REVIEW
`
`Small bowel review: Part I
`
`1, A Thiesen MD1,
`
`1, M Keelan PhD
`ABR Thomson MD FRCPC
`
`MT Clandinin PhD1, MJ Ropeleski MD
`1, G Wild MD DM PhD FRCPC
`
`2
`
`ABR Thomson, M Keelan, A Thiesen, MT Clandinin, MJ Ro-
`peleski, G Wild. Small bowel review: Part I. Can J Gastroen-
`terol 2000;14(9):791-816. In the past year, there have been
`many advances in the area of small bowel physiology and pathol-
`ogy. More than 1500 papers were assessed in preparation for this
`review. Some were selected and reviewed, with a particular focus
`on presenting clinically useful information for the practising gas-
`troenterologist. Relevant review articles have been highlighted,
`and important clinical learning points have been stressed. The
`topics are varied in scope, and wherever possible show a logical
`progression from basic physiology to pathophysiology to clinical
`disorders and management.
`
`Key Words: Absorption; Adaptation; Celiac disease; Motility;
`Secretion
`
`Revue de l’intestin grêle : 1re partie
`RÉSUMÉ : De nombreux progrès ont été réalisés au cours de la dernière
`année en ce qui concerne la physiologie et la pathologie de l’intestin grêle.
`Plus de 1 500 articles ont été évalués dans le cadre de la présente revue. On
`a d’abord sélectionné et examiné un certain nombre d’entre eux, notam-
`ment ceux qui contenaient de l’information utile sur le plan clinique pour
`les gastro-entérologues praticiens, puis on a retenu les articles les plus inté-
`ressants et fait ressortir les points importants à retenir pour l’apprentissage
`clinique. Les sujets traités sont très diversifiés et les articles présentent,
`dans la mesure du possible, un lien logique entre la physiologie, la physio-
`pathologie, les troubles cliniques et le traitement.
`
`GASTROINTESTINAL HORMONES
`AND PEPTIDES
`The topic of the biology of gut cholecystokinin (CCK) and
`gastrin receptors has been reviewed (1). Hyperinsulinemia
`increases plasma noradrenaline concentrations as well as
`muscle sympathetic nerve activity, even in the absence of hy-
`poglycemia. In guinea pig-isolated ileal synaptosomes, insu-
`lin stimulates in a concentration-dependent manner the
`secretion of noradrenaline. This is mediated by signalling
`that involves insulin receptors through downstream activa-
`tion of calcium influx (2). The luminal CCK-releasing factor
`is present throughout the gastrointestinal tract. Immunohis-
`tochemical analysis shows diffuse CCK immunoreactivity
`throughout the gastrointestinal tract and the pancreas (3).
`Luminal nutrients and neuroendocrine peptides exert dif-
`ferential effects on somatostatin-28 release from the rat in-
`testine compared with those of somatostatin-14 (4). The
`somatostatin analogue octreotide is effective in the treat-
`ment of the diarrhea and flushing that occur in patients with
`
`carcinoid syndrome. Octreotide retards colonic and small
`bowel transit. This action may be mediated by the associated
`reduction in circulating levels of peptide Y (PYY), neuro-
`tensin, vasoactive intestinal polypeptide (VIP) and substance
`P (SP); however, octreotide has no effect on plasma motilin
`concentrations (5). The topics of VIP and secretin receptors,
`and the G protein-coupled receptors have been reviewed (6).
`The inactive proforms of gastrointestinal peptide hor-
`mones and neuropeptides (such as VIP, PYY and glucagon-
`like peptides) are processed in part by specific endoproteases
`through selective cleavage at the C-terminal side of paired
`basic amino acid sites. Prohormone convertase (PC)-6A
`mRNA is expressed throughout the entire gastrointestinal
`tract, with the highest levels in the small intestine (7). Ileal
`PC-6A mRNA expression increases with fasting and de-
`clines with refeeding, whereas dietary fat increases PC-6A
`mRNA levels in the ileum.
`Neuropeptide Y (NPY) and PYY are structurally related
`peptides that mediate inhibitory activity in terms of gastro-
`
`Cell and Molecular Biology Collaborative Network in Gastrointestinal Physiology, 1Nutrition and Metabolism Research Group, Division of
`Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta; 2Division of Gastroenterology, and Department of
`Anatomy and Cell Biology, McGill University, Montreal, Quebec
`Correspondence: Dr Alan BR Thomson, 519 Newton Research Building, University of Alberta, Edmonton, Alberta T6G 2C2.
`Telephone 403-492-6490, fax 403-492-7964, e-mail alan.thomson@ualberta.ca
`Received for publication February 12, 1999. Accepted September 23, 1999
`
`Can J Gastroenterol Vol 14 No 9 October 2000
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`791
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`MYLAN EXHIBIT - 1017
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd. - IPR2022-00722
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`Thomson et al
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`intestinal motility, secretion and blood flow. NPY receptors
`are present in the rabbit ileum and are subject to interaction
`by receptor antagonism (8). Several receptor subtypes of
`these peptides have been identified and cloned. Double im-
`munofluorescence studies demonstrate that subpopulations
`of Y1 receptor-positive nerve cell bodies are immunopositive
`for NPY, VIP and nitric oxide synthase (NOS) (9). The Y re-
`ceptor subtypes for PYY, NPY and pancreatic polypeptide
`bind to intestinal receptors and exert an antisecretory effect
`(10). Intestinal fluid secretion occurs in conjunction with
`some enteric infections and is mediated by prostaglandin
`(PG) H synthase (11).
`After raising the intraluminal pressure, serotonin is re-
`leased into the cytoplasmic matrix and then diffuses or is
`transported into the intestinal lumen (12).
`
`INTESTINAL INFECTIONS
`AND INFLAMMATION
`The bacterial, viral and parasitic infections of the intestine
`have been reviewed (13-15). Also reviewed are the topics of
`gastrointestinal infections in children (16) and their treat-
`ment (17). The Practice Parameters Committee of the
`American College of Gastroenterology has suggested guide-
`lines for the care of adults with acute infectious diarrhea (18).
`Entamoeba histolytica: E histolytica is caused by two geneti-
`cally distinct species, the invasive parasite E histolytica
`(which is the etiological agent of amoebic colitis and liver ab-
`scess) and the noninvasive Entamoeba dispar. A new ap-
`proach to the detection of E histolytica and E dispar is based on
`antigen detection in the stool (19). In the severe combined
`immunodeficient mouse-human intestinal xenograft model
`of disease, infecting the human xenografts with E histolytica
`trophozoites increases the production of interleukin (IL)-1
`and IL-8 (20). Humans are the only important host for E his-
`tolytica, and an effective vaccination program could poten-
`tially eradicate amebiasis. In gerbils, protective immunity
`against E histolytica after vaccination is correlated with the
`development of an antibody response to a region of 25 amino
`acid residues of the galactose- and N-acetylgalactosamine-
`inhibitable lectin (21). The use of such vaccines would be of
`great value in countries where the environmental conditions
`are not ideal.
`Giardia lamblia: G lamblia is a highly relevant gastrointesti-
`nal protozoal disease that usually manifests as a self-limited
`clinical course. Trophozoites are usually found in the mucosa
`of the duodenum (83%), ileum (12%), gastric antrum (9%)
`and jejunum mucosa (2%) (22). In less than 5% of giardia-
`infected subjects, the histological lesion resembles celiac
`sprue in the mild intestinal villus shortening, as well as in-
`flammation in the lamina propria.
`Yersinia enterocolitica: The enterobacterium Y enterocolitica
`causes a broad range of gastrointestinal syndromes, ranging
`from acute enteritis and enterocolitis to mesenteric lympha-
`denitis. Y enterocolitica invades M cells located in the follicle-
`associated epithelium overlying Peyer’s patches, and this in-
`fection results in the secretion of IL-8 (23). The clinical rele-
`vance of this cytokine production is unknown.
`
`Vibrio cholera: Both V cholera and enterotoxigenic
`Escherichia coli (ETEC) colonize the small intestine and pro-
`duce diarrhea by elaborating enterotoxins. The secretory ef-
`fect of cholera toxin (CT) and of the heat-labile ETEC
`declines in the aboral direction along the small intestine. In
`contrast, the effect of the heat-stable ETEC is greatest in the
`distal small intestine. Mucosal glucose and amino acids
`stimulate electroneutral and electrogenic sodium ion absorp-
`tion to the same degree in the normal and cholera-treated
`small intestine. This is the physiological basis for placing glu-
`cose in oral electrolyte replacement solution. There is no seg-
`mental difference in stimulated electroneutral
`sodium
`chloride absorption, while electrogenic sodium ion absorp-
`tion is highest in the mid and distal portions of the small in-
`testine (24).
`V cholera liberates its classic CT, a zonula occludens
`toxin. A membrane-damaging toxin, a hemolysin, also
`known as the V cholera cytolysin, is a second type of vibrio
`exotoxin. V cholera cytolysin produces pores in the entero-
`cyte, resulting in ATP depletion and cell death (25). These
`toxins interact with specific high-affinity receptors on the
`intestinal brush border membrane (BBM). This activates
`adenylate cyclase within the enterocytes, thereby increasing
`the cellular concentration of the second-messenger 3':5'-
`cAMP. The CT then ribosylates alpha subunits of G protein
`(Gs), inhibiting GTPase activity, which results in mainte-
`nance of Gs in its activated state (simulating adenylate cy-
`clase). This increase in cAMP results in secretory diarrhea.
`E coli: In the critically ill patient, translocation of enteric
`bacteria across the intestinal mucosa is thought to play a criti-
`cal role in the pathogenesis of multiple organ failure. The in-
`teraction between enteric bacteria and their products with
`enterocytes, the influence of gut-associated lymphoid tissue
`and the secretion of cytokines by the enterocyte may alter in-
`testinal function. Polarized monolayers of human entero-
`cytes (Caco-2 cells) in culture increase the secretion of IL-6
`and tumour necrosis factor (TNF) upon stimulation with
`E coli) (26). The cytokines may ‘crosstalk’ with mucosal
`mononuclear cells as well as with neutrophils, and may
`modulate intestinal epithelial barrier function. Also, the cy-
`tokines may increase enterocyte surface expression of mole-
`cules such as major histocompatibility complex antigens.
`Interferon (IFN)-
`and IFN- are upregulated by rotavirus
`infection, suggesting that cytokines also play a role in host
`defence against viral agents (27). While proinflammatory cy-
`tokines can be detected in biopsy specimens from the intesti-
`nal mucosa of individuals with inflammatory bowel disease
`(IBD), celiac disease or infectious colitis, their precise pa-
`thophysiological role in these diseases remains to be deter-
`mined.
`
`Clinical learning point: Cytokines modify intestinal func-
`tion, and some may play a role in host defence against in-
`fections.
`
`There is a growing body of evidence that suggests that en-
`terocytes function as ‘nonclassical’ immune cells. Specifi-
`
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`cally, enterocytes play a major role as a source of proinflam-
`matory cytokines and cytotoxins. A key proinflammatory
`mediator produced in the intestinal mucosa is the free radi-
`cal nitric oxide, which is synthesized by inducible NOS
`(iNOS). Bacterial-induced expression of iNOS in Caco-2
`cells induces the synthesis of nitric oxide, which can be
`blocked by inhibitors of nuclear factor kappa B such as gluco-
`corticosteroid (GC) and of tyrosine kinase activation (28).
`ETEC causes significant morbidity and mortality in chil-
`dren as well as in travellers. ETEC produces a heat-labile
`toxin and/or a heat-stable enterotoxin (either STa or STb).
`E coli 0157:H7 is increasingly recognized as a cause of bacte-
`rial diarrhea in the United States, and molecular subtyping
`methods are used to discriminate the various strains of the
`organism (29). In some geographic areas and in some age
`groups, isolation proportions from fecal specimens for E coli
`0157:H7 surpass those of other common enteric pathogens
`(30). STa is an important causative agent of diarrheal dis-
`ease. STa binds to specific receptors in the intestine, acti-
`vates the guanylate cyclase C receptor, elevates cGMP levels
`and stimulates chloride secretion via cystic fibrosis (CF)
`transmembrane conductance regulator (CFTR). Knockout
`mice lacking guanylate cyclase C receptor are refractory to
`the secretory action of STa (31). Pharmacological inhibition
`of guanylate cyclase C and/or blocking of the guanylate cy-
`clase C receptor could be targets for possible therapy in E coli
`infections.
`With verotoxin (VT)-producing E coli, the diarrhea may
`be associated with hemorrhagic colitis and with the hemo-
`lytic uremic syndrome. Human intestinal epithelial cells
`(IECs) lack a receptor for VT, but VT-producing E coli bac-
`terial strains lower the transmonolayer resistance of cells in
`culture. Immunoelectron microscopy confirms the transcel-
`lular transport of VT (32).
`Enteropathogenic E coli (EPEC) are an important cause
`of gastroenteritis in infants under the age of one year. EPEC
`infections may lead to reductions in both villous height and
`the ratio of the villous height to crypt length (33). EPEC in-
`duce phosphorylation of the 20 kDa myosin light chain and
`thereby alter intestinal epithelial permeability (34).
`Binding of E coli to the 32 to 33 kDa BBM proteins plays
`an important role in bacterial colonization (35). EPEC are
`not invasive and result in diarrhea as the result of a charac-
`teristic ‘attaching and effacing’ lesion in the BBM. After the
`initial attachment, signal transduction to the host cells leads
`to disruption of the BBM cytoskeleton and effacement of the
`microvilli. This is followed by further adhesion of bacteria to
`the BBM and accumulation of host cell cytoskeletal ele-
`ments beneath the attached bacteria. Signal transduction to
`the host cells requires EPEC-secreted proteins. After initial
`adhesion, EPEC stimulate chloride secretion via CFTR, for
`which signal transduction to the host cells is a prerequisite
`(36). Infection with EPEC activates nuclear factor kappa B,
`which in turn initiates
`transcription of
`the
`anti-
`inflammatory cytokine and IL-10 (37). A pathogenic island
`of 35 kilobases, known as the ‘locus of enterocyte efface-
`ment’, achieves this effect by encoding an outer membrane
`
`Small bowel review: Part I
`
`adhesin called ‘intimin’, a type III secretion apparatus, as
`well as EspA, EspB and a new gene espD (38). The EspD pro-
`tein is secreted via the type III apparatus.
`Enteroaggregative E coli are also an important cause of
`persistent diarrhea, especially in children in the developing
`world. These E coli release IL-8 from Caco-2 cells by way of a
`new heat-stable, high molecular weight protein (39). En-
`teroaggregative E coli may be a cause of outbreaks of gastroin-
`testinal illness (40).
`A proteolytic extract obtained from a chemical in pineap-
`ple, known as bromelain, prevents intestinal fluid secretion.
`This bromelain-inhibited secretion is mediated by secreta-
`gogues that act via 3':5'-cAMP, 3':5'-cGMP and calcium-
`dependent signalling cascades (41). Bromelain needs to be
`tested in humans to determine its antidiarrheal potency.
`Antimicrobial proteins and peptides are components of
`phagocytes, one of which is known as defensin. Defensins are
`a group of microbicidal peptides expressed in Paneth cells.
`Human intestinal defensin may protect against invasion and
`parasitization by microbes (42,43). The clinical application
`of this observation is awaited.
`
`Clinical learning point: The toxins produced by V chol-
`erae and by ETEC bind to BBM receptors, increase intra-
`cellular
`second messengers and result
`in secretory
`diarrhea. The clinical usefulness of bromelain, an extract
`of pineapple, needs to be tested in persons with secretory
`diarrhea.
`
`Human immunodeficiency virus: In human immunodefi-
`ciency virus (HIV)-infected persons, the incidence of diar-
`rhea varies from 30% to 60% of patients from industrialized
`countries, to 97% of patients from developing countries. The
`topic of the therapy of gastrointestinal infections associated
`with acquired immune deficiency syndrome (AIDS) has
`been reviewed (44). When controlling for the level of lipid
`malabsorption, HIV-infected patients have lower energy in-
`take than do HIV-negative patients with chronic malabsorp-
`tion (45). The diarrhea is often associated with cytomega-
`lovirus or Mycobacterium avium infection. HIV replication in
`the mucosa may lead to villus shortening, but there is no evi-
`dence that AIDS is associated with mucosal T-cell activa-
`tion. In persons with HIV-associated diarrhea and malab-
`sorption, wasting is greater in those with cryptosporidiosis
`than with microsporidiosis. While patients with HIV-related
`diarrhea have reduced villous height and increased crypt
`death compared with healthy controls, there is no difference
`between HIV-positive controls (46).
`The entry of HIV into human intestinal cells involves
`both the gp120 receptor galactosylceramide and the
`CXCR4/fusin receptors (47). The intestinal permeability to
`lactulose/mannitol is greater in HIV-positive patients with
`or without diarrhea, as well as in those with diarrhea due to
`cryptosporidiosis, than in controls (48).The clinical presen-
`tation of cryptosporidiosis may mimic that of Crohn’s dis-
`ease (49). In addition, cryptosporidiosis may cause an acute
`exacerbation of symptoms in patients with IBD. The intra-
`
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`Thomson et al
`
`epithelial lymphocyte (IEL) may be important in the genera-
`tion of immunity to cryptosporidium through a mechanism
`involving the production of IFN-
`(50). The depletion of
`CD4 T cells in the lamina propria is an early event in the
`course of HIV infection. This may lead to impaired secretory
`immunity because these cells play a critical role in mucosal
`B-cell differentiation and antibody production. Interest-
`ingly, immunoglobulin (Ig) A and IgM levels are normal in
`the supernatant of short term cultured biopsy samples from
`HIV-infected patients, whereas IgG levels are increased
`(51). HIV core protein p24 may be detected in higher con-
`centrations in intestinal biopsies of HIV-infected patients
`than in serum. However, proviral loads may be similar in
`blood and intestinal biopsies, indicating that the intestinal
`mucosa is a major reservoir for HIV in these patients (52).
`Computed tomography scanning of the abdomen may
`complement colonoscopy and biopsy for diagnostic purposes
`in patients with HIV-associated intestinal symptoms (53).
`Microsporidiosis: Microsporidiosis has been reported in up
`to 39% of patients with AIDS and diarrhea, and is the most
`common organism detected among enteric pathogens pres-
`ent in this group of individuals. Two main species, Enterocy-
`tozoon bieneusi, the most commonly identified species, and
`Encephalitozoon intestinalis, may be responsible for dissemi-
`nated disease. A recently described polymerase chain reac-
`tion (PCR) assay appears to be a rapid and reproducible
`method for the detection and identification of each intesti-
`nal species (54). Transmission and establishment of a persis-
`tent infection of E bieneusi from a human with AIDS to
`simian immunodeficiency virus-infected rhesus monkey
`have been described (55).
`Albendazole may successfully eradicate E intestinalis from
`the intestinal tract of HIV-seropositive patients. Albenda-
`zole and metronidazole may reduce the volume of diarrhea,
`although neither clears the spores from the stool. Thus,
`clinical relapse is common. Thalidomide inhibits TNF-
`which is elevated in microsporidiosis, and has been shown to
`reduce stool frequency and improve weight in subjects with
`E bieneusi (56,57).
`
`Clinical learning point: Microsporidiosis is a common
`cause of diarrhea in patients with AIDS. Treatment is with
`albendazole, metronidazole or possibly thalidomide.
`
`Salmonella typhi and shigellosis: Strains of S typhi that are
`resistant to chloramphenicol, ampicillin and trimethoprim
`have been responsible for numerous outbreaks in countries in
`the Indian subcontinent, Southeast Asia and Africa. Cipro-
`floxacin and azithromycin may be useful in the treatment of
`shigellosis (60). Unfortunately, resistance to ciprofloxacin
`has now emerged in multidrug-resistant strains of S typhi (61).
`Strains of Shigella dysenteriae type 1, the most virulent sero-
`type of Shigella species, are caused by strains that are resistant
`to ampicillin and to trimethoprim-sulphamethoxazole. The
`shigella toxin induces fluid secretion by a process that in-
`volves protein kinase C (PKC), intracellular (but not extra-
`cellular) calcium stores and PGs (62). Growth retardation
`following diarrheal diseases in children has been documented
`in several studies, and a randomized clinical trial in Bangla-
`desh demonstrated that feeding children an energy-dense,
`high-protein diet in addition to antibiotics during the acute
`phase of shigellosis is associated with greater weight for age
`and weight for height sustained at home one month after dis-
`charge (63).
`
`Clinical learning point: Energy and protein supplementa-
`tion in addition to antibiotics may be needed in the treat-
`ment of acute shigellosis in children.
`
`Tropheryma whippelii: Whipple’s disease is a chronic disor-
`der with both intestinal and extraintestinal symptoms. It is
`caused by a Gram-positive, rod-shaped bacterium named
`T whippelii. Involvement of the central nervous system
`(CNS) is a serious problem for some patients with Whipple’s
`disease. CNS involvement is not always possible to diagnose
`using cerebral spinal fluid (CSF) examination for periodic
`acid-Schiff-positive particles. In some patients with Whip-
`ple’s disease, a brain biopsy is necessary to diagnose CNS in-
`volvement. PCR testing of CSF may be useful to diagnose
`Whipple’s disease of the CNS, both in persons with and per-
`sons without neurological symptoms (64).
`
`Clinical learning point: PCR technology may be applied
`to the CSF of patients with Whipple’s disease to diagnose
`CNS involvement with T whippelii, without the need to
`perform a brain biopsy.
`
`HIV-infected patients display severe impairment of gas-
`trointestinal function, characterized principally by diarrhea
`and malabsorption despite the absence of demonstrated op-
`portunistic infections. HIV-1 proteins and nucleic acids
`have been detected in several cell types of the intestinal mu-
`cosa. HIV-1 infection impairs cellular differentiation, de-
`creases transepithelial electrical resistance and inhibits BBM
`sodium/glucose cotransporter (sodium-dependent glucose
`transporter) 1, possibly by disrupting microtubules rather
`than necessarily directly infecting the IECs (58). Intestinal
`protein leakage may contribute to the hypoalbuminemia
`seen in some patients with AIDS (59).
`
`In patients with Whipple’s disease, there is altered cell-
`mediated immunity and delayed-type hypersensitivity, ac-
`companied by persistent immunological alterations in the
`peripheral blood mononuclear cells. The peripheral blood
`mononuclear cells in patients with Whipple’s disease have
`reduced monocyte IL-12 production, as well as decreased
`IFN-
`secretion (65). The pathophysiological significance
`of this finding is unknown.
`Clostridium difficile: C difficile toxin A mediates intestinal
`inflammatory responses by binding to a specific receptor on
`intestinal cells. This binding leads to activation of enteric
`nerves and immune cells in the lamina propria. Capsaicin, an
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`agent that ablates sensory neurons, inhibits fluid secretion
`and intestinal inflammation in response to C difficile toxin A.
`The inflammation and hypersecretion produced by toxin A
`from C difficile are abolished when rats are treated with anti-
`secretory factor (AF). AF also markedly reduces the intesti-
`nal fluid response induced by this toxin (66). IL-11 is a novel
`cytokine that may have a protective effect against gastroin-
`testinal injuries, altering the intestinal effects of C difficile
`toxin A activity. This may occur through the inhibition of
`the release of inflammatory mediators from mucosal mast
`cells and intestinal macrophages by IL-11 (67).
`Guidelines have been published for the diagnosis and
`management of patients with C difficile-associated diarrhea
`and colitis (68). The C difficile toxin increases intestinal
`calcitonin gene-related peptide (CGRP) in the ileal mucosa
`and in the dorsal root ganglia. Pretreatment with a CGRP
`antagonist before installation of toxin A into ileal loops
`inhibits the toxin-mediated fluid secretion, as well as the
`altered mannitol permeability and histological damage (69).
`
`Clinical learning point: An antagonist to CGRP inhibits
`the effect of C difficile on the intestine. AF and IL-11 may
`have a protective effect. The therapeutic potential of
`these observations needs to be explored.
`
`Rotavirus: Rotaviruses are the major cause of infectious diar-
`rhea in developing countries as well as in North America.
`These infections are characterized by viral replication within
`enterocytes, cell lysis and villus blunting. Rotaviruses con-
`tain two outer capsid viral proteins – the spike protein VP4
`and the major capsid component VP7. Both of these capsid
`proteins are implicated in the entry of rotavirus into the cell.
`This rotavirus VP4-mediated cell entry may involve the
`2 1 integrin, whereas VP7 appears to interact with x 2
`and 4 1 integrins (70). BBM disaccharidase activities are
`reduced in rotavirus infection, and osmotically induced wa-
`tery diarrhea and dehydration may ensue.
`Protein-energy malnutrition prolongs diarrhea and delays
`small intestinal recovery in response to rotavirus infections
`(71). Natural rotavirus infection results in a specific circulat-
`ing memory CD4+ response that is limited to the gut-
`homing 4 7 subpopulation of lymphocytes. This may com-
`prise cellular memory for intestinal antigens. The regulated
`expression of 4 7 may help to target and segregate intesti-
`nal versus systemic immune responses (72).
`The rotavirus vaccines that have been evaluated to date
`are live, attenuated virus vaccines that are derived from bo-
`vine or simian strains. These vaccines are delivered orally to
`mimic natural infections. However, these vaccines have
`been shown to be only partially protective in humans. Im-
`portantly, T and/or B cells are necessary for clearing primary
`rotavirus infections. CD8+ T cells mediate an in vivo antivi-
`ral effect, either by direct lysis of the virus-infected host cell
`or by the release of cytokines that induce an antiviral effect.
`This antirotaviral effect of CD8+ T cells is not mediated by
`perforin nor by Fas and the release of IFN- (73).
`
`Small bowel review: Part I
`
`Clinical learning point: Vaccination against rotavirus
`infection is not yet sufficiently developed for widespread
`use.
`
`Enterocytes are active participants in the intercellular
`crosstalk with immune effector cells such as mononuclear
`cells and neutrophils. This interaction is mediated to a large
`extent by cytokines, and allows localized and specific modu-
`lation of epithelial and immune effector responses. In Caco-
`2 and HT-29 cells, IFN-
`and IFN-
`induce rotaviral resis-
`tance. This suggests that cytokines play a role in host de-
`fence against viral agents, possibly by changing the
`phenotype of IECs (27).
`Astrovirus: Astroviral infections are a leading cause of
`acute, nonbacterial gastroenteritis in children. Helper T cells
`residing in the normal duodenal mucosa of adults recognize a
`common enteral pathogenic virus, and these CD4+ T cells
`are presumed to be important in mucosal defense against re-
`current astroviral infections (74). Protection against fre-
`quent reinfections with astrovirus may be maintained by
`cellular immune responses in the small intestinal mucosa.
`Blastocystis hominis: It is controversial whether B hominis is
`a cause of diarrhea because it is a common inhabitant of the
`human gastrointestinal tract. A case-control study among
`German tourists returning from tropical countries suggests
`that B hominis may be associated with the development of di-
`arrhea in travellers to tropical destinations, but the diarrhea
`may also be associated with concurrent infections (75).
`Infections and IBD: The cause of IBD remains elusive, and it
`is now disputed that a previous measles infection may be im-
`portant in the cause of Crohn’s disease (76). The immuno-
`suppression used to treat some patients with IBD may
`increase their risk of developing a varicella infection. This is
`uncommon but must be promptly diagnosed and treated with
`acyclovir, and with the concomitant reduction in immuno-
`suppressive therapy (ie, reduction in steroid dosage and dis-
`continuation of azathioprine) (77).
`
`DRUG ABSORPTION
`Curiously, a glass of grapefruit juice (rich in fructose) in-
`creases the bioavailability of some drugs such as nifedipine,
`verapamil, midazolam and cyclosporin A. This may be the re-
`sult of selective downregulation by constituents of the fruit
`juice of CYP3A4, a member of the cytochrome P-450 gene
`superfamily responsible for the metabolism of different drugs
`(78). There is considerable variability in the oral bioavail-
`ability of beta-lactam antibiotics. These are absorbed by the
`peptide transport system, as well as by a passive process. Some
`of the variability in the absorption of this class of drugs is due
`to the involvement of an energy-dependent efflux system
`that is distinct from the P-glycoprotein (Pgp)-mediated
`transporter (79). 5-Fluorouracil is widely used in the treatment
`of solid tumours, but their bioavailability varies widely due to
`the large and variable hepatic first-pass extraction (80).
`Pgp is one of the important factors involved in the mul-
`tidrug resistance of tumour cells. It is expressed in the intes-
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`tine and restricts the absorption of various compounds
`including methylprednisolone (81). In the presence of the
`calcium channel blocker verapamil, the retarded absorption
`of methylprednisolone is normalized. This suggests that Pgp
`is responsible for the unique features of methylprednisolone
`absorption. The multidrug resistance-reversing agent for
`verapamil inhibits secretion of Pgp substrates and, hence, in-
`creases apical to basolateral permeability (82). No associa-
`tion between Pgp and new nonsystemic steroids such as
`budesonide has been reported.
`
`Clinical learning point: Certain food substances may in-
`fluence the metabolism and, therefore, the bioavailability
`of some drugs.
`
`New drug development has been accelerated by molecu-
`lar diversity technology, with drug candidates derived by
`combinatorial synthesis and screening paradigms. Based on
`the chemical properties of a drug, its intestinal absorption
`characteristics can be predicted; however, direct testing of
`the absorption is still necessary. In situ perfusion prepara-
`tions of rat intestine can be used to predict the in vivo ab-
`sorption properties of drugs in humans (83). Caco-2 cells
`have been used to predict directly the in vivo human absorp-
`tion of drugs (84). Mixtures of drugs can be tested in Caco-2
`cells to obtain information on potential absorption proper-
`ties (85). However, the experimental conditions need to be
`controlled carefully (86). The absorption of drugs by Caco-2
`cells can be modified by absorption enhancers such as so-
`dium caprate, sodium deoxycholate and dipotassium glycyr-
`rhizinate (87).
`Nonsteroidal anti-inflammatory drugs (NSAIDs) com-
`monly cause damage to the gastrointestinal tract by a
`number of mechanisms. These include the inhibition of
`cyclo-oxygenase, alterations
`in intestinal permeability,
`changes in the margination of neutrophils and the uncou-
`pling of oxidative phosphorylation by mitochondrial dam-
`age (88). The attachment of a nitric oxide group to an
`NSAID modifies the carboxylic group, which is essential for
`the effective inhibition of cyclo-oxygenase. These so-called
`‘NO-NSAIDs’ may be associated with less macroscopic dam-
`age to the small intestine, but increases in intestinal perme-
`ability still occur (89). Early after intestinal exposure to
`NSAIDs, rats develop slowing of the blood flow to the mes-
`enteric circulation, stasis, microvascular distortion, clump-
`ing and shortening of the epithelium (90). The importance
`of NSAIDs on the intestinal blood flow of humans is
`unknown.
`Biodegradable microparticles have been developed as a
`drug carrier system for the gastrointestinal delivery of thera-
`peutic agents and to enhance drug absorption. The orally ad-
`ministered microparticles also gain entry into the gut-
`associated lymphoid tissue. Using the Caco-2 cell system, it
`appears that microparticle uptake is dependent on the di-
`ameter and concentration of the microparticles, as well as on
`the incuba