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

Invited Review

Association of Helicobacter 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 andJDepartment of Bacteriology, Okayama UniversityMedical School,
Shikata‑cho 2‑5‑1 , Okayama 700‑8558, Japan(Received October 22, 1999)

SUMMARY: Helicobacter pylori 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
infection throughout a person's life if there is no medical intervention･ Numerous persons are infected with theorganism around the world, and the rate of infection in Japan is nearly 50% of the population･ However, the routeof infection remains unclear because the organism has not been isolatedfromany environment other thanseveral
animals･ H･ pylori is now recognlZed as a causative agent of gastritis and peptic ulcers･ Though gastritis, andespecially 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 bacteria are needed for the developmentof peptic ulcer disease･ 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 anantisecretory 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･●

2. BacteriologICal features

1. 1mtroduction

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 ishumangastriC mucosa without the copresence of other bacterial

motile by means of a tuft of up to eight sheathed flagella atspecies. 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 theit was asslgned to the new genus Helicobacter, and is now
known as Helicobacter pylori (3).
The first paper relating to H. pylori described its association

first isolation from gastric biopsy, Ski汀OW's medium iscommonly recommended･ However, H･ pylori can grow in aserum‑free medium containing 0.1‑0.2% of dimethyl β‑cause human gastritis by oral self‑administration of the living

cyclodextrin (7,8). The growth of H･ pylori i.n a synthetic
medium was reported, but it contained largeamounts of tDVinebacteria to the stomach (4,5). H. pylori infection is now recog‑

serum albumin (9). In liquid culture, shaking is necessary forwith gastritis ( 1 ). Researchers indicated that the organism can●nized as the pnmary cause of active chronic gastritis and as

good quality and uniform growth･

an important causal factor in peptic ulcers. Furthermore, theBy 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 inor under any artificial conditions･ However, it is reported thatmongolian. gerbils (6)･

the oral inoculation of the coccoid body induces gastritis inThis 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 thea viable but non‑culturable state (VNC).

organism and gastroduodenal diseases.

In representatives of conventional biochemical tests, 〃･pylori is positive for oxidase, catalase, urease, alkaline phos‑*Corresponding author: Tel: +81 ‑285‑58‑733 1 , Fax: +81 ‑285‑44‑

phatase, and T‑glutamyl transpeptidase, and is negative fわrnitrate reduction･ The organism utilizes glucose but gives no1175

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 toTokyo,21May1999.

other ureases (Table l ). Furthermore, the large content of urease183

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 Enterobacteriaceae(20,21). However, the LPS is recognized as an importantfactor 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‑

lipids. The organism cannot synthesize cholesterol in the same

tive staining).

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 uniqueexists at the su血ce ofcells (17), whereas it exists only in thecytoplasm of other bacteria. Therefわre, the organism exhibits

feature of genus Helicobacter, because they are present in 1 6
of 18 Helicobacter species (25,26).
As mentioned above, urease is located on the outer mem‑very high urease activity in the whole cell, which is commonlybrane. Heat shock protein (HSP) 60 is also fわund in the sameused as a method for diagnosis of H. pylori infection. H. pylori

location. It was reported that this was synthesized in theitself 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‑
charide (LPS), Compared with lipid A of members of Enter?‑bacteriaceae, the lipid A of H. pylori has an unusual composl‑tion of fatty acids (310H C18:0) and also a different phos‑

strains, J99 (28) and 26695 (29), of H. pylori. The generalfeatures are listed in Table 2. The annotated genome sequences●

and further information concernlng Strains J99 and 26695 areavailable on the World Wide Web site (http://www.tigr.org/
tdb/mdb/hpdb/hpdb.html) and in the H･ pylori databasephorylation pattern, with 1 '‑ but not 4'‑phosphate present in184

Table 1 ･ Biochemical characters of purified ureases
Kml)
(mM)

Helicobacter

pyloriO･

17

specific
acti

1

,

‑0.48

Klebsiella aerogenes

I

v

i

ty

native
1

00

･2)

Mr

subunit

(kDa)

(kDa)

530

‑ 1 ,700

2.8

2,200

224

Mrs)

subunitcomposl

metal

tlOn

COntent

1.0 Ni/β

α =26.6(α･β)β =60.5×6α=9(α2･β2･γ)

2.1 Niβ=11×2/(α2･β2･γ)γ =72Ureaplasma

urealyticum

2.5
‑4.

Jack

bean(plant)

5

2.9

‑

1

33,530

150

1

‑380

80,000,000α=66α2or α5or α6

‑76

590

α=98

2.0 Ni/αα6‑5,5001)These data were measured with different buffers, temperatures, and pHs･
2) LLmol of urea/min per mg of protein3)The small, mediumand large subunits are designated as a, B, and T, respectively.
(from refs. ll‑16 )CGL (G･2):
Cholesteryl･a･D･glucopyranoside (base substance)

Table 2･ General features of the H･ pylori genomes
strain 26695

Patient(Country)

gastritis

strain J99

duodenal

ulcer(the UK)(the USA)

Size (base pairs)

1 ,667,867

1 ,643,83 I

G+C content (%)

39

39

8*(5)

9

Regions of different
G+C content

vacA genotypesla/mlslb/mlOH

Open reading frames (ORf)

CAG (G･1):

Coding % of genome

C holeste ryl ･6 ･ 0 I te tradec anoyl ･ α･ D･ glucopyranoside

Number of ORF

91.0

1 ,552*(1 ,590**)

90.8

1 ,495Functionally classified

895

Conserved with no function

290

275

H･ pylori specific

367

346

Number with signal sequence

517

502

average length (base pairs)

954

998

874

Insertion elements (IS)CPG (G･3):13(5)IS606 (complete copies)4(2)n1Ju EuJHU

5 5 01

Eil PuRNA elements

C holesteryl･ 6･ 0 ･ phosphatidyl･ α I D･ glucopyranoside

23S‑5S rRNA

H2CO ‑ CO‑R 2

2 つー 62 2 人V

16S rRNAtRNAs

H‑CO‑CO‑R3tIS605 (complete copies)

b .i.

3

3

(refe汀ed and modified mainly from ref･ 29･)?

*: The data are recalculated in ref. 29.

H2C‑ 0‑ p‑0‑cH2**: indicate the onglnal data in ref･ 28･

1

performed within several hours. Therefore, the combination1of several methods, especially culture, a rapid urease test, and0H

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 ofspecific IgG antibody in serum. The determination of specific
IgA levels in the saliva may also be used for the diagnosis･(www･astra‑boston･com/hpylori or wyw･genomecorp･ com/
hpylori), respectively.

However, the use of specific lgM levels is not helpful fわrdiagnosis 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
infection (Table 3)･ In group A, gastric endoscopic exami.na‑tion is necessary･ For these methods,the culture of the organlSm

antigens in feces are non‑invasive methods. Especially, theis the gold standard method･ Recently, strains resistant toequlpment are needed for the test.

The urea breath test (UBT) and the detection of H. pylori

UBT has very highsensitivity. However, 13C‑urea and costly●●

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 endoscopyI) 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. ureaanda pH‑indicator･ The color will change with ammonia production bystrong urease activitywhen HP exists in thetissue.

3) Histologicalexamination
Stain formalin‑fixedtissues by severalmethods.
Detection of HP in thetissue stained withhematoxylin‑eosin isquite 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 willchange bythe same reaction as 2).
5) PCR (Polymerase chain reaction)

OlJhOPq

Detect HP‑Specific genes uslng PCR in the gastric tissues.

6tIOt

6N‑ON

6の‑OS

6寸‑0寸

69‑0g

69‑09

(age group)

nimers to genes of the urease or 16S rRNA areusuallyused.
The PCR canbe applied to saliva or feces.
B: Others6) Detection ofanti HP IgGantibdy

Fig. 4. Distribution of seropositivity for H･ p̲vlori 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)
Give liquid containing I3C‑urea to patients orally.

associated with H. pylori infection. The disease associations

13C‑Carbon dioxide is produced from urea bythe same reaction as 2).

are summarized below.

A. Gastritis
A･1) acute gastritis (first infection)
In most cases of H. pylori infection,the causal events are

The carbon dioxide is absorbed in血e intestine and is exhausted in thelung･ Measure content of t3C‑Carbon in breathing 1 5‑30 min after theadmimistration.
8) Detection of HP‑antigensin feces

not well known because the infection has been long‑standing(A commercialkit is available)by the time of diagnosis. Most cases of childhood infection
may be asymptomatic. However, H. pylori infection was deter‑

HP‑antigens are detectedwith polyclonalantibody in ELISA.
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 andis rare, and the frequency of seropositivity in adults is underwere free of the organism at the time of their first endoscopy

50%. In these countries, the rate of seroconversion is estimatedat O･5% per year. In Japan, the frequency of seropositivity indeveloped abdominal paln 1‑2 weeks after the endoscopy,

younger people (under 30 years old) is similar to that offound 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%).
H･ pylori is cultured from human gastric mucosa and has(32,33). It has not been isolated from extemal environments,

One feature of the onset of infect10n is the disappearanceof acid secretion for a few months (40,41). Clinical signs ofacute gastritis, especially AGML, disappear 1 ‑2 weeks after
onset. However, in most people infected with H･ pylori, thealthough the DNA of Helicobacter species has been detected

infection is life‑long, and acute gastritis proceeds to chronic

acute gastritis (acute gastric mucosal lesion; AGML) was

been cultured to some extent from human saliva and fecesby 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
infection is not known. Based mainly on seroepidemiology

peared spontaneously 314 Weeks after the onset ofAGML insome people infected by endoscopy or afterthe onset of acutedata, the contamination of drinking water could playanimpor‑gastritis in a volunteer's infection (42,43)･●

A･2) chronic gastritis

tant role in the transmission in certain developlng countries,

Most people with H･ pylori infection do not exhibit any

and acquisition of the infection would occur easily during●

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‑
tions intheir youth around or before the Second World War.

histologlCally associated with chronic active gastritis, and its●

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
in the volunteers mentioned above. In addition, the oralfrom pets would not be of great importance.

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

diseasessensitivity to colonization by the organism and shows the mostMany gastroduodenal diseases are now recognlZed to be

severe gastritis.

186

In chronic gastritis with H. pylori, infiltrations of chronicmucosa,and colonizes it. The sheathed flagella and the ureaseinflammatory 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 termmutant strains did not colonize the mucosa in the stomach ofof 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

motility without a degradation in the acid envlrOnment Of theto 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 theminal centers) are often observed in the mucosa of infectedorganism, utilizing a low concentration of urea in the gastricpersons, especially children, whereas uminfected gastric mucosa

JulCeS･●●

contain minimal lymphocytes. These lymphoid follicles are

Adhesion isanessential step for infection byall pathogens.

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 theactually important for adhesion to occur in the human gastricCOrpuS･

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 bywhich are important. The organism has cholesteryl glucosides,

H･ pylori infection, the prevalence and severity of glandular
atrophy increases steadily with age. Patients without H. pylori
infection rarely develop atrophic gastritis. H. pylori inhabits

LPS, urease and HSP 60, and produces phospholipase andactivity (23). Ammonia, which is produced from urea by thethe gastric mucosa, including the mucus layer. The loss ofurease, can cause mucosal damage (67,68). Furthermore,mucinase. The cholesteryl glucosides indicate hemolytic●

glandular tissue and the thinnlng Of the mucosa reduce thedensity of the organism. In Japan there are many patients withmon∝hloramine, which is pr∝luced by the reaction between

severe atrophic gastritis.

radicals fomed by neutrophils, is also toxic to cells (69).
H. pylori also produces and releases a vacuolating cyto‑
toxin (VacA) which produces vacuoles in many cell lines

ammonia and chloride ions in the presence of oxgen freeIntestinal metaplasia is frequently observed in chronic 〟.

pylori gastritis･ The report (44) sYggests that H･ pylori infec‑●

tion and bile renux act synerglStlCally to produce intestinal(Fig.5) (70). The vαCA gene encodes a precursor protein of

139.6 kDa consisting of a 33‑amino acid signal sequence,

petaplasia･ The intestinal epithelium (intestinal metaplasia)

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 throughmucosa. 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 theouter membrane; and the cytotoxin domain is cleaved off andrepeated injections of gastrin (45), and is not seen i.n patientswith 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 canof VacA to mice caused some tissue damage resembling thatcolonize gastric mucin cells and can be detected only at thefound in patients with H. pylori infection (72)･ Furthermore,
VacA may not be the only virulence factor, because threesites of gastric metaplasia in the duodenum.

A･4) pathogenic mechanisms in gastritis

proteins which show moderate similarities (26‑31%) to thecarboxy‑terminal end of VacA exist in strain 26695 (28)･

H. pylori reaches the gastric mucosa, the ecologlCal niche●●

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

19.6 kDa protein

laminingangl i otetraosyl ceramide

25 kDa protein

1 amini n

75 kDa protein (Bah A)

Lewis B antlgen

61 kDa protein

H type2, Lewis A,Lewis Bantigens

16 kDa protein

Lewis Xantigen, mucin

60

59 kDa hemoagglutinin
Gi 糾65砧

60 kDa heat shock protein(HSP B)

GM3 , 1actosylceramide sulfate

GM3, sulfatides
heparansul phate187

B. peptic ulcer diseases lduodenalulcer (DU)and gastriculcer (GU)】H. pylori infection rates in patients with peptic ulcers arehigh. 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 developmentof GU was observed (81). The eradication of the organism inpatients 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 pathogen inpatients withpeptic ulcers (8乎)･ However, peptic ulcer diseases

Fig･ 5･ Vero cells vacuolated by VacA (vacuolating cytotoxin) of 〟.

are caused only in part by H･ pylori infection･ Other drugs,
especially non‑steroidal anti‑innammatory drugs (NSAIDs),

pylori.

Vero cells were incubated witha concentrated culuture‑supematantof 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 certainlyof 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‑tion of the cell proteins, resembling that of enteropathogenic

ulcers in patients with H. pylori infection are not clear. Acid

E･ coli (73)･ Further, the adhesion of the bacteria to gastricalthough the pathosis in each ulcer disease is different･ In●

secretion plays an important role both in GU and DU diseases,

epithelial cell lines induces IL‑8 expression and secretion inpatients 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 thesecrete, on average, less.acid than controls (9 1 )･ However, acidproducts of cag PAI are considered to be major PrOteins which
induce IL‑8 expression in the cells (74). The G+C percentage

secretion also plays an Important role in GU disease becauseof cag PAI is low (35% in strain 26695) Compared to that of
the whole genome (39% in strain 26695), and this gene cluster
is likely acquired horizontally (28,29). CagA (the product ofis suppressed (92). Detailed mechanisms and associations

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, thesetwo proteins are found to be independent. Furthermore, CagA

UnconJugated bile salts are more toxic to H･ pylori than the
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 conjugatesulcer healing is faster and recurrence is less when acid secretion

based on clinical findings are not included in this review･H. pylori is sensitive to bile salts (93),although the organism●●●

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, cigarettecell‑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
and CagA (cag fAI) are not critical factors for the induction

etc･ have been reported･ In inherited factors, it was reported

that HLAIDQAI was associated with peptic ulcer disea.sesof 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 thecytokine production, has been carried out. Only some recent

bacteria･ The vαCA gene is classified by the sequence at theworks are summarized here. In the gastric mucosa of micesites of the slgnal sequence and the middle reglOn tO Sl andwith 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
was reported that THI cells enhanced gastritis, and that TH2

show the high biological activity of VacA (96)･ It was reported
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 otherof 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 geneto 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 inEurope and the U･S･A･ that patients with ulcers were infected

mice, does not cause gastric inflammation (79).

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

188

with gastric MAIJoma among gastric diseases with H.

Japan the differences in the rates of possesslng CagA‑positive
strains between ulcer and non‑ulcer patients with H･ pylori●

infection were of little import because most strains in this

pylori infection (1 1 1).
Conversely, human lymphocytes can be transplanted toregion have the cαgA gene (101).

severe combined immunodeficient (SCID) mice that have

C. gastric MALT lymphoma
Isaacson developed the concepts of gastric MAIJ and MAIJ
lymphoma (MAIJoma) ( 102, 103). A MAIJoma is generated
from MAI:Ts, which are collections of B‑cells. The MALToma
is classified as a Marglnal zone B‑cell lymphoma inperipheral

neither mature T‑ nor B‑cells. One month after peripheral

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epatients with the disease. These data suggestthat host immune
responses agalnSt H. pylori are involved in the developmentof gastric ulcers in patients with gastric MAI:Tomas･
D. gastric cancer O

blood mononuclear cells from H. pylori infected patients withgastric MALTomas were transplanted to SCID mice, oral
administration of live H. pylori to the SCID mice led to gastric●ulcers within 3 days, most commonly by day 1 (1 12) (Fig.6).

formerly referred to as reactive lymphoreticular hyperplasla●

is considered to be included in the category of MAIJomas･
It remains debatable whether all MALTomas are strictly.T(

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

pylori (92% in ref. 105). MALTs are often observed in thegastric mucosa with H. pylori infection. Furthermore, somelow‑grade MAIJomas disappear or regress after the eradica‑tion of H･ pylori (106,107). Therefore, H. pylori infection
appears to be associated with gastric MAIJoma. However,some low‑grade MAIJomas and most high‑grade MALTomascancer in Japan. Early gastric cancers develop ln areas Of

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

●

甘T
∵

intestinal metaplasia or chronic atrophic gastritis, which are●observed frequently ln Patients with long‑term H･ pylori
infection. Many groups have indicated significantly higher
seroprevalences of H. pylori in patients with gastric cancer
in case‑control studies (113‑115), althoughin soヮe studies

Although the ass∝iation of H･ pylori with lymphomagenesis

between H. pylori infection and the development of gastricof 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 thehas 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 ofantibodies 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 gastriccancer at the antrum andthe corpus (125), and is not ass∝iatedwith 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 cardiaof 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 isobserved 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 oxgenand an inhibitor of Ⅳ一mitrosation. A reduction of thesechemopreventive 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 theplanted 1 month before the administration of the orgamism･

ammonia produced by urease･ Cell division is vital to theTable 5･ Prospective studies of the association between H･ p̲vlori (HP) and the developmentof 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 can14

92/109(84%)

66/109(61%)

3.6

119

83/109 (76%)

6.0

120

(Cal ifbmi a)
Japanese‑AmeriCan

13

103/109 (94%)(Hawaii)189●are significantly decreased after the eradication of H･ pylori

development of cancer.

(140).
Recent studies have suggested that chronic infections with

6.Treatment

Chlamydia pneumoniae and cytomegalovirus are associatedH･ 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 firstalso associated with these diseases (141 ,142), but this remains

isolation. However, it is difficult to eradicate the organism fromcontroversial ( 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 ahumam 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

in the stomach. At a low pH, the MICs (minimum inhibitory(Table 6). H. heilmannii (Gastrospirilluhl hominis) is a spiralbacteria 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 aboutcantly (1 29) compared with at neutral pH. The administration

1 % of human gastritis･ This bacteria has not been cultured invitro, but it can grow readily in the mouse stomach･ Analysts
has revealed a difference in the 16Sribosomal RNA gene,
resulting ln its classification as a new species, Helicobacter
heilmannii. In patients with H. heilmannii, the rapid urease test
indicates positive, but the culture uslng media for H･ pylorib Iof antisecretory agents secures the efficacy of antimicrobial
agents in addition to an acceleration of the cure of ulcers and●erosions. Among antisecretory agents, proton pump inhibitors(PPIs) (H'‑K'ATPase antagonist) are usually used in eradica‑●●tion therapleS, and these inhibitors have a stronger antisecretory

effect than histamhe H2 reCePtOr antagonists. Furthermore,
PPIs show direct antimicrobialeffects agalnst H. pylori in vitro,
but not against other bacteria (130) (Histamine H2 reCeptOr
antagonists do not show this effect). Although PPIs inhibit

isolation is negative.

urease (131), this activity is found to have.no relation to thedeficient. H. westmeadii and Helicobacter specleS Strain Mainz●

H. fenneliae, H. cinaedi, H. pullorum, H. cants, and H･rappini (Flexispira rappini) have been isolated fromthe stoolsof patients with diarrhea･ Most of these patients are immuno‑●anti‑H. pylori effect ( I 32), and the mechanlSm Of the effect isunclear. It is controversial whether the anti‑H. pylori effectin vitro IS Practically effective in vivo in eradication therapleS.
Among antimicrobial agents, representatives in the latest
eradication ther?pie? are amoxcillin (AMPC), clarithromycin●

have been isolated from the blood of patients with immuno‑

deficiency. Conversely, some species such as H･ hepaticus,
H. canis, H. cholecystus. H. pullorum, and H. bilis have been●

isolatedfromanimal liversand/or biles. Especially, H. hepaticus
has been isolated from inbred strains of mice with hepatitis,(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
antimicrobial agents. Acquired resistance by mutations to

PCR amplicons of Helicobacter‑Specific 16Sribosomal RNA

CAM have been demonstrated (1 33, 1 34). Plasmid一mediateddetected in samples obtained from human patients with chromic

resistance has not been reported inany drug. Nitroimidazoles

cholecystitis ( 174). These Helicobacter spp･ mentioned in thisare widely used to treat anaerobic bacteria and protozoa suchparagraph may frequently enter the human intestine, Or may

primers (H. billis, H. pullorum, and H･ rappini) have been

as Trichomonas and Gialldia. The higher frequencies and doses
produce higher rates of resistance. The rate of resistance inbe members of a group constituting a small part of the normal

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

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190

Table 6･ A list of species in genus Helicobacter

SpecleS

Hosts

S

i

tes

Referencel･ H･ pylori

hum anstomach1‑3

2. H. ciyuZedi(monkey, cat, dog)
human, hamster

intestine ,144, 145

blood (human)(〃･ sp･ CL0‑1*)

3･ H. fennelliae

human (AIDS)i ntestine144, 145(〃･ sp･ CL0‑2*)

4. H. Westmeadii
5. H. nemestrinae
6. H. canis

human (AIDS )monkey; pig tailed macaque

blood

146

stomach147

dog, (human)i ntesti ne

148

7. H. bi〜･,=oZeroniidog

i ntesti ne

149

8. H. salmonis
9･ H. fellslO･ H･ acinonyxll. H. mustelae
12･ H･ cholecystus
13. H. muridarum
14･ H. trogontum
15. H. rodentium
16･ H･ hepaticus
17. H. bilis
18. H. suncus
19･ H. pamentensis

dog

i ntestine150

cat, (dog)s tomach

151,152

cheetahs tomach

153,154

fe rre ts tomach

155,156

Syrian hamstergal 1 bladder157

mouse, rat

intestine, (stomach)

158,159rat

i ntesti ne

160

mouse

intesti ne

161

mouse

intestine, liver

162

mouse

intestine, liver, bile

163

house musk shrews tomach

bird; gull, tumi ntestine(〃･ sp･ Bird‑A*)

20･ H･ pullorum

bird; chicken, (human)21･ H･ rapplni

Iamb lfetus], dog lstomach], human lintesline]

intestine, liver(Flexispira rappini*)

22. H. heilmannii

humans tomach(Gaslrospirillum hominis*)23･ H. sp. Mainz
human (AIDS)
24･ H･ sp. CL0‑3
human (homosexual)

blood, joint
i ntestine

25･ 〃･ sp･ Bird‑B

bird; tumi ntestine

26･ 〃･ sp. Bird‑C

bird; spa汀OW

i ntesti ne*: The former name

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