . [ 1 ]  Each of these arteries travel through the  mesentery , within which they branch several times before reaching the gut. In humans, many of these branches are named, but in smaller animals the branches are more variable. In some animals, including humans, branches of these arteries join with the  marginal artery of the colon , which means that occlusion of one of the main arteries does not necessarily lead to the death of the part of the gut that it usually supplies.


The term  mesenteric artery  is also used to describe smaller branches of these vessels which, particularly in smaller animals, provide a significant source of vascular resistance. These branches have a dense innervation by  sympathetic  nerves, allowing the brain to control their diameter and hence the resistance to blood flow to the gut. This is of particular importance when blood flow is required elsewhere, such as in exercise or shock, where a large proportion of the blood is required to supply the needs of  skeletal muscle ; by constricting the smaller mesenteric vessels, the resistance of blood flow to the gut increases, and hence blood flows more readily to other organs. [ 2 ]


In  human anatomy , the  mesentery , an  organ  that attaches the  intestines  to the  posterior abdominal wall , comprises the double fold of the  peritoneum . It helps (among other functions) in storing  fat  and allowing  blood vessels ,  lymphatics , and  nerves  to supply the intestines. [ 1 ]


The  mesocolon   (the part of the mesentery that attaches the colon to the abdominal wall) was formerly thought to be a fragmented structure, with all named parts—the ascending, transverse, descending, and sigmoid  mesocolons , the  mesoappendix , and the  mesorectum —separately terminating their insertion into the posterior abdominal wall. [ 2 ]  However, in 2012, new  microscopic  and  electron microscopic   examinations  showed the mesocolon to be a single structure derived from the  duodenojejunal flexure  and extending to the distal mesorectal layer. [ 2 ] [ 3 ]  Thus the mesentery is an  internal organ . [ 4 ] [ 5 ]


The mesentery of the  small intestine  arises from the  root of the mesentery  (or  mesenteric root ) and is the part connected with the structures in front of the  vertebral column . The root is narrow, about 15 cm long, 20 cm in width, and is directed obliquely from the  duodenojejunal flexure  at the left side of the second  lumbar vertebra  to the right  sacroiliac joint . The root of the mesentery extends from the duodenojejunal flexure to the  ileocaecal junction . This section of the small intestine is located centrally in the abdominal cavity and lies behind the transverse colon and the  greater omentum .


The mesentery becomes attached to the  colon  at the gastrointestinal margin and continues as the several regions of the mesocolon. The parts of the mesocolon take their names from the part of the colon to which they attach. These are the transverse mesocolon attaching to the transverse colon, the sigmoid mesocolon attaching to the sigmoid colon, the mesoappendix attaching to the appendix, and the mesorectum attaching to the upper third of the rectum.


The mesocolon regions were traditionally taught to be separate sections with separate insertions into the posterior abdominal wall. In 2012, the first detailed observational and  histological  studies of the mesocolon were undertaken and this revealed several new findings. [ 6 ]  The study included 109 patients undergoing open, elective, total abdominal  colectomy . Anatomical observations were recorded during the surgery and on the post-operative specimens.


These studies showed that the mesocolon is continuous from the ileocaecal to the rectosigmoid level. It was also shown that a mesenteric confluence occurs at the ileocaecal and rectosigmoid junctions, as well as at the  hepatic and splenic flexures  and that each confluence involves peritoneal and omental attachments. The proximal rectum was shown to originate at the confluence of the mesorectum and mesosigmoid. A plane occupied by perinephric fascia was shown to separate the entire apposed small intestinal mesentery and the mesocolon from the  retroperitoneum . Deep in the  pelvis , this fascia coalesces to give rise to  presacral fascia . [ 6 ]