Abstract
The alimentary system may be thought of as an open-ended tube within a tube that begins at the oral cavity and ends at the anus. Gastrointestinal lumens are potential spaces that accommodate ingested substances and are lined by polarized epithelium that is smooth and shiny (with the exception of the rumen) when healthy and intact. Because xenobiotics most frequently enter the body via ingestion, the gastrointestinal system and its ancillary glands are the first line of defense against foreign materials and pathogens of all types. The anatomic, biochemical, physical, secretory, and endocrinologic properties of the epithelium, resident, and blood-borne effector cells, microbiota, genetic polymorphisms, and gut-associated lymphoid tissue (which comprises one-quarter of the body’s total) must be physically or functionally altered for diarrhea to occur. The average person ingests 700 tons of antigens in their lifetime. That enteritis does not occur more often than it does is testimony to the efficacy of gastrointestinal protective systems.
Introduction
The alimentary system is an interactive complex of glands, tissues, and organs. Most substances enter the body via the oral cavity and in spite of the constant bombardment by ingesta and other xenobiotics, the body rarely shows other than mild symptoms of rejection, such as ptyalism, regurgitation, vomiting, abdominal pain, gas production, and/or diarrhea. In most cases, homeostasis is quickly restored without medical intervention. As a result, our understanding of this complex system has been neglected compared to other less well, self-regulated systems.
Anatomy
The alimentary system may be considered as a tube within a tube extending from the oral cavity to the rectum. The tubular portions of this system, the esophagus, stomach, small intestine, cecum, large intestine, colon, and rectum are potential spaces that expand to accommodate ingested substances. All portions of the digestive system contain smooth and/or striated muscle in their walls which is used to propel ingesta aborad through the tract. The length of the system varies among species with the shortest tracts occurring in carnivores and the longest, most complicated tracts in herbivores. In addition, herbivores require a fermentation chamber to digest cellulose; the forestomachs in ruminants and camelids or an enlarged cecum in equids, rodents, and lagomorphs. A rendering of general gastrointestinal morphology is presented in Figure 1.
Schematic diagram of the anatomic and histologic organization of the digestive tube. From Kierzenbaum, A. L. (2002). Histology and Cell Biology: An Introduction to Pathology, Mosby, St. Louis. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc., an affiliate of Elsevier Inc.
At various locations throughout the tract, extraintestinal substances are added to the ingesta. These include saliva that contains electrolytes such as sodium, potassium, calcium, magnesium, chloride, bicarbonate, and phosphate; iodine; mucus which serves as a lubricant; antibacterial compounds such as thiocyanate and hydrogen peroxide, secretory immunoglobulin A, epidermal growth factor (EGF); and the digestive enzymes α-amylase, lipase, and kallikrein. Antimicrobial enzymes secreted include lysozyme, lactoperoxidase, proline-rich proteins, acid phosphatases A + B, N-acetylmuramoyl-L-alanine amidase, NAD(P)H dehydrogenase (quinone), superoxide dismutase, glutathione transferase, class 3 aldehyde dehydrogenase, and glucose-6-phosphate isomerase. Saliva also contains a bacterial rich flora and at least in humans, opiorphin, an analgesic. Gastrointestinal protective mechanisms are listed in Table 1.
Defense mechanisms of the gastrointestinal system.
Esophagus
The esophagus is a muscular tube that connects the oral cavity with the stomach. It passes through the neck and thorax and secretes mucus to aid in the passage of ingesta. The lining epithelium is keratinized in swine, equids, ruminants, rats, and mice and nonkeratinized in carnivores and humans. The epithelial cell turnover rate is 5 to 8 days. The muscularis is striated in ruminants and dogs, smooth in equids (distal third) which are unable to vomit, and variably mixed in other species. Mice and rats, although they contain primarily striated muscle in their esophagus, are also unable to vomit (Treuting, Valasek, and Dintzis 2011). This is principally due to a limiting fold separating the nonglandular from the glandular stomach and the diaphragmatic crura that cannot be contracted independent of each other to allow propulsion of contents. Submucosal mucus glands are present throughout the esophagus in swine, dogs, and humans and at the pharyngeal junction in cats, equids, and ruminants. A serosa is absent in all but the abdominal portion of the esophagus. Because the serosa is composed of collagen, it is crucial in holding sutures. Therefore, esophageal resection is seldom attempted and rarely successful. The strong muscular contractions of the esophagus, together with its poor blood supply and lack of serosa, mean that healing from caustic or penetrating wounds renders a poor prognosis for a functional return to normalcy.
Stomach
The forestomachs in ruminants and camelids are dilations and modifications of the esophagus. They are designed to house a digestive flora necessary for producing short chain fatty acids from forage that are subsequently directly absorbed into the bloodstream along with sodium and chloride. Most clinical disease of the forestomachs relates to disruptions in coordinated motility and changes in pH. Camelid forestomachs have glandular sacculations. Equids and some rodents have stomachs that are divided into anterior stratified and aboral glandular portions. Swine have only a small stratified portion that directly surrounds the esophageal os. The abomasum/C3 functions similarly to the stomachs of monogastric mammals.
The glandular stomach (abomasum, C3) is responsible for enzymatic and hydrolytic digestion of ingesta. The glandular stomach is composed of a variety of cell types with bidirectional proliferation of cells from the neck of the gastric glands (Figure 2). The epithelial layer is 1 cell thick and the turnover rate is 2 to 4 days. The parietal cells produce rennin that coagulates milk protein, intrinsic factor for vitamin B12 absorption, and HCl. The low luminal pH destroys many ingested pathogens, but there is a resident bacterial flora that cannot be cultured by conventional methods. Chief cells produce zymogen and pepsin, and enteroendocrine cells produce serotonin, gastrin, ghrelin, somatostatin, endothelin, histamine, enteroglucagon, and others. Mucus cells produce bicarbonate and an unstirred protective layer on the cell surface.
Schematic illustration, microanatomy of the stomach. Adapted with permission from Ito, S., and Winchester, R. J. (1963). The fine structure of the gastric mucosa in the bat. J Cell Biol
Gastric ulcers occur in all species. Although the cause of ulcers, other than caustic agents and those caused by bacteria that can survive the extremely low pH of the stomach (Helicobacter spp.), is imprecisely understood, conditions necessary for ulcer development include local disturbances or trauma to the mucosal epithelial barrier, normal or high gastric acidity, and local disturbances to blood flow, including stress-induced and sympathetic nervous system–mediated, arteriovenous shunts leading to ischemia. These physiologic changes allow pepsin and HCl into the submucosa where they cause chemical erosion of the protective epithelium. In addition, exogenous or endogenous steroids and NSAIDs depress PGE1 and E2 decreasing phospholipid secretions that are gastroprotective. Anecdotal evidence suggests that a propensity toward ulcer formation may be hereditable.
Small Intestine
The small intestine functions in digestion, secretion, and absorption. Its length varies greatly among species, being the longest in herbivores and the shortest in carnivores. The small intestinal functional surface area is 1 cell thick and is markedly increased by the presence of numerous mucosal folds that contain villi (Figure 3). Each absorptive cell on these villi has a microvillus border that further increases surface area and contains a glycocalyx housing the digestive enzymes (Figure 4).
Targets for microbial infection in the intestine. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
Organization of the intestine. The digestive and absorptive surfaces of the intestine are markedly increased by the presence of villi and microvilli on the enterocytes. (A) Intestinal villus. Villus epithelial cells are present on basement membranes (not seen) on a core of lamina propria. Hematoxylin and eosin. (B) Small intestine, intestinal villi, scanning electron microscopy. Carbon sputter coat. (C) Enterocyte microvilli. Transmission electron microscopy (TEM). Uranyl acetate, lead citrate stain. From Damjanov, I., and Linder, J. (1996). Anderson’s Pathology, 10th ed., Mosby, St. Louis. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
The epithelial cells rest on a basement membrane subjacent to which is a mesenchymal lamina propria containing blood vessels and a central, blind-ended lymphatic or lacteal (Figure 5). Villous height and crypt depth decrease aborally while the number of goblet (mucus) cells increases.
Schematic diagram of the anatomic and histologic organization of the digestive tube. From Kierzenbaum, A. L. (2002). Histology and Cell Biology: An Introduction to Pathology, Mosby, St. Louis. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
There are a variety of epithelial cell types in the intestine, all of which are produced by progenitor cells in the crypts (Figure 6) via notch signaling (Sander and Powell 2004). Notch and Wnt signals in combination are necessary for proliferation of enterocyte precursors, but differentiation of cell types is independent of Wnt. Wnt and Notch synergy appear to induce intestinal adenomas (Fre et al. 2009). The intestine has the highest cell turnover of any of the body’s tissues. In a neonatal piglet that has not achieved climax flora, the epithelial turnover rate is approximately 7 days. In the mature gut, the turnover rate is 2 to 3 days. The immature, recently produced cells, with the exception of the enteroendocrine cells, mature as they slide along the basement membrane to the villous tip where senescent cells are extruded and become part of the fecal mass by a process of apoptosis termed anoikis.
Schematic illustration of the epithelial cell types of the small intestine. Progenitor cells, located in the intestinal crypts, give rise to all other epithelial cell types lining the crypts and covering the villi. From Damjanov, I., and Linder, J. (1996). Anderson’s Pathology, 10th ed., Mosby, St. Louis. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
The crypt or progenitor (stem) cells have short, sparse microvilli and little digestive or absorptive capacity. They proliferate and migrate to replace absorptive cells. Each crypt produces 300 to 400 cells/day. The migration rate is dependent on many factors, one of which is adaptation to gut microflora. Thus, in germfree animals, the replacement rate is similar to neonates. Crypt cells have secretory functions (secretory component, NaCl) and may be involved in IgA and IgM transport.
The absorptive cells or enterocytes are tall and columnar with luminal microvilli. They harbor a surface glycocalyx that contains digestive and absorptive enzymes and shed unilaminar vesicles into the lumen that contain alkaline phosphatase and catalase that are bactericidal and attachment sites for pathogens. Enterocytes are connected to each other by an apical junctional complex composed of a cadre of more than 40 transmembrane proteins and other molecules. They are an end-stage cell that does not proliferate, but they provide negative feedback inhibition to the progenitor cells by secreted chalones. The absorptive cells are pinocytotic early in life for colostrum absorption and in general are responsible for nutrient and xenobiotic absorption. They contain class II major histocompatibility complexes (MHCs) and a complement of biotransformation enzymes (Figure 7). In humans with inflammatory bowel disease, there is downregulation of genes encoding enzymes such as cytochrome P450 on colonic mucosa (Wilke et al. 2012).
Cellular location of metabolic enzymes. Haschek, Rousseaux, and Wallig, Fundamentals of Toxicologic Pathology, 2nd ed., Copyright © 2010 by Academic Press, an affiliate of Elsevier Inc.
Goblet cells occur in both villus and crypt regions increasing in number aborally. They produce mucus. Mucus exerts a variety of protective effects including trapping of bacteria with resultant passage in the fecal mass, lessening of shear forces of particulate matter on the enterocytes, and housing of bacteriophages that reduce the bacterial population of the intestine by 104.
Paneth cells are not present in cats, dogs, raccoons, and pigs. In other species, they constitute a cellular mass similar to that of the pancreas. Their functions are largely unknown, but they are believed to have phagocytic and secretory ability. They secrete heavy metals and are injured during this process. They also produce cryptdins, lysins, peptidases, and lysozymes that are toxic to bacteria, perhaps protecting the crypt cells. They migrate toward the crypts rather than the villus tips. Paneth cell function and microbial composition vary among strains of mice, suggesting a genetic influence of the host (Sonnenberg et al. 2012).
Enteroendocrine (argentaffin, enterochromaffin) cells produce serotonin, catecholamines, gastrin, somatostatin, serotonin, cholecystokinin, secretin, bombesin, enteroglucagon, fibroblast growth factor 19, and other hormones that are delivered directly into the bloodstream rather than into the intestinal lumen. The gastrointestinal system is the largest endocrine organ in the body (Table 2).
Hormone secretion by the gastrointestinal system.
M (microfold, membranous) cells occur in most species except rats. They are associated with the dome or follicle-associated epithelium of Peyer’s patches or gut-associated lymphoid tissue (GALT). They are important in the uptake of antigens including particulate toxins (i.e., asbestos) from the intestinal lumen and transport to the lymphatic system. They contain basal recesses that house lymphoid cells that allow more rapid interaction with phagocytosed antigens. They also allow bidirectional movement of lymphocytes between the lamina propria and intestinal lumen (Nicoletti 2000). They are exploited for the entry of a variety of pathogens such as Salmonella, Yersinia, Rhodococcus, and some viruses (bovine virus diarrhea). Figure 8 illustrates the anatomic and mechanistic relationships of M cells to the underlying lymphoid tissue.
Schematic illustration of gut-associated lymphoid tissue (GALT). DC, dendritic cell; IEL, intraepithelial lymphocyte; M, microfold cell; MC, mast cell; N, neutrophil. Adapted from Cominelli, F., Arseneau, K. O., Blumberg, R. S., et al. (2009) The mucosal immune system and gastrointestinal inflammation. In Textbook of Gastroenterology (Yamata T., ed.), 5th ed., Wiley-Blackwell, West Sussex, UK. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
A variety of mesenchymal cell types are found in the lamina propria. Among these is a resident population of lymphocytes that increase with exposure to antigens, especially the microbiota (Gulati et al. 2012). The immune system and microbiota have profound influences on each other (Mueller et al. 2012). The classification and functions of these innate immune cells are currently being elucidated (Sonnenberg et al. 2012; Walker, Barlow, and McKenzie 2013; Figures 9, 10). They arise from the same progenitor cell as (Natural killer) NK T cells, do not contain T cell receptors, and produce a plethora of interleukins and other soluble mediators that parallel those of the antigen-specific immune effector cells. Current theory holds that the innate lymphoid cells hold infections in check until specific immune responses can be generated (Leslie 2012). Dendritic cells may be innate lymphoid cells (ILC 3) cells and along with macrophages have toll-like receptors.
Innate lymphoid cell subsets, functions, and disease associations. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology. Walker, J. A., Barlow, J. L., and McKenzie, A. N. J. (2013). Innate lymphoid cells—How did we miss them? Nature Rev Immun
Schematic of the roles for immune lymphoid cells in intestinal immune function. Reprinted by permission from Macmillan Publishers Ltd., Nature Reviews Immunology. Walker, J. A., Barlow, J. L., and McKenzie, A. N. J. (2013). Innate lymphoid cells—How did we miss them? Nature Rev Immun 13, 75–87.
Neutrophils in the lamina propria are transient as they pass through the intestine to become part of the fecal mass and expelled from the body. Human neutrophils spend about 5 days in the bloodstream and about 2 days in tissues. However, there is marked variation in neutrophil life span among species. In mice for example, it is approximately 0.75 days (Pillay et al. 2010).
Mast cells are very important in maintaining intestinal integrity. Intestinal mast cells differ in important ways from mast cells in other portions of the body. They lack membrane-bound IgE. They perform such functions as regulating the epithelial barrier, controlling blood flow, coagulation, smooth muscle contraction, stimulation of the enteric nervous system, peristalsis, and antibody-dependent recognition of parasites and microorganisms. They also release proinflammatory mediators through paracrine cytokines.
Globule leukocytes occur in a number of submucosal locations including the lamina propria. Their function is largely unknown but may be similar to those of Paneth cells. Likewise, their origin is unknown. Theories include derivation from mast cells, plasma cells, large granular lymphocyte lineages, or from a distinct precursor (Spoor, Royal, and Berent 2011). They are most common in parasitic infections and rarely form neoplasms.
With that as background, there are a variety of mechanistic targets for intestinal injury and resultant diarrhea. These include diseases of crypt cells, diseases of absorptive cells, abnormalities of the glycocalyx, diseases caused by separation of apical junctional complexes, diseases in which epithelial targets are unknown or nonspecific, diseases of the lamina propria, diseases of the vasculature, and disorders of innervation.
Diseases of Crypt Enterocytes
Loss of crypt enterocytes results in lack of replacement of normal absorptive epithelial cells. The crypts and villi eventually become depleted. Agents that attack mitotically active cells are termed radiomimetic since they act similar to radiation. A variety of chemotherapeutic agents, many of which are designed to destroy rapidly dividing neoplastic cells, cause this kind of injury. In carnivores and pinnipeds, parvoviruses are radiomimetic (Figure 11). Other tissues, such as those of neonates and hematopoietic precursors, also divide rapidly and are targets of these agents. Conversely, some bacteria such as Lawsonia in pigs cause crypt cell proliferation.
Panleukopenia virus enteritis, small intestine, cat. Sloughed crypt cells preclude replacement of enterocytes lost due to normal senescent turnover. Hematoxylin and eosin. Zachary and McGavin: Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
Diseases of Absorptive Enterocytes
Agents targeting absorptive enterocytes may or may not be fatal depending on the number of cells affected and whether the basement membrane is intact. In the interim, surviving immature enterocytes elongate to cover basement membranes and prevent, among other things, endotoxin absorption from the gut lumen. The lost cells are rapidly replaced by migrating crypt cells providing they have a basement membrane on which to orient and reconstruct villi. Once basement membranes touch, they fuse resulting in permanently stunted villi and loss of absorptive and digestive surface area. Many agents target absorptive enterocytes including viruses (rotavirus, transmissible gastroenteritis virus of swine [Figures 12 and 13], and coronaviruses of most mammalian species), intracellular bacteria (Escherichia coli), and parasites such as coccidia and cryptosporidia.
Small intestine of a piglet with group a rotavirus infection. Immunohistochemical (red) staining denotes villus enterocytes containing viral antigen. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
Wet mount of intestinal villi from a pig with transmissible gastroenteritis. Normal tissue on top and diseased tissue on bottom. Villus atrophy is severe. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
Diseases of the Microvilli and Glycocalyx
Agents, including some toxins, which destroy the glycocalyx result in specific or general enzyme deficiencies with a resultant lack of digestive capabilities. An example of this is congenital lactase deficiency (lactose intolerance). Undigested lactose ferments in the intestinal lumen with a resultant osmotic drain and diarrhea. Pathogens such as attaching and effacing E. coli damage microvilli and disrupt enzyme systems. The antibiotic neomycin can cause reversible enzyme deficiency via fragmentation of microvilli and destruction of the glycocalyx.
Separation of Apical Junctional Complexes
This phenomenon is most common in parasitic and bacterial infections where opening of the apical junctional complexes results in transfer of large molecules such as antibody that helps clear the pathogen. This is sometimes called the leaky membrane concept of enteritis.
Diseases in Which Epithelial Targets Are Unknown or Nonspecific
This category of intestinal disease production is often the result of bacterial or ingested toxins. Some bacteria colonize the small intestine overcoming the washout effect due to pilus antigens. An example is enterotoxic E. coli where release of toxins causes the small intestine to secrete electrolytes and water. When secretion exceeds colonic absorption, diarrhea results. There is no histologic evidence of cell damage in these secretory diarrheas. Hypersecretion is a net intestinal efflux of water and electrolytes independent of permeability changes, absorptive capacity, or endogenously generated osmotic gradients.
All Clostridia spp. produce enterotoxemia but unlike the case with E. coli, the toxins are markedly cytolytic causing necrosis of villus absorptive cells and subsequent extension into the lamina propria and blood vessels, much like caustic agents. The result is ulceration and hemorrhage.
Diseases of the Lamina Propria
Diseases of the lamina propria include necrotizing processes and space occupying lesions. Often, necrosis of lymphoreticular tissue is how the damage commences with extension to the overlying epithelium. This occurs in both viral disease (bovine virus diarrhea of cattle; Figure 14) and bacterial disease (Rhodococcus equi of equids).
Ileal mucosa of a cow. Peyer’s patches and the overlying epithelium are necrotic and covered with exudate. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
By mechanisms that are poorly understood, space occupying lesions of the lamina propria interfere with mucosal diffusion of nutrients into the lacteals (malabsorption) resulting in diarrhea. This occurs whether the lamina propria is filled with immune cells (inflammatory bowel disease), mycobacteria-filled macrophages (Johne’s disease of cattle; Figure 15), or neoplastic infiltrates (lymphoma).
Ileum from a cow with Johne’s disease. Mycobacterium-containing macrophages distend the lamina propria. Ziehl-Neelsen stain. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
Intestinal Motility
Intestinal motility changes are a part of many mechanisms of diarrhea production but are not considered to be a primary means. Decreased motility allows for bacterial overgrowth. Increased motility hinders digestion and absorption.
Vascular Diseases
The prototypical vascular disease is verminous arteritis of equids caused by Strongylus vulgaris. The larvae of these parasites live in the anterior mesenteric artery causing vasculitis, thromboembolic disease, and bowel infarction. Endotoxemia may result in injury to the enteric nervous system and the tunica muscularis secondary to vasoconstriction and vasospasm (Oikawa et al. 2007). Lymphangiectasia may be congenital as a result of vascular malformations or acquired secondary to space occupying lesions of the lamina propria. Most often, it is idiopathic. It results in malabsorption, steatorrhea, and protein-losing enteropathy.
Problems with Innervation
Agangliosis and dysautonomia, malfunction of the cranial nerves, spinal nerves, ganglia, and/or autonomic nervous system can have profound influences on intestinal motility. There are a great variety of agents that cause these changes ranging from botulinum toxin to inflammatory diseases. Many cases are idiopathic or may be hereditary. In addition, there is a bidirectional neurohormonal interchange between intestinal microbiota and the brain. Thus, alteration of the microbiota may result in changes in the gut–brain axis (Collins, Surette, and Bercik 2010). Dysbiosis has effects on early brain development in mice, irritable bowel syndrome, Crohn’s disease, ulcerative colitis, demyelination in multiple sclerosis, hepatic encephalopathy, and psychiatric disorders such as early onset autism. Finally, the interstitial cells of Cajal are of mesenchymal origin and are the pacemakers of the gut. Inflammation or loss of these cells affects coordinated movement of the alimentary system.
Diarrhea
Normal feces are 75% water. Diarrheic feces are more than 85% water. One may conceptualize diarrhea as a result of 1 of 3 mechanistic pathways: secretory, inflammatory, and invasive. Thus, there are inflammatory and noninflammatory causes of diarrhea. Noninflammatory causes disrupt absorptive or secretory pathways but do not kill the enterocytes and are generally active in the proximal intestine (Figure 16). Inflammatory diarrheas are a result of pathogenic processes that are lethal to enterocytes and are generally relegated to the distal small intestine, cecum, and colon (Figure 17).
Schematic diagram of the mechanism of action for enterotoxin-mediated bacterial diarrhea. Adapted with permission from Navaneethan, U., and Giannella, R. A. (2008). Mechanisms of infectious diarrhea. Nat Clin Pract Gastroenterol Hepatol
Schematic diagram of the mechanism of invasive and cytotoxin-mediated bacterial inflammation. Adapted with permission from Navaneethan, U., and Giannella, R. A. (2008). Mechanisms of infectious diarrhea. Nat Clin Pract Gastroenterol Hepatol
Mechanisms of Diarrhea Production
It is unlikely that any one mechanism of diarrhea production is independent of other mechanisms. Additionally, there are confounding variables in diarrhea production including pancreatic disease, liver disease, and so on. Combinations of mechanisms are present in specific diseases as follows (Gelberg 2012): Malabsorption with or without fermentation leads to osmotic diarrhea whether the cause is loss of digestive enzymes secondary to microvillus disruption, crypt, or villus enterocyte death or space occupying lesions of the lamina propria. Generally, this is a problem of the small intestine, but secondary colonic malfunction can occur because of malabsorption of bile salts and fatty acids that stimulate fluid secretion in the large intestine. Chloride (Cl−) hypersecretion by the cystic fibrosis transmembrane regulator (CFTR) of a structurally intact mucosa. CFTR is regulated by kinases that are dependent on cyclic adenosine monophosphate (cAMP) which acts as a second messenger. Prostanoids, bacterial toxins, and protein kinases all increase cAMP, thus increasing Cl− secretion. Ca ion (Ca2+) also plays a role in opening Cl− channels by increasing acetylcholine interaction with epithelial muscarinic receptors via cholinergic nerves in intestinal plexi. Through a different mechanism but also involving the CFTR, bicarbonate secretion is also increased. This osmotic activity results in a net efflux of fluid and electrolytes independent of permeability changes, absorptive capacity, or exogenously generated concentration gradients. Exudation caused by an increased capillary permeability (protein-losing enteropathy) by leaky tight junctions between enterocytes. Hypermotility is generally involved in diarrhea but usually not as a primary mechanism in domestic animals. Hypermotility is defined as an increased rate, intensity, or frequency of peristalsis. Theoretically, with decreased mucosal contact time, digestion and absorption of nutrients and water should be less efficient. It is suspected that decreased motility in some diseases allows for increased bacterial proliferation (Figure 18). Conversely, some enterotoxins can stimulate intestinal motility in some motility disorders of humans such as achalasia, Hirschsprung’s disease, and inflammatory bowel disease. Diarrhea occurs when there is an alteration in the network of interstitial cells of Cajal within the smooth muscle of the bowel wall. Whether this is a cause or effect of bowel motility disorders is not known. Toll-like receptors (TLRs) and associated molecules produced by enterocytes and leukocytes are very important in the regulation of intestinal inflammation and in the host’s response to intestinal pathogens. Intestinal inflammation can lead to neoplasia (Arthur et al. 2012). M cells regulate the presentation of antigens to GALT. Other factors (prostaglandins, leukotrienes, and platelet-activating factor) act on enteric nerves to induce neurotransmitter-induced intestinal secretion by crypt cells. Cell damage is possibly a consequence of inflammation mediated by T lymphocytes or proteases and oxidants produced by mast cells. T lymphocytes also may affect epithelial cell maturation, causing villous atrophy and crypt hyperplasia. Cell death can result from pathogen invasion into enterocytes, multiplication of the pathogen, and extrusion of the affected enterocytes. These changes lead to notable distortion of villus architecture with a lack of mature absorptive enterocytes accompanied by nutrient malabsorption and osmotic diarrhea. Mast cells of the lamina propria are in close association with enteric neurons and the enteric vasculature. They release histamine, prostaglandins, 5HT, and proteolytic enzymes that also play a role in diarrhea production.
Schematic diagram of the mechanism of how intestinal bacterial overgrowth causes malabsorption and diarrhea. From Damjanov, I., and Linder, J. (1996). Anderson’s Pathology, 10th ed., Mosby, St. Louis. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
The nuts and bolts of the process are of course much more complicated. Pathogens enter or attach to enterocytes and may release enterotoxins. This triggers the enterocytes to release cytokines (IL-8), which activate resident macrophages and recruit new blood-borne macrophages into the lamina propria. The activated macrophages release soluble factors (histamine, serotonin, and adenosine) that increase intestinal secretion of chloride and water and inhibit absorption. Other factors (prostaglandins, leukotrienes, and platelet-activating factor) act on enteric nerves to induce neurotransmitter-mediated intestinal secretion. The subsequent cell damage is possibly a consequence of inflammation mediated by T cells or proteases and oxidants secreted by mast cells (Figure 19). T cells also affect epithelial cell growth producing villus atrophy and crypt hyperplasia. Cell death results from pathogen invasion, multiplication, and extrusion. The end result is marked distortion of villus architecture accompanied by nutrient malabsorption and osmotic diarrhea.
Schematic diagram of chemotactic factors during intestinal inflammation. ECF, eosinophil chemotactic factor; IFN-γ, interferon-γ; IL, interleukin; LTB4, leukotriene B4; PAF, platelet-activating factor; TGF-β, transforming growth factor-β. Adapted from Cominelli, F., Arseneau, K. O., Blumberg, R. S., et al. (2009). The mucosal immune system and gastrointestinal inflammation. In Textbook of Gastroenterology (T. Yamata, ed.), 5th ed., Wiley-Blackwell, West Sussex, UK. Zachary and McGavin, Pathologic Basis of Veterinary Disease, 5th ed., Copyright © 2012 by Mosby, Inc, an affiliate of Elsevier Inc.
Consequences of Diarrhea
Intestinal fluid loss, in the absence of replacement therapy, gives rise to dehydration and acidosis secondary to electrolyte imbalances. Dehydration also causes hypovolemia and hemoconcentration with inadequate tissue perfusion. Energy generation shifts to anaerobic glycolysis leading to hypoglycemia and ketoacidosis. Acidosis, a lowering of blood and tissue pH, affects pH-dependent enzyme system function, which is further exacerbated by
Summary
There are a variety of mechanisms by which the gastrointestinal system protects itself from the almost infinite variety of potential pathogenic agents, most of which are ingested. Equally impressive are the evolutionary means that pathogenic agents have developed to overcome these barriers and cause damage to the host. Modern biomedical research is aimed toward investigating means to augment or downregulate innate biochemical systems to return the gut to homeostatic bliss.
Footnotes
Acknowledgment
The author thanks Dr. J. F. Zachary for assistance with the illustrations.
The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The author received no financial support for the research, authorship, and/or publication of this article.