untitled

Transcription

1 REVIEW ISSN , The Korean Journal of Helicobacter and Upper Gastrointestinal Research, 2018;18(2): 위암화과정에서발생하는세균총의변화 이선영 건국대학교의학전문대학원내과학교실 Changes in Gastric Microbiota during Gastric Carcinogenesis Sun-Young Lee Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea After World War II, the incidence of gastric cancer decreased rapidly in most of the developed countries; however, it remained high in countries where secondary prevention of gastric cancer is practiced without primary prevention (Helicobacter pylori eradication). In such countries, changes in gastric microbiota contribute to gastric carcinogenesis, and the composition of gastric microbiota is mainly determined by the status of H. pylori infection. In non-infected individuals with no history of H. pylori infection, gastric microbiota includes various bacteria, creating ideal microbial diversity. Because it is difficult for most bacteria to proliferate in an acidic environment in stomach, only few bacteria are present in non-infected individuals. Conversely, microbial dysbiosis with H. pylori predominance is often observed in infected individuals with unimpaired gastric secretory ability, because other bacteria cannot survive at low intragastric ph. Such microbial dysbiosis may rapidly lead to gastric carcinogenesis, resulting in diffuse-type gastric cancer. It is more frequent in young patients with unimpaired gastric secretory ability than in elderly patients with gastric atrophy and metaplasia. Lastly, bacteria producing carcinogenic N-nitrosamine compounds are often detected in individuals with past or chronic H. pylori infection, because of the loss of gastric secretory ability. Such an unideal microbial diversity observed at high intragastric ph may slowly lead to gastric carcinogenesis, in turn resulting in gastric adenoma or intestinal-type gastric cancer. To prevent gastric carcinogenesis, changes in the composition of gastric microbiota should be studied in conjunction with intragastric acidity, which depends on the status of H. pylori infection. (Korean J Helicobacter Up Gastrointest Res 2018;18:95-102) Key Words: Carcinogenesis; Helicobacter pylori; Microbiota; Stomach 서 론 분자생물학기법의발달로세균의 16S ribosomal RNA (rrna) 가변영역 (variable region) 을분석할수있게되면서, 인체에는 1,000 종류이상의장내세균총 ( 미생물무리 ) 이존재한다는것이밝혀졌다. 1,2 장내세균총의변화가특정장기에질환을유발하는이유에대해서는명확하게밝혀지지않았으나, 세균총의조성이감염, 암, 당뇨, 비만, 염증성장질환, 과민성대장증후군, 식품알레르기, 아토피성피부염, 기관지천식, 류마티스관절염, 다발성경화증, 자폐증, 치매, 우울증등과연관이있다고보고되었다. 3 세균총조성의변화가 T 세포의면역체계변화를유발해서질환을유발한다는주장도있으나, 세균총이 Received: January 6, 2018 Revised: March 10, 2018 Accepted: March 11, 2018 Corresponding author: Sun-Young Lee Department of Internal Medicine, Konkuk University School of Medicine, Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea Tel: , Fax: , sunyoung@kuh.ac.kr ORCID: This study was supported by the Korean National Research Foundation (NRF 2016R1D1A1B ). 병의원인으로작용했는지병의결과로나타난것인지는아직불명확하다. 위내세균총의양은 colony forming units (CFU)/g 로, 대장내세균총의 CFU/g 에비해서월등히적다. 4,5 그러나소장이나대장에비해서 Proteobacteria 와 Actinobacteria 문 (phylum) 의비율이높으며, 이에속하는다양한세균총이존재한다. 6,7 세균총의조성이다양할수록각세균이보유한분해, 부패, 합성, 발효, 동화등의다양한대사능력을지니게되어면역력증강, 원소의순환, 단쇄슬지방산 (short chain fatty acid) 생성, 영양소의소화와흡수, 에너지생산등으로이어진다. 8,9 나아가서다양한세균총은특정균의증식을억제함으로써질병을예방하고, 상재균으로존재하면서미생물의다양성 (microbial diversity) 을보인다. 1,3,8,9 반대로특정균이증식해서조성이바뀌는것을미생물의불균형 (microbial dysbiosis) 이라고하며, 위에서가장흔한것은 Helicobacter pylori 감염이다. 10,11 제2차세계대전이후에선진국을중심으로위암의유병률은 80% 이상감소했으나, 우리나라와일본에서는위암의일차예방인 H. pylori 제균치료보다이차예방인위내시경검 Copyright 2018 Korean College of Helicobacter and Upper Gastrointestinal Research The Korean Journal of Helicobacter and Upper Gastrointestinal Research is an Open-Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Korean J Helicobacter Up Gastrointest Res: Vol 18, No 2, June 2018 진이활성화되어위암이여전히많다 이에본론에서는 H. pylori 감염여부에따른위내세균총의구성과위암화과정중에발생하는세균총의변화에대해서알아보고자한다. 본 론 1. H. pylori 에감염된적이없는사람의위내세균총 사람의세균총은분만경로, 음식물, 약물, 감염, 위장관의연동운동, 노화현상등의다양한요인에의해서결정된다. 1,3 Table 1. Gastric Microbiota Found in a Human Stomach (in Alphabetical Order) Phylum Genus reported in gastric cancer patients Genus often reported in normal subjects Acidobacteria Acidobacter, Solibacter, etc. Actinobacteria Bifidobacterium Actinomyces, Bifidobacterium, Corynebacterium, Dermacoccus, Corynebacterium a Micrococcus Propionibacterium a Slackia Geodermatophilus, Microbacter, Micrococcus, Nocardia, Propionibacterium, Rothia, etc. Arthropoda Spodoptera a Planococcus, etc. Bacteroidetes Alloprevotella Alloprevotella, Bacteroides, Capnocytophaga, Chryseobacterium, Bacteroides Prevotella Cloacibacterium, Cyclobacter, Flavobacterium, Hymenobacter, Pectobacterium, Porphyromonas, Prevotella, Sediminibacterium, Sphingobacter, etc. Leptolyngbya, Oceanitalea, etc. Cyanobacteria Deinococcus-Thermus Deinococcus Deinococcus, Thermus, etc. Firmicutes Bacillus Aerococcus, Bacillus, Carnobacter, Clostridium, Enterococcus, Eubacterium, Flectobacillus, Gemella, Lachnospira, Lactobacillus, Leuconostoc, Mycoplasma, Paenibacillus, Peptoniphilus, Peptostreptococcus, Staphylococcus, Streptococcus, Veillonella, etc. Catonella Clostridium Dialister Enterococcus Eubacterium Gemella Lachnospira Lactobacillus Parvimonas Peptococcus Peptostreptococcus Staphylococcus a Streptococcus a Veillonella Fusobacteria Fusobacterium Fusobacterium, Leptotrichia, etc. Leptotrichia Nitrospirae Nitrospira Proteobacteria Acinetobacter Acetobacter, Acinetobacter, Actinobacillus, Aeromonas, Burkholderia Campylobacter a Escherichia Haemophilus Helicobacter a Klebsiella Neisseria Proteus Pseudomonas Shigella Stenotrophomonas Sulfurospirillum a Aurantimonas, Bradyrhizobium, Brevundimonas, Burkholderia, Campylobacter, Caulobacter, Citrobacter, Coronobacter, Dechloromonas, Enhydrobacter, Enterobacter, Escherichia, Haemophilus, Helicobacter, Klebsiella, Hydrogenophilus, Lautropia, Massilia, Methylobacter, Moraxella, Neisseria, Nevskia, Pantoea, Paracoccus, Phyllobacterium, Proteus, Pseudomonas, Ralstonia, Serratia, Shigella, Sphingomonas, Stenotrophomonas, Tetracoccus, Trabulsiella, Variovorax, Vibrio, Xanthomonas, Yersinia, etc. Spirochaetes Brachyspira, Spirochaeta, Treponema, etc. a Often found with H. pylori. 17,26 96

3 Sun-Young Lee: Changes in Gastric Microbiota during Gastric Carcinogenesis 대부분이후천적인요인이라서인종등의유전학적요인보다는지역별풍습등의환경적요인에좌우될것으로추정된다. 자연분만으로태어나면대장의상재균인 Bacteroides, Escherichia, Pectobacterium, Prevotella, Shigella속 (genus) 이우세한세균총이형성되고, 제왕절개로태어나면피부상재균인 Corynebacterium, Propionibacterium, Rothia, Staphylococcus, Streptococcus 속이우세한세균총이형성된다. 10 또한모유수유시에는 Bifidobacterium속이증가하고, 분유수유시에는 Enterobacter속이증가한다. 6,7,10 그러나이들중낮은위내 ph 에서생존할수있는것은위산에강한 Lactobacillus, Vibrio, Yersinia 속이나요소분해효소 (urease) 를생성할수있는 Actinomyces, Citrobacter, Corynebacterium, Enterobacter, Helicobacter, Klebsiella, Proteus, Staphylococcus, Streptococcus 속에불과하다. 2,4,5 위내세균총은대장에비해서 Bacteroidetes 와 Firmicutes 문의비율이낮으며, 대부분은 Proteobacteria, Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria문에속한다 (Table 1). 2. H. pylori에감염되어있는사람의위내세균총 H. pylori 감염상태는크게 1) 위점막분비능이항진된활동성감염상태와 2) 위점막분비능이저하된만성감염상태로나눌수있으며, 위내시경소견과혈청펩시노겐 (pepsinogen) 수치로구분할수있다. 11,15 활동성감염시에는펩시노겐 I, II 수치가모두증가하고, H. pylori 가위내세균총의 72 99% 를차지한다. 16,17 반면에만성감염시에는위축성및화생성변화가일어나면서펩시노겐 I 수치와 I/II 비가감소한다. 위축성위염이진행될수록위내 ph는상승하므로 H. pylori 의비율은 서서히줄어들고, 위산에취약한 non-h. pylori Proteobacteria, Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, Spirochaetes, Acidobacteria 문은점차늘어난다 (Fig. 1). 그러나위점막에부착하지못하고위액에섞여서스쳐지나가는균도있으므로, 위내세균총을분석하기위해서는위액이아닌위점막을채취해야한다 H. pylori 에감염된적이있는사람의위내세균총 과거감염자의대부분은 H. pylori 제균치료에성공한경우지만, 일부는위축성및화생성변화가심해서 H. pylori 가저절로소멸된경우이다. 자가소멸된사람들은위산분비능이이미손상된과거감염자들과유사해서혈청펩시노겐수치는낮고위내 ph는높으며, 위내세균총은상재균이아닌다양한균들로구성된다. 19,20 즉장상피화생이심해질수록위내세균총의조성이대장이나소장과유사해져서, Proteobacteria 와 Actinobacteria 문은감소하고 Bacteroidetes 와 Firmicutes 문은증가한다. 이렇게다양한세균총이존재하는위내환경에서 H. pylori 가사라진후에도위점막의분비능이회복되지못하면, 장상피화생상태에서선종이나이시성 (metachronous) 장형선암이발생할위험성이높다. 21,22 반면에위축성및화생성위염이진행되지않은단계에서제균치료에성공하면위점막의분비능이회복되므로, 다시미감염시의낮은위내 ph 환경이조성되어미생물의다양성을유지한다. 4. H. pylori 가위암화과정에미치는영향 위산분비능이손상되지않은 H. pylori 감염자의위내세균총의대부분은 H. pylori 이므로, 위점막의세균밀도는높고조 Fig. 1. Changes in gastric microbiota observed in gastric carcinogenesis. The ideal microbial diversity is affected by active Helicobacter pylori infection. At low intragastric ph, relative H. pylori abundance gives rise to microbial dysbiosis, because there is no microbiota producing large quantities of urease to survive in an acidic environment in stomach, apart from H. pylori. This rapid carcinogenesis pathway may result in diffuse-type gastric cancer with normal surrounding gastric mucosa. Conversely, the slow carcinogenesis pathway may result in intestinal-type gastric cancer with atrophic or metaplastic surrounding gastric mucosa. Unideal microbial diversity, comprising bacteria that produce carcinogenic N-nitroso compounds, is often observed in hypochlorhydric conditions induced by chronic H. pylori infection. 97

4 Korean J Helicobacter Up Gastrointest Res: Vol 18, No 2, June 2018 작분류단위 (operational taxonomic unit, OTU) 는낮다 활동성감염상태에서빠른속도로진행하는미만형위암은젊은여성에서흔하며, 병변이흰색으로탈색되어주변의붉은색정상위점막과구분된다. 27 빠른속도로암이진행하기에현미부수체불안정성 (microsatellite instability, MSI) 이드물고, 양전자방출단층촬영 (positron emission tomography, PET) 검사에서관찰될가능성도적다. 28 한편, 만성이나과거감염자에서발생한위암은 H. pylori 음성위암이아니라 H. pylori 가사라진후의위암이므로, H. pylori 양성위암에비해서위내세균총의조성이다양하고 OTU가높다. 24,25 이미위축성및화생성변화가진행된위암환자에서는장형위암과미만형위암이모두진단될수있다. 15 후자의경우, 장형위암이미만형위암으로진행된것이므로일부는혼합형 (Lauren s mixed-type) 으로진단되기도하며, 천천히진행하므로만성위염시관찰되는다양한위내세균총이발견된다. 16,19,24 H. pylori 가사라진후에도위암화과정을촉진시키는아질산염 (nitrite) 생성균들은계속증식해서미생물의다양성을이룬다. 20 나아가서당대사에관여하는균들까지많아지면당흡수 (glucose uptake) 도증가하며, 만성감염상태에서의장형위암은 MSI 와 PET 검사에서양성으로나올확률이미만형위암에비해서높다. 28,29 5. H. pylori 가아닌위내세균총이위암화과정에미치는영향 1) Proteobacteria 위암환자에서 H. pylori 다음으로흔한 Proteobacteria 문은 non-h. pylori Helicobacter (NHPH) 로서, 대부분은 H. pylori 와함께진단되거나 H. pylori 가사라진후에진단된다. 30 NHPH 의유병률은약 % 로보고되며, 애완동물과의접촉이나육류섭취등의경로를통해서감염된다. 31 NHPH 중 Helicobacter suis (Helicobacter heilmannii type 1), H. heilmannii (H. heilmannii type 2), Helicobacter bizzozeronii, Helicobacter bovis, Helicobacter salomonis 는위암뿐만아니라위의말트림프종, 결절성위염, 위궤양환자의위에서도보고되며, 이들을통칭해서 H. heilmannii-like organism (HHLO) 이라고부른다. 32 HHLO 이외에위암환자에서보고된 NHPH 로는 Helicobacter cinaedi와 Helicobacter mustelae가있다. 33,34 NHPH는 H. pylori 보다길이가 3배길고편모가많아서 Giemsa 염색시흔히양성으로보고되지만, H. pylori 처럼많은양의요소분해효소를생성하지못해서 Campylobacter-like organism (CLO) 검사나요소호기검사 (urea breath test) 에서는흔히음성으로보고된다. 35 따라서 CLO 검사나요소호기검사에서는음성이지만, Giemsa 염색에서만양성으로나오면 NHPH 감염을의심할수있다. 일반적으로 Proteobacteria 문은위암환자에서증가하지만, Bergeriella denitrificans와 Epsilonproteobacteria종 (species, sp.), Haemophilus parainfluenzae 를제외한 Haemophilus sp. 와 Neisseria mucosae를제외한 Neisseria sp. 는오히려감소한다 (Table 2). 위암환자에서자주발견되는 Proteobacteria 문으로는 NHPH, Burkholderia, Escherichia, Haemophilus, Klebsiella, Neisseria, Pseudomonas, Shigella, Sulfurospirillum, Campylobacter속이있으며, 그중에는발암성질산니트로질소화합물 (N-nitroso compound, NOC) 을생성하는균도있다. 17,36,37 반면에 Campylobacter나 Helicobacter속은질산염 (nitrate) 의대사에관여하지만, 발암성 NOC 는생성하지않는다. 따라서같은위암환자라도위내세균총에발암성 NOC 를생성하는 Escherichia coli, H. parainfluenzae, Klebsiella pneumonia, N. mucosae, Proteus morgana, Pseudomonas aeruginosa 가많은환자는 H. pylori 나 NHPH 에감염된환자보다 NOC 농도가높게측정되며, 위내세균총에서생성된 NOC 는흡연등으로외부에서유입된 NOC 보다발암성이높다. 38,39 2) Bacteroidetes 위암환자에서보고된 Bacteroidetes 문으로는 Alloprevotella, Bacteroides, Prevotella 속등이있으며, 대부분이그람음성균에해당한다. 36,37 위암환자에서는 NOC 를생성하는 Bacteroides fragilis가흔하며, H. pylori 에감염된후에 Bacteroides속까지감염되어야위암이발생한다는동물실험연구결과도있다. 40 반면에위내세균총의조성이위암과무관하다는동물실험결과도있다. 41 하지만동물의세균총은단조로워서복잡한인체의세균총을대변하지못하기에임상에적용하는데한계가있다. 3) Firmicutes 위암환자에서보고된 Firmicutes 문으로는 Bacillus, Catonella, Clostridium, Dialister, Enterococcus, Eubacterium, Gemella, Lachnospira, Lactobacillus, Parvimonas, Peptococcus, Peptostreptococcus, Staphylococcus, Streptococcus, Veillonella 속등이있으며, 대부분은그람양성균에해당한다 발암성 NOC 를생성하는 Clostridium colicanis, Lactobacillus coleohominis, Veillonella parvula, Enterococcus sp., Peptococcus sp. 은위축성및화생성변화가심해질수록증가한다. 46 Firmicutes 문중에서 Lactobacillus 와 Streptococcus 속에해당하는일부균은유익균으로알려져있다. 5 Lactobacillus 속은젖산 (lactic acid) 을분비해서위점막의표면층을산화시킴으로써 H. pylori, Clostridium difficile, E. coli 등의유해균이증식하는것을방해하지만, 위축성및화생성변화가진행되면서점차감소한다. 한편, Streptococcus 속중 Streptococcus sinensis는일반적으로위암환자에서감소하지만, Streptococ- 98

5 Sun-Young Lee: Changes in Gastric Microbiota during Gastric Carcinogenesis Table 2. Species Reported in Gastric Cancer Patients in the Absence of H. pylori (in Alphabetical Order) Phylum Increased in gastric cancer Decreased in gastric cancer Actinobacteria Rhodococcus sp. Corynebacterium sp. Propionibacterium sp. Bacteroidetes Bacteroides fragilis a Porphyromonas sp. Prevotella sp. (except P. pallens) Prevotella pallens Firmicutes Bacillus sp. Bulleidia sp. Clostridium colicanis a Staphylococcus sp. Enterococcus sp. a Streptococcus sinensis Lactobacillus coleohominis a Peptococcus sp. a Streptococcus anginosus Streptococcus oralis Streptococcus pseudopneumoniae Streptococcus parasanguinis Veillonella parvula a Fusobacteria Fusobacterium nucleatum Leptotrichia sp. Proteobacteria Achromobacter sp. Bergeriella denitrificans Acinetobacter baumannii Epsilonproteobacteria Campylobacter hyointestinalis Haemophilus sp. (except H. parainfluenzae) Citrobacter sp. Neisseria sp. (except N. mucosa) Escherichia coli a Haemophilus parainfluenzae a Helicobacter bizzozeronii Helicobacter bovis Helicobacter cinaedi Helicobacter heilmannii Helicobacter mustelae Helicobacter salomonis Helicobacter suis Klebsiella pneumoniae a Neisseria mucosa a Phyllobacterium sp. Proteus morganii a Pseudomonas aeruginosa a sp., species. a N-nitroso compound producing bacteria. 37,38 cus oralis, Streptococcus anginosus, Streptococcus pseudopneumoniae, Streptococcus parasanguinis 등은 H. pylori 가없는위암환자에서증가한다. 42 그이유는 H. pylori 가없는위암환자대부분이실제로미감염상태가아닌과거감염상태이기때문으로추정된다. 즉, 위축성및화생성변화로위내 ph가상승되어미생물의다양성이형성되기때문에 Streptococcus속중일부는계속해서살아남는것으로추정된다. 4) Actinobacteria Actinobacteria 문의대부분은 Bifidobacterium, Corynebacterium, Propionibacterium, Slackia 속에해당하는상재균으로, 위축성및화생성변화가진행되면서 Corynebacterium 과 Propionibacterium 속은감소한다. 42,44 반면에 H. pylori 활동성감 염이있는위암환자에서는 Corynebacterium 과 Propionibacterium속이 H. pylori 와함께진단되는경우가많다. 17,26 그러나 H. pylori 에비해위내세균총에서차지하는비율이낮아서, 단독적으로위암을유발하지는못할것으로추정된다. 5) Fusobacteria 외기타위암환자에서보고된 Fusobacteria 문으로는 Fusobacterium 과 Leptotrichia속이있다. 29 Fusobacterium 속중에는당, 젖산, 단쇄슬지방산등을생성해서위암화과정을억제하는유익균도있지만, 위암환자에서는유익균보다발암성 NOC 를생성하는 Fusobacterium nucleatum이흔하다. 46 이외에도 Arthropoda 문의 Spodoptera 속과 Deinococcus- Thermus 문의 Deinococcus 속이위암환자에서보고되었지만, 99

6 Korean J Helicobacter Up Gastrointest Res: Vol 18, No 2, June 2018 H. pylori 에비해서차지하는비율이적어서위암화과정에는직접적으로관여하지않을것으로추정된다. 17,26 6. 위내세균총연구의한계와전망 많은연구가진행되고있지만, 위내세균총연구가비용대비효율성 (cost-effectiveness) 이낮고, 임상적으로크게유용하지않을것으로추정되는이유는다음과같다. 첫째, 위에는세균뿐만아니라바이러스나곰팡이, 기생충과같은미생물도존재하며그중에는엡스테인바바이러스 (Epstein-Barr virus), 칸디다 (Candida), 아니사키스 (Anisakis) 처럼위암과의연관성이보고된미생물도있다 그러나아직까지세균외다른미생물총까지종합해서분석한연구는없으며, 이는주로업체를통해서진행되는차세대염기서열분석 (next generation sequencing analysis) 의한계점으로생각된다. 지금처럼분석결과가고가에상업적으로거래되는한, 임상에실제적인도움이되는연구결과를도출하기는어려울것으로예상된다. 둘째, 16S rrna 분석법이널리알려지면서연구자간의실험기법의차이는줄었으나, 기저질환이나약물의영향력까지일관성있게통제한위내세균총연구는드물다. 항생제나위산억제제뿐만아니라항우울제 (Bacteroides 감소 ), 변비약 (Clostridium 감소, Bacteroides 증가 ), 지질강하제 (Bacillus 증가, Ruminococcus 증가 ), 당뇨약 (Bacillus 증가 ), 항혈소판제 ( 균의다양성증가 ) 등의약물도세균총에영향을미친다. 50 예를들면, 양성자펌프억제제 (proton pump inhibitor, PPI) 복용시위산이억제되어위내 ph가 3.8을초과하면 NOC 를생성하는균들이 1,000배까지증가할수있지만, 대부분이병인성이낮은 Enterococcus, Micrococcus, Staphylococcus, Streptococcus 속이라서 PPI 복용만으로는위암이발생하지않는다. 37,51-53 또한자가면역성위축성위염이있으면위내 ph가상승하지만, 위점막손상이심하지않아서위내상재균이보존된다. 54 하지만어느정도의약물복용력과기저질환이세균총의조성에영향을주는지알수없기에, 대부분의세균총연구에는연구자조차인지하지못한선택적비뚤림 (selection bias) 이있을것으로추정된다. 나아가서무수히많은위내세균총의조성을각각의약물과질환별로분석해서인과관계를밝히기는어려울것으로추정된다. 셋째, 점막을직접감염시킨세균총에대한분석이중요함에도불구하고, 여전히많은연구들이분비물이나배설물의세균총분석에집중되어있다. 또한동물의세균총은사람의세균총에비해단순해서동물실험결과를임상에적용하기어려움에도불구하고, 40,41 많은동물실험연구결과물이마치질병에대한해결책을제시한것처럼환상적으로포장되어발표되고있다. 이러한문제점들을해결하지못하면세균총연구는게놈 (genome) 연구처럼임상에도움이될만한실질적인답을제시하지못한채, 일상진료에는무용지물인연구분야로자리매김할가능성도있다. 결 론 그동안위내세균총에대한많은연구가진행되었으나, H. pylori 처럼위암화과정에깊게관여하는균은아직발견되지않았다. 위암화과정중에관찰되는대부분의위내세균총의변화는 H. pylori 감염에의한이차적인변화로, 기저질환이나복용약물에영향을받는다. H. pylori 에감염된적이없거나활동성감염이있는상태에서는위내세균총내 Proteobacteria 와 Actinobacteria 문의비율이 Bacteroidetes 와 Firmicutes 문의비율보다높지만, 위축성및화생성변화로인해위점막이손상된만성감염자나과거감염자에서는그비율이역전된다. 따라서활동성감염상태에서발생한미만형위암환자의위내세균총은대부분이 H. pylori 로구성되지만, 위산분비능이손상된장형위암환자의위내세균총은발암성물질을생성하는균을포함한다양한세균총으로구성된다. 즉, 위암화과정에서관찰되는세균총의변화는위내 ph에의해결정되므로장형위암과미만형위암환자의위내세균총은상이하다. 발암성물질을생성하는균들조차 H. pylori 감염에의한손상으로인해위내 ph가상승해야만증식할수있으며, NHPH 나 Campylobacter속이 H. pylori 없이단독적으로위암을유발하는경우는드물다. 그러나아직바이러스나곰팡이를포함한다른미생물총까지종합해서분석한위내세균총연구는없으므로, H. pylori 이외의미생물총이위암화과정에미치는영향력에대해서는판단하기어렵다. REFERENCES 1. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010;90: Bik EM, Eckburg PB, Gill SR, et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci U S A 2006;103: Pope JL, Tomkovich S, Yang Y, Jobin C. Microbiota as a mediator of cancer progression and therapy. Transl Res 2017;179: Nardone G, Compare D, Rocco A. A microbiota-centric view of diseases of the upper gastrointestinal tract. Lancet Gastroenterol Hepatol 2017;2: Hunt RH, Yaghoobi M. The esophageal and gastric microbiome in health and disease. Gastroenterol Clin North Am 2017;46: Maslowski KM, Mackay CR. Diet, gut microbiota and immune 100

7 Sun-Young Lee: Changes in Gastric Microbiota during Gastric Carcinogenesis responses. Nat Immunol 2011;12: De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 2010;107: Kim JM. Roles of enteric microbial composition and metabolism in health and diseases. Korean J Gastroenterol 2013;62: Spiljar M, Merkler D, Trajkovski M. The immune system bridges the gut microbiota with systemic energy homeostasis: focus on TLRs, mucosal barrier, and SCFAs. Front Immunol 2017;8: Yasmin F, Tun HM, Konya TB, et al. Cesarean section, formula feeding, and infant antibiotic exposure: separate and combined impacts on gut microbial changes in later infancy. Front Pediatr 2017;5: Lee SP, Lee SY, Kim JH, Sung IK, Park HS, Shim CS. Link between serum pepsinogen concentrations and upper gastrointestinal endoscopic findings. J Korean Med Sci 2017;32: Carneiro F. Stomach cancer. In: Steward B, Wild CP, eds. World cancer report. Lyon: International Agency for Research on Cancer, 2014: Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol 2017;3: Peleteiro B, Bastos A, Ferro A, Lunet N. Prevalence of Helicobacter pylori infection worldwide: a systematic review of studies with national coverage. Dig Dis Sci 2014;59: Lee SY. Endoscopic gastritis, serum pepsinogen assay, and Helicobacter pylori infection. Korean J Intern Med 2016;31: Eun CS, Kim BK, Han DS, et al. Differences in gastric mucosal microbiota profiling in patients with chronic gastritis, intestinal metaplasia, and gastric cancer using pyrosequencing methods. Helicobacter 2014;19: Jo HJ, Kim J, Kim N, et al. Analysis of gastric microbiota by pyrosequencing: minor role of bacteria other than Helicobacter pylori in the gastric carcinogenesis. Helicobacter 2016;21: Sung J, Kim N, Kim J, et al. Comparison of gastric microbiota between gastric juice and mucosa by next generation sequencing method. J Cancer Prev 2016;21: He C, Yang Z, Lu N. Imbalance of gastrointestinal microbiota in the pathogenesis of Helicobacter pylori-associated diseases. Helicobacter 2016;21: Aviles-Jimenez F, Vazquez-Jimenez F, Medrano-Guzman R, Mantilla A, Torres J. Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer. Sci Rep 2014;4: Choi HS, Lee SY, Kim JH, et al. Combining the serum pepsinogen level and Helicobacter pylori antibody test for predicting the histology of gastric neoplasm. J Dig Dis 2014;15: Li TH, Qin Y, Sham PC, Lau KS, Chu KM, Leung WK. Alterations in gastric microbiota after H. pylori eradication and in different histological stages of gastric carcinogenesis. Sci Rep 2017;7: Maldonado-Contreras A, Goldfarb KC, Godoy-Vitorino F, et al. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J 2011;5: Ferreira RM, Pereira-Marques J, Pinto-Ribeiro I, et al. Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut 2018;67: Wang L, Zhou J, Xin Y, et al. Bacterial overgrowth and diversification of microbiota in gastric cancer. Eur J Gastroenterol Hepatol 2016;28: Thorell K, Bengtsson-Palme J, Liu OH, et al. In vivo analysis of the viable microbiota and Helicobacter pylori transcriptome in gastric infection and early stages of carcinogenesis. Infect Immun 2017;85:e doi: /IAI Lee HH, Lee SY, Yoon HY, et al. Change of mucosal color in early gastric cancer. J Dig Dis 2012;13: Chung HW, Lee SY, Han HS, et al. Gastric cancers with microsatellite instability exhibit high fluorodeoxyglucose uptake on positron emission tomography. Gastric Cancer 2013;16: Castaño-Rodríguez N, Goh KL, Fock KM, Mitchell HM, Kaakoush NO. Dysbiosis of the microbiome in gastric carcinogenesis. Sci Rep 2017;7: Nakamura M, Takahashi T, Matsui H, et al. About another intragastric Helicobacter bacteria HHLO, H. heilmannii, H. suis - history of discovery, characteristic, diagnosis, treatment. Jap J Helicobacter Res 2013;15: Okiyama Y, Matsuzawa K, Hidaka E, Sano K, Akamatsu T, Ota H. Helicobacter heilmannii infection: clinical, endoscopic and histopathological features in Japanese patients. Pathol Int 2005;55: Baele M, Pasmans F, Flahou B, Chiers K, Ducatelle R, Haesebrouck F. Non-Helicobacter pylori helicobacters detected in the stomach of humans comprise several naturally occurring Helicobacter species in animals. FEMS Immunol Med Microbiol 2009;55: Han HS, Lee KY, Lim SD, Kim WS, Hwang TS. Molecular identification of Helicobacter DNA in human gastric adenocarcinoma tissues using Helicobacter species-specific 16S rrna PCR amplification and pyrosequencing analysis. Oncol Lett 2010;1: Seo TH, Lee SY, Uchida T, et al. The origin of non-h. pylori-related positive Giemsa staining in human gastric biopsy specimens: a prospective study. Dig Liver Dis 2011;43: Osaki T, Mabe K, Hanawa T, Kamiya S. Urease-positive bacteria in the stomach induce a false-positive reaction in a urea breath test for diagnosis of Helicobacter pylori infection. J Med Microbiol 2008;57: Jakszyn P, Bingham S, Pera G, et al. Endogenous versus exogenous exposure to N-nitroso compounds and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST) study. Carcinogenesis 2006;27:

8 Korean J Helicobacter Up Gastrointest Res: Vol 18, No 2, June Bryan NS, Alexander DD, Coughlin JR, Milkowski AL, Boffetta P. Ingested nitrate and nitrite and stomach cancer risk: an updated review. Food Chem Toxicol 2012;50: Kobayashi J. Effect of diet and gut environment on the gastrointestinal formation of N-nitroso compounds: a review. Nitric Oxide 2018;73: Peng X, Zhou L, Gong Y, et al. Non-pylori Helicobacters (NHPHs) induce shifts in gastric microbiota in Helicobacter pylori-infected patients. Front Microbiol 2017;8: Lee CW, Rickman B, Rogers AB, Ge Z, Wang TC, Fox JG. Helicobacter pylori eradication prevents progression of gastric cancer in hypergastrinemic INS-GAS mice. Cancer Res 2008;68: Lertpiriyapong K, Whary MT, Muthupalani S, et al. Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis. Gut 2014;63: Sohn SH, Kim N, Jo HJ, et al. Analysis of gastric body microbiota by pyrosequencing: possible role of bacteria other than Helicobacter pylori in the gastric carcinogenesis. J Cancer Prev 2017;22: Seo I, Jha BK, Suh SI, Suh MH, Baek WK. Microbial profile of the stomach: comparison between normal mucosa and cancer tissue in the same patient. J Bacteriol Virol 2014;44: Dicksved J, Lindberg M, Rosenquist M, Enroth H, Jansson JK, Engstrand L. Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls. J Med Microbiol 2009;58: Delgado S, Cabrera-Rubio R, Mira A, Suárez A, Mayo B. Microbiological survey of the human gastric ecosystem using culturing and pyrosequencing methods. Microb Ecol 2013; 65: Hsieh YY, Tung SY, Pan HY, et al. Increased abundance of Clostridium and Fusobacterium in gastric microbiota of patients with gastric cancer in Taiwan. Sci Rep 2018;8: Wu WK, Yu J, Chan MT, To KF, Cheng AS. Combinatorial epigenetic deregulation by Helicobacter pylori and Epstein-Barr virus infections in gastric tumourigenesis. J Pathol 2016;239: Vogelaar IP, Ligtenberg MJ, van der Post RS, et al. Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect. Fam Cancer 2016; 15: Garcia-Perez JC, Rodríguez-Perez R, Ballestero A, et al. Previous exposure to the fish parasite anisakis as a potential risk factor for gastric or colon adenocarcinoma. Medicine (Baltimore) 2015;94:e Takagi T, Naito Y, Inoue R, et al. The influence of long-term use of proton pump inhibitors on the gut microbiota: an age-sex-matched case-control study. J Clin Biochem Nutr 2018;62: Imhann F, Vich Vila A, Bonder MJ, et al. The influence of proton pump inhibitors and other commonly used medication on the gut microbiota. Gut Microbes 2017;8: Jackson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 2016;65: Tsuda A, Suda W, Morita H, et al. Influence of proton-pump inhibitors on the luminal microbiota in the gastrointestinal tract. Clin Transl Gastroenterol 2015;6:e Parsons BN, Ijaz UZ, D'Amore R, et al. Comparison of the human gastric microbiota in hypochlorhydric states arising as a result of Helicobacter pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use. PLoS Pathog 2017;13:e