The Structural and Functional Relationships of the Digestive System with a Primary Focus on the Small Intestine, and a Minor Focus on the Stomach

Austin JelcickGenetics Cell Biology and Anatomy

May 2010

INTRODUCTION

The body consists of multiple systems. From the endocrine system, the nervous system, and the respiratory system to the reproductive system and circulatory system, each serves a specific function allowing for the proper orchestration of all biological functions performed by an organism. These systems are not isolated however, and communicate with other systems within the body to maintain homeostasis. Of particular importance is the digestive system which consists of the tubular gut as well as solid organs. The digestive system functions not only as the means by which nutrients enter the body and are absorbed, but also serves additional functions as well. Digestion is confined to the organs of the digestive system, alimentary tract, and its related glands. The digestive organs are not located in one central region, but rather are situated partly in the head and neck, and partly within the trunk of the body as well. The digestive system can then be divided into several distinct parts. The anterior portion, or foregut, consists of the oral cavity, the lower parts of the pharynx or throat, and continues on to include the beginning of the esophagus, or gullet. Food is taken in by means of the lips, teeth and tongue where it is then chewed and lubricated with saliva which is produced by 3 pairs of large salivary glands. Saliva not only serves a lubricating function, but contains enzymes as well as immunocompetent substances as well. Numerous small glands are also present, and in the case of starches, some digestion actually begins in the mouth. Where the foregut ends, the trunk section of the digestive system begins, starting at the beginning of the esophagus and extending to the end of the gut at the anus. The trunk section is divided into multiple regions and organs, beginning at the esophagus, continuing to the stomach, then to the small intestine which consists of the duodenum, the jejunum, and the ileum. The trunk section then continues to the large intestine or colon which includes the cecum, appendix, the ascending, transverse, descending, and sigmoid colon, and the rectum. While most portions of the digestive system serve multiple functions, the esophagus serves only as a tube for the transport of food. Following transport, food is partly broken down in the stomach, with breakdown completing in the small intestine. There are a numerous small digestive glands present in the trunk section of the digestive system, as well as two large digestive glands, the liver and pancreas. Food that is unabsorbed following digestion is thickened in the colon by means of water extraction, and is then transformed to feces by decomposition and fermentation. In this review of the gastrointestinal system, overall features of the immune, neuronal, and hormonal components of the gastrointestinal system will be touched upon, while each section of the anterior and trunk portions of the digestive system will be highlighted in the order that they occur, with an emphasis on the functions, as well as the cellular and molecular characteristics of the stomach and small intestine.

GENERAL FEATURES OF IMMUNE DEFENSE, NEURAL AND HORMONAL INTEGRATION

Because the gastrointestinal tract features a large internal surface area, an effective immune defense system is required. This immune defense system begins with the saliva secreted which contains mucins immunoglobulin A (IgA), as well as lysozyme which helps to prevent the penetration of pathogens. Similarly, the gastric juice produced has a bactericidal effect, adding to the efficiency of this defense system. The gastrointestinal tract features immunocompetent lymph tissue as well, organized into structures known as Peyer’s patches, which antigens will enter by means of M cells in the mucosal epithelium. The Peyer’s patches elicit immune responses by means of IgA secretion along with macrophages. Peyer’s patches will be discussed in greater detail later on. The secreted IgA is transported to the intestinal lumen through transcytosis, and binds with a secretory component to prevent its digestion. The mucosal epithelium also features intraepithelial lymphocytes such as killer T cells which contribute further to the defense mechanisms of the digestive system. Transmitter substances allow for reciprocal communication between the intraepithelial lymphocytes and neighboring enterocytes, while the macrophages of the hepatic sinusoids as well as the Kupfer cells confer additional defense mechanisms. Lastly, the intestine is colonized by colonies of intestinal flora which serve to inhibit the spread of pathogens.

The motility, secretory function, perfusion and growth of the gastrointestinal system is controlled by endocrine and paracrine hormones, as well as neurotransmitters. The local reflexes of the gastrointestinal system are triggered by stretch sensors in the walls of the esophagus, stomach, and gut by means of chemosensors present in the mucosal epithelium. These reflexes serve various functions, such as the peristaltic reflexes which extend further to the oral and anal regions. These reflexes help to propel the contents of the intestinal lumen, and are mediated partially by interneurons. The gastrointestinal system is externally innervated by the parasympathetic nervous system, beginning at the lower esophagus and extending to the ascending colon where the sympathetic nervous system innervates as well. This innervation is also provided by visceral afferent fibers, both in parasympathetic and sympathetic nerves.

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The neurons responsible for the various impulses regulating the gastro intestinal system utilize many types of neurotransmitters to perform their functions. For example, vasoactive intestinal peptide mediates the relaxation of the circular and vascular muscles of the gastrointestinal system. Another example, leu-enkephalin, serves to intensify the contraction of the pyloric, ileocecal, and lower esophageal sphincters through their binding to opioid receptors, while gastrin releasing peptide mediates the release of gastrin. It should be noted that all of the endocrine hormones that are active in the gastrointestinal system are peptide produced in endocrine cells present in the mucosa. Gastrin is secreted in the antrum and duodenum due to neuronal control, but can also be released as a response to protein fragments present in the stomach, as well as the stretching of the wall of the stomach. The secretion of gastrin is inhibited however, when the pH of the gastric or duodenal lumen falls below 3.5, which regulates the function of gastrin as it causes acid secretion and gastric mucosal growth. Another chemical, cholecystokinin (CCK), is produced throughout the mucosa of the small intestine and is released due to a stimulation caused by the presence of long chain fatty acids, amino acids, and oligopeptides being present in the lumen. CCK functions by causing gall bladder contraction, and inhibits the emptying of the stomach. It also serves to stimulate growth, the production of enzymes, as well as the secretion of carbonate (HCO3) by means of secretin in the pancreas. Secretin is produced in the duodenum, and is stimulated for release by the acid chyme. It functions as an inhibitor of acid secretion and gastric mucosal growth, but stimulates the production of HCO3, as well as the flow of hepatic bile and pancreatic growth. Another peptide that functions in regulation is that of glucose dependent insulinotropic peptide, or GIP. This is produced by the duodenum and jejunum and released due to the presence of protein, fat, and carbohydrate fragments. GIP serves to inhibit acid secretion and well as stimulating the release of insulin. It is because of its insulin stimulatory effect as a result of the presence of food particles that causes oral glucose to result in the release of more insulin than glucose administered intravenously. Motillin, another chemical released by the neurons of the small intestine, serves to regulate the interdigestive motility of the gastrointestinal system, while histamine, somatostatin, and prostaglandin are the main paracrine transmitters of the gastrointestinal system.

ORAL CAVITY

The oral cavity consists of multiple structures, each with their own specialized functions. The vestibulum of the mouth, or cavity proper of the mouth, lies between the cheeks and lips on one side, and the teeth and alveolar process of the jaws on the other side. The true oral cavity is the actual space inside of the rows of teeth, and is completely separated from the vestibule when the jaws are closed. If the jaws remain open however, the posterior border, formed by the posterior palatine arch, is now visible. The vestibule contains an elastic wall, made up of the lips and cheeks. Muscles present in the vestibule include the orbicularis oris and the buccinators muscle, with skin following the movements of the muscles, with the muscle plate being loosely covered by the mucus membrane of the mouth. As mentioned previously, the teeth separate the vestibule from the oral cavity proper by forming an arch. The teeth are distinguished from one another by four primary types of teeth; incisors, canines, premolars, and molars. The incisors function in biting, while the canines are specialized for tearing and gripping. The premolars serve as effective surfaces for grinding and crushing, while the molars perform most of the chewing during feeding.

The oral cavity includes the tongue, which is necessary for chewing, sucking, and also serves as a carrier for sense organs related to taste and touch. The tongue is subdivided into three major regions, the root, the dorsum or back, and the apex or tip. The tongue musculature arises from the lower jaw, as well as the hyoid bone and the styloid process of the skull. The tongue has a three dimensional network of extrinsic fibers which merge with the intrinsic muscles of the tongue. In this regard, the tongue musculature can be divided into two groups, the extrinsic and the intrinsic muscles. The extrinsic muscles are the genioglossus, the hyoglossus, and the styloglossus. The genioglossus, which is the strongest of the three, is paired and arises from the center of the inner surface of the mandible. It functions to pull the tongue forward with its lowest fibers, while the other fibers pull the tongue towards the floor of the mouth. The hyoglossus reaches laterally from the genioglossus into the margin of the tongue. It functions by pulling the tongue backward, assuming that the hyoid bone is fixed, and arises as a thin four sided plate. The styloglossus functions to pull the tip of the tongue backward, and also moves the entire tongue up and towards the back. This muscle arises from the styloid process and extends along the side of the tongue anteriorly to the apex of the tongue. The intrinsic muscles of the tongue consist of the longitudinales superior, the inferior linguae, the transverse linguae, and the verticalis muscle. These intrinsic muscles serve to change the overall shape of the tongue body, and do so by working as an antagonist for the other intrinsic muscles. The mucus membranes of the tongue are distinguished by their locations, and are made up of stratified squamous non-keratinized epithelium. Those on the inferior surface of the tongue are loosely connected to the body, and form the trenulum of the tongue in the center. Present in this region is the sublingual gland, which resides on the floor of the oral cavity beside the tongue, but is effectively hidden

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underneath a sublingual fold. This fold features an opening of the submaxillary duct in the caruncula lingualis at its anterior end. In contrast to the loose connection of the mucus membrane of the inferior surface, the mucosa of the dorsum (the back) of the tongue is fixed to the tongue’s tough aponeurosis. This fixation is accomplished by a connective tissue layer of the mucosa interlocking with the epithelium by means of tall papillae. The mucosa of the dorsum is interspersed with strands of intrinsic muscle, and is divided into left and right halves by means of a shallow medial groove. Similarly, a V-shaped terminal sulcus separates the dorsum from the root of the tongue. A blind hole, the foramen caecum, resides at the apex of this V, and is the origin of anlage for the thyroid. The dorsum of the tongue is covered with papillae, of which there are multiple types. The first type of papillae, the filiform papillae, are distributed across the entire dorsum, and are small keratinized epithelial elevations that are directed toward the pharynx. This type of papillae is further characterized by its sensitivity to touch. The second type of papillae, the fungiform papillae, are primarily distributed around the margin and apex on the tongue. This type of papillae is more numerous in newborns, and do not contain taste glands, which are also known as gustatory glands. The third type of papillae, the vallate papillae, project very little from the surface of the tongue, and occur in a V formation in front of the root of the tongue as well as at the terminal sulcus. Each of these vallate papillae is surrounded with a vallum or trench. These trenches are lined by epithelium containing three to five rows of taste buds. Leading into the bottom of the trenches are serous gustatory glands whose secretions wash away flavors from the taste buds. The last type of papillae, follate papillae, are located in transverse folds at the posterior lateral margin of the tongue. Similar to vallate papillae, they contain taste buds in epithelium and contain serous gustatory glands. These glands open into the depth of mucosal folds.

The oral cavity is home to both the soft and hard palate, which each have unique functions. The hard palate forms the anterior 2/3 of the roof of the oral cavity, while the posterior 1/3 is formed by the soft palate. The hard palate is formed by a palatine process of maxilla as well as by horizontal plates of the palatine bones. The bone of the hard palate is covered by a periosteum and mucus membrane. Features of the hard palate include a longitudinal ridge known as the raphe palate which occurs in the middle of the hard palate. On either side of the raphe palate lays mucosa which carries shallow transverse ridges. These ridges serve as a surface the tongue uses to press food against. In between the mucosa and the periosteum lies an additional area containing small mucus glands, the palatine glands, which function by producing mucus which serves as a lubricant for food. The soft palate hangs down from the hard palate at its posterior, with the uvula projecting in the midline of the soft palate. On each side of the uvula lie two folds. These folds are known as the palatoglossal arch and the palatopharyngeal arch. The palatoglossal arch extends to the lateral border of the tongue, while the palatopharyngeal arch extends to the wall of the pharynx. There it forms the narrowing of the pharynx and can be closed by means of muscle contraction. This narrowing is also known as the isthmus of the fauces. The soft palate serves to shut off the food passage from the upper airway when it is combined with the posterior wall of the pharynx bulging.

The oral cavity is also home to the salivary glands, the glands responsible for the production of saliva. Food that enters the oral cavity is mixed with saliva, which effectively acts to lubricate the food for subsequent passage in the esophagus. The lubrication effect is due to the presence of mucins in saliva. Saliva serves to dissolve compounds in food, a prerequisite for taste bud stimulation, while the lower salt concentration and hypotonic nature of saliva make it an excellent medium for rinsing the taste receptors following stimulation. Saliva also serves a function in the initial digestion of food as it contains alpha amylase for the conversion of starches. This alpha amylase catalyzed digestion occurs optimally at a pH of about 7, which is maintained in saliva due to the high concentration of HCO3. This same feature of a neutral pH is what makes saliva essential as a buffer for the acidic gastric juice that may be refluxed into the esophagus. This buffering effect also serves to protect the enamel of the teeth from the acidic nature of gastric juice. This amylase serves a secondary bactericidal function as well. In addition, the presence of IgA and lysozyme further serve as immunocompetent characteristics of saliva. The act of saliva secretion occurs as a result of a reflex action that is prompted by chemoreceptors in the mouth being stimulated. There are various types of salivary glands in the mouth, some with serous, and some with mucosal secretions. The serous glands secrete an electrolyte and protein rich saliva that serves a diluting function, while the mucus glands secrete tough stringy mucoid saliva that contains few electrolytes and proteins in contrast to that of the serous glands. This mucoid saliva is the saliva that serves as a lubricant. Saliva is secreted in two phases, with the acini

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Figure 1. Micrograph depicting a vallate papillae, featuring the mucus membrane of the moat(1), gustatory glands(3), and the papilla base(4) where the ducts of the gustatory gland connect with the moat

producing the primary saliva, followed by a modification of the primary saliva into secondary saliva occurring in the excretory ducts. It should be noted that primary saliva production occurs as a result of transcellular chloride transport. Salivary glands occur in varying sizes, with numerous small salivary glands occurring in the mucosa of the lips, cheek, tongue, and palate. These glands have short ducts, and vary in their composition with their location, as those closer to the pharynx contain more mucus elements. In contrast, the gustatory glands that occur with taste buds are serous glands. Aside from the numerous small salivary glands, three large salivary glands exist in the oral cavity; the parotid gland, the submandibular gland, and the sublingual gland. Stimulation for the production of saliva occurs in the larger salivary glands due to numerous triggers/stimuli such as smell, taste, mastication, nausea, and tactile stimulation of the buccal mucosa. The parotid gland is the largest of the salivary glands and resides in front of the ear on the ramus of the mandible and the masseter. The submandibular gland in contrast, is the salivary gland of the lower jaw, while the sublingual gland forms the sublingual fold. The sublingual fold consists of the predominantly mucus secreting major sublingual gland, with numerous smaller mucus secreting minor sublingual glands. An additional, almost purely mucus secreting salivary gland, the anterior lingual gland, occurs at the apex of the tongue, and resides on both sides of the tongue.

PHARYNX

Following the oral cavity, prior to the esophagus, is the pharynx. Approximately 12 cm. long, the pharynx is a tube which merges into the esophagus at the level of cricoid cartilage. The posterior wall of the pharynx is flat and resides in the frontal plane without any gaps, with nasal cavities opening into the pharynx at its front, while the oral cavity opens into the lower end. The pharynx can be subdivided into three general areas; the nasal pharynx, the oral pharynx, and the laryngeal pharynx. The nasal pharynx contains the pharyngeal tonsil, which is located in the roof of the pharynx, while the oral pharynx contains both palatine and lingual tonsils. The laryngeal pharynx, while lacking tonsils, is home to the piriform recess, a groove which leads to the entrance of the esophagus. The wall of the pharynx, the pharyngeal wall, is composed of three layers; a mucus membrane, a muscularis, and connective tissue layer or adventitia. The mucus membrane, also known as the tunica mucosa, is loosely connected with the tunica muscularis. This tough elastic longitudinally directed membrane broadens downward, and is the key contributor to the reversible extensibility characteristic of the pharynx. The nasal portion of the mucosa is covered by nasal epithelium, while the oral and laryngeal portions consist of the same epithelium as the oral cavity. The mucus produced by this layer is a product of the pharyngeal glands, and serves as a lubricant, similar to those of the oral cavity. The tunica muscularis consists of striated muscles, which serve as elevators and constrictors of the throat. The muscles are structured such that they overlap to a degree where the lower portions of the superior end and middle constrictor muscles are always covered on the outside by the upper margin of the next muscle. This muscular layer of tissue is not present in all areas of the pharynx, as it is absent superiorly under the base of the skull. At this location, the pharyngeal wall consists of a tough fibrous membrane instead. The muscle tube of the pharynx is covered by a thin facia of adventitial connective tissue which extends laterally into the parapharyngeal space. It may be moved against the vertebral column due to the retropharyngeal space which serves as a connective tissue space. Both the parapharyngeal and retropharyngeal spaces are continuous with the mediastinum.

The pharynx is involved in the act of swallowing, which consists of a voluntary phase, followed by two involuntary or reflex phases. The act of swallowing prevents food from entering the airway by momentarily closing the airway by means of a reflex action. The voluntary phase occurs by the muscles of the floor of the mouth contracting, while the tongue is pressed against the soft palate. Subsequent movements occur as a result of receptor stimulation in the mucosa of the palate. These subsequent reflex actions consist of an elevation and tension of the soft palate which occurs due to tensor and levator veli palatine muscles. This serves to press the soft palate against the posterior wall of the pharynx. The superior pharyngeal constrictor muscle is also contracted, causing a protrusion which effectively separates the upper airways from the food passage. Because of this function, if the soft palate is paralyzed as in the case of diphtheria, the passage will not be blocked, and food will enter the nose. Further reflex action occurs as the floor of the mouth is contracted to assist with elevation of the hyoid bone and larynx, while the entrance to the larynx itself approaches the epiglottis. The epiglottis moves as well, lowering near the roof of the tongue with the aid of aryepiglottic muscles. This serves to close the larynx entrance incompletely, while the rima glotidis closes as well, and breathing ceases. Following swallowing, food is transported by means of additional muscle contractions. The slit of the pharynx unfolds in an upward and forward direction as the larynx ascends. Meanwhile, the tongue is pulled and pushes the food being swallowed into the pharynx, passing the food partially over the epiglottis and through the piriform recesses. The pharyngeal wall shortens, with the constrictors above the food contracting, resulting in the food being pushed through the dilated esophagus. The food can also be propelled in a

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similar manner to the stomach by means of continuous waves of circular muscle contraction. These waves of contraction are commonly known as peristalsis. The swallowing reflex is not limited to the waking hours, as it can occur during sleep. This reflex is maintained in most situations due to afferent and efferent nerve fibers occurring in several cranial nerves, with the coordination of the reflex occurring in the deglutition center of the medulla oblongata.

ESOPHAGUS

The esophagus, a 25-30 cm. long tube, primarily serves as a conveyance mechanism, for food traveling to the stomach. Within the esophagus are three regions where the esophagus narrows. The uppermost narrowing includes the esophageal sphincter which lies at the level of the circoid cartilage. The sphincter functions as a closure to the entrance of the esophagus and is the narrowest segment at just 14 mm. The sphincter performs its function as a closure mechanism by constricting and relaxing for 0.5-1 second during swallowing. A problem known as a pressure diverticulum can occur if a thin walled area within the posterior surface becomes pushed out. The middle narrowing of the esophagus, also known as the aortic narrowing, occurs due to the esophagus being crossed by the aortic arch. In this region the esophagus descends behind the bifurcation of the trachea, but is prone to another type of diverticulum known as a traction diverticulum. This clinical problem is due to scar formation that occurs as a result of hilar lymph gland inflammation, which causes the esophageal wall to be pulled towards the hilus. The third narrowing of the esophagus, the diaphragmatic narrowing, is located in the esophageal hiatus of the diaphragm. This region is connected with a complex closure mechanism at the lowest 2-5 cm. of the esophagus which functions by relaxing during swallowing.

The tissue of the esophagus is composed of multiple layers which resemble that of the remainder of the gastrointestinal system. A mucosa is present, made up of stratified, non-keratinized squamous epithelium. A small number of mucus glands (esophageal glands) are present in the submucosa, and increase along the course of the esophagus. The mucosa is pleated into longitudinal folds in the un-dilated esophagus by muscles which run in spiral tracts. The musculature varies somewhat in the upper third of the tunica muscularis, as the muscles here are striated, but autonomically innervated. These striated muscles are gradually replaced with smooth muscle as one enters the middle and progresses to the lower third of the esophagus. The esophagus is similar to the trachea in that it is under longitudinal tension, which serves in maintaining stability, aids in the facilitation of food passage during swallowing, and assists with the closure of the lower esophageal portion. This lower portion of the esophagus is twisted on its longitudinal axis at the level where it transitions into the cardia. The longitudinal tension caused by twisting aids in the sphincter effect of the intra-abdominal pressure on the abdominal portion of the esophagus. The sphincter effect is maintained by a connective tissue membrane that is suspended between the esophagus and the opening of the diaphragm. It should be noted that the connective tissue of the adventitial layer contains smooth muscle fibers.

The act of swallowing is mediated in part by the composition of the esophageal wall which consists of smooth muscle in the lower 2/3, and striated muscle in the upper third. The tongue pushes the food being swallowed towards the back of the throat while the nasopharynx is blocked due to reflex. At this same time, respiration is momentarily stopped, as the vocal chords close, and the trachea is sealed off by the epiglottis. The upper esophageal sphincter then opens, as peristaltic waves force the food toward the stomach. The lower esophageal sphincter opens at the beginning of swallowing due to a receptive relaxation that occurs due to VIP and nitric oxide releasing neurons. If not stimulated, the lower esophageal sphincter remains closed; a mechanism to prevent the reflux of gastric juices. This sort of reflux occurs quote often however, sometimes due to the increased pressure that occurs as a result of a full stomach, but also due to transient openings of the sphincter. When reflux does occur, damage to the esophageal mucosa is prevented by a rapid return of the reflux to the stomach by means of the esophageal peristaltic reflex, while the pH is maintained by the buffering action of saliva.

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Figure 2. Micrograph of the esophagus featuring the multilayered nonkeratinizing squamous epithelia of the lamina epithelialis mucosae(1), the lamina propria mucosae(2), the lamina muscularis mucosae(3), and the esophogeal glands(4).

STOMACH

The general features and characteristics of the stomach will be described here, with greater detail to the molecular and cellular features occurring later under its own heading. The stomach is a digestive organ with a capacity of approximately 1200-1600mL that can be subdivided into various regions. The initial region of the stomach, the cardiac stomach, is a continuation of the orifice of the esophagus. Prominent features of this region include the cupola of the fundus which arises on the left of the cardia, and a cardiac notch, which forms the plica cardiac inside of the stomach and resides between the fundus and the esophagus. The main portion of this region is the body which is continuous with the fundus of the stomach, and merges into the pyloric region of the stomach. This area dilates to form the antrum pyloricum and then terminates at the opening of the stomach into the duodenum, known as the pylorus. The cardiac region features longitudinal folds in the mucosa which run along the lesser curvature of the stomach, and are accompanied by additional folds that run in a transverse direction. These transverse folds serve as demarcations of mucosal niches which serve as areas for larger food particles to be temporarily stored.

The peritoneum is covered by a serous membrane which allows organs within the peritoneal cavity to freely move against each other as it is lubricated with approximately 50mL of fluid. The peritoneum is separated into a visceral and a parietal layer, which together are continuous and form a peritoneal sac containing a capillary space. Connections between these two layers are formed by thin peritoneal reduplications, the tissue lamina of which carries vessels and nerves to organs. The peritoneal epithelium is actually a mesothelium as it is derived embryonically from the mesoderm. This mesothelium is composed of flat, simple cuboidal cells that feature a border of microvilli that confer an absorptive capacity. Subserous connective tissue is present that is partly loose and mobile, and forms a somewhat firm connection between the serosa and adjacent organs. It should be noted that only the parietal peritoneum has sensory innervations and as a result, it can react violently when inflamed.

The muscle layer of the stomach, also known as the tunica muscularis, is composed of bundles of smooth muscle fibers that are subdivided into an inner circular, outer longitudinal, and an innermost layer of oblique fibers. This third type of muscle, the oblique fibers, is absent in the pyloric region, the body boundary, and the lesser curvature of the stomach. The longitudinal layer of muscle runs the entire length of the stomach, and serves to control the length of the stomach. In between the circular and longitudinal muscle layers resides the myenteric plexus. This structure is the vegetative nerve supply to the muscles, while the submucosa is supplied by a separate plexus, the submucosal or Messener’s plexus which innervates both the muscularis mucosa as well as the glands. Another feature of the stomach is the angular notch, which acts as a boundary between the two portions of the stomach and is divided into two sections. The upper section of the angular notch serves a digestive function, while the lower section serves in emptying the contents of the stomach.

As the stomach fills, the additional contents are accommodated without an increase in gastric wall tension. Because of this, the pressure inside the stomach is equal to that of the peritoneal cavity. As the upper stomach contracts, layers of chyme adjacent to the mucosa are pushed away, while deeper layers are brought into contact with the mucosa. The mixing movements, known as peristaltic waves, occur every 3 minutes and take approximately 20 seconds to move from the fundus to the pylorus. Following movement of food through the stomach, the stomach is then emptied due to pressure conditions between the duodenum and the stomach. These gastric movements are under the control of various tissue hormones which are released from cells in the gastric and duodenal glands containing basal granules.

The mucus membrane, or tunica mucosa of the stomach, is responsible for the production of the protein cleaving enzyme pepsinogen. This proenzyme is activated by the hydrochloric acid (HCl) of the stomach, which converts it into its active form, pepsin. This activation occurs optimally at the acidic pH of 1.5-2. The mucosa is responsible for other products that regulate the secretory and some of the motor functions of the stomach. It also secretes intrinsic factor, which is vital for the absorption of vitamin B12. The surface of the tunica mucosa is characterized by large mucosal folds, as well as gastric areas and small gastric pits known as foveolae gastricae which feature gastric glands within each pit. Both the mucosa and the foveolae are covered by a single layer of columnar

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Figure 3. Gross features of the stomach. The locations of the types of cells including chief, parietal, and mucus neck cells are also indicated

epithelium which liberates mucus, effectively protecting the tissue from autodigestion. Similar to the gastric glands of the mucosa, the connective tissue is characterized by the presence of tubular glands.

The glands present in the stomach vary both in function and structure depending on the type of gland and its location. Those present in the fundus and body of the stomach are elongated and densely arranged, and consist of three cell types. Mucoid cells, which resemble the epithelial cells of the mucosa, serve to form the neutral mucus that is present. Chief cells, which reside in the middle of the gland, are basophilic and are responsible for the production of pepsinogen. Similarly, the parietal cells are also located in the middle of the glands, but serve as separate function as they produce gastric acid. These parietal cells can be further distinguished by their more acidophilic appearance as well as their location on tubuli. The glands in the cardiac region of the stomach, referred to as cardiac glands, are the same shape as fundal cells, but contain only mucus producing cells. Because of this, their primary function is to form an alkaline barrier between the stomach and the esophagus to protect the esophagus from the harmful gastric juices of the stomach. In the pyloric region reside pyloric glands, which appear extremely convoluted, and mainly produce mucus. These glands feature cells with basal granules, as well as lymph follicles commonly found in the connective tissue of the mucosa. Aside from the secretions mentioned thus far, the stomach is responsible for the secretion of gastric juice, the process of which occurs in two distinct phases. The nervous secretion is dependent upon impulses received from the vagus nerve, and is triggered by sensory impressions. In contrast, gastric secretion is primarily stimulated by the ingestion of food, and is turned off by gastrin which is produced by cells containing basal granules in the pyloric region.

STOMACH MOTILITY

Upon swallowing, the vagovagal reflex is triggered which causes the esophageal sphincter to open, while the proximal stomach dilates in a process known as receptive relaxation. The proximal stomach propels food towards the distal stomach as a result of tonic contraction, while a pacemaker region is located near the upper border. This zone generates the peristaltic waves of contraction that occur as a result of gastrin and reflex stimulation of the stomach wall. The peristaltic waves generated are strongest in the antrum and spread to the pylorus of the stomach. Similarly, chyme is driven towards the pylorus, but is then compressed and propelled back again following the closure of the pylorus. In this manner, food taken in and entering the stomach is processed. Chyme serves as a suspension medium for food until it is broken down, when it is then passed on to the duodenum. Similar to the upper border of the proximal stomach, the distal stomach contains pacemaker cells as well, which produce slow waves as a result of an oscillation of membrane potential. This oscillation can be increased by gastrin, which increases both the response frequency as well as the pacemaker rate itself. With regards to motility control, GIP inhibits motility directly, while somatostatin does so indirectly by inhibiting the release of GRP.

Motility of the stomach stimulates its emptying, while other stimulatory effects result in the inhibition of its emptying. Gastric emptying can be inhibited by a decrease in pH or osmolality of the chyme, as well as an increase in the presence of long chain free fatty acids and amino acids. Sensory reception is made even more possible by the presence of chemosensitive enterocytes and brush cells in the small intestine, which are regulated by CCK, GIP, secretin, gastrin, as well as enterogastric reflexes. During the emptying of the stomach, the pylorus is typically open, and will only contract at the end of the antral systole so that solid food is retained. It will also contract when the duodenum contracts as well to prevent the reflux of bile salts. During the digestive phase of stomach motility, indigestible substances such as bone, cellulose, etc. do not vacate the stomach. Instead, the transport of indigestible substances occurs during the interdigestive phase, when migrating motor complexes pass through the stomach and small intestine. This transports these substances, as well as bacteria from the small intestine to the large intestine. Lastly, the clearing phase which follows the digesting and interdigestive phases occurs and is controlled by motillin.

GASTRIC JUICE

The tubular glands of the gastric fundus and corpus actively secrete on average, 3-4 liters of gastric juice. The components of gastric juice vary, and are secreted by varying types of cells, each specialized in their function. For example, pepsinogen and lipases are released by the chief cells, whereas HCl and intrinsic factor are released by parietal cells. Additionally, mucins as well as HCO3 are released by the mucus neck cells as well as other mucus cells that reside on the surface of the gastric mucosa.

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The pepsins produced serve as endopeptidases in protein digestion, as they are split from pepsinogens exocytosed from chief cells. This splitting process occurs in the glandular and gastric lumen, while acetylcholine (ACh) is released in response to hydrogen ions which serves as the primary activator of this reaction. As mentioned previously, gastric juice has a low pH due to its acidic nature, which helps to aid in the denaturation of proteins, while serving secondary functions such as a bactericidal function as well as providing an optimal pH for pepsins and gastric lipases. The HCl secreted by the parietal cells is secreted due to a hydrogen potassium ion ATPase residing in the luminal membrane of the parietal cells. This drives the hydrogen ions into the glandular lumen in exchange for potassium ions. Activation of the parietal cells will cause the opening of canaliculi; due to the presence of a bush border on the canaliculi, the surface area is increased, allowing for an increase in the secretion of hydrogen ions. Gastric acid secretion as whole is stimulated in phases, due to neural and local gastric factors, as well as intrinsic factors. The intake of food results in a reflex secretion of these gastric juices, but other occurrences, such as decreased brain glucose levels can stimulate gastric juice secretion as well. The gastric secretion reflex is a partly conditioned reflex, as external stimuli such as optic, gustatory and olfactory stimuli can trigger it. These nerves perform this function by sending nerve impulse via the vagus nerve. Gastrin is released by a series of events, beginning with a direct activation of the parietal cells by Ach, while gastrin releasing peptide (GRP) is released by neurons and thereby stimulates the secretion of gastrin by G cells present in the antrum. Gastrin is thereby released into the circulation, where it can then activate parietal cells through CCK receptors. Gastrin also activates histamine or ECL cells present in the glands of the fundus, which can also be stimulated by Ach and beta3 adrenergic substances as well. These cells function by releasing histamine, which in turn has a paracrine effect on the parietal cells. A paracrine effect can be triggered by SIH secretion as well, which is produced by D cells located in the antrum, if the activity of G cells is inhibited by a low pH (<3) being present in the antral lumen. SIH secretion also serves to inhibit the H cells that reside in the fundus, as well as the G cells located in the antrum. D cells, which also reside in the antrum as well as the fundus, are activated by CGRP, which is released by neurons.

Gastric juice secretion is further regulated by secretin and GIP, both of which are secreted from the small intestine and serve a retrograde function. This thereby adjusts the composition of the chyme from the stomach to the requirements of the small intestine. Because gastric juice is so acidic, the gastric mucosa must have mechanisms to be protected, such as the layer of mucus present on the gastric mucosa, as well as HCO3 secretion performed by the underlying mucus cells of the gastric mucosa. This HCO3 secretion is promoted by the prostaglandins PGE2 and PGI2, which can be inhibited by anti-inflammatory drugs, resulting in the increased risk of ulcers that anti-inflammatory drugs have associated with them.

FINE STOMACH STRUCTURE

The esophagogastric junction is a transitional tissue residing between the esophagus and the gastric cardia of the stomach. At this region, the mucus membrane of the esophagus terminates, while the mucus membrane of the stomach begins. This transition area shows an abrupt end of the multilayered non-keratinizing squamous epithelium of the esophagus, and the first region where the single layered columnar epithelium of the gastric mucus membrane is present. The short cardia, or pars cardiac of the stomach exhibits cardiac glands which have complexly branching tubules that occur in irregular shapes, with occasional extensions of the ampulla. These cardiac glands are only made of one cell type, and do not feature any parietal or background cells.

The pars cardiac itself is a 2-3 mm ring of mucous membranes that occurs at the entrance to the stomach. It is covered by a single layer of columnar epithelium, including the mucus membranes of the foveolae. The foveolae gastricae then continue on in the deeper tubules of the mucus cardiac glands that reside within the mucus membrane. The cardiac glands are essential in their role of secreting alkaline mucus as well as the enzyme lysozyme.

The corpus and fundus of the stomach feature additional glands, the gastric glands. These glands are approximately 1.5-2 mm long, and feature tubules that rarely branch, and eventually split in two prior to reaching the lamina muscularis mucosae. These tubules are densely packed and feature a lumina that is approximately 3-6 um wide. Chief cells, also known as zymogenic cells, as well as parietal or oxyntic cells, neck mucus cells, and enteroendocrine cells make up the

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Figure 4. Electron micrograph of a parietal cell featuring abundant mitochondria

lining of these secretory tubules. The gastric glands are demarcated by the deepest points of the short gastric pits known as the fovolae gastricae. The surface of the mucus membrane, as well as that of the fovolae gastricae, is covered by a single layered columnar epithelium, which acts to sequester alkaline mucus. The same pits are the destination for the tubules of the gastric glands. The gastric glands themselves have an isthmus, a neck, a main body, and a fundus. The glands are made up of tubules that feature moderate branching, and widen at their ends. These tubules are approximately 1.5 um long, and extend into the lamina muscularis mucosae. Because of their extension into the lamina muscularis mucosae, there is little room left for the lamina propria. The gastric glands also feature a highly vascularized submucosa, as well as an uneven distribution of parietal cells which feature crista-type mitochondria. While unevenly distributed, the parietal cells are most dense in the neck of the gastric glands. These mitochondria are easily visualized by immunohistochemistry labeling for succinate dehydrogenase, which serves as a marker for these mitochondria.

The fundus of the stomach feature gastric foveolae as well, which feature a columnar epithelial lining, with nuclei located in the basal cell region of the epithelia. This single layered columnar epithelium is made of mucus secreting cells which positively stain with PAS. The mucus they secrete forms a protective barrier that guards against the acidic HCl and the lytic enzymes, thereby preventing autodigestion from occurring. The gastric glands feature three types of merocrine cells, the chief cells, the parietal cells, and the neck mucus cells. The chief cells which characterize the glandular body or fundus of the gland, produce pepsinogen as well as lipase, and feature characteristics of protein synthesis. The parietal cells are numerous in the neck of the glands and as mentioned previously, produce acid. These cells typically outnumber the other types of cells and feature large, rounded nuclei. These cells are rich in mitochondria, and therefore stain heavily with acidic dyes such as eosin or congo red. The neck mucus cells are named after their primary location; the neck of the gland.

The pyloric section of the stomach features glands as well, but pyloric glands rather than gastric glands. In contrast to the gastric glands, these pyloric glands feature tubules that branch out and form coils only in the deeper regions of the mucus membrane. These foveolae are also deeper than those of the gastric corpus and fundus, and feature considerable undulation of their tubules. These foveolae are covered with a columnar surface epithelium as well, and consist primarily of mucus cells. As such, when cut in cross section, these glands exhibit a honeycomb like structure, featuring nuclei in the basal cell region. The pyloric portion of the stomach also features unicellular glands, which serve a homocrine function, along with mucus producing glandular cells with endocrine sporadically mixed in. The upper 2/3 of the mucus membrane in this region features a lamina propria rich with cells, as well as an intermediary layer approximately 1cm wide that lies between the fundus and the pylorus.

The cardiac portion of the stomach is characterized by gastric glands with relatively deep foveolae, which feature branching tubules. These tubules have an irregular appearance and often distend to the ampulla and feature a loose organization. In contrast, the body and fundus of the stomach which as previously mentioned, feature gastric glands, as well as unicellular glands. These unicellular glands consist of homocrine glands in the foveolae and heterocrine glands in the tubules.

The stomach also features the myenteric plexus, which is also known as the auerbach plexus. This plexus consists primarily of ganglion cells surrounded by glial cells, as well as a network of nerve fibers. These ganglion cells feature large nuclei which only lightly stain, as opposed to the darkly stained nuclei of the glial cells. This staining is in reference to preparations using methylene blue-azure II.

The stomach features raised gastric areas as well as foveolae of varying depths in all of its segments. All segments additionally feature uniform prismatic epithelial cells that range in height upwards to 40 mm. These epithelial cells are responsible for mucus cells, as opposed to the goblet cells which usually perform this function.

SMALL INTESTINE – GENERAL FEATURES

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As with the stomach, only the general features and characteristics of the small intestine will be discussed here, with a latter section going into further detail. The small intestine follows the stomach and is 3-4 m. long. It primarily serves in the digestion and absorption of food, and is subdivided into three sections; the duodenum, the jejunum, and the ileum. These sections are not clearly separated from one another, and can initially be distinguished by their locations. The duodenum resides almost entirely in the retroperitoneal space on the posterior abdominal wall, while the jejunum and ileum form mobile intraperitoneal coils within a space framed by the large intestine. The duodenum is C-shaped, and winds around the pancreas with the beginning of its superior portion being dilated. This dilation is referred to as the duodenal bulb. Two ducts, the bile duct and pancreatic duct open into the duodenum at its middle, while the transition to the jejunum is known as the duodenjejunal flexure. The jejunum and ileum feature a mesentery that folds during the shortening of the intestine, and is fixed at the root of the posterior abdominal wall. The jejunum and ileum can be distinguished from one another by their location as the jejunum corresponds to the upper 2/5, and the ileum the lower 3/5 of the intraperitoneal section of the small intestine.

The wall of small intestine features multiple layers similar to that of the other portion of the GI system. The tunica mucosa is comprised of three sub-layers, an epithelial mucosal layer, a connective tissue mucosal layer, and a mucularis mucosae which are also known as the lamina epithelialis, the lamina propria, and the muscular epithelia layer respectively. The tela submucosa is a mobile layer of connective tissue, while the tunica muscularis is a muscular layer composed of two components, the stratum curculare and the stratum longitudinal. A tunica serosa with a tela subserosa is present in the peritoneum, while in the retroperitoneal and extraperitoneal regions, this is replaced with a tunica adventitia. In the intraperitoneal position however, the mesentery carries the blood vessels and nerve supply for the intestine.

The mucosa of the small intestine features considerably enlarged epithelial surface due to the presence of mucosal folds, villi, and microvilli, and serves to facilitate digestion and absorption. These plicae and villi do decrease in number however as one progresses towards the lower portions of the small intestine. Circular folds, known as Kerching folds project approximately 1 cm into the lumen of the gut and are formed by a folding of the mucosa and submucosa. These structures effectively enlarge the surface area by approximately one third. The villi of the small intestine are leaf like, finger shaped structures, originating from the epithelium and lamina propria of the mucosa. It should be noted that villi formation does not involve the muscularis mucosa. These villi convey a velvety appearance to the mucosa, and effectively increase the surface area further by approximately 5-6 fold. In between these villi reside the intestinal crypts, or crypts of Lieberkuhn. These structures feature the intestinal glands, and reach as far down as the muscularis mucosa.

Aside from their location within the small intestine, the duodenum, jejunum, and ileum, can be further distinguished and characterized by the types of structures found within them. The duodenum features numerous high folds, as well as high, leaf shaped villi, and shallow crypts. These shallow crypts are home to the Brunner’s Glands, which are clustered grounds of glands residing in the submucosa. The jejunum has numerous high folds and villi as well, but diminish in number and height towards the ileum. As one gets closer to the ileum, the crypts within the jejunum become deeper as well. The ileum features folds and villi that gradually disappear, while lymphoid tissue increases. While lymph follicles are distributed over the entire intestine, the ileum is characterized by a concentration of lymph follicles in clusters of 20-30 on the side opposite the attachment to the mesentery. These aggregations of lymphoid follicles are known as Peyer’s patches. In contrast to the small intestine, the colon features no villi, deep crypts, and features lymph follicles as well.

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Figure 5. Features of the small intestine including the the tunica serosa(1), longitudinal muscle(2), Auerbach’s plexus(3), circular muscle(4), Meissner’s plexus(5), tunica mucosa(6), epithelial cells (13–15), blood vessels(8), lymph vessels(9), nerves(10), Kerckring’s folds(11), intestinal villi(12), and microvilli(13)

The villi and crypts of the small intestine are covered by an epithelium, while the crypts themselves feature an epithelial lining. The epithelium of the small intestine varies in composition, featuring multiple cell types with specific functions. The epithelium of the mucus membrane for example is one layer thick, and consists of polygonal cells that are further distinguished as either secretory or absorptive. Secretory cells of the epithelium are not universal in their function or products, as different types exist. Goblet cells, which are common in the crypts and villi, produce mucus to lubricate and protect the intestine. The portion of the goblet cell pointing toward the lumen of the intestine is filled with mucus particles while being surrounded by a membrane that originates from the Golgi of the cell. When intracellular pressure increases, the cell membrane eventually bursts, releasing the mucus and allowing it to enter the intestine. In contrast, secretory paneth cells appear in small grounds in the fundi of intestinal crypts, and contain apical acidophilic granules. These cells may also contain lysozyme enzymes. Basally granulated cells, such as the GI endocrine cells, function as hormone producers, producing peptide hormones and monoamines that control the motility and secretion of the digestive system. Aside from secretory cells, absorptive cells cover the villi and feature a brush border of microvilli that confer an absorptive capacity to these cells. These villi increase the surface area of the absorptive epithelia approximately 30 times. These cells contain alkaline phosphatase for carbohydrate absorption, with lipases and esterases being present in the microvilli and deeper zones. Absorption is performed by means of active transport against the concentration gradient, with some facilitated diffusion also occurring as evidenced by the observation of pinocytosis using electron microscopy. Additionally, the intercellular space of absorptive epithelia is shut off from the lumen of the gut due to the cellular contacts; the zonulae adherens and the zonulae occludens. The life span of epithelial cells in the small intestine is brief, with epithelial cells also being sensitive to injury. To replace damaged and dead epithelial cells, new epithelium is regenerated from the epithelium of the crypts, as daughter cells migrate toward the villus where the old cells are then shed into the contents of the intestine. This migratory process takes approximately 36 hours, with the entire tract being replaced every 2-4 days.

The connective tissue of the mucosa of the small intestine consists mainly of reticular connective tissue, and contains lymphocytes and other immunocompetent cells. The connective tissue also contains arteries, venules, lymphatics, and terminal branches of the submucus venous plexus. The connective tissue features muscle fibers which radiate from the muscularis mucosa into the connective tissue of the villi. These fibers extend into the basement membrane of the epithelia and function by contracting, thereby squeezing venous blood and lymph into the vessels of the submucosa.

The muscle layer of the small intestine features an inner circular layer that is much more developed than that of the outer longitudinal layer. These two layers act as antagonists, with a myenteric plexus residing between the two layers that features numerous nerve fibers and nerve cells. The movement of the small intestine consists of both mixing and transportation based movements, which are the products of pendulum and segmentation movements, with the transportation of intestinal contents being provided by peristaltic waves.

A network of capillaries in the connective tissue of the small intestine, below the epithelium constitutes the blood vessels of the villi. These capillaries are supplied by one or more arteries that run undivided to the summit of the villi, with arteriovenus shunts being present at the summit of the villi. An interesting feature of these capillaries is a fenestrated endothelium. Within the vascular coat is a lymph vessel, the central lacteal. This vessel contains chyle, the lymph drained from the intestine. It should be noted that fatty acids are carried with the lymph stream following their re-synthesis in the mucosa, as well as triglycerides. The bulk of the material absorbed by the epithelium is carried via the portal vein to the liver.

SMALL INTESTINAL FUNCTION

As mentioned previously, the intestinal glands, or crypts of Lieberkuhn, are located at the bases of the villi and feature undifferentiated and mitotic cells that differentiate into various cell types including villous, mucus, immune, endocrine, and paracrine cells. The composition of the chyme present in the small intestine triggers the secretion of endocrine hormones as well as paracrine mediators, For example, the tubuloacinar duodenal glands, or Brunner’s glands, which are located in the tela submucosa, secrete a HCO3 rich fluid that contains urogastrone. Urogastrone, also known as human epidermal growth factor, acts as a stimulator for the proliferation of epithelial cells. These hormones, as well as external innervations, serve to autonomously regulate the motility of the intestine. The motility of the intestine consists of multiple types of movements, each with their own regulatory mechanisms and functions. Local pendular movements are produced by the longitudinal muscles as well as the contraction of circular muscle, effectively mix the intestinal contents and bring these contents into contact with the mucosa of the intestine. This

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movement is greatly enhanced by the movement of the intestinal villa that is present. Aside from these pendular movements, reflex peristaltic waves also occur, which, similar to those of the stomach, propel the contents along. In the case of the small intestine, these waves propel food towards the rectum, and are particularly strong during the interdigestive phase. As the intestinal wall stretches as food passes along, a reflex is triggered that causes the lumen behind the food to constrict, while the lumen ahead of the food opens. This process is controlled by interneurons, with cholinergic type 2 motoneurons featuring a prolonged excitation activating the circular muscle behind the food as well as the longitudinal muscle ahead of the food. Similar to the pacemaker cells of the stomach, the small intestine contains pacemaker cells as well, known as interstitial cajal cells. The cells oscillate their membrane potential, which produces slow waves, the amplitude of which can change depending on neural, endocrine, or paracrine stimuli. If the trough of these waves exceeds the membrane potential, muscle spasms can occur. The impulse conduction involved in these processes is performed by myocytes that rhythmically contract, following the reception of signals via gap junctions. This conduction flows in the direction of the anus, and diminishes past a particular distance. Because of this, distal cells must assume the role of pacemakers, therefore the peristaltic waves progress only in the anal direction.

FINE STRUCTURE OF THE DUODENUM

The duodenum features a tissue surface similar to that of the rest of the upper small intestine, with circular folds also known as plicae circulars and Kerckrings folds. These folds serve to form an articulated relief in the duodenum and are technically part of the mucus membranes as well as submucosal tissue. These folds can be up to 8mm high, but do not involve the tunica muscularis. Their surface features intestinal villi or villi intestinales, which are approximately 0.5-1.5 mm high and 0.15 mm thick. These are covered in a columnar epithelium featuring enterocytes as well as absorptive cells. The lamina propria of the villi features smooth muscle cells which extend down to this layer from the lamina muscularis mucosae. The villi themselves are actually protrusions of the mucus membranes and feature tubular canals which extend from the cellular surface at the bottom of the inter-microvilli invaginations all the way to the lamina muscularis mucosae. These same glands are commonly known as the crypts of Lieberkuhn. In the submucosal layer, an additional type of gland, the duodenal or Brunner’s glands, are present and further characterize the duodenum. These duodenal glands are the key feature that distinguishes the duodenum. It should be noted that while the surface epithelium of the Kerckring’s fold contain goblet cells, there are also bindles of collagen fibers located between the glands. The valve of the fold, the Kerckring valve, features tall circular folds that are covered with either long and slender villi, or wide, leaf like villi. These same villi feature a single layer of epithelium that is composed of columnar cells (enterocytes), but are also interspersed with goblet cells as well.

The tubular canals of the crypts of Lieberkuhn run from the bottom of the villi to the lamina muscularis mucosae. These glands vary in depth, ranging from 200-400 um, and are composed of tubular invaginations of the intestinal epithelium that feature partial branching. This is in contrast to the aforementioned Brunner’s glands which are tubuloalveolar glands that feature branching as well. The surface epithelium of the intestinal glands is characterized by slender columnar cells with an easily distinguishable brush border on their apical surface. The microvilli comprising this brush border are approximately 1.2-1.5 um long, and 0.1 um thick, with an average 2500-3000 microvilli being present on a given epithelial cell. Enterocytes are present in the epithelium, ranging in size from approximately 15-30 um tall, and 5-10 um wide, and feature nuclei in the lower third of these cells. It should be noted that the brush border of the epithelium does not extend to the goblet cells which are also present here. Also present in the epithelium of the intestinal surface are paneth and endocrine cells, as well as other types of cells. At the fundus of the crypts reside cells that feature apical granulation, which are commonly known as paneth cells. They receive their name after the first individual to describe them, Joseph Paneth, but are also referred to as oxyphillic granule cells due to their

12Figure 7. Electron micrograph of a paneth cell. The golgi, lysosomes, microvilli, nucleus, and secretory granules are visible.

Figure 6. Micrograph of the duodenum featuring the tela submucosa(1), Brunner's glands(2), and lamina propria mucosae(3)

staining characteristics. The paneth cells are technically exocrine glands, with their secretory granules containing peptidases as well as the bacteriolytic enzyme lysozyme. These cells are not solely confined to the duodenum as they are also found in the jejunum, but are found in greater number at the lower portion of the ileum as well as the vermiform appendix.

FINE STRUCTURE OF THE JEJUNUM

The jejunum, while featuring the circular plicae or Kerckring’s folds similar to the duodenum, does not feature Brunner glands which are confined to the duodenum. The upper portion of the jejunum is characterized by high plicae, as well as a dense brush border composed of microvilli. These villi protrude from the tunica mucosa, and consist of not only the surface epithelium, but also the lamina propria mucosae as well as some smooth muscle cells of the lamina muscularis mucosae, which are intermittently present. As one moves down the jejunum towards the ileum, the circular plicae gradually become shorter, their frequency decreases, and the density of their villi decreases as well. Additionally, as the ileum is approached, the distance between the plicae increases. Between shorter villi, crypts of Lieberkuhn are present, while higher jejunal plicae are supported by the connective tissue of the tela submucosa. The goblet cells here are increased in number towards the distal side, while the short crypts present here feature numerous paneth cells. The villi here, like that of the other intestinal mucosae, features a single layered columnar epithelial surface made of enterocytes, with their nuclei being located in the basal region of the cell. The inner face of the villi is lined with reticular connective tissue, which may contain free cells, as well as lymphocytes, microphages, eosinophilic granulocytes, mast cells, and even plasma cells. In contrast, the inner portion of the villi is characterized by a dense capillary network, as well as lymphatic vessels and smooth muscle cells which are present along the long axis of the villi. The muscle cells present here originate from the lamina muscularis mucosa, which is responsible for the generation of the rhythmic contractions of the villi. While some of these villi are long and round, others appear to be flattened, with small grooves subdividing the villi into smaller surface areas. The granulocytes present feature a lightly staining cytoplasm, while the secretory granules contained within may be better visualized by the use of chromium silver salts. These cells, the enterochromaffin cells, produce hormones with their cellular population composing the gastroenteropancreatic system or GEP. To date, 19 types of GEP cells have been identified, and produce 18 peptide hormones as well as serotonin.

CRYPTS OF LIEBERKUHN

It is important to describe in detail, the composition of the intestinal glands of Crypts of Lieberkuhn, as they are composed of multiple cell types, each with their own particular function. The crypts contain stem cells that feature an exceptionally high rate of mitosis, being able to replace the surface absorptive cells and goblet cells every 3-6 days. The crypts also contain paneth cells as previously mentioned which secrete lysozyme, which serves an antibacterial function. The enteroendocrine cells present in the crypts are made of multiple cell types, including I cells, S cells, K cells, and L cells. The I cells actively secrete CCK in response to the presence of small peptides, amino acids, and fatty acids within the lumen of the gut. Secreted CCK stimulates the pancreas to secrete enzymes, as well as the gall bladder to release bile. The S cells secrete secretin as a response to the presence of fatty acids as well as hydrogen ions in the lumen of the gut. The secretin produced stimulates the subsequent release of bicarbonate from the pancreas as well as the bilary tract. The K cells actively secrete gastric-inhibitory peptide, or GIP, as a response to glucose taken orally. GIP secretion is also released due to the presence of amino acids and fatty acids in the lumen of the gut. GIP is responsible for the stimulation of insulin secretion from pancreatic islet cells. As previously mentioned, it is this process that explains the increased serum insulin levels that result from oral glucose as opposed to intravenous glucose administration. Lastly, the L cells secrete glucagon like peptide (GLP-1) is response to the presence of amino acids and fatty acids in the lumen of the gut, as well as oral glucose. The GLP-1 secreted stimulates insulin secretion from the pancreatic islet cells as well, and additionally inhibits the secretion of glucagon by these same pancreatic islet cells. As such, GLP-1 may be an effective therapeutic agent for individuals with type 2 diabetes as this stimulatory effect on insulin by GLP-1 is maintained in these individuals.

FINE STRUCTURE OF THE ILEUM13

Figure 8. Micrograph of the jejunal wall featuring intestinal villi(1), crypts of Lieberkuhn(2), tela submucosa(3), and tunica muscularis(4).

When compared with the rest of the small intestine, there is very little enlargement of the surface area in the ileum, a characteristic which defines the ileum. The circular plicae present here are shorter, and then decrease in number until they are complete absent. Additionally, the villi here become shorter as well as few in number in contrast to those in the jejunum. Some of the villi here feature branching, while small crypts occupy the spaces at the bottom of the inter-villi space. There is a prominent development of the lymphoreticular organs in the ileum, as these develop to form what are known as Peyer’s patches, or Peyer’s plaques. These patches do not have villi on their surface, and are present in the connective tissue of the mucosa as well as the submucosa. The Peyer’s patches are the only location where M-cells can be found, and along with solitary lymphatic follicles, compose the gut-associated lymphoid tissue, or GALT. The solitary lymphatic follicles that also compose the GALT typically occur as in the tela submucosa opposite of the attachment of the mesentery, with all lymphatic follicles lacking villi in their mucosa. The M cells present in the Peyer’s patches sample the contents of the intestine, and thereafter present specific antigens to the immature lymphocytes present there. The mature lymphocytes will then differentiate into plasma cells which function by secreting IgA antibodies into the lamina propria. The majority of this IgA enters the bloodstream and will reach the liver by means of the sinusoids. Once in the liver sinusoids, the IgA will bind to receptors present on the hepatocytes and become endocytosed, while that at the bile canaliculi will be released into the bilary tract along with a portion of its secretory piece. This secretory IgA will then enter the intestinal lumen with the bile.

MOLECULAR CHARACTERISTICS OF THE MUCOSA

The mucosa of the small intestine is lined with surface absorptive cells which are joined together by juxtaluminal tight junctions. As mentioned previously, these cells possess microvilli, which are coated with a glycocalyx. The glycocalyx, which is composed of filamentous glycoproteins, contains critical enzymes that function in digestion such as lactase, maltase, peptidases, and enterokinase. It is the enterokinase that is responsible for converting the inactive forms of pancreatic enzymes into their active forms. These surface absorptive cells function by absorbing carbohydrates, lipids, proteins, vitamins, calcium, as well as iron from the intestinal lumen; thereafter they are transported to the blood or lymph. The digestion of carbohydrates occurs by carbohydrates being broken down into monosaccharaides such as glucose, fructose, and galactose. Glucose and galactose are absorbed by means of a sodium dependent cotransporter, while fructose is absorbed through facilitated diffusion. Similarly, proteins are digested into amino acids, dipeptides, and tripeptides, and then absorbed through a sodium dependent cotransporter. Bile salts serve to emulsify the tricylglycerols, which are then digested further into fatty acids and monoacylglycerols. Long chain fatty acids made of more than 12 carbon molecules, as well as monoacylglycerols, cholesterol, and fat soluble vitamins such as vitamins A, D, E and K, are packaged into micelles and then subsequently absorbed. Tricylglycerols are re-synthesized within the surface of the absorptive cells in their smooth endoplasmic reticulum, followed by the packaging of these triacylglycerols as well as cholesterol and fat soluble vitamins with apoproteins. This packaging creates chylomicrons which are subsequently released into the lymph. Short and medium chain fatty acids consisting of less than 12 carbon molecules are not packaged with apoproteins into chylomicrons, but rather are released into the portal blood directly. This process can be affected pharmacologically, as in the case of the weight loss drug Xenical, which prevents the absorption of approximately 30% of dietary fat. Water soluble vitamins absorbed by the surface absorptive cells are taken in using a sodium dependent cotransporter. However, vitamin B12 requires a product of the parietal cells of the stomach, intrinsic factor, in order to be absorbed properly. Calcium is also absorbed by these absorptive cells, but requires 1,2 OH2 Vitamin D3, a product of the kidney, to facilitate its absorption. Lastly, iron is absorbed in one of two ways; either bound to hemoglobin or myoglobin as ferroheme, or as free Fe2+, and is subsequently transported in the plasma via a protein called transferrin.

CLINICAL CONSIDERATIONS OF THE SMALL INTESTINE

Multiple disorders of the small intestine can occur, some due to external factors like bacteria, while others can be congenic diseases due to genetic factors. Celiac disease is characterized by a hypersensitivity to gluten and gliadin, proteins commonly found in wheat and other grains. When these proteins are ingested, numerous lymphocytes, plasma cells, macrophages, and eosinophils will

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Figure 9. Micrograph of the ileum featuring villi(1), lymphatic nodules(2), and tunica muscularis(3).

congregate in the lamina propria of the intestinal mucosa. The antibodies to gliadin are usually detectible in the blood, but these factors may cause damage to the mucosa by means of an immunologic response. Celiac disease causes multiple symptoms, including chronic diarrhea, flatulence, as well as weight loss and fatigue.

Crohn’s disease, whose etiology is currently not known, is classified as a type of inflammatory bowel disease. It is characterized by a formation of a granuloma, and can be distinguished by a clear demarcation between diseased and adjacent unaffected bowel segments. In Crohn’s disease, neutrophils will infiltrate the intestinal glands and will ultimately destroy them. This can cause ulcers, which can then join together to form long, serpentine ulcers known as liner ulcers that occur along the axis of the bowel. Crohn’s disease features intermittent diarrhea, as well a weight loss and weakness.

The gram negative bacteria Vibrio cholera produces cholera toxin, an enterotoxin. It is this enterotoxin that results in the disease cholera, by catalyzing the ADP ribosylation of the As chain of Gs protein. This will result in increased levels of cAMP, which will activate the chloride ion channels that reside on the surface absorptive cells, causing them to release chloride into the lumen, with sodium and water following. Certain strains of E.coli are able to use a similar mechanism to cause what is known as traveler’s diarrhea. Both traveler’s diarrhea and cholera feature severe, watery diarrhea.

Lastly, another type of intestinal issue is that of lactose intolerance. In this disease, lactose cannot be digested due to the lack of the enzyme lactase from the glycocalyx. The unabsorbed lactose remains in the lumen, causing osmotic diarrhea. Lactose intolerance can occur many ways, with a congenital lactase deficiency being the rarest. Typically lactose deficiency is acquired, either due to rotavirus gastroenteritis, kwashiorkor caused by a pack of dietary protein, or by old age as well. As mentioned, lactose intolerance is characterized by osmotic diarrhea, but can also cause abdominal distention, and explosive watery diarrhea.

LARGE INTESTINE

The large intestine primarily functions to reabsorb water and electrolytes. The large intestine is 1.5-1.8 m long, and begins with the colic valve, while the appendix is seen hanging from the cecum as a dilated intestinal pouch. The large intestine has many regions, with the cecum being followed by the colon which is divided into the ascending, transverse, descending, and sigmoid colon. The ascending colon runs close to the anterior abdominal wall on the right side under the liver, while the transverse colon runs in an arch along the anterior abdominal wall to the upper left corner of the abdominal cavity. It then turns at right angles to the descending colon at the level of the lower pole of the spleen. The descending colon is covered by convolutions of the small intestine, and passes downward and posteriorly along the left lateral abdominal wall. The bend located at the left fixture is an obstacle for travelling intestinal contents and must be overcome by additional peristalsis. The sigmoid colon lies in an S-shaped loop, located in the left iliac fossa and enters the false pelvis. Lastly, the rectum begins in front of the 2nd and 3rd sacral vertebrae and continues on ultimately ending at the anus. It should be noted that when empty, the colon rests lower than that of a full colon which floats on the abdominal viscera.

The external longitudinal muscles of the large intestine are compressed into three, 1 cm wide longitudinal bands known as the teniae coli. The colon itself is sacculated, and has folds protruding into the lumen, known as the semilunar folds. As mentioned previously, no villi exist in the large intestine, while the crypts are extremely deep. Additionally, the crypts in the mucosa of the large intestine reside very close together, and feature an epithelium consisting predominantly of goblet cells. The remaining epithelia of the crypts of the large intestine have a ciliated border of microvilli, while solitary lymphoid nodules further characterize the mucosa of the large intestine.

The cecum is the widest segment of the large intestine, a pouch-like segment residing on the right upper portion of the ileum near the anterior abdominal wall. The distal portion of the ileum protrudes as a round or oval papiliform projection which is known as the colic valve, which marks the beginning of the large intestine. This projection pushes aside the circular muscle layer of the cecum. The colic valve

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Figure 10. Light micrograph of the colon featuring simple columnar epithelium of the intestinal gland, the lamina propria, and the muscularis mucosa.

is located in front of the mesocolic band, whose muscle fibers partially are inserted into the muscular valve of the circular muscle fibers of the cecum. Because of this, it can open the end of the ileum, with constriction assisting in the dilation of the end of the ileum, forming an ampulla before the colic valve. If the longitudinal muscle layer of the invaginated end of the ileum and tenia shortens, the papilla are thereby shortened and the ostium is dilated. Conversely, if the circular muscle layer of the ileum and cecum is contracted, the papilla are extended and the osteum is closed. The sphincter of the cecum opens periodically, allowing contents from the small intestine to enter the large intestine, as well as hindering reflux. This reflux function is maintained even if the cecum is tightly filled due to the mechanical valvular mechanism.

The vermiform appendix, which is part of the large intestine, arises like a funnel from the end of the cecum. At the origin of the appendix, the three tenia of the colon (libera, omentalis, and mesocolica) meet in a star formation after running across the cecum. These tenia form a closed longitudinal muscle layer in the wall. The mesoappendix carries the appendicular artery and vein to the appendix behind the end of the ileum, and is a continuation of the mesentery of the small intestine. Of particular clinical importance is the position of the appendicular projection on the abdominal wall. In the diagnosis of appendicitis, the position of the projection of the appendix on the abdominal wall can indicate whether or not the appendix is descended. The origin of the appendix is projected on the center of a line between the right anterior superior iliac sine and the umbilicus under normal conditions. If the appendix is descending, the appendix then projects roughly toward the border between the right and the middle third of a line connecting the two anterior superior iliac spines.

The appendix features a mucus membrane that has crypts, but contains no villi. These villi do not however, serve for digestion or absorption in humans, but rather serve as part of the immunologic system and as such, the appendix is referred to as the “tonsil of the intestine”. Continuing with its immunologic functions, the appendix is full of lymph follicles, which penetrate into the submucosa. These follicles function as a defensive mechanism against infection, but may sometimes react violently and hyperactively with a risk of suppuration and perforation of the appendicular wall into the abdominal cavity. The appendix lumen frequently features cellular debris and residues of intestinal contents.

The rectum is an S-shaped structure, roughly 15-20 cm long and consists of a sacral flexure, a perineal flexure, and an anal canal, terminating at the anus. A projection of the rectum to the left is formed by the Kohlrausch fold, while the sacral flexure lies behind the peritoneum and is covered anteriorly by said peritoneum. Sacculations and bands are absent from the rectum as the longitudinal muscle layer present in the rectum is continuous. Of particular interest is the upper 1/3 of the rectum which is very extensible, and is commonly known as the rectal ampulla. This region of extensibility is responsible for the urge to defecate when it becomes filled and begins to stretch. Three constant transverse folds project like wings into the lumen of the intestine, with two smaller folds residing on the left, and one larger fold on the right. These are known as Kohlrausch’s fold. When the circular muscle is contracted, the folds approximate to each other, while contraction of the longitudinal muscle results in the folds moving apart from each other.

The anal canal has a thin lightly keratinized skin lining its lower two thirds. This skin is innervated with sensory structures, and merges to the external skin. The external skin then reaches into the end of the anal canal and is characterized by the presence of a cornifying pigmented epidermis which features hair follicles as well as sebaceous and sweat glands. The mucosa of the colon extends to the upper third of the anal canal. In this region, about 6-10 roll shaped longitudinal folds are present, with anal columns arching into the lumen, being thrown up by knots of vessels. These folds are covered by several layers of non-keratinized squamous epithelium. At the lower ends of the anal columns, they are joined together by transverse folds. In between these longitudinal folds are grooves which terminate in shallow pockets at the anal ends. Within the anal columns are branches of the superior rectal artery, which lie underneath the mucosa and form the bases of the internal hemorrhoids. These columns also serve as a contributor to the closure of the anus by forming a cavernous body which serves this function.

The closure of the anus is facilitated by multiple muscles and structures. The anal cavity itself is actively closed by the smooth muscle continuation of the circular muscle layer of the intestine. This muscle is known as the internal sphincter muscle of the anus, but is not solely responsible for the closure of the anus as striated muscle of the external sphincter muscle also serves in anal closure. Another muscle involved in anal closure is the puborectal muscle, which resides above the internal and external sphincter muscles. It is the puborectal muscle that closes the anus, and also forms a portion of the levator ani muscles. The puborectal functions by pulling the perineal flexure forward in a loop, which closes the anus. Because of the importance of this muscle in anal closure, damage to this muscle is more serious with regards to incontinence than any other muscle involved in anal closure. In addition to

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these muscles, the pubococcygeal muscle also partly contributes to anal closure, and is kept under constant tension like all other muscles involved in anal closure. This tension is only released when the body defecates.

Defecation, the act of excreting feces from the body, is preceded by the transport of feces to the rectum. The wall of the rectum increases in tension, and thereby acts as a stimulus for the urge to defecate. The involuntary sphincter muscles are relaxed by reflex while other intestinal muscles contract. The external sphincter and levator muscles are relaxed voluntarily, with pressure being applied by the abdominal muscles to excrete the feces.

As previously mentioned, the terminal end of the gastrointestinal tract is composed of the cecum, colon and rectum, and features crypts present in the mucosa of the large intestine lined with mucus forming goblet cells. In addition, some of the surface cells may be equipped with a brush border to aid in the re-absorption of water and minerals. In this sense the large intestine functions as a sort of reservoir, absorbing water and electrolytes. Because of this relatively non-specialized function, the large intestine can be surgically removed if necessary. Also of interest, is the absorptive nature of the intestinal wall. Because of this absorptive capacity, drugs and water may be delivered anally as is in the case of suppositories, which effectively bypass the liver, as well as avoiding the digestive enzymes and gastric acid.

At birth, the intestinal tract is virtually sterile, but quickly becomes colonized during the first few weeks of life by orally introduced anaerobic bacteria. While there are virtually no bacteria in the upper part of the small intestine, the large intestine features bacteria that serve not only as a defense mechanism against pathogens, but also in metabolism as well. The intestinal bacteria are able to synthesize vitamin K, as well as convert indigestible substances or partially digested saccharides such as lactose into digestible compounds. These compounds include short chain fatty acids, as well as gasses such as methane, hydrogen, and carbon dioxide.

LIVER

Besides the tubular portions of the gut, solid organs are also part of the digestive system, such as the liver and pancreas which are the large intestinal glands. The liver effectively acts as an exocrine gland, and is responsible for the production of bile. The bile it produces serves as an emulsifier for fat in the intestine. Bile is tinted yellowish, which is a result of the catabolism of hemoglobin. The bile accumulates in the gall bladder from which it is then discharged into the duodenum as needed.

The liver is the largest organ involved in the metabolism of carbohydrate, protein, and fat. It is held together by a tense connective tissue capsule known as the Glisson’s capsule. Most of the liver is covered by peritoneum, while posteriorly it is joined to the diaphragm at its tendinous center. At this joining, band-like structures exist on the diaphragm which are formed by the reflect fold between the visceral and parietal peritoneum of the liver. The anterior surface of the liver is divided into two lobes by the hepatic falciform ligament. This ligament also forms the hepatic coronary ligament on the superior surface of the liver beneath the diaphragm. This connects the liver and the diaphragm, as well as delimiting the bare area of the liver not covered by peritoneum. At this bare portion, the liver is in direct contact with the diaphragm while the inferior vena cava runs behind the peritoneum to the diaphragm. The entrance to the liver, known as the porta hepatis, forms a cross connection between the sagittal grooves of the liver. These grooves are divided into the left and right sagittal groove, each with their own function. The left sagittal groove accommodates remnants of fetal vessels as well as the remnants of the umbilical vein and venous duct. The right sagittal groove is home to the gall bladder in its anterior portion while the inferior vena cava resides at its posterior end.

The liver is made up of numerous small liver units, or liver lobules, that consist of parenchema and blood vessels. These are part of s sponge-like network of connective tissue extending from the tough capsule down into the liver. The liver lobules, or hepatic lobules, are approximately 1-15 mm in diameter and 2mm long,, with several lobules comprising one lobe. The central veins of these lead into intermediate veins which then drain into the hepatic veins by means of the sublobular and collecting veins. The branches thereby enter the lobule to carry blood from the portal vein to the sinusoidal capillaries. The blood vessels present in the lobules are branches of the portal vein and hepatic artery, and extend to the thicker end of the lobule along with the interlobular veins and arteries. These thereby supply the surrounding vasculature. It should be noted that the oxygen concentration varies with the region of the lobule, with the periphery containing higher levels of oxygen than that of the center. When cut in sections and examined, the hepatic lobules feature triangular periportal areas of connective tissue that exist between the lobules. These connective tissue regions feature three vessels; the branches of the hepatic artery and portal vein, as well as a bile duct. Each lobule features a

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centrally located central vein, while isolated veins are either intermediate, sublobular, or collecting veins. The portal vein lobule is actually grouped around Glisson’s triad. The three branches of the portal vein from Glisson’s triad form the axis of a liver acinus, the functional unit of the liver. The epithelia of the lobule radiate from the center and extend to the periphery, and form the cribose laminae that are only one or two cells thick. In between the cribose laminae run the sinusoidal capillaries while a space runs between the vessel wall of these capillaries and the surface of the liver wall known as Disse’s space. On the surface of the hepatic epithelium exists microvilli, which come into contact with material being carried in the blood by means of capillary gaps in Disse’s space. Within the hepatic endothelium exists another specialized cell type, the stellate Kupffer cells which are phagocytic and thought to help breakdown hemoglobin.

The exchange of material involved in the various metabolic processes occurs on the blood vessel side of each liver cell, while those materials involved with bile production are allowed to pass through the body of the cells. Bile flows in bile ducts from the center to the periphery of each liver lobule. These bile ducts have an epithelial lining present, and are commonly referred to as the bile canaliculi. These tub-like spaces lack walls, and as such exist between the hepatic epithelial cells. They do, however, feature a prominent elastic network as well as a muscle layer, and a thin layer of tall epithelial cells, with mucus ducts emptying into the bile ducts. Bile production, like other functions of the liver, occurs at various times of the day, which allows for a sort of division of labor within the various regions of the lobule. The production of bile begins in the morning at the periphery, and works its way to the center with peak production occurring in the evening. Similarly, the storage of glycogen begins at the center of the lobule and exhibits peak operation in the morning. This temporal operation is also true of the infiltration of fat from digested food, as it begins in the afternoon at the periphery but occurs in the center around midnight.

The bile produced, while transported via bile ducts to the esophagus, is stored and concentrated in the gall bladder. The gall bladder resides in a fossa within the liver, and is connected to the liver through connective tissue. The lumen of the neck of the gall bladder, as well as its connections and cystic duct are subdivided by spiral diaphragmatic folds known as spiral folds. These folds do not subdivide completely, and are part of the mucosa. The ducts form a common heatopancreatic ampulla which features its own sphincter, the sphincter ampullae, which serves to close the ampulla. The ampulla features a mucosa with characteristic folds that prevent the reflux of bile and pancreatic secretion into the ducts.

The liver features many characteristics that are observed histologically, such as mucosal folds outlining polygonal areas. These are seen as mucosal “bridges” in section. The epithelium is simple columnar, and features microvilli containing absorptive cells, as well as granule containing secretory cells. In addition to these secretory cells, goblet cells are also present, and will increase in number when chronic inflammation is present. The remainder of the wall of the liver is composed of loose connective tissue and a thin muscle layer, similar to other portions of the intestine.

LIVER EXCRETORY FUNCTION

In order to perform its tasks of detoxifying and excreting substances (mainly lipophillic), the liver requires these substances to be biotransformed to facilitate this

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Figure 12. Diagram depicting the path of the enterohepatic circulation.

Figure 11. Light micrograph of the liver featuring a lymphatics vessl, as well as branches of the hepatic artery, portal vein, and bile duct.

excretory process. Reactive groups (OH, NH2, COOH) are enzymatically added to hydrophobic substances, followed by the conjugation of these substances with other chemicals. Glucuronic acid, acetate, glutathione, glycerin, and sulfates all serve as conjugates for these substances, conferring water solubility to the substances after conjugation. These can then be further processed in the kidneys where they can subsequently be excreted in the urine, or they can be secreted into the bile by the liver, where they will ultimately be secreted in the feces. The canalicular membrane of hepatocytes contains carriers that are directly fueled by ATP, such as MDR1, MDR3, and cMOAT. MDR1 carries relatively hydrophobic and cationic metabolites, while MDR3 carries phosphatydilchiline, and cMOAT carries conjugates and other organic anions. One chemical critical to liver function is bilirubin, which originates from the hemoglobin within the erythrocytes, as well as other hemoproteins like cytochrome. It should be noted however, that approximately 85% of bilirubin produced is produced from hemoglobin. When hemoglobin is degraded, various globulin and iron components are cleaved, while billiverdin and bilirubin are formed from porphyrin residue.It is bilirubin that gives bile its characteristic yellow tint. Unconjugated free bilirubin will complex with albumin when it is present in the blood, but will not do this when it is absorbed by hepatocytes. When in hepatocytes, bilirubin will conjugate with two molecules of UDP-glucuronate, forming bilirubin diglucuronide. This water soluble substance is then secreted into the bile canaliculi via primary active transport mechanisms. Bilirubin is primary excreted from the body in the feces, and is responsible for contributing the classic brown pigment to feces due to its breakdown in the gut into stercobilinogen and subsequent partial oxidization into sterocobilin. Only 10% of bilirubin is not excreted in the feces, and is instead de-conjugated by intestinal bacteria and then returned to the liver through the enterohepatic circulation. A very small proportion of bilirubin, about 1%, will reach the systemic circulation, where it will be ultimately excreted by the kidneys as urobilinogen; this percentage increases when liver damage is present. A common clinical manifestation of liver damage is jaundice, or a yellowing of the skin. Jaundice can be due to varying problems, and as such, there are varying types of jaundice. Prehepatic jaundice is due to excessive amounts of bilirubin being formed, resulting in an increased level of unconjugated bilirubin, and is due to an increase in the lysis of hemoglobin (hemolysis). Intrahepatic jaundice is primarily caused by liver damage due to toxins or infection, and occurs as a result of an impairment of bilirubin transport and conjugation. It can also be due to a deficiency or absence of the glucuonyltransferase system, as occurs in Crigler-najjar Syndrome, or due to an inhibition of glucuronyltransferase, which can result from the use of steroids. Dubin Johnson Syndrome, which features a congenital defect that impairs the secretion into the bile canaliculi, can also cause this type of jaundice. Lastly, posthepatic jaundice, which is caused by an impairment of bile flow, is usually the result of an obstruction such as a stone or tumor in the bile ducts; and is usually accompanied by conjugated billirubin concentration becoming elevated in serum.

BILE AND BILE PRODUCTION

Bile itself may contain electrolytes, bile salts, cholesterol, lecithin, bilirubin diglucuronide, steroid hormones, and medication taken in by the body. Bile is essential for fat digestion, while most of its other components will be excreted from the body in the feces. As mentioned previously, bile is secreted by the hepatocytes into the bile canaliculi, while the sinusoidal and canalicular membranes of the hepatocytes absorb bile components from the blood and secrete them into the canaliculi by means of carriers. The bile salts, cholate and chenodeoxycholate, are synthesized from cholesterol by the liver. Bacteria present in the intestine convert some of these primary bile salts into secondary bile salts such as deoxycholate. The bile salts themselves are conjugated with either taurine or glycine in the liver and thereafter secreted into the bile. This conjugation process is critical for the formation of micelles in the bile and the gut. If the conjugation process does not occur, the unconjugated bile salts are immediately reabsorbed from the bile ducts. If the conjugation occurs, the conjugated bile salts will then enter the duodenum. They are ultimately reabsorbed from the terminal ileum by ISBT, a sodium symport carrier; thereafter they will be circulated back to the liver following use in fat digestion. This is known as the enterohepatic circulation. This circulatory process effectively increases the concentration of bile salts in the portal vein during the digestive phase. This high concentration inhibits the hepatic synthesis of additional bile salts, and also stimulates the secretion of bile salts into the bile canaliculi, thereby increasing the flow of bile due to osmotic water movement. This process can also occur outside the influence of bile salt concentrations due to other bile components being secreted into the canaliculi, while HCO3 is secreted into the bile ducts. HCO3 secretion into the bile ducts can be increased by secretin, as well as by signals from the vagus nerve.

In between the common bile duct and the duodenum resides the sphincter of Oddi, which when closed, causes hepatic bile to be diverted to the gall bladder for concentration and storage. In the gall bladder, sodium, chloride, and water are reabsorbed from the bile by the epithelium of the gallbladder. If bile is required for fat digestion, or if during the interdigestive phase, peristaltic waves

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occur, the gall bladder will contract, causing its contents to be combined with the duodenal chyme in portions. This contraction of the gall bladder is caused by CCK which will bind to CCK receptors. Contraction can also occur due to the neuronal plexus of the gall bladder wall, which features innervations of preganglionic parasympathetic fibers from the vagus nerve. The musculature of the gallbladder can also be stimulated indirectly by increases in the release of Ach, caused by secretions of the sensory fibers. Contractions of the gall bladder can also be inhibited by the sympathetic nervous system through A2 adrenoreceptors. Cholesterol in the bile is transported inside of micelles, which are formed by aggregations of cholesterol, lecithin and bile salts. If the ratio of these substances in altered in favor of cholesterol, cholesterol will precipitate out and form what are commonly known as gallstones.

PANCREAS

Of the entire digestive system, the pancreas is perhaps the most important intestinal gland. It functions by producing and secreting pancreatic juice, the composition of which varies depending on the types of food ingested. The secretion of the pancreatic juice is activated via nervous stimulation initially, followed by stimuli provided by the stomach filling, and then lastly by means of hormones released by the duodenum. Gross features of the pancreas include a thick head, which fits into the duodenal loop at the right hand side of the spine. It has a horizontal body as well which bulges into the omental bursa, and thereafter bends around the spine, towards the hilus of the spleen. Similar to the liver, the pancreas is divided into lobules, and is covered by connective tissue, with the entire organ being loosely connected to the posterior wall of the trunk. Despite being attached, the loose attachment allows for the pancreas to move during respiration. The primary excretory duct of the pancreas, the pancreatic duct, is approximately 2 mm in diameter and runs throughout the length of the gland. It is the receptacle for many short tributaries from each of the pancreatic lobules. The pancreas’s secretions classify it as a primarily serous gland, and terminate in acini. The pancreas features epithelial cells that contain prosecretory granules at their apex, while widespread basophilic ergastoplasm occupies their base. The system of excretory ducts contained in the pancreas is confined to long intercalated segments, which ultimately lead into larger, major excretory ducts. At the origin of these ducts, the ducts are invaginated into the acini, which feature centroacinar cells when viewed in section.

The pancreas secretes approximately 1-2 liters of pancreatic juice, which is secreted into the duodenum and contains HCO3, effectively neutralizing the HCl rich chyme. The pancreatic juice also features mainly inactive precursors of digestive enzymes, or proenzymes. The pancreas secretions are produced similar to saliva, in that their production occurs in two phases. Chloride ions are secreted in the acini by active secondary transport, and are then followed by the passive transport of sodium ions and water. HCO3 is then added to the primary secretions in the secretory ducts, with sodium ions and water following via passive transport. This secretion primarily occurs during the digestive phase. The HCO3 secreted originates from the luminal membrane of the ductules, and is done so by means of an anion exchanger. This anion exchanger functions by reabsorbing chloride from the lumen, returning chloride to the lumen by a chloride channel that is frequently opened due to secretin. This ensures that the secretion of HCO3 is not limited by the availability of chloride. This function can be severely disrupted if this channel is impaired, as in the case of cystic fibrosis.

The secretion of pancreatic juice is under control of both cholinergic as well as hormonal mechanisms. These controlling chemicals include CCK and secretin, with the stimulation of pancreatic juice secretion being enhanced by CCK receptors present in the cholinergic fibers of the acini. CCK is stimulated for release by the presence of fat in the chyme, and serves to increase the proenzyme content of the pancreatic juice. CCK is signaled to stop being released by trypsin originating from the lumen of the small intestine, thereby creating a sort of feedback loop. CCK and Ach both potentiate the increase of HCO3 and water secretion by the pancreatic ductules, which itself occurs due to secretin. HCO3 serves to help neutralize the acidic nature of chyme, as pancreatic enzymes function optimally in a pH of 7-8. If HCO3 secretion is impaired, the suboptimal conditions created by a more acidic environment impair the process of digestion. Of the proenzymes present in the pancreas, some belong to the class of proteases, which upon activation catalyze the process of proteolysis. These

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Figure 13. Light micrograph of the exocrine pancreas featuring pancreatic acinar cells as well as a small capillary and duct.

proenzymes will not be active until they reach the intestine, as they are converted to their active form by an enteropeptidase. This enteropeptidase converts trypsinogen to trypsin which in turn converts chymotrypsinogen to chymotrypsin. Trypsin also functions as an activator for other pancreatic proenzymes. Trypsins, chymotrypsins, and elastases are all endoproteases and are able to split particular peptide bonds within protein chains. Similarly, carboxypeptidases A and B are exopeptidases which function by splitting amino acids off of the polypeptide chain at the carboxyl end. If this proenzyme activation process is misregulated, such as in the case of acute pancreatic necrosis, the proenzymes will be pathologically activated, causing the pancreas to begin to digest itself. Aside from protein metabolism, other enzymes are present to digest carbohydrate and fat. Carbohydrate catabolism is performed by alpha amylase, which is secreted in its active form and functions by splitting starch and glycogen into maltose, maltotriose, and a-limitdextrin. These three products are then further digested by enzymes produced by the intestinal epithelium. Fat digestion is facilitated by lipolysis, which is made possible by pancreatic lipase. This lipase is the most critical enzyme as it is secreted in its active form and functions by breaking triacylglycerol into 2-monoacylglycerol and free fatty acids. The activity of pancreatic lipase relies on the presence of colipases which are produced from procolipases in pancreatic secretions, with the assistance of trypsin, with bile salts also being required for proper fat digestion.

GREATER AND LESSER OMENTUM, BLOOD VESSELS, AND LYMPHATICS

The greater and lesser omentum serve predominatly as the location for the blood and lymph vessels of the upper abdominal organs. The lesser omentum originates and develops from the ventral mesogastrium and features a peritoneal fold. This fold stretches between the lesser curvature of the stomach to the upper duodenum, as well as the portal hepatis. The greater omentum is a flap-like double peritoneal fold that is rich with fat. Similar to the lesser omentum it develops from the mesogastrium, but from the dorsal mesogastrium as opposed to the ventral. Its location is different from that of the lesser umentum as it hangs down from the greater curvature of the stomach, as well as the transverse colon, the spleen, and the fundus of the gall bladder.

The stomach, spleen, liver and portions of the duodenum and pancreas, have their blood supply provided by the cellac trunk. The origin of this blood supply is located in the aoertic hiatus of the diaphragm, as it originates from the aorta, and is covered by ganglia from the autonomic nervous system. The cellac trunk ultimately divides into three portions, the common hepatic artery, the left gastric artery, and the splenic artery; with the hepatic artery further dividing into the gastroduodenal artery and the hepatic artery. The gastroduodenal artery descends behind the duodenal bulb, and branches off to form the right gastroepiploic artery extending to the greater curvature of the stomach. The gastroduodenal artery and the left gastric epiploic artery form an anastomosis, while the gastroduodenal artery terminates at the superior pancreatico-duodenal arteries. As their name implies, the pancreatico-duodenal arteries are the main supply of the duodenum and the head of the pancreas.

The right gastric artery, a branch of the hepatic artery, divides into two branches at the porta hepatis. The right branch usually gives rise to the cystic artery, which supplies the anterior and posterior surfaces of the gallbladder. The left gastric artery however, runs within the peritoneal pouch to the cardia. It is the source for the esophageal branches which arise from the left gastric artery, and runs along the lesser curvature of the stomach, anastomosing with the right gastric artery. In contrast the splenic artery runs along the upper margin of the body as well as the tail of the pancreas and within the gastrosplenic ligament. It continues on to reach the greater curvature of the stomach as well as the short gastric arteries, ultimately reaching the fundus of the stomach. It should be noted that the venous blood originating from the upper abdominal organs eventually drain into the liver by means of the portal vein.

Following the course of the arteries run the lymph vessels and nodes, with the right and left gastric lymph nodes residing alongside the lesser curvature of the stomach. These lymph nodes drain into the celiac lymph nodes, while the lymph from portions of the gastric fundus and the upper portion of the body of the stomach will drain into the celiac lymph nodes as well. This is done by means of the left gastoepiploic lymph nodes. The lymph from the lower portion of the body and pyloric stomach drain by means of the right gastroepiploic lymph nodes, and the pyloric nodes as well. These partially drain into the celiac lymph nodes, and partially to the liver

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Figure 14. Micrograph of the greater omentum. The network of connective tissue is visible which is made up of collagen fibers, elasticfibers, and reticular fibers. Perivascular adipocytes are also visible.

lymph via the hepatic lymph nodes. The lower abdominal viscera feature additional arteries and lymph networks to facilitate the flow of blood and lymph. The jejunum, ileum and colon are completely supplied by the superior and inferior mesenteric arteries, while these same arteries only partially supply the duodenum and pancreas.

The superior mesenteric artery arises from the aorta immediately below the celiac trunk, and runs behind the head of the pancreas, thereafter entering the mesentery in between the lower margin of the pancreas and the upper margin of the inferior portion of the duodenum. This artery features a dense nervous network which envelops it, known as the superior mesenteric plexus. On the left side, the superior mesenteric artery gives rise to the jejunal and ileal arteries, while each of these divide into two additional branches, which are connected with neighboring arteries. These connections with the neighboring arteries occur as rows of transverse cross connections, commonly known as arcades. The outer arcades feature parallel blood vessels that run to the intestine. These vessels are end arteries, and as such, if blockage occurs, a local lesion of the intestine will follow.

The first arteries arising behind the head of the pancreas are the inferior pancraticduodenal arteries, which originate from the right side of the mesenteric artery. These are connected by the superior duodenal arteries to the arch, and ultimately give rise to three arteries extending to the large intestine. Following the ileal arteries’ supply area is that of the ileocolic artery; a terminal branch of the superior mesenteric artery. This artery gives rise to branches extending to the cecum as well as to the lower portion of the ascending colon. Similarly an appendicular artery extends to the appendix.

The right colic artery features branches that extend to the right colic fixture, followed by the middle colic artery. This supplies approximately 2/3 of the transverse colon and anastomoses with adjacent branches of the left colic artery. While it arises from the inferior mesenteric artery, it is the superior mesenteric artery which supplies its veins, which then drain into the portal vein. The left colic artery on the other hand, divides into an ascending branch, and then a descending branch, continuing the supply to the intestine from the middle colic artery. The lymphatics of this region run from the area of the superior mesenteric artery, and follow the arteries to eventually reach the left lumbar trunk, also known as the cistema chili. Of particular interest is the structure of the lymphatics here, which feature more than one hundred small superior mesenteric lymph nodes. The inferior mesenteric artery arises from the aorta, and is covered by a dense network of autonomic nerve fibers. The final branch of the inferior mesenteric artery is the rectal artery, which supplies the rectum all the way to the internal sphincter of the anus. This artery may divide into two branches which are joined above the pelvic floor and either side. This joining is facilitated by branches of the middle rectal artery, which arises from the internal iliac artery. Below the pelvic floor however, these are then joined by branches of the inferior rectal artery.

While important, the anastomoses of the middle and lower rectal arteries with the superior rectal artery are not sufficient by themselves, and are not a substitute for the superior rectal artery, which features a single communication with the sigmoid artery. Veins in this area obtain their supply from the inferior mesenteric artery, and drain into the portal vein similar to the veins from the upper portions of the rectum. Veins from the middle and lower rectum however, drain by means of the internal iliac veins, ultimately draining into the inferior vena cava. The lymphatics of the lower anal region flow subcutaneously into the superficial inguinal lymph nodes, while that of the upper anal region flow by means of the internal iliac lymph nodes. Lymph originating from the pelvic portion of the rectum will drain into the sacral and common lymph nodes as well as the mesenteric lymph nodes by means of the mesosigmoid folds. Lastly, lymph originating from the descending colon flows into the intestinal trunk and then the cisterna chyli by means of the inferior mesenteric and left colic lymph nodes.

The portal vein allows for the flow of venous blood originating from the gastrointestinal tract, the gall bladder, the pancreas, and the spleen (unpaired abdominal viscera) to reach the liver. The unpaired abdominal viscera are supplied by three unpaired abdominal arteries; the celiac trunk, the superior mesenteric artery, and the inferior mesenteric artery. Upon receiving the venous flow from these arteries, the venous flow runs through the hepatic veins to the inferior vena cava. The portal vein is actually formed from three root veins; the splenic, inferior mesenteric, and superior mesenteries veins. The splenic vein, similar to the splenic artery, runs along the upper margin of the pancreas and receives short gastric veins such as the gastroepiploic vein on the left, as well as the pancreatic and duodenal veins. The splenic vein then unites with the inferior mesenteric vein behind the head of the pancreas where it drains with the superior mesenteric vein into the portal vein. The inferior mesenteric vein transports blood from the descending and sigmoid colon, as well as the upper rectum, while the superior mesenteric vein transports blood from the small intestine, the cecum, and the ascending and transverse colon. The superior mesenteric vien is accompanied by the superior mesenteric artery

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behind the head of the pancreas, and will throughout its course, receive the duodenal, pancreaticduodenal, and right gastroepiploic veins.

There are multiple veins which terminate directly in the trunk of the portal vein, including the right and left gastric veins from the lesser curvature of the stomach, the cystic vein from the gall bladder, the prepyloric vein from the anterior surface of the pylorus, as well as the paraumbilical veins. These will form anastomoses between the subcutaneous veins of the abdominal wall and the portal vein. These open up into the left main branch of the portal vein. When cirrhosis of the liver occurs, these anastomoses will become congested in the liver. When this occurs, the liver will be bypassed by a portion of the portal venous blood, resulting in prominent varicose veins. This can also cause esophageal varices, as well as external hemorrhoids and a congestion of the subcutaneous abdominal veins.

CONCLUSION

While composed of multiple tubular structures, organs, glands, and cell types, the gastrointestinal system functions as an entire system with finely coordinated movements and processes. If it were not for the signaling pathways, reflexes, and stimuli that allow for the communication between segments of the gastrointestinal system, the process of digestion would not be the fluid process that it is. Likewise, by understanding the complex networks of communication, it is easy to understand how even slight perturbations of any given portion of this system might have disastrous effects locally, and even downstream. Through understanding these complex mechanisms, we can then shed light on the causes behind the clinical manifestations, and be able to develop new specific therapies that could not exist without the knowledge and comprehension of not only the entire system, but its communication pathways and the molecules, peptides, and hormones behind them.

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