Jpn. J. Infect. Dis., 52, 183-197, 1999

Invited Review Association of pylori with Gastroduodenal Diseases

Yoshikazu Hirai*, Shunji Hayashi, Hirofumi Shimomura, Keiji Ogumal and Kenji Yokotal

Department of Microbiology, Jichi Medical School, Yakushiji 3311 -1 , Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498 and JDepartment of Bacteriology, Okayama UniversityMedical School,

Shikata-cho 2-5-1 , Okayama 700-8558, Japan

(Received October 22, 1999)

SUMMARY: was first cultured in vitro in 1982･ This bacterium is a spiral gram-negative rod which grows under microaerophilic conditions･ The ecological● niche is the mucosa bf the human stomach which had been thought to be aseptic before the discovery of this bacterium･ This organism causes a long-lasting throughout a person's life if there is no medical intervention･ Numerous persons are infected with the organism around the world, and the rate of infection in Japan is nearly 50% of the population･ However, the route of infection remains unclear because the organism has not been isolatedfromany environment other thanseveral animals･ H･ pylori is now recognlZed● as a causative agent of and peptic ulcers･ Though gastritis, and especially chronic active gastritis, is observed at least histologlCally● in all persons with H. pylori, peptic ulcers develop ln● Only some infectedpersons. Specific factors in the host and/Or the are needed for the development of ･ Furthermore, H･ pylori is considered to be related to the development of gastric mucosa- associated lymphoid tissue (MAIJ) lymphoma, especially those of low grade. Also, H. pylori infection is a major● determinant for initiating the sequence of events leading to gastric cancer･ In some patients with low-grade gastric MAIJ lymphoma, the eradication of H. pylori led to a regression of lesion. Gastric cancer has been induced in Mongolian gerbils with long-term H･ pylori infection･ The combinations of drugs, which consist of an antisecretory agent (acid-supressing agent) and antimicrobial agents, are used for the eradication of the organism.

● Eradication therapy lS recommended at least fわr patients with peptlC ulcers･

● 1. 1mtroduction 2. BacteriologICal features

Helicobacter pylori is a curved or splral gram-negative H. pylori is a short spiral or S-shaped gram-negative rod,

bacterium, and can colonize in and under the mucus layer of 0.5-0.9 〝m wide and about 3 〝m long, in the stomach. It is humangastriC mucosa without the copresence of other bacterial motile by means of a tuft of up to eight sheathed flagella at . The bacterium was first cultured in Perth, Western one pole (Fig. 1). The sheath is a kind of membrane and its

Australia, and was first reported in 1983 as a Campylobacter- bi∝hemical composition resembles that of the outer membrane･ like organism ( I ,2). The organism was named Campylobacter The organism grows under microaerophilic conditions･ pyloridis, but this was later changed to C. pylori. Subsequently, Mediathat contain serum or blood are usually used. For the it was asslgned to the new Helicobacter, and is now first isolation from gastric biopsy, Ski汀OW's medium is known as Helicobacter pylori (3). commonly recommended･ However, H･ pylori can grow in a

The first paper relating to H. pylori described its association serum-free medium containing 0.1-0.2% of dimethyl β- with gastritis ( 1 ). Researchers indicated that the organism can cyclodextrin (7,8). The growth of H･ pylori i.n a synthetic cause human gastritis by oral self-administration of the living medium was reported, but it contained largeamounts of tDVine bacteria to the stomach (4,5). H. pylori infection is now recog- serum albumin (9). In liquid culture, shaking is necessary for

● nized as the pnmary cause of active chronic gastritis and as good quality and uniform growth･ an important causal factor in peptic ulcers. Furthermore, the By a time-expired culture or changes in gas conditions, 〃･ infection is regarded to be deeply associated with low-grade pylori transforms to a coccoid form (Fig･ l)･ The coccoid B-cell gastric lymphoma and gastric cancer. It was reported form of the bacteria (C∝coid body) cannot grow in any media in 1998 that H. pylori infection induced gastric cancer in or under any artificial conditions･ However, it is reported that mongolian. gerbils (6)･ the oral inoculation of the coccoid body induces gastritis in This revleW fauses onand summarizes mainly the bacteri0- mice (10). It remains unclear whether the coccoid body is in logicalfeatures of H. pylori and the association between the a viable but non-culturable state (VNC).

organism and gastroduodenal diseases. In representatives of conventional biochemical tests, 〃･

pylori is positive for oxidase, catalase, , alkaline phos- *Corresponding author: Tel: +81 -285-58-733 1 , Fax: +81 -285-44- phatase, and T-glutamyl transpeptidase, and is negative fわr nitrate reduction･ The organism utilizes glucose but gives no 1175 indication of acid production･ Some Helicobacter spp･ have periplasmic fibers (Fig･ 2), but H･ pylori does not･ Of these ThisarticleisanⅠnVitedReviewbasedonalecturepresentedat characteristics, urease is of the most importance. The urease the9thSymposlumOftheNationalInstituteofInfectiousDiseases, of the organism indicates a low Km value as compared to Tokyo,21May1999. other (Table l ). Furthermore, the large content of urease

183 Fig･ l･ Electron micrographs of Helicobacter pylori (negative staining) A; A spiral form of the bacteria with sheathed flagella at the end of the cell･ B; A curved-rod form of the bacteria. C; Coccoid forms induced by a time-expired culture･ Sheathed nagella remain･ D', Sheated nagella (highmagnification)･ True nagella are observed at the site indicated by arrows.

the backbone of lipid A, D一gulcosamine disaccharide (19)･

● Because of these unlque features, the endotoxic activity of the LPS is very low compared with that of (20,21). However, the LPS is recognized as an important factor in the inducement of gastritis, becausethe C3H/He mouse which minimally responds to LPS shows very low-grade gastritis in H. pylori infection compared with the C3H/H mouse which is a responder (22). H. pylori has three kinds of cholesteryl glucosides (CGs) (Fig. 3) (23). CGs are very rare in animals and bacteria･ In bacteria, CGs have been reported only ln● Mollicutes (Acholeplasma spp. , Mycoplasam gallinarum, Spiroplasma citri) and Borrelia hermsii. We, however, found for the first time a phosphate-linked cholesteryl glucoside like cholesteryl phosphatidyl glucoside (CPG) in Helicobacter･ In the organism, CGs contribute about 25% by weight of the total extractable Fig･ 2･ An electron micrograph ofH･ rappini (Flexispira rawini) (nega- tive staining). lipids. The organism cannot synthesize cholesterol in the same Periplasmic fibers (PFs) are observed. In this photograph, views or way as other bacteria, but appears to accumulate free choles- PFs on the upside and downside or a bacterium are overlapped･ terol from media (24). Furthermore, CGs appear to be a unique feature of genus Helicobacter, because they are present in 1 6 exists at the su血ce ofcells (17), whereas it exists only in the of 18 Helicobacter species (25,26). cytoplasm of other bacteria. Therefわre, the organism exhibits As mentioned above, urease is located on the outer mem- very high urease activity in the whole cell, which is commonly brane. Heat shock protein (HSP) 60 is also fわund in the same used as a method for diagnosis of H. pylori infection. H. pylori location. It was reported that this was synthesized in the itself is intolerant of strong acids, but the organism prefers cytoplasm and absorbed on the su血ce after spontaneous mildly acidic conditions and can withstand a pH as low as autolysis (27)･ Theseチre majo.r proteins in the organism･

1.5 when urea is present (18). The overall genomlC OrganlZation has been fわund in two H･ pylori shows unlque● membrane features. On lipopolysac- strains, J99 (28) and 26695 (29), of H. pylori. The general charide (LPS), Compared with lipid A of members of Enter?- features are listed in Table 2. The annotated genome sequences

● bacteriaceae, the lipid A of H. pylori has an unusual composl- and further information concernlng Strains J99 and 26695 are tion of fatty acids (310H C18:0) and also a different phos- available on the World Wide Web site (http://www.tigr.org/ phorylation pattern, with 1 '- but not 4'-phosphate present in tdb/mdb/hpdb/hpdb.html) and in the H･ pylori database

184 Table 1 ･ Biochemical characters of purified ureases

Kml) specific native Mr subunit Mrs) subunit metal

(mM) acti v i ty 1 ･2) (kDa) (kDa) composl tlOn COntent

Helicobacter pylori O･ 17 1 , I 00 530 α =26.6 (α･β) 1.0 Ni/β -0.48 - 1 ,700 β =60.5 ×6

Klebsiella aerogenes 2.8 2,200 224 α=9 (α2･β2･γ) 2.1 Ni β=11 ×2 /(α2･β2･γ)

γ =72

Ureaplasma urealyticum 2.5 33,530 150 α=66 α2or α5or α6 -4. 5 - 1 80,000 -380 -76

Jack bean(plant) 2.9 1 ,000 590 α=98 α6 2.0 Ni/α -5,500 1)These data were measured with different buffers, temperatures, and pHs･ 2) LLmol of urea/min per mg of protein 3)The small, mediumand large subunits are designated as a, B, and T, respectively.

(from refs. ll-16 )

CGL (G･2): Table 2･ General features of the H･ pylori genomes Cholesteryl･a･D･glucopyranoside (base substance) strain 26695 strain J99

Patient (Country) gastritis duodenal ulcer

(the UK) (the USA)

Size (base pairs) 1 ,667,867 1 ,643,83 I

G+C content (%) 39 39

Regions of different 8*(5) 9 G+C content

vacA genotype sla/ml slb/ml OH Open reading frames (ORf) CAG (G･1): Coding % of genome 91.0 90.8 C holeste ryl ･6 ･ 0 I te tradec anoyl ･ α･ D･ glucopyranoside Number of ORF 1 ,552*(1 ,590**) 1 ,495

Functionally classified 895 874

Conserved with no function 290 275

H･ pylori specific 367 346

Number with signal sequence 517 502

average length (base pairs) 954 998

Insertion elements (IS)

n1Ju EuJHU Eil Pu IS605 (complete copies) 13(5) 5 5 0 1

IS606 (complete copies) 4(2) CPG (G･3): RNA elements C holesteryl･ 6･ 0 ･ phosphatidyl･ α I D･ glucopyranoside 23S-5S rRNA 2 2 人V 2 つー 6 H2CO - CO-R 2 16S rRNA

tRNAs 3 3 H-CO-CO-R3

t ? (refe汀ed and modified mainly from ref･ 29･) H2C- 0- p-0-cH2 *: The data are recalculated in ref. 29. b~.i.1 **: indicate the onglnal data in ref･ 28･

performed within several hours. Therefore, the combination 1 0H of several methods, especially culture, a rapid urease test, and the observation of stained tissue, is usually used. Fig･ 3･ Structures of cholesteryl glucosides of H･ pylori･ H. pylori infection is detected bythe elevation of titers of specific IgG antibody in serum. The determination of specific (www･astra-boston･com/hpylori or wyw･genomecorp･ com/ IgA levels in the saliva may also be used for the diagnosis･ hpylori), respectively. However, the use of specific lgM levels is not helpful fわr diagnosis because long-term infection is usually diagnosed long after IgM levels peak, which most often occurs in youth 3. Diagnosis while the infection is asymptomatic. There are many methods for the detection of H. pylori The urea breath test (UBT) and the detection of H. pylori infection (Table 3)･ In group A, gastric endoscopic exami.na- antigens in feces are non-invasive methods. Especially, the tion is necessary･ For these methods,the culture of the organlSm UBT has very highsensitivity. However, 13C-urea and costly

● is the gold standard method･ Recently, strains resistant to equlpment are needed for the test. antibiotics, especially Clarithromycln,● Which are used for the

● eradication of the organism, are increaslng･ Strains are isolated 4. Epidemiology only by culture. However, the cultures need over 1 week, and

● this method sometimes glVeS false-negatives, especially after The seroepidemiology of H. pylori has been studied in antibiotic treatment. Conversely, the rapid urease test can be many countries (Fig. 4). The high frequency of seropositivity

185 Table 3･ Methods for diagnosis of H. pylori (HP) infection

A: SpeclmenS from gastric endoscopic biopsy or Gastric endoscopy I) Culture

Grind a gastric speclmen, in∝ulate onto agar media, and culture the media for a week undermicroaerophilic conditions･ Brain heart infusion agar medium with5-7% horse bloodand antimicrobialS (VanComycin, trimethoprim, Polymyxin B,and amphotericin B)are corrmonlyused for the first isolation. 2) Rapid urease test (Commercialkits indicating positive within severalhours are available.) In∝ulate gastric specimen (grinded or not) to kits containing. ureaand a pH-indicator･ The color will change with ammonia production by strong urease activitywhen HP exists in thetissue. 3) Histologicalexamination Stain formalin-fixedtissues by severalmethods. Detection of HP in thetissue stained withhematoxylin-eosin is

quite hard･ Giemsa stain, W如hin-Starry stain, Genta stain, stain with acridine orange,and immunostairungare used･ 4) Dye-spraying endoscopy Perform endoscopy ln Patients admimistered withacid-Supresslng agentS･ Spray liquid contaiming ureaand dye (phenol red or a dye from red cabbage) to the gastric mucosa･ The color of the HP-positive area will change bythe same reaction as 2). 5) PCR (Polymerase chain reaction) OlJhOPq 6tIOt 6N-ON 6の-OS 6寸-0寸 69-0g 69-09 Detect HP-Specific genes uslng PCR in the gastric tissues. (age group) nimers to genes of the urease or 16S rRNA areusuallyused. The PCR canbe applied to saliva or feces. B: Others 6) Detection ofanti HP IgGantibdy Fig. 4. Distribution of seropositivity for H･ p_vlori immunogloblin G (Commercialkitsare. available･) antibodies by age and country of origin (from ref･ 30,31)･ Vdousantigens(sonlCated bacteria, acid-exbTaCtS, ureおe, etC. ) aqeused. 7) Urea breathteat (UBT) associated with H. pylori infection. The disease associations Give liquid containing I3C-urea to patients orally. 13C-Carbon dioxide is produced from urea bythe same reaction as 2). are summarized below.

The carbon dioxide is absorbed in血e intestine and is exhausted in the A. Gastritis lung･ Measure content of t3C-Carbon in breathing 1 5-30 min after the A･1) acute gastritis (first infection) admimistration. In most cases of H. pylori infection,the causal events are 8) Detection of HP-antigensin feces not well known because the infection has been long-standing (A commercialkit is available) HP-antigens are detectedwith polyclonalantibody in ELISA. by the time of diagnosis. Most cases of childhood infection may be asymptomatic. However, H. pylori infection was deter- and the acquisition of infection during infancy are character- mined by seroconversion or culture-positive in children who istic of disadvantaged s∝ioeconomic groups living under poor exhibited abdominal pain (36,37)･ Acute gastritis was caYsed hyglenic conditions. In higher socioeconomic groups such as in volunteers (researchers) who ingested the living organlSm･ those found in European countries, acquisition during infancy When somepeople who exhibited a normalgastric mucosa and is rare, and the frequency of seropositivity in adults is under were free of the organism at the time of their first endoscopy 50%. In these countries, the rate of seroconversion is estimated developed abdominal paln 1-2 weeks after the endoscopy, at O･5% per year. In Japan, the frequency of seropositivity in acute gastritis (acute gastric mucosal lesion; AGML) was younger people (under 30 years old) is similar to that of found and the organism was detected in the second endoscopy European countries. However, that in older people (over 40 (38,39)･ Based on these data, H･ pylori. can cause acute gastritis･ years old) is high (over 70%). One feature of the onset of infect10n is the disappearance H･ pylori is cultured from human gastric mucosa and has of acid secretion for a few months (40,41). Clinical signs of been cultured to some extent from human saliva and feces acute gastritis, especially AGML, disappear 1 -2 weeks after (32,33). It has not been isolated from extemal environments, onset. However, in most people infected with H･ pylori, the although the DNA of Helicobacter species has been detected infection is life-long, and acute gastritis proceeds to chronic by PCR (polymerase chain reaction) methods from waters iT gastritis･ However, it was reported that the organism disap- Peruand Sweden (34,35). The route of transmission of H. pylorl peared spontaneously 314 Weeks after the onset ofAGML in infection is not known. Based mainly on seroepidemiology some people infected by endoscopy or afterthe onset of acute data, the contamination of drinking water could playanimpor- gastritis in a volunteer's infection (42,43)･

● tant role in the transmission in certain developlng countries, A･2) chronic gastritis and acquisition of the infection would occur easily during Most people with H･ pylori infection do not exhibit any

● infancy, compared with adults. The high frequency of seroposl- climiCalsigns･ However, the presence of the organism is always

● tivityin olderpeople of Japan may renect poor hygiemic condi- histologlCally associated with chronic active gastritis, and its tions intheir youth around or before the Second World War. eradication is fわllowed by the resolution of gastritis･ Acute H. pylori canalso be isolated from cats, but the transmission gastritis proceeded to chronic gastritis with clinical symptoms from pets would not be of great importance. in the volunteers mentioned above. In addition, the oral administration of the living organism causes chronic gastritis in animals (mice, mongolian gerbils, piglets, monkeys)･ 5. The adSS∝iatiOn between H. pybriand gastroduodenal Among these animals, the mongolian gerbil has the highest diseases sensitivity to colonization by the organism and shows the most Many gastroduodenal diseases are now recognlZed to be severe gastritis.

186 In chronic gastritis with H. pylori, infiltrations of chronic mucosa,and colonizes it. The sheathed flagella and the urease inflammatory cells (lymph∝ytes and plasma cells) and neutro- are considered to be critical factors for colonization because phil polymorphs are present in the gastric mucosa･ The term mutant strains did not colonize the mucosa in the stomach of of chronic active gastritis indicates the period in which an the mouse (47-49)･ The sheathed flagella γould indicate infiltration of neutrophil polymorphs has occurred･ Damage without a degradation in the acid envlrOnment Of the

● ● to the surface epithelium is a feature of chronic active gastritis･ gastric JulCeS,and the urease which showthe lowest Km values Lymphoid follicles (aggregates of B-lymphocytes with ger- would neutralize the acidic microenvironment around the minal centers) are often observed in the mucosa of infected organism, utilizing a low concentration of urea in the gastric

● ● persons, especially children, whereas uminfected gastric mucosa JulCeS･ contain minimal lymphocytes. These lymphoid follicles are Adhesion isanessential step for infection byall . a kind of acquired MAIJ (mucosa-ass∝iated lymphoid tissue) For H. pylori, many adhesins and their receptors have been - as opposed to Peyer's patches which are normally present. reported (Table 4). The organism adheres well not only to The levels of chronic innammatory infiltrates correlates human gastric cell lines, but also to other cell lines. Among

+- ● closely with the denslty Of the bacterialcolonization. Generally, these adhesins and rqCeptOrS, it is not known which are

● ● the infiltration orlglnateS in the antrum and proceeds to the actually important for adhesion to occur in the human gastric COrpuS･ muCOSa. A･3) atrophic gastritis and other changes (intestinal The changes in acute gastr8itis (first infection) are likely metaplasia and gastric metaplasia of the duodenum) due to direct actions of bacterial products. However, in addi- Atrophy in the mucosa of the stomach is caused by a loss tion to the direct action, immune responses appear to play an

● ● of glandular tissue･ Repeated tissue Injury Causes atrophy important role in chronic gastritis.

● and leads to a thinnlng Of the gastric mucosa, which induces Many vilurence factors were nominated, but it is not known hypochlorhydria･ In patients with chronic gastritis induced by which are important. The organism has cholesteryl glucosides, H･ pylori infection, the prevalence and severity of glandular LPS, urease and HSP 60, and produces phospholipase and atrophy increases steadily with age. Patients without H. pylori mucinase. The cholesteryl glucosides indicate hemolytic infection rarely develop atrophic gastritis. H. pylori inhabits activity (23). Ammonia, which is produced from urea by the the gastric mucosa, including the mucus layer. The loss of urease, can cause mucosal damage (67,68). Furthermore,

● glandular tissue and the thinnlng Of the mucosa reduce the mon∝hloramine, which is pr∝luced by the reaction between density of the organism. In Japan there are many patients with ammonia and chloride ions in the presence of oxgen free severe atrophic gastritis. radicals fomed by neutrophils, is also toxic to cells (69). Intestinal metaplasia is frequently observed in chronic 〟. H. pylori also produces and releases a vacuolating cyto- pylori gastritis･ The report (44) sYggests that H･ pylori infec- toxin (VacA) which produces vacuoles in many cell lines

● tion and bile renux act synerglStlCally to produce intestinal (Fig.5) (70). The vαCA gene encodes a precursor protein of petaplasia･ The intestinal epithelium (intestinal metaplasia) 139.6 kDa consisting of a 33-amino acid signal sequence, lS resistant to bile acids, and is not colonized by the organism. the 87-kDa cytotoxin and a 50-kDa C-terminal domain (71 )･ The definition of gastric metaplasia of the duodenum is the The secretion of the cytotoxin through bacterial membranes appearance of gastric mucin cells on the surface of the dudenal is considered as fわllows: the precursor protein passes through mucosa. Gastric metaplasia is also observed in duodenal the bacterial cytoplasmic membrane by a sec-dependent Crohn's disease. This condition can be induced in rats by pathway; the 50-kDa C-terminal domain is inserted into the repeated injections of gastrin (45), and is not seen i.n patients outer membrane; and the cytotoxin domain is cleaved off and with achlorhydria (46). Therefore, gastric metaplasla is prob- released into the supematant (7 1 ). Intra-gastric administration ably a non-specific response to injury by acid. H. pylori can of VacA to mice caused some tissue damage resembling that colonize gastric mucin cells and can be detected only at the found in patients with H. pylori infection (72)･ Furthermore, sites of gastric metaplasia in the duodenum. VacA may not be the only virulence factor, because three A･4) pathogenic mechanisms in gastritis proteins which show moderate similarities (26-31%) to the H. pylori reaches the gastric mucosa, the ecologlCal niche carboxy-terminal end of VacA exist in strain 26695 (28)･

● ● ● of the organism, through the gastric JulCeS, adheres to the Most H. pylori are free-swimmlng in the mucosa, but some

Table 4･ Adhesins of H･ pylori andtheir receptors in host cells

Adhesins Receptors References

20 kDa protein (HpaA) N-acetyl neurami nyl I actose 50-52

63 kDa protein phosphati dyl ethanol amine 53-55 (exoenzyme S-like adhesin) gangl i otriaosyl ceramide gangl i otetraosyl ceramide 19.6 kDa protein laminin 25 kDa protein 1 amini n 75 kDa protein (Bah A) Lewis B antlgen

61 kDa protein H type2, Lewis A,Lewis Bantigens 60 16 kDa protein Lewis Xantigen, mucin 59 kDa hemoagglutinin 60 kDa heat shock protein Gi 糾65砧 (HSP B) GM3 , 1actosylceramide sulfate GM3, sulfatides heparansul phate

187 B. peptic ulcer diseases lduodenalulcer (DU)and gastric ulcer (GU)】 H. pylori infection rates in patients with peptic ulcers are high. A report in Japan mentioned that the infection rate was 97% in patients with DUs and 98% in patients with GUs, whereas it was about 40% in asymptomatic persons (80)･ In ananlmal infection model (mongoliangerbil), the development of GU was observed (81). The eradication of the organism in

patients with peptic ulcers suppresses the recu汀enCe Of ulcers (82,83). The recurrence rate a year after therapy is below 20% in the eradicated patients, and over 50% in those without eradi- cation. These data, especially the latter, clearly indicate that H.

● pylori is the major Cause Ofpeptic ulcers. The NIH Consensus ヽ■ Development Panel on H. pylori in PePtic Ulcer Disease in the United States recommended the eradication of the in

Fig･ 5･ Vero cells vacuolated by VacA (vacuolating cytotoxin) of 〟. patients withpeptic ulcers (8乎)･ However, peptic ulcer diseases

pylori. are caused only in part by H･ pylori infection･ Other drugs, Vero cells were incubated witha concentrated culuture-supematant especially non-steroidal anti-innammatory drugs (NSAIDs), of H･ pylori for 10 h. also cause peptic ulcer diseases. Therefわre, additional or specific factors in the host and/Or the bacteria are certainly of the organisms adhere to gastric epithelial cells. This adhesion needed for the development of peptic ulcer diseases.

● induces cytoskeletal rearrangements in AGS cells (a human The mechanisms concernlng the development of peptic gastric adenocarcinoma cell line) and tyrosine phosphoryla- ulcers in patients with H. pylori infection are not clear. Acid tion of the cell proteins, resembling that of enteropathogenic secretion plays an important role both in GU and DU diseases, E･ coli (73)･ Further, the adhesion of the bacteria to gastric although the pathosis in each ulcer disease is different･ In epithelial cell lines induces IL-8 expression and secretion in patients with DU, acid secretion persists for a longer period the cells･ Ⅰし8 attracts and activates neutrophiles and exhibits after meals (85,86) and gastrin release is stimulated (87,88), various bioactivities as a proinnammatory chemokine･ The whereas somatostatin decreases (89,90). Patients with GU cag pathogenicity island (cag FAI) is a geヮe cluster, and the secrete, on average, less.acid than controls (9 1 )･ However, acid products of cag PAI are considered to be major PrOteins which secretion also plays an Important role in GU disease because induce IL-8 expression in the cells (74). The G+C percentage ulcer healing is faster and recurrence is less when acid secretion of cag PAI is low (35% in strain 26695) Compared to that of is suppressed (92). Detailed mechanisms and associations the whole genome (39% in strain 26695), and this gene cluster based on clinical findings are not included in this review･ is likely acquired horizontally (28,29). CagA (the product of H. pylori is sensitive to bile salts (93),although the organism cytotoxin-associated geneA) is a I 20- I 28 kDa protein. Although was detected at sites of gastric metaplasia in the duodenum･ CagA was fbmerly thought to be associated with VacA, these UnconJugated● bile salts are more toxic to H･ pylori than the two proteins are found to be independent. Furthermore, CagA conjugates (93)･ Bile salts without taurine conjugates are

● does not affect the induction of IL-8 expression in the epithe- precipitated in an acidic environment･ Taunne conjugates have 1ial cells, although previously it was thought to induce IL-8 only low toxicity to the organism. One report (94) mentioned

● expression. The products of genes other than cag A (cagE, G, that the precipitation of bile salts without taurine conjugates H, I, L, M) in cag PAI are found to affect the induction of IL- in acid would allow the colonization of the duodenal bulb. The 8 expression (74). colonization at the sites of gastric metaplasia in the duodenum Strains which do not exhibit VacA activity (the vacuolation may be key to the development of duodenal ulcers･ to epithelial cells by the addition of a culture-supernatant to a In terms of additional or specific factors in the host, cigarette cell-line culture) or are missing the cαgA gene are also isolated smoking, blood group 0 and non-secretors, inherited factors, from patients with chronic H. pylorl gastritis. Thus, VacA etc･ have been reported･ In inherited factors, it was reported and CagA (cag fAI) are not critical factors for the induction that HLAIDQAI was associated with peptic ulcer disea.ses of gastritis. These might play more important roles in peptic (Persons having D(〕Al *0102 are resistant and those havlng ulcer diseases. DQAl*0301 are sensitive.) (95). VacA and cagFAI (cagA)

● ● Much research concernlng Immune responses including are considered to be the representative specific factors in the cytokine production, has been carried out. Only some recent bacteria･ The vαCA gene is classified by the sequence at the

● ● works are summarized here. In the gastric mucosa of mice sites of the slgnal sequence and the middle reglOn tO Sl and with Helicobacter infection (H. pylori or H. felis), the THl s2, and ml and m2, respectively (96). Strains of type sl/ml (T helper cell 1) response is dominant in CD4-T cells (75). It show the high biological activity of VacA (96)･ It was reported was reported that THI cells enhanced gastritis, and that TH2 in Europe and the U･S･A･ that patients with ulcers were cells reduced the bacterial load (76). In human gastric mucosa infected with strains of type sl/ml more often than with other of patients with chronic H. pylorl gastritis, the TH I phenotype types, compared with non-ulcer patients (96,97)･ However, is also dominant (77,78). Certainly, the THl response is likely this difference in the type distributions of the vacA gene to enhance gastritis. Among TH 1 responses, gamma interferon between the strains from ulcer and non-ulcer patients was qNF- γ) appears to playanimrx)rtant role in gastric innammation not observed in Japan, because the type of vαCA gene is sl/ because H. pylori which colonizes the IFN-r gene knockout ml in most strains (98,99). Conversely, it was also reported in mice, does not cause gastric inflammation (79). Europe and the U･S･A･ that patients with ulcers were infected

● with strains havlng the cαgA gene more often than with other types, compared with non-ulcer patients (100)･ However, in

188 Japan the differences in the rates of possesslng● CagA-positive with gastric MAIJoma among gastric diseases with H. strains between ulcer and non-ulcer patients with H･ pylori pylori infection (1 1 1). infection were of little import because most strains in this Conversely, human lymphocytes can be transplanted to region have the cαgA gene (101). severe combined immunodeficient (SCID) mice that have C. gastric MALT lymphoma neither mature T- nor B-cells. One month after peripheral Isaacson developed the concepts of gastric MAIJ and MAIJ blood mononuclear cells from H. pylori infected patients with lymphoma (MAIJoma) ( 102, 103). A MAIJoma is generated gastric MALTomas were transplanted to SCID mice, oral from MAI:Ts, which are collections of B-cells. The MALToma administration of live H. pylori to the SCID mice led to gastric

● is classified as a Marglnal zone B-cell lymphoma inperipheral ulcers within 3 days, most commonly by day 1 (1 12) (Fig.6). B-cell neoplasms in the Revised European-American Classi- Gastric ulcers and erosions are occasionally observed in rlCation of Lymphoid Neoplasms of 1994 (104)･ A diseaヲe patients with the disease. These data suggestthat host immune formerly referred to as reactive lymphoreticular hyperplasla responses agalnSt● H. pylori are involved in the development is considered to be included in the category of MAIJomas･ of gastric ulcers in patients with gastric MAI:Tomas･ .T( It remains debatable whether all MALTomas are strictly D. gastric cancer O neoplasmas. Even though the number of patients with gastric cancer in

● Most patients with gastric MAIJoma are infected with H. Japan is decreaslng, there are still many patients with gastric 甘T

∵ pylori (92% in ref. 105). MALTs are often observed in the cancer in Japan. Early gastric cancers develop ln areas Of gastric mucosa with H. pylori infection. Furthermore, some intestinal metaplasia or chronic atrophic gastritis, which are low-grade MAIJomas disappear or regress after the eradica- observed frequently ln● Patients with long-term H･ pylori tion of H･ pylori (106,107). Therefore, H. pylori infection infection. Many groups have indicated significantly higher appears to be associated with gastric MAIJoma. However, seroprevalences of H. pylori in patients with gastric cancer some low-grade MAIJomas and most high-grade MALTomas in case-control studies (113-115), althoughin soヮe studies do not exhibit any regression after eradication of the organism there are no differences between the seroprevalence ln POSltlVe

(108,109). cases and controls ( I 16, 1 17). Strong evidence foranass∝iation Although the ass∝iation of H･ pylori with lymphomagenesis between H. pylori infection and the development of gastric of gastric MAIJoma is unclear, the pathosis of this disease, cancer has come from prospective (cohort) studies (Table 5)･ especially ln relationship to low-grade cases, appears to be In 1994, the World Health Organization added H･ pylori to

● associated with the immune response agalnSt the HSP 60 its list of known carcinogens (121 ). Furthermore, gastric cancer family･ Follicular dendritic cells of germinal centers in the has been induced in Mongolian gerbils with long-tem 〃･ gastric mucosa affected by low-grade MAIJoma were pylori infection ( I 22- 1 24). Now H. pylori infection is regarded

● immunostained positively with anti-H･ pylorl POlyclonal as a major determinant in the first stage of the sequence of antibodies and with anti-human HSP 60 monoclonal antibody events leading to gastric cancer. It has been estimated that (1 10). The antibody titers to the recombinant human HSP 60 nearly 80% of gastric cancers may be attributable to H･ pylori

● Were observed to be slgnificantly elevated only in patients infection. H. pylori is epidemiologlCally● associated with the intestinal type(well-differentiatedtype) but not the diffusetypeof gastric cancer at the antrum andthe corpus (125), and is not ass∝iated with cancers of the gastric cardia･ In contrast, Epstein-Barr virus

is considered to be ass∝iated with most lymphoepithelia1-like

● gastric carcinoma and nearly 10% of typical type cancers (differentiated and diffuse) involving the corpus and the cardia of the stomach (126). There is no evidence that H. pylori infection is, in itself, directly genotoxic or mutagenic･ A number of ideas regarding carcinogenic mechanisms have been proposed･ First, a

● ● slgnificant decrease in ascorbic acid in the gastric JulCeS is observed in patients with chronic H･ pylori gastritis ( 1 27, I 28), although the reason is unclear･ Ascorbic acid is an antioxidant which indicates functions as a scavenger of reactive oxgen

and an inhibitor of Ⅳ一mitrosation. A reduction of these chemopreventive effects mayallow the development of cancer･ Fig･ 6･ A gastric ulcer induced by oral admimistration of live H･ pylori to SCID mice to which periferal blood mononuclear cells from a H･ Second, H･ pylori infection increases the rates of gastric pylori-infected patient with gastric MAIJ lymphoma were trans- epithelial cell turnover, which may result as an effect of the planted 1 month before the administration of the orgamism･ ammonia produced by urease･ Cell division is vital to the

Table 5･ Prospective studies of the association between H･ p_vlori (HP) and the development of gastric cancer

Region (aOeliodWy-euaPr) aapTCpe.rsitive nHOpn;C.asTtcie:e oddsratio reference

British & Welsh 6 20/29(69%) 54/116(47%) 2.8 118

Ameri can 14 92/109(84%) 66/109(61%) 3.6 119 (Cal ifbmi a)

Japanese-AmeriCan 13 103/109 (94%) 83/109 (76%) 6.0 120 (Hawaii)

189 ● development of cancer. are significantly decreased after the eradication of H･ pylori (140). 6.Treatment Recent studies have suggested that chronic with Chlamydia pneumoniae and cytomegalovirus are associated H･ pylori is sensitive to many antimicrobial agents in vitro, with an increased risk of coronary artery disease and athero- thoughit is resistant to trimethopnm,● Polymyxin B, and vanco- sclerosis. Some reports suggested that H. pylori infection is

● mycln Which are contained in the medium used for the first also associated with these diseases (141 ,142), but this remains isolation. However, it is difficult to eradicate the organism from controversial ( 143).

● the stomach with a slngle use of an effective antimicrobial agent. It is generally accepted that a combination of at least 8.Associations of helicobacters without H. pyloriwith two, and possibly three, effective drugs should be given for a humam diseases minimum of 1 week to eradicate the organism. All combina-

● tions contain an antisecretory agent and antimicrobial agents. Many s阿leS Or Stmins/grPupS are listed in genusHelicobwter The administration of antisecretory agents increases the pH (Table 6). H. heilmannii (Gastrospirilluhl hominis) is a spiral in the stomach. At a low pH, the MICs (minimum inhibitory bacteria larger thanH. pylori and is urease-positive･ It has been concentration) of most antimicrobial agents increase signifi- detected in the human stomach and is thought to cause about b I cantly (1 29) compared with at neutral pH. The administration 1 % of human gastritis･ This bacteria has not been cultured in of antisecretory agents secures the efficacy of antimicrobial vitro, but it can grow readily in the mouse stomach･ Analysts agents in addition to an acceleration of the cure of ulcers and has revealed a difference in the 16Sribosomal RNA gene, erosions. Among antisecretory agents, proton pump inhibitors resulting ●ln its classification as a new species, Helicobacter (PPIs) (H'-K'ATPase antagonist) are usually used in eradica- heilmannii. In patients with H. heilmannii, the rapid urease test

● ● tion therapleS, and these inhibitors have a stronger antisecretory indicates positive, but the culture uslng media for H･ pylori effect than histamhe H2 reCePtOr antagonists. Furthermore, isolation is negative. PPIs show direct antimicrobialeffects agalnst● H. pylori in vitro, H. fenneliae, H. cinaedi, H. pullorum, H. cants, and H･ but not against other bacteria (130) (Histamine H2 reCeptOr rappini (Flexispira rappini) have been isolated fromthe stools antagonists do not show this effect). Although PPIs inhibit of patients with diarrhea･ Most of these patients are immuno-

● urease (131), this activity is found to have.no relation to the deficient. H. westmeadii and Helicobacter specleS Strain Mainz anti-H. pylori effect ( I 32), and the mechanlSm Of the effect is have been isolated from the blood of patients with immuno- unclear. It is controversial whether the anti-H. pylori effect deficiency. Conversely, some species such as H･ hepaticus, in vitro ●IS Practically effective in vivo in eradication therapleS. ● H. canis, H. cholecystus. H. pullorum, and H. bilis have been Among antimicrobial agents, representatives in the latest isolatedfromanimal liversand/or biles. Especially, H. hepaticus eradication ther?pie? are amoxcillin (AMPC), has been isolated from inbred strains of mice with ,

(CAM), and nltrOlmidazoles 【metronidazole (MTZ) or and is considered to increase the risk of hepatic carcinoma. tinidazole]･ H･ pylori rapidly acqu.ires resistance to some PCR amplicons of Helicobacter-Specific 16Sribosomal RNA antimicrobial agents. Acquired resistance by mutations to primers (H. billis, H. pullorum, and H･ rappini) have been CAM have been demonstrated (1 33, 1 34). Plasmid一mediated detected in samples obtained from human patients with chromic resistance has not been reported inany drug. Nitroimidazoles cholecystitis ( 174). These Helicobacter spp･ mentioned in this are widely used to treat anaerobic bacteria and protozoa such paragraph may frequently enter the human intestine, Or may as Trichomonas and Gialldia. The higher frequencies and doses be members of a group constituting a small part of the normal produce higher rates of resistance. The rate of resistance in intestinal nora in humans. isolated strains of H. pylori is about 80% in Africa and 30% in the U.S.A. CAM, a new macrolide, is administered to REFERENCES patients with other infectiousdiseases, especially respiratory infectious diseases. The rate of resistance is over lO% in Japan 1. Warren, J. R. (1983): Unidentified curved bacilli on

(I 35). Few resistant stminstoAMPC have been found,although gastric epithelium in active chronic gastritis･ Lancet, Ⅰ, AMPC has been used fわr a long period throughout the world. 1273. However, a stable strain of H. pylori resistant to AMPC was 2. Marshall, B. (1983): Unidentified curved bacilli on reported in the Netherlands in 1998 (136). gastric epithelium in active chronic gastritis･ hncet, I, 1 273- 1 274. 7. Disease associations of H. pylori infectionwith extra･ 3. G∝dwin, C. S., Armstrong, J. A., Chilvers, T･ L･, Peters, M., Mcconell, W. and Happer,W. E. S. (1989): Transfer gastroduodenaldiseases of Campylobacter pylori and Campylobacter mustelae The curlng Of H. pylori infection may provoke reflux to Helicobacter gen･ nov･ as Helicobacterpylori comb･ esophagitis (137,138). Acid secretion is low in patients with nov.and Helicobacter mustelae comb. nov. respectively. severe corpus gastritis. Successful eradication of H. pylori Int. J. Syst. Bacteriol･ 39, 397-405･ increases acid secretion, which may cause reflux esophagitis 4. Marshall, B. J. (1986): Campylobacter pyloridis and (gastroesophagal renux diseases). gastritis･ J･ Infect･ Dis･, 153, 650-657･ H. pylori infation may tx ass∝iated withhypemmmonaemia. 5. Morris,A. ∫.,Ali, M. 良., Nicholson, G. Ⅰ., Perez-Perez,

Hyperammonia in patients with severe liver damage is con- G. I. and Blaser, M. ∫. (1991): Long-term follow-up of sidered to be produced by bacterial urease in the intestine. H. voluntary Ingestion● of Helicobacter pylori･ Ann･ Intem･ pylori also produces ammonia by means of its strong urease Med., 114, 662-663. activity. The rate of hepatic encephalopathy in acute alcoholic 6. Watanabe,T., Tada, M., Nagai, H., Sasaki, S･ and Nakao, hepatitis is reported to be higher in patients with H. pylori M. ( 1998): Helicobacter pylori infection induces gastric infection (1 39). In some patients with cirrhosis, ammonia levels cancer in Mongolian gerbil･ Gastrccnterology, I I 5, 642-

190 Table 6･ A list of species in genus Helicobacter

SpecleS Hosts S i tes Reference

l･ H･ pylori hum an stomach 1-3 (monkey, cat, dog) 2. H. ciyuZedi human, hamster intestine , 144, 145

(〃･ sp･ CL0-1*) blood (human) 3･ H. fennelliae human (AIDS) i ntestine 144, 145

(〃･ sp･ CL0-2*) 4. H. Westmeadii human (AIDS ) blood 146 5. H. nemestrinae monkey; pig tailed macaque stomach 147 6. H. canis dog, (human) i ntesti ne 148 7. H. bi～･,=oZeronii dog i ntesti ne 149 8. H. salmonis dog i ntestine 150 9･ H. fells cat, (dog) s tomach 151,152 lO･ H･ acinonyx cheetah s tomach 153,154 ll. H. mustelae fe rre t s tomach 155,156 12･ H･ cholecystus Syrian hamster gal 1 bladder 157 13. H. muridarum mouse, rat intestine, (stomach) 158,159 14･ H. trogontum rat i ntesti ne 160 15. H. rodentium mouse intesti ne 161 16･ H･ hepaticus mouse intestine, liver 162

17. H. bilis mouse intestine, liver, bile 163 18. H. suncus house musk shrew s tomach

19･ H. pamentensis bird; gull, tum i ntestine

(〃･ sp･ Bird-A*)

20･ H･ pullorum bird; chicken, (human) intestine, liver 21･ H･ rapplni Iamb lfetus], dog lstomach], human lintesline] (Flexispira rappini*) 22. H. heilmannii human s tomach (Gaslrospirillum hominis*) 23･ H. sp. Mainz human (AIDS) blood, joint

24･ H･ sp. CL0-3 human (homosexual) i ntestine

25･ 〃･ sp･ Bird-B bird; tum i ntestine

26･ 〃･ sp. Bird-C bird; spa汀OW i ntesti ne

*: The former name

648. 15. Turbett, G. R., Hoj, P. B., Home, R.andMee, B. J. (1992): 7･ Olivieri, R., Bugnoli, M.,Armellini, D., Bianciardi, S., Purification and characterization of the urease enzymes

● Rappuoli, R･, Bayeli, P･ F･, Abate, L･, Esposito, F･, De of Helicobwおr s阿1eS from hum arKl aninds. Infect. Gregori0, L･,Aziz, J･, Basagni, C. and Figura, N. (1993): Immun., 60, 5259-5266. Growth of Helicobacter pylori in media containing 16･ Mobley H. L T., Island, M. D. and Hauslnger,● R. P.

cyclodextrins. ∫. Clin. Microbio1., 31, 160-162. (1!粉5): Molecularbiology ofmicrobialuRa父S. Microbiol. 8･ Marchini, A･, d'Apolito, M･, Massari, P., Atzeni, M., Rev., 59, 451-480. Copass, M･ and Olivieri, 良. (1995): Cyclodextrins fわr 17. Hawtin, P. R., Stacey,A. R. and Newell, D. G. (1990): growth of the Helicobacter pylori and production of Investigation of the structure and localization of the vacuolating cytotoxin. Arch. Microbio1. , 164, 290-293. urease of Helicobacter pylori uslng● mOnOClonal anti-

9･ Reynolds, D. J. and Penn, C. W. (1994): Characteristics bodies. ∫. Gen. Microbio1., 136, 1995-2000.

of Helicobacterpylorl grown in a defined medium and 18. Marshall, B. ∫., Ba汀et, L ∫., Prakash, C., McCallum, 良. detemination of its amino acid requlrementS･● Micro- W.and Guerrant, R. L. ( I 990): Urea protects Helicobacter biology (Reading), 140, 2649-2656. (Campylobacter) pylori from the bacteriocidal effect of 10･ Cellini, L･,Alluati, N･,Angelucci, D･, Iezzi,T･, Di-Campli, acid. Gastroenterology, 99, 697-702. E･, Marzio, L and Dainelli, B. (1994): Coccoid 19. Moran,A. P., Helander, I. M. and Kosunen,T. U. (1992): Helicobacter pylori not culturable in vitro reverts in Compositional analysts Of Helicobacter pylori rough- mice. Microbiol. Immuno1., 38, 843-850. form lipopolysaccharides. J. Bacteri01., 174, 1 370- I 377. 11･ Hu, L T. and Mobley, H.し. (1990): Purification and 20. Muotiala, A., Helander, I. M., Pyhala, L., Kosunen, T. N-terminal analysts Of urease from Helicobacter pylori･ U. and Moran, A. It (1992): Low biological activity of Infect. Immun., 58, 992-998. Helicobacter pylori lipopolysaccharide. Infect. Immun. , 12･ Dun, B･ E., Campbell, G. P., Perez-Perez, G. I. and 60, 1714-1716.

Blaser, M. ∫. ( 1990): Purification and characterization 21. Birkholz, S., Knipp, U., Nietzki, C.,Adamek, 良. ∫. and of urease from Helicobacterpylori. J. Biol. Chem., 265, Opferkuch, W (1993): Immunological activity of 9464- 9469. lipopolysaccharide of Helicobacter pylori on human

13･ Evans, D･ J･, EvanS, D･ G･,Kirkpatrik, S･ S･and Graham, peripheral mononuclear blood cells in comparison to D･ Y･ (1991 ): Characterization of the Helicobacter pylori lipopolysaccharides of other intestinal bacteria. FEMS urease and purification of its subunits･ Microb･ Pathog･ , Immunol. Med. Microbio1., 6, 3 17-324. 10, 15-26. 22. Sakagami, T., Vella, J., Dixon, M. F., 0'Rourke, J., 14. Hawtin, P. R., Delves, H. T. and Newell, D. G. (1991): Radcliff, F., Sutton, P., Shimoyama, T, Beagley, K. and The demonstration ofmickel in the urease of Helicobacter Lee, A. (1997): The endotoxin of Helicobacter pylori mkm'by atomic atxsorpion spblWPy. FEMS Microbiol. is a modulator of host-dependent gastritis. Infect. Immun. , Lett., 77, 51-54. 65, 3310-3316.

191 23･ Hirai, Y., Haque, M., Yoshida, T., Yokota, K., Yasuda, T. 35. Hulten, K., Enroth, H., Nystrom, T. and Engstrand,し, and Oguma, K･ (1995): Unique cholesteryl glucosides ( 1998): Presence ofHelicobacter species DNA in Swed- in Helicobacter pylori: Composition and structural ish water. ∫. Appl. Microbio1., 85, 282-286.

● analysIS. ∫. Bacterio1., 177, 5327-5333. 36. Hassel, E. and Dimmick, ∫. E. (1991): Unique features 24･ Haque, M･, Hirai,Y.,Yokota, K. and Oguma, K. (1995): of Helicobacter pylori disease in children. Dig. Dis. Lipid profiles of Helicobacter pylori and Helicobacter Sci., 36, 417-423.

mustelae grown in serum-supplemented and serum-free 37. Prieto, G., Polanco, Ⅰ., Larrauri, ∫., Rota,し., Lama, 良. media. Acta Med. Okayama, 49, 205-21 1. and Camsco, S. (1992): Helicobacter pylori infection in

o I I I I + 25･ Haque, M., Hirai,Y,Ybkota, K. and Oguma, K. (1995): children: clinical, endscopIC,and histologlC COrrelations. Steryl dy00sides: a chruterisdc fature of the Helicobacter J. Pediatr. Gastroenterol. Nutr., 14: 420-425. spp.? J. Bacteri01., 177, 5334-5337. 38. Langenberg, W., Rauws, E. A., Oudbier, J･ H･ andTytgat,

26. Haque, M., Hirai, Y., Yokota, K., Mori, N., Jahan, I., G. N. (1990): Patienトto-patient transmission of Ito, H･, Hotta, H･, Yan°, Ⅰ., Kanemasa, Y and Oguma, Campylobacter pylori infection by gastroduodenoscopy K･ (1996): Lipi.d profile of Helicobacter spp.: presence and biopsy. J. Infect. Dis., 161, 507-511.

● of cholesteryl glucoside as a characteristic feature. J. 39. Suglyama, T., Naka, H., Yabana, T., Awakawa, T., Bacterio1., 178, 2065-2070. Fumyama, S., Kawauchi, H., Yamaguchi, 0., Uchizawa, 27･ Phadnis, S･ H･, Parlow, M･ H･, Levy, M･, Ilver, D･, M., Matsuura, K., Masdda, K. and Yachi, A. (1992): Is Caulkins, C. M., Connors, J. B. and Dunn, B. E. (1996): Helicobacter pylori responsible for postendoscopIC Surface localization of Helicobacter pylori urease and a gastric mucosal lesions? Eur. J. Gastroenterol･ Hepatol･, ● heat shock protein homolog requlreS bacterial autolysis. 4 (suppl. 1), S93-96.

Infect. Immun., 64, 905-912. 40. Ramsey, 已 ∫., Carey, K. V, Peterson, W L., Jackson, J･ 28･ Tomb, J-F., White, 0., Kerlavage, A. R., Clayton, R. J., Murphy, F. K., Read, N. W.,Taylor, K. B.,Trier, J･ S･

A., Sutton, G. G., Fleischmann, R. D., Ketchum, K. A., and Fordtran, ∫. S. (1979): Epidemic gastritis with Klenk, H･ P., Gill, S., Dougherty, B. A., Nelson, K., hypochlorhydria. Gastroenterology, 76, 1449- 1457･ Quackenbush, J., Zhou, L., Kirkness, E. F., Peterson, 41. Graham, D. Y.,Alpert, L C., Smith,J. L andYoshimura, S., Loftus, B., Richardson, D., Dodson, R., Khalak, H. H. H. ( 1 988) : Iatrogenic Campylobacter pylori infection G･, Glodek, A., Mckenney, K., Fitzegerald, L M., Lee, is a cause of epidermic achlorhydria. Am. J. Gastrcnterol･ , N･,Adams, M･ D･, Hickey, E. K., Berg, D. E., Gocayne, 83, 974-980.

J･ D･, Utterback, T. 良., Peterson, ∫. D., Kelley, ∫. M., 42. Marshall, B. ∫.,Armstrong, ∫. A., McGechie, D. B. and Cotton, M･ D., Weidman, J. M., Fujii, C., Bowman, C., Glancy, R. J. (1985): Attempt to fulfil Koch's postulates Watthey, L., Wallin, E., Hayes, W. S., Bordovsky, M., forpyloric Campylobacter. Med. J. Aust., 142, 436-439･ Karp, P. D., Smith, H. 0., Fraser, C. M. andVenter, J. C. 43. Miyaji, H., Kohli, Y.,Azuma, T., Ito, S･, Hirai, M･, Ito, (1997): The complete genome sequence of the gastric Y., Kato, T. and Kuriyama, M. (1995): Endoscopic pathogen Helicobacter pylori. Nature, 388, 539-547. cross-infection with Helicobacter pylori. Lancet, 345, 29･ Alm, R･ A., Ling, LS.し., Moir, D. T., King, B.し., 464. Brown, E. D., Doig, P. C., Smith, D. R., Noonan, B., 44. Sobala, G. M., 0'Connor, H. J., Dewar, E. P., King, R. Guild, B. C., Dejonge, B. L., Camel, G., Tummino, P. J., F, Axiom, A. T. and Dixon, M. F (1993): Bile renux

Caruso, A., Uria-Nickelsen, M., Mills, D. M., Ⅰves, C., and intestinal metaplasia in gastric mucosa･ J･ Clin･ Gibson, R., Merberg, D., Mills, S. D., Jiang, Q., Taylor, Patho1., 46, 235-240. D. E., 帆)vis, G. F and Trust, T. ∫. (1999): Genomic- 45. Tasuta, M., Iishi, H., Yamamura, H., Yamamoto, R. and sequence, comparison of two unrelated isolates of the Taniguchi, H. (1989): Enhancement by tetragastrin of human gastric pathogen Helicobacter pylori. Nature, experimental induction of gastric epithelium in the 397, 176-180. duodenum. Gut, 30, 311-315.

30･ Gmham, D･ Y･ (1991): Helicobacterpylori: its epidemio1- 46. Rhodes, ∫., Evans, K. T., Lawrie, ∫. H. and Fo汀eSt, A.

ogyand its role in du∝lenal ulcer disease. Ⅰ. Gastruntrol. P. (1968): Coase mucosal folds in the duodenum. Q. J. Hepato1., 6, 97-105. Med., 37, 151-169.

31. Asaka, M., Kimura, T., Kudo, M., Takeda, H., Mitani, 47. Baton, K. A., Morgan, D. 良. and Krakowka, S･ (1992): S., Miyazaki, T., Miki, K. and Graham, D. Y (1992): Motility as a factor in the colonisation of gnotobiotic

● Relationship of Helicobacter pylori to serumpepslnOgens piglets by Helicobacterpylori･ J･ Med･ Microbiol･, 37, in an asymptomatic Japanese population. Gastroenter- 123-127. ology, 102, 760-766. 48. Tsuda, M., Karita, M., Morshed, M. G., Okita, K. and

32･ Kelly, S. M., Pitcher, M. C. L., Farmery, S. N. and Nakazawa, T. (1994): A urease一megative mutant of Gibson, G. R. (1994): Isolation of Helicobacter pylori Helicobacter pylori constructed by allelic exchange from feces of patients with dyspepsla● in the United mutagenesis lacks the ability to colonizethe nude mouse Kingdom. Gastroenterology, 107, 1671- 1674. stomach. Infect. Immun., 62, 3586-3589.

33. Li, C., Ha, T., Ferguson, D. A., Chi, D. S., Zhao, 良., 49. bton, K. A. and Krakowka, S. (1994): Effect of gastric Patel, N. 良., Krishnaswamy, G. andThomas, E. (1996): pH on urease-dependent colonization of gnotobiotic A newly developed PCR assay of H. pylori in gastric piglets by Helicobacter pylori･ Infect･ Immun･, 62, biopsy, saliva and feces. Dig. Dis. Sci., 41, 214212149. 3604- 3607. 34. Hulten, K., Ham, S.W., Enroth, H., Klein, P. D., 0pekun, 50. Evans, D. G., Evans, D. J., Jr., Moulds,J. J., Graham, D.

A. 良., Gilman, 良. H., Evans, D. G., Engstrand,し., Y. ( 1988): N-acetylneuraminyllactose-binding fibrillar Graham, D. Y. and E1-Zhatari, F. A. ( 1996): Helicobacter hemagglutinin of Campylobacter pylori: a putative colo- pylori in the drinking water in Peru. Gastroenterology, nization factor antigen. Infect. Immun. , 56, 2896-2906･ 110, 1031-1035. 51. Evans, D. G., Evans, D. ∫.,Jr. andGraham, D.Y (1992):

192 Adherence and internalization of Helicobacter pylori 66. Ascencio, F., Fransson, L A. and Wadstrom, T. (1993): by HEp-2 cells. Gastroenterology, 102, 1557-1567. Affinity of the gastric pathogen Helicobacter pylori for 52. Evans, D. G., Karjalainen, T. K., Evans, D. J., Jr., the N-sulphated glycosaminoglycan heparan sulphate･ Graham, D. Y.andLee, C. H. (1993): Cloning, nucleotide J. Med. Microbio1., 38, 240-244. sequence, and expression of a gene encoding an adhesin 67. Kawano, S., Tsujii, M" Fusamoto, H., Sato, N. and

● subunlt Protein ofHelicobacterpylori. J. Bacteri01., 175, Kamada, T. (1991): Chronic effect of intragastric 674-68 3. ammonia on gastric mucosal structure in rats. Dig. Dis. 53. Lingwood, C. A., Huesca, M. and Kuksis, A. (1992): Sci., 36, 33-38. The glycerolipid receptor for Helicobacter.pylori (and 68. Tsuji, M., Kawano, S., Tsuji, S., Fusamoto, H., Kamada, exoenzyme S) is phosphatidylethanolamlne. Infect. T. and Sato, N. (1992): Mechanism of gastric mucosal Immun. , 60, 2470-2474. damage induced by ammonia. Gastroenterology, 102, 54･ Lingwood, C. A., Wasfy, G., Ham, H. and Huesca, M. 1881-1888. ( I 993): Receptor afrlnity purification of a lipid-binding 69. Suzuki, M., Miura, S.,_ Suematsu, M., Fukumura, D., ち adhesin from Helicobacter pylori. Infect. Immun., 61 , Kurose, I., Suzuki, H., Kai, A., Kudbh, Y., Ohashi, M.

2474- 2478. and Tsuchiya, M. ( 1 992): Helicobacter pylori ass∝iated

55･ Gold, B. D., Huesca, M., Sherman, P. M. and Lingwood, ammonia production enhances neutrophiトdependent 甘I C. A. ( 1993): Helicobacier mustelae and Helicobacter gastric mucosal cell injury. Am. J. Physio1., 263, G719- pylori bind to common lipid receptors in vitro. Infect. G725. Immun., 61, 2632-2638. 70. Leunk, R. D., Johnson, It T., David, B. C., Kraft, W. G. 56･ Doig, P.,Austin, J. W., Kostrzynska, M. andTrust, T. J. and Morgan, D. R. (1988): Cytotoxic activityin broth- ( 1 992): Production of a conserved adhesin by the human culture filtrates of Campylobacter pylori. J･ Med･

gast血udenalpathogen Helicobacterpykm'. J. Bacteri01. , Microbio1., 26, 93-99. 174, 2539-2547. 71. Schmitt, W and Haas, 良. (1994): Genetic analysis of 57. Valkonen, K. H., Wadstr6m, T. and Moran,A. P. (1997): the Helicobacter pylori vacuolating cytotoxin: structural Identification of the N-acetylneuramlnyllactose-● Specific similarities with the lgA protease type of exported laminin-binding protein of Helicobacter pylori. Infect. protein. Mol. Microbio1., 12, 307-319･ Immun., 65, 916-923. 72. Telford, J. L., Ghiara, P., Dell'Orco, M., Comanducci, 58. Boren,T., Falk, P., Roth, K. A., IArSOn, G. and Normark, M･, Burroni, D･, Bugnoli, M･, Tecce, M･ F･, Censini, S･, S. ( 1 993): Attachment of Helicobacterpylori to human Covacci, A., Xiang, Z., Papini, E., Montecucco, C･, gastric epithelium mediated by blood group antigens. Parente, L and Rappuoli, 良. (1994): Gene structure of Science, 262, 1892-1895. the Helicobacter pylori cytotoxin and evidence of its 59. IIver, D.,Amqvist,A., Ogren, J., Frick, I. M., Kersulyte, key role in gastric disease･ J･ Exp･ Med･, 179, 1653- D･, Incecik, E. T., Berg, D. E., Covacci, A., Engstrand, 1658. L and Boren, T. (1998): Helicobacter pylori adhesin 73. Segal, E. D., Falkow, S. and Tompkins, L S･ (1996): binding fucosylated histo-blood group antigens revealed Helicobacter pylori attachment to gastric cells induces by retagglng. Science, 279, 373-377. cytoskeletal rearrangements and tyrosine phosphoryla-

60. Alkout, A. M., Blackwell, C. C., Weir, D. M., Poxton, tion of host cell proteins･ Pr∝･ Natl･ Acad･ Sci･ USA,

Ⅰ. 良., Elton, 良. A., Luman, W and Palmer, K. (1997): 93, 1259-1264. Isolation of a cell surface component of Helicobacter 74･ Censini, S･, IAnge, C･, Xiang, Z･, Crabtree, J･ E･, Ghiara, pylori that binds H type2,Lewisa,andLewisb antigens･ P., Bordovsky, M., Rappuoli, R.and Covacci, A･ (1996): Gastroenterology, 1 12, 1 179-1 187. cag, a pathogenicityisland of Helicobacterpylori, enc∝les 61. Namavar, F., Sparrius, M., Veerman, E. C.,Appelmelk, B. typeI-specific and disease-associated virulence factors･ J.and Vandenbroucke-Grauls, C. M. ( 1998).. Neutrophil- Proc. Natl. Acad. S°i. USA, 93, 14648-14653. activating protein mediates adhesion of Helicobacter 75. Mohammadi, M., Czin, S., Redline, 良. and Nedmd, ∫. pylori to sulfated carbohydrates on high-molecular- (1996): Helicobacter-Specific cell-mediated immune weight salivary mucin. Infect. Immun., 66, 444-447. responses display a predominant Thl phenotypeand 62. Huang, J., Keeling, P. W.and Smyth, C. J. (1992): Identi- promote a delayed-typehypersensitivityresponse in the fication of erythruyte-bindingantigens in Helicobacter stomachs of mice. J. Immuno1., 156, 4729-4738. pylori. J. Gen. Microbio1., 138: 1503-1513. 76. Mohammadi, M., Nedrud, J., Redline, R., Lycke, N. ● 63. Huesca, M., Borgla, S., Hoffman, P.and Lingw∝山, C. A. and Czinn, S. J. (1997): Murine CD4T-cell response to ( 1 996): Acidic pH changes receptor binding specificity of Helicobacter infection: TH I cells enhance gastritis and Helicobacterpylori: a binary adhesion model in which TH2 cells reduce bacterial load. Gastroenterology, I I 3, surface heat shock (stress) proteins mediate sulfatide 1848-1857.

● ● recognlt10n in gastric colonization. Infect. Immun., 64, 77. Lindholm, C., Quiding-Jaerbrink, M., Loenroth, H･, 2643-2648. Hamlet, A. and Svennerholm, A. M. (1998): Local 64. Slomiany, B. L., Piotrowski, J., Samanta, A., VanHom, cytokine resrx)nse in Helicobuter pylori-infected subj ects･

K., Mu托y, V. L.and Slomiany, A. ( 1989): Campylobacter Infect. Immun., 66, 5964-5971. pylori colonization factor shows specificity for 78. Bamford, K. B., Fan, X., Crowe, S. E., Leary, J. F., lactosylceramide sulfateand GM3 ganglioside. Bi∝hem. Gourley, W K･, Luthra, G･ K･, Br00ks, 已 G･, Graham, Int., 19, 929-936. D. Y., Reyes, V. E. and Emst, P･ B･ (1998)'･ Lymphocytes 65. Saitoh,T., Natomi, H., Zhao, W. L., Okuzumi, K., Sugan0, in the human gastric mucosa during Helicobacter pylori K., Iwamori, M. and Nagai, Y. (1991): Identification of have aT helper cell I phenotype. Gastroenterology, I 14, glycolipid receptors for Helicobacter pylori by TLC- 482-492. immunostalnlng. FEBS Lett., 282, 385-387. 79. Sawai, N., Kita, M., Kodama, T., Tanahashi, T,

193 Yamaoka, Y., Tagawa, Y., Iwakura, Y. and Imanishi, J. Am. ∫. Gastroentero1., 91, 1135-1137.

(1999): Role of gaヮma interferon in Helicobacter 95. Azuma, T., Konishi, J., Tanaka, Y., Hirai, M., Ito, S., pylori-induced gastrlC inflammatory responses in a Kato, T. and Kohli, Y (1994): Contribution of HLA- mouse model. Infect. Immun., 67, 279-285. DQA gene to host's response against Helicobacter pylori･

80. Kuwayama, H. (1996): Peptic ulcer diseases without 〟. Lancet, 343, 542-543. pylori infection. p.67-70. In M. Namiki (ed.), Gastric 96. Atherton, J. C., Cao, P., Peek, R. M., Jr., Tummuru, M. diseases. Igaku-Tosho-Syuppan, Tokyo (in Japanese). K. 良., Blaser, M. ∫. and Cover,T.し. (1995): Mosaicism 81. Hirayama, F., Takagi, S., Kusuhara, H., Iwao, E., in vacuolating cytotoxin alleles of Helicobacterpylori･ Yokoyama, Y. and Ikeda, Y. (1996): Induction of gastric J. Biol. Chem., 270, 17771-17777. ulcer and intestinal metaplasia in Mongolian gerbils 97. Tee, W., Lambert, J. R. and Dwyer, B. (1995): Cytotoxin infected with Helicobacterpylori. J. Gastroentero1. , 3 1 , production by Helicobacter pylori from patients with 755-757. upper disease. ∫. Clim Microbiol･, 82･ Marshall, B･ J･, Goodwin, C. S., Warren, J. R., Murray, 33, 1203-1205.

●~ R･, Blincowf E･ D., Blackbourn, S. J., Phillips, M., 98. Ito, Y., Azuma, T., Ito, S., Miyaji, H., Hirai, M., Waters, T･ E. and Sanderson, C. R. (1988): Prospective Yamazaki, Y., Sato, F., Kato, T., Kohli, Y. and Kuriyama, double-blind trial of duodenal ulcer relapse after eradi- M･ (1997): Analysis弓Pd typing of the vacA gene from cation of Campylobacterpylori. Lancet, II, 1437- 1442. cagA-positive strains of Helicobacterpylori isolated in

83. Graham, D. Y., Lew, G. M., Klein, P. D., Evans, D. G., Japan. ∫. Clin. Microbio1., 35, 1710-1714･ Evans, D. J., Jr., Saeed, Z. A. and Malaty, H. M. (1992): 99. Maeda, S., Ogura, K., Yoshida, H., Kanai, F, Ikenoue, Effect of treatment of Helicobacter pylori infection on T., Kato, N., Shiratori, Y. and Omata, M. (1998): Major

the long-term recu汀enCe Of gastric or duodenal ulcer: a virulence factors, VacA and CagA, are commonly randomized, controlled study. Ann. Intern. Med., 1 16, positive in Helicobacter pylori isolates in Japan･ Gut, 705-708. 42, 338-343.

84. NIH Consensus Development Conference (1994): loo° C血ing, C･ K･, Wらng, B･ C･, Kwok, E･, Ong, L･, Covacci, Helicobacter pylori in peptic ulcer diseases. JAMA, A. and Lam, S. K. (1996): Prevalence of CagA-bearing 272, 65-69. Helicobacter pylori strains detected by anti-CagA assay

● 85･ Malagelada, ∫. 良., Longstreth, G. F, Deerlng, T. B., in patients with peptic ulcer disease and in controls･

Summerskill, W H. and Go, V.し. (1977): Gastric Am. ∫. Gastroentero1., 91, 949-953. secretion and emptying after ordinary meals in duode- 101. Shimoyama, T., Fukuda, S., Tanaka, M., Mikami, T･, nal ulcer. Gastroenterology, 73, 989-994. Saito, Y. and Munakata, A. (1997): High prevalence of 86. Moss, S. and Calam, J. (1992): Helicobacterpylori and the CagAIPOSiti ve Helicobacter pylori strains in Japanese peptic ulcers: the present position. Gut, 33, 289-292. asymptomatic patients and gastric cancer patients･ 87･ Levi, S., Beardshall, K., Haddad, G., Playford, 良., Scand. ∫. Gastroentero1., 32, 465-468. Ghosh, P. and Calam, J. (1989): Campylobacter pylori 102. Isaacson, P. and Wright, D. H. (1983): Malignant

and duodenal ulcers: the gastrin link. Lancet, Ⅰ, 1 167- lymphoma of mucosa-associated lymphoid tissue - a 1168. distinctive type of B-cell lymphoma･ Cancer, 52, 1410- 88. Beardshall, K., Moss, S., Gill, J., Levi, S., Ghosh, P., 1416.

Playford, 良. ∫. and Calam, ∫. (1992): Suppression of 1 03. Isaacson, P. G. ( 1990): Lymphomas of mucosa-ass∝iated Helicobacter pylori reduces gastrin releaslng● PePtide lymphoid tissue (MALT). Histopathology, 16, 617-61 9･ stimulated gastrin release in duodenal ulcer patients. 104. Harris, N. L., Jaffe, E. S., Stein, H., Banks, P. M., Chan,

Gut, 33, 60ト603. J. K., Cleary, M.し., Delsol, G･, De Wわlf-Peeters, C･,

89･ Moss, S. F, Legon, S., Bishop,A. E., Polak, ∫. M. and Falini, B. and Gatter, K. C. (1994): A revised European-

Calam, J. (1992): Effect of Helicobacter pylori on gastric AmeriCan classiflCation of lymphoid neoplasmas: a somatostatin in duodenal ulcer disease. hncet, 340, 930- proposal from the International Lymphoma Study 932. Group. Blood, 84, 1361-1392･ 90. Kaneko, H., Nakada, K., Mitsuma, T., Uchida, K., 105･ Wotherspoon,A･ C･, 0ritz-Hidalgo, C･, Falzon, M･ R･ and Furusawa, A., Maeda, Y. and Morise, K. (1992): Isaacson, P. G. ( 1991): Helicobacter pylori-associated

● Helicobacter pylori infection induces a decrease in gastritis and pnmary B-cell gastric lymphoma･ Lancet, i mmunoreacti ve-Somatostati n concentrations of human 338, 1175-1176.

stomach. Dig. Dis. S°i., 37, 409-416. 106･ Wotherspoon,A･ C･, Doglioni, C･, Diss, T･ C･, Pan, L･, 91. Bodemar, G., Walan, A. and,Lundquist, G. (1978): Moschini, A., de Boni, M. and lsaacson, P G. (1993): Food-stimulated acid secretion measured by intragastric Regression of pnmary low-grade B-cell gastric lymphoma

titration with bicarbonate in patients with duodenal and of mucosa-ass∝iated lymphoid tissuetypeafter eradica-

gastric ulcer disc,ase and in controls. Scand. J. tion of Helicobacter pylori. Lancet, 342, 575-577･ Gastruntero1., 13, 911-918. 107. Montalban, C., Manzanal,A., Boixeda, D., Redondo, C.

92. Massoomi, F, Savage, ∫. and Deatache, C. ∫. (1993): and Bellas, C. (1995): Treatment of low-grade gastric Omeprazole: a comprehensive review. Pharmacotherapy, MAIJ lymphoma with Helicobacter pylori eradication･ 13, 46-59. Lancet, 345, 798-799. 93. Haminen, M.L. (1991): Sensitivity of Helicobacterpylori 108･ Bayerd6rffer, E･, Neubauer, A･, Rudolph, B･, Thiede, C･, to different bile salts. Eur. J. Clin. Microbiol. Infect. Lehn, N., Eidt, S. and Stolte, M. (1995): Regression of

● Dis., 10, 515-518. pnmary gastric lymphoma of mucosa-ass∝iated lymphoid 94. Ham, S. W, Evans, D. G., El-Zaatari, F A. K., Go, M. tissuetype after cure of Helicobacter pylori infection･ and Graham, D. Y (1996): The interaction of pH, bile, Lancet, 345, 1591-1594. and Helicobacter pylori may explain duodenal ulcer. 109. Thiede, C., Morgner, A., Alpen, B., Wundisch, T･,

194 Herrmann, ∫., Ritter, M., Ehninger, G., Stolte, M., Health Organization (1994): Schistsomes, liver flukes Bayerdorffer, E.and Neubauer, A. ( I 997): What role does and Helicobacter pylori. IARC monographs on the evalu-

● Helicobacter pylori eradication play ln gastric MAIJ ation of carcinogenic risks to humans. 61, 218-220. and gastric MAIJ Lymphoma? Gastroenterology, 1 1 3, 122. Suglyama,A.,● Maruta, F., Ikeno, T., Ishida, K., Kawasaki, S61 -S64. S., Katsuyama, T., Shimizu, N. and Tatematsu, M･ 1 10. Kobayashi, K., Yokota, K., Yoshino, T., Kawahara, Y., (1998): Helicobacter pylori infection enhances N- Dey, A･, Hirai, Y, Oguma, K. and Akagi, T. (1998): methyl -N-nitrosourea-i nduced stomach carci nogenesi s Detection of Helicobacter pylori associated antigen and in the Mongolian gerbil. Cancer Res., 58, 2067-2069･ heat shock protein 60 0n follicular dendritic cells in the 123. Watanabe,T., Tada, M., Nagai, H., Sasaki, S. and Nakao, germinalcentres of low grade B cell lymphoma of gastric M. ( 1 998): Helicobacter pylori infection induces gastric mucosa associated lymphoid tissue (MALT). J. Clin. cancer in Mongolian gerbils. Gastrunterology, I 15, 642- Patho1., 51, 396-398. 648. I 1 1. Kawahara,Y.,Yokota, K., Mizuno, M.,Yunoki, N., Uesu, 124. Honda, S., Fujioka, T., Tokieda, M., Satoh, R･, Nishizono, T･, Okada, H･, Kobayashi, K., Hirai, Y, Oguma, K. and A. and Nasu, M..(1998): Development of Helicobacter Tsuji, T･ (1999): Antibodies to human gastric epithelial pylori-induced gastric carcinoma in Mongolian gerbilsI cells and heat shock protein 60 in Helicobacter pylori Cancer Res., 58, 4255-4259.

i;い positive mucosa ass∝iated lymphoid tissue lymphoma･ 125. Parsonnet, ∫., Vandersteen, D., Goates, ∫., Sibley, 良. K., Gut, 45, 20-23. Pritikin, J. and Chang, Y. (1991): Helicobacter pylori 1 12･ Yokota, K･, Kobayashi, K･, Kawahara, Y･, Hayashi, S･, infection in intestinal- and diffuse-type gastric adeno- Hirai, Y･, Mizuno, M., Okada, H., Akagi, T., Tsuji, T. carcinomas. lpublished erratum appears in J･ Natl ･ Cancer and Oguma, K. (1999): Gastric ulcers in SCID mice Inst., 83, 881] J. Natl. Cancer Inst., 83, 640-643.

induced by Helicobacter pylori infection after transplant- 126. Koshiishi, N., Chong, ∫., Kaizaki, Y and Fukayama,

● 1mg lymphocytes from patients with gastric lymphoma. M. (1999): Epstein-Barr virus and gastric cancer･ Gastroenterology, 1 1 7, 893-899. Gendai-Iryou, 31 , 1449-1453 (in Japanese). 113･ Blaser, M. J., Kobayashi, K., Cover, T. L., Cao, P., 127. Sobala, G. M., Schorah, C. J., Sanderson, M., Dixson, M. Feurer, I. D. and Perez-Perez, G. I. (1993): Helicobacter F., Tompkins, D. S., Godwin, P.and Axon, A･ T･ (1989): pylori infection in Japanese patients with adenocarci noma Ascorbic acid in the human stomach. Gastrunterology, of the stomach. tnt. ∫. Cancer, 55, 799-802. 97, 357-363. 114. Asaka, M., Kimura, T., Kato, M., Kudo, M., Miki, K., 128･ Zhang, Z･ W･, Patchett, S･ E･, Perrett, D･, Katelaris, P･ Ogoshi, K., Kato, T., Tatsuta, M. and Graham, D. Y. H., Domizio, P. and Farthing, M. J. (1998): The relation (1994): Possible role of Helicobacter pylori infection between gastric vitamin C concentrations, mucosal in early gastric cancer developoment. Cancer, 73, 269 I - histlogy, and CagA seropositivity in the human stomach･ 2694. Gut, 43, 322-326.

1 15･ The EUROGAST Study Group (1993): Epidemiology 129. McNulty, C.A., Dent, ∫. C., Ford, G.A･ andWilkinson, of, and risk factors for, Helicobacter pylori infection S. P. (1988): Inhibitory antimicrobial concentrations

● among 3 194 asymptomatic subjects in 17 populations. agalnSt Campylobactr pylori in gastric mucosa･ J･ Gut, 34, 1672-1676. Antimicrob. Chemother., 22, 729-738. 116･ Lin, J-T., Wang, J-T., Wang,T-H., Wu, M-S.,Lee, TIK. 1 30. Nakao, M. and Malfertheiner, P. (1998): Growth inhibi- and Chen, C-J. (1993): Helicobacterpylori infection in tory and bactericidal activities of lansoprazole compared a randomly selected population, healthy volunteers, and with those of omeprazole and pantoprazole agalnSt

patients with gastric ulcerand gastric aden∝arcinoma. A Helicobacter pylori. Helicobacter, 3, 2 I -27･ seroprevalence study in Taiwan. Scand. J. Gastroentero1. , 131･ Nagata, K･, Satoh, H･, Iwahi, T･, Shimoyama, T･ and 28, 1067-1072. Tamura, T. ( 1 993): Potent inhibitory action of the gastric

● 117･ Fukuda, H., Saito, D., Hayashi, S., Hisai, H., Ono, H., proton pump inhibitor lansoprazole agalnSt ureaSe Yoshida, S., Oguro, Y, Noda, T., Sato, T., Katoh, M., activity of Helicobacter pylori: unlque● action selective Terada, M･ and Sugimyra, T･ (1995): Helicobacter pylori for H. pylori cells. Antimicrob. Agents Chemother･, 37, infection, serum pepslnOgen level and gastric cancer: a 769-774.

case-control study in Japan. Jpn. J. Cancer Res., 86, 64- 132. McGown, C. C., Cover,T.し. and Blaser, M. ∫. (1994): 71. The proton pump inhibitor omeprazole inhibits acid 118. Forman, D., Newell, D. G., Fullerton, F.,Yarnell, J. W., survival of Helicobacter pylori by a urease-independent Stacey, A. R., Wald, N. and Sitas, F. (1991): Associa- mechanism. Gastroenterology, 107, 1573- 1578･ tion between infection with Helicobactrpylori andrisk 133. Versalovic, J., Shortridge, D., Kibler, K., Griffy, M･ V･, of gastric cancer: evidence from a prospective investiga- Beyer, J･, Flamm, R･ K･, Tanaka, S･ K･, Graham, D･ Y･ aJld tion. Brit. Med. J., 302, 1302-1305. Go, M. F. (1996): Mutations in 23S rRNA are associated 119. Parsonnet, J., Friedman, G. D., Vandersteen, D. P., with clarithromycln● resistance in Helicobacter pylori･

Chang, Y, Ⅵ)gelman, ∫. H., Orentreich, N. and Sibley, Antimicrob･ Agents Chemother･ , 40, 477-480･ R. K. (1991): Helicobacterpylori infection and the risk 134. Hulten, K., Gibreel, A., Skold, 0. and Engstrand, L･ of gastric cancer. N. Engl. J. Med., 325, 1127-1131. (1997): Macrolide resistance in Helicobacter pylori: ■ 120. Nomura,A., Stemmermann, G. N., Chyou, P-H., Kato, Mechanism and stability in strains from clarithromycln-

Ⅰ., Perez-Perez, G. Ⅰ. and Blaser, M. ∫. (1991): treated patients. Antimicrob･ Agents Chemother･, 41 , Helicobacter pylori infection and gastric carcinoma 2550-2553.

among Japanese-Americans in Hawaii. N. Engl. ∫. Med., 135. Murakami, K. and Kimoto, M. (1999): Antibiotic- 325, 1132-1136. resistant H. pylori strains in the last ten years in Japan･

121. International Agency fわr Research on Cancer, Wわrld Jpn. ∫. Clin. Med., 57, 8ト86 (in Japanese)･

195 136. van Zwet, A. A., Vandenbrouke-Grauls, C. M. J. E., 150. Jalava, K., Kaartinen, M., Utriainen, M., Happonen, J. Thijs, J. C., van der Wouden, E. J., Gerrits, M. M. and and Hanninen, M. L. (1997): Kusters, J. G. (1998): Stable resistance in sp. nov., a canine gastric Helicobacter sp･ related to Helicobacter pylori. Lancet, 352, 1 595. and Helicobacter bizzozeronii. Int.

● 137. bbenz, J., Blum,A. L., Bayerd∝rffer, E., Meinlng,A., J. Syst. Bacterio1., 47, 975-982.

Stolte, M. and Boersch, G. (1997): Curing Helicobacter 151. Lee,A., Hazell, S.し., 0'Rourke, ∫. L and Kouprach, pylori infection in patients with duodenal ulcer may S. (1988): Isolation of a spiraトshaped bacterium from provoke renux esophagitis. Gastroenterology, 1 12, cat stomach. Infect. Immun., 56, 2843-2850. 1442- 1447. 152. Paster, B. J.,Lee,A., Fox, J. G., Dewhirst, F. E.,Tordoff, 138. Labenz, J. and Malfertheiner, P. (1997): Helicobacter L A., Fraser, G. J., 0'Rourke, J. L., Taylor, N. S. and pylori in gastr0-0esophageal reflux disease: casual Ferrero, R. ( 1991): Phylogeny of Helicobacterfelis sp･ agent, independent or protective factor? Gut, 41 , 277- nov., Helicobacter mustelae, and related bacteria. Int. 280. J. Syst. Bacterio1., 41, 31-38･ 139. Gubbins, G. P., Moritz, T. E., Marsano, L. S., Talwalkar, 153. Eaton, K. A., Radih, M. J., Kramer, L., Wack, R., R., McClain, C. ∫. and Mendenhall, C.し. (1993): sherding, R., KrAkowa, S. and Morgan, D. R. (1991):

● Helicobacter pylori is a risk factor for hepatic encepha- Gastric splral bacilli in captive cheetahs･ Scand･ J･ lopathy in acute alcholic hepatitis: the ammonia hypoth- Gastroentero1., 181 (Sujbl.), 38-42.

esis revisited. Am. ∫. Gastroentero1., 88, 1906-1910. 154. Baton, K. A., Dewhirst, F E., Radin, M. ∫., Fox, ∫. G.,

140. Ito, S., Miyaji, H.,Azuma,T., Li,Y., Ito,Y., Kato,T., Kohli, Paster, B. ∫., Krakowa, S. and Morgan, D. 良. (1993): Y and Kuriyama, M. (1995): Hyperammoniaemia and Helicobacter acinonyx sp･ nov･ , isolated from cheetahs Helicobacter pylori. Lancet, 346, 124- 125. with gastritis･ Int･ J･ Syst･ Bacteriol･, 43, 99-106･

● 141. Mendall, M. A., Goggln, P. M., Molineaux, N., Levy, 155. Fox, ∫. G., Edrise, B. M., Cabot, E. B., Beaucage, C., J., Toosy, T.,Strachan, D., Camm, A. J. and Northfield, Murphy, J. C. and Prostak, K･ S･ (1 986): Campylobacter- T. C. (1994): Relation of Helicobacter pylori infection like organisms isolated from gastric mucosa of ferrets･ and coronary heart disease. Br. Heart J., 71, 437-439. Am. J. Vet. Res., 47, 236-239. 142. Ossei-Gemlng,● N., Moayyedi, P., Smith, S., Braunholtz, 156. Fox, J. G., Paster, B. J., Dewhirst, F. E., Taylor, N. S., D., Wilson, J. I.,Axon,A. T. R. and Grant, P. J. (1997): Yan, L L., Macuch, P. J. and Chmura, L M. (1992): Helicobacter pylori infection is related to atheroma in Helicobacter mustelae isolation from feces of ferrets:

● ● patients undergolng coronary ang10graPhy. Cardiovas- evidence to support fecal-Oral transmission of a gastric cular Res., 35, 120-124. helicobacter. Infect. Immun., 60, 606-61 1.

● 143. Regnstr∝m, J., Jovlnge, S., Bavenholm, P., Ericsson, C. 157. Franklin, C. L., Beckwith, C. S., Livingston, R. S., Riley, G., De Faire, U., Hamsten,A., Hellenius, M. L., Nilsson, L K., Gibson, S. V., Besch-W111iford, C. L.and Hook, R. J. and Tomvall, P. ( 1998): Helicobacter pylori seroposi- R., Jr. (1996): Isolation of a novel Helicobacter species, tivity is not associated with inflammatory parameters, Helicobacter cholecystus sp. nov. , from the gallbladders lipid concentrationsand degree of coronary artery disease. of Syrianhamsters with cholangiofibFOSisand centrilobular J. Intem. Mらd., 243, 109-113. pancreatitis･_ J･ Clin･ Microbiol･, 34, 2952-2958･ 144. Fennel, C. L., Totten, P. A., Quinn,T. C., Patton, D. L., 158. Phillips, M. W. andLee, A. (1983): Isolation and Char- Holmes, K. K. and Stamm, W. E. (1984): Characteriza- acterization of a spiral bacterium from the crypts of tion of Campylobacter-like organisms isolated from rodent gastrointestinal tracts･ Appl･ Environ･ Microbiol ･ , homosexual men. J. Infect. Dis., 149, 58-66. 45, 675-683. 145. Totten, P. A., Fennell, C. L., Tonver, F. C., Wezenberg, J. 159･ Lee,A･, Phillips, M･ W, 0'Rourke, J･ L･, Faster, B･ J･,

M., Perine, P. L., Stamm,W. E.and Holmes, K. K. (1985): Dewhirst, F E., Fraser, G. ∫., Fox, ∫. G., Sly,し. Ⅰ., Campylobacter cinaedi (sp. nov.) and Campylobacter Romniuk, P. J., Trust, T. J. and Kouprach, S. (1992): fenneliae (sp. nov.): two new Campylobacter species Helicobacter muridarum sp. nov., a Microaerophilic associated with enteric disease in homosexual men. ∫. helical bacterium with a novel ultrastructure isilated

Infect. Dis., 151, 131-139. from the intestinal mucosa of rodents. tnt. ∫. Syst.

146. Trivett-Moore, N.し., Rawlinson, W D., Yuen, M. and Bacterio1., 42, 27-36. Gilbert, G. L. (1997): Helicobacter westmeadii sp. nov., 160. Mendes, E. N., Queiroz, D. M., Dewhirst, F. E., Paster,

a new species isolated from blo∝l cultures of twoAIDS B. J., Moura, S. B. and Fox, J. G. (1996): Helicobacter patients. J. Clin. Microbio1., 35, 1 144-1150. trogontum sp･ nov･, isolated from the rat intestine･ Int･ 147. Bronsdon, M. A. and Schoenkpecht, F. D. (1988): J. Syst. Bacterio1., 46, 916-921･

Campylobacter pylori isolated from the stomach of the 161. Shen, Z., Fox, ∫. G., Dewhirst, F E., Faster, B. ∫., Foltz,

monkey, Macaca nemestrina. ∫. Clin. Microbio1., 26, C. ∫., Yam,し., Shames, B. and Perry,し. (1997): 1725- 1728. Helicobacter rodentium sp･ nov･, a urease-negative 148. Stanly, J., Linton, D., Burnens, A. P., Dewhirst, F. E., Helicobacter species isolated from laboratory mice･ Int･ Owen, R. J., Porter,A., On, S. L. and Costas, M. (1993): J･ Syst･ Bacteriol･, 47, 627-634･ 上し Helicobacter canis sp. nov., a new species from dogs: 162. Fox, ∫. G., Dewhirst, F E., Tully, ∫. G., Faster, B ウ ● ph an integrated study of phenotype and genotype. ∫. Gen. Yam, LL･, Taylor, N･ S･, Collins, M･ J･, Gorelick, Microbio1., 1 39, 2495-2504. and Ward, J. M. ( 1 994): sp･ nov･,

149. Hanninen, M.し., Happonen, Ⅰ., Saari, S. and Jalava, K. a microaerophilic bacterium isolated from livers and

● (1996): Culture and characteristics of Helicobacter intestinal mucosal scraplng from mice･ J･ Clin° bizzozeronii, a new canine gastric Helicobacter sp. Microbio1., 32, 1238-1245.

【published emtum appears in lnt. ∫. Syst. Bacterio1., 163. Fox, ∫. G., Yam, L L, Dewhirst, F E., Faster, B. ∫., 46, 839日nt. ∫. Syst. Bacterio1., 46, 160-166. Shames, B･, Murphy, J･ C･, Hayward,A･, Belcher, J･ C･

196 ● and Mendes, E. N. (1995): sp. nov., tured gastric splral organism is a newly identified a novel Helicobacter species isolated from bile, livers, Helicobacter in humans. J. Infect. Dis., 168, 3791385.

and intestines of aged, inbred mice. ∫. Clin. Microbio1., 170. Solnick, J. V., 0'Rourke, J.,Lee, A. and Tompkins, L 33, 445-454. S. (1994): Molecular analysis of urease gene from a 164. Goto, K., Ohashi, H., Ebukuro, S., Itoh, K., Tohama, newly identified uncultured species of Helicobacter. Y, Takakura,A., Wakana, S, Ito, M. and Itoh, T. (1998): Infect. Immun., 62, 1631-1638. Isolation and characterization of Helicobacter species 171. Stolte, M., Wellens, E., Bethke, B., Ritter, M. and from the stomach of the house musk shrew (∫〟〝C〟∫ Eidt, H. (1994): Helicobacter heilmanii (formerly murinus) with chronic gastritis. Curr. Microbio1., 37: Gastrospirillum homonis) gastritis: an infection trans-

44-51. mitted by animals? Scaれd. ∫. Gastoentero1., 29, 106ト

165. Dewhirst, F E., Seymour, C., Fraser, G. ∫., Faster, B. ∫. 1064. and Fox, J. G. (1994): Phylogeny of Helicobacter isolates 172. Husmann, M., Gries, C., Jehnichen, P., Woelfel, T., from birdand swine fecesand description of Helicobacter Gerken, G･, Ludewi.g, W･, and Bhakdi, S･ (1994): pametensis sp. nov. Int. J. Syst. Bacterio1., 44, 553-560. Helicobacter sp. stFaln mainz isplated from an AIDS 166. Stanly, J., Linton, D., Burnens, A. P., Dewhirst, F. E., patient with septic arthritis: case report and nonradio- On, S. L W., Porter, A., Owen, R. J. and Costas, M. activeanalysis of 16S rRNA sequence. J･ Clin･ Microbiol･, (1994): Helicobacter pullor?m Sp･ nOV･ -genOtypeand 32, 3037-3039. " phenotype of a new species isolated from poultry and 173. Fleish, F., Bumens,A., Wetx:r, R. andZbinden, R. (1998): from human patients with gastroenteritis. Microbiology Helicobacter species strain Mainz isolated from cultures (Reading), 140, 3441 -3449. of blood from two patients withAIDS･ Clin･ Infect･ Dis･, 167. Kirkbrige, C.A., Gates, C. E. and Collins, ∫. E. (1985): 26, 526-527. Ovine abortion associated with anaerobic bacterium. J. 174. Fox, J. G., Dewhirst, F. E., Shen, Z., Fens, Y., Taylor,

Am. Vet. Assoc., 186, 789-791. N. S., Faster, B. ∫., Ericson, 良.し., Lau, C. N., Co汀ea, 168. Schauer, D.由., Ghori, N. and Faikow, S. (1993): Isola- P., Araya, J. C. and Roa, I. (1998): Hepatic Helicobacter tion and characterization of "FlexISPlra raPPlni" from species identified in bile and gallbladder tissue from laboratory mice. J. Clin. Microbio1., 3 I , 2709-2714. Chileans with chronic cholecystitis. Gastroenterology,

169. Solnick, ∫. V., 0'Rourke, ∫., Lee, A., Faster, B. ∫., 1 14, 755-763. Dewhirst, F. E. andTompkins, L S. (1993): An uncul-

197