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1 REVIEW ISSN , The Korean Journal of Helicobacter and Upper Gastrointestinal Research, 2016;16(2):68-72 위미생물무리에영향을줄수있는요인 박홍준 연세대학교원주의과대학내과학교실 Factors Influencing Gastric Microbiota Hong Jun Park Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea Researches on microbiota in the stomach have entered a revolutionary period in recent years due to the advanced technology that can detect culture-independent gastric microfloras. In spite of its harsh environment, stomach plays a role as an ecosystem for some microbiota. Their composition and number of colony forming units are influenced by several innate defense mechanisms such as low gastric ph, gastric mucus layer, migrating motor complex and some external factors such as gastric acid lowering medications and diet patterns. Here, we review the literatures concerning factors that influence the gastric microbiota.we believe this will be helpful for understanding the role of microbiota in the stomach. (Korean J Helicobacter Up Gastrointest Res 2016;16:68-72) Key Words: Stomach; Microbiota; Gastic acid; Proton pump inhibitors; Gastric juice 서 론 대장세균총에비해서위장세균총에대하여는아직까지알려진바가많지않다. 이는오랜기간동안위장의위산등의환경으로인하여미생물이살기어려운기관이라는개념이보편적으로받아들여져왔고, 연구를위한샘플을채취하기어려웠으며, 위장세균총에서는배양이되지않는세균이약 80% 를차지하는데비해이를확인할수있는효과적인분자생물학적인방법이없었기때문이다. 1 따라서 1983년위장에서 Helicobacter pylori 가발견되기전까지위장내에서발견되는세균들은구강내또는구- 인두에서넘어온일시적인세균들일뿐이라고생각되었다. 2,3 그렇지만 H. pylori 의발견과더불어위장의 Streptococcus, Neisseria 및 Lactobacillus 같이강한산성환경에서도살아남을수있는세균총이존재함이밝혀졌다. 4 최근위장관내시경이널리시행되면서위액뿐만아니라, 위장관점막을비교적쉽게얻을수가있게되었고, 또한, 2006 년 Bik 등 5 이 temporal temperature gradient gel electrophoresis of PCR 을이용하여위장의세균총에대한분류를하는등배양비의존적분자생물학적기법 (culture-independent Received: May 30, 2016 Accepted: June 4, 2016 Corresponding author: Hong Jun Park Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea Tel: , Fax: , ppakongs@daum.net molecular method) 을이용한연구가활발해지고있다. 6-8 위장의효과적인세균의억제방법은위내낮은산도와위장의운동등이있는데, 7 이와같은사람의생리적환경뿐만아니라약물, 위장질환, 식이습관등의외부적인환경에의해서도위장세균총의차이를가져올수있다. 5,9 본고에서는 H. pylori 를제외하고현재까지연구된위장세균총에영향을미치는요인에대하여정리하였다. 본론 1. 연구검체및종의특성위장세균총의기원으로는음식물에섞여서들어온세균들중위산에저항성이있는세균이집락화를이루는경우, 구강에서상재균이넘어온경우및소장에서역류되어집락화를이룬경우등을생각해볼수있다. 16S rdna clone library approach 를이용한사람의위장세균총연구들을살펴보면세균총은구강세균과약 67% 정도일치하여위장세균총의많은부분이구강에서기원하였다고할수있다. 5,10,11 위액만을이용한연구에서는구강에서기원하여일시적으로위장내에존재하는세균이실제로위점막에집락화를이루면서사람에게영향을미치는지여부를알수가없고, 그렇다고하여점막만을이용한연구는실제로존재하는세균에대해과소평가할위험이있다. 12 실제위액을이용한연구에서흔하게발견되는계통형인 Firmicutes, Bacteroidetes, Actinobacteria 등은위점막 Copyright 2016 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 Hong Jun Park: Factors Influencing Gastric Microbiota 에서흔하게발견되는 Firmicutes, Proteobacteria 등과차이가있기때문에, 위장세균총의실체를밝히기위해서는이들모두를이용한연구가필요하다. 5 위장세균총에대한연구결과들은동물및사람을대상으로한연구에서차이가있으며, 또한각동물마다조금씩다른세균총을보여주어종특성에따라달라질수있다 이는각동물의식이와연령에따른차이일수도있지만위장의 ph 정도가중요한결정요인이될수있는데, 쥐의경우위장내 ph 는약 3 4 로비교적높은반면몽골리안저빌이나, 기니피그등의위장내산도는 2 미만으로서로다른미생물생태환경을이루고있다 위장내생태학적환경에따른다양성 1) 위점액 (gastric mucus) 위장에서부터대장에걸친소화관은점액이덮고있는데, 소장및대장점액은세균과장점막의직접적인접촉을막는역할을하고있으며, 위점액은위산으로부터점막세포를보호하는중요한역할을하고있다. 24 위장의점액은대장과마찬가지로안쪽층 (inner mucus layer) 과바깥층 (outer mucus layer) 으로구성되며, 안쪽층은점액을세포벽과고정을담당하고바깥층은단백분해효소등에의해서안쪽층이분해되어형성된다 대장점액보다는적지만위장세균총은점액의바깥층에존재한다고알려져있다. 26 위점액은점액당단백 (mucin glycoprotein) 으로구성되어있는데, 중앙부당화영역 (central glycosylated domain) 에다수의올리고당 (oligosaccharide) 이결합된형태로되어있다. 당화영역은특정세균이결합될수있는리간드 (ligand) 의역할을하게되며, 각개인마다당화전달효소 (glycosyltransferase) 가다르기때문에이로인해당화정도가달라지면서, 약간씩다른세균총을가지게되며, 이것이위장세균총의개인적인다양성의원인이될수있다. 29 2) 위산 (gastric acid) 위- 세균장벽 (gastric bacterial barrier) 에있어서위산은음식과같이들어온세균억제에중요한역할을담당하고있으며, 위내 ph가 4 미만일때, 효과적인억제를할수있다. 30 저염산증 (hypochlorhydria) 은위액의 ph가 4 7인경우, 무염산증 (achlorhydria) 은 7 이상인경우로정의된다. 만성위축성위염과관련하여발생할수있으며, 위산관련위장질환에대한치료로사용되는히스타민수용체억제제 (histamine 2 receptor antagonist, H2RA) 및프로톤펌프억제제 (proton pump inhibitor, PPI) 사용과관련하여저염산증이비교적흔하게발생될수있다. 31 이러한위내산도의변화는상부위장관세균총의종류변화와이에따른하부위장관세균총의변화, 위장 세균의과증식및유해세균의유입을증가시켜위장관감염등을유발시킬수있다고알려져있다. 31 위장관감염증을유발시킬수있는유해세균들은위산관용반응 (acid tolerance response) 을가지고있는데, 이는세균단백의변형을통하여위내와같은척박한환경에적응한결과이다. Escherichia coli, Shigella flexneri 등은 ph 에서일부가살아남을수있으며, Salmonella typhimurium은 ph 3.0 이하에서사멸되기는하나, 적은균수만으로도감염을유발시킬수있도록적응해왔다. 32,33 따라서, 위내 ph가높아지게되는경우이러한세균들에의한위장관감염증의발생이증가할수있다. 최근보고된위산억제제사용과위장관감염증의관련성에대한연구들에대한체계적고찰에서 PPI 의사용은 Clostridium difficile 위장관감염증을약 2배 (OR, 1.96; 95% CI, ), H2RA의사용은약 1.4배 (OR, 1.40; 95% CI, ) 증가시켰으며, Salmonella, Campylobacter 및다른세균등에의한위장관감염증에대해서도 PPI 는약 3.3 배 (OR, 3.33; 95% CI, ), H2RA의사용은약 2배 (OR, 2.03; 95% CI, ) 정도증가시킨다고보고하였다. 34 이러한효과는 H2RA 와는관련성이낮은반면, PPI 사용에서두드러지고특히고용량 PPI 를사용한경우발생률이증가하여위산억제정도와깊은연관성이있는것을보여주었다. 35 일반적으로위장에서발견되는세균총의농도는위액 1 ml 당 10 3 개보다적은 colony forming unit (CFU) 가존재하며, 위장세균총과증식은 10 5 CFU 이상을의미한다. PPI는 H. pylori 이외세균총의과증식을유발하였으며, 이는주로구강- 인두양세균 (oro-pharyngeal like flora) 들이었는데, 정상대조군 (21.3%) 및 H2RA 사용군 (27.8%) 에비해서 PPI 사용군 (58.7%) 이유의하게높은비율을보여주었다. 36 위산억제가어떤종류의세균총의변화를유발시키는지에대한연구는아직까지별로없으나, Garcia-Mazcorro 등 15 은건강한개를대상으로 omeprazole 을투여하였을때, Proteobacteria 문 ( 특히, Acinobacillus), Firmicutes 문 ( 특히, Streptococcus, Fusobacteria) 의증가를보고하였다. 최근 2 18세의소아환자들 100 명을대상으로 PPI 사용전후호흡기및위장내세균총의변화를알아본연구에서는 Firmicutes 문 (Streptococcus, Staphylococcus, Veillonela), Actinobacteria 문 (Rothia, Dermabacter) 등이통계적으로유의한증가가있음을보여주었다. 37 이러한 PPI 의장기간사용은특정위장세균총의지속적인증가를유발하게되는데, 4개월이상 PPI 를사용한경우특히 sulphite-reducing bacteria나 coliform bacteria 의증가와 Lactobaillus 의감소를유발하였으며, 이때, 특정 Lactobacillus 를투여하였을경우, 비정상적으로증가되었던특정세균총이 69

3 Korean J Helicobacter Up Gastrointest Res: Vol 16, No 2, June 2016 감소되어위장생리적장벽 (gastric physiological barrier) 을유지시키는데도움이될수있다는연구결과도보고되었다. 38 위산억제는사람및쥐를대상으로한실험에서위장세균총의과증식뿐만아니라, 대장및분변내특정세균총의과증식을유발하였고, 39 소장내세균과증식도유발시키는것으로여러연구에서보고되어 PPI 사용과관련된위산억제는위장세균총뿐만아니라소장및대장의세균총에도영향을미치는것으로생각된다 ) 식이식이는위장세균총에매우중요한역할을할것으로생각되나, 아직이에대한연구는거의없는실정이며, 이또한동물실험에국한된경우가대부분이다. 쥐를대상으로한실험에서정제되지않은음식을먹인경우가정제된음식을먹인경우보다 Lactobacillus가증가함을보여주었고, 이는 Lactobacillus 의세균벽에있는 peptidoglycans, lipoteichoic acid 에대한고유면역을담당하는 Toll-like receptor 2의감소와연관이있다고하였다. 44 위장세균총과식이와의연관성은향후많은연구가필요한분야이다. 3. 기타특수한상황에서의위장세균총의변화 삼킴장애, 구-인두의병변, 뇌혈관등으로장기간경장영양이필요한경우정상적인위장의세균억제장벽과같은고유방어기전을거치지않고음식내의세균이장내로도달하게되어상부위장관세균총의과증식을유발하게된다. 또한, 경장영양은위산의분비를감소시키게되는데, 이에대한기전은명확하게밝혀지지는않았지만, 음식에의한자극결여, 타액감소및연동운동의감소와더불어위내 nitrate 농도의감소등이그이유로제시되었다. 45 Smith 등 46 은이러한경장영양으로인하여위장세균총중 Enterobacteria 의과증식이발생한다고발표하였고, 이뿐아니라점막고유염증반응의감소, 점막내로세균의이동및전신적인패혈증도증가할수있다고보고하였다. 47 비위관을가지고있는환자의경우하부식도조임기능이감소하여위식도역류증의발생이증가되며식도- 위양방향의세균총의이동이쉽게되어흡인성폐렴의위험이증가하게된다. 48 경피적위루관 (percutaneous endoscopic gastrostomy) 을가진환자의경우, 다른사람들과비슷한구인도세균총을보이지만, 음식이구-인두를통하여위장에도달하지않기때문에, 위장세균총은 Proteus 문, Corynebacterium 문등의균주가주를이루는다른양상을보이게된다. 49 결 론 2000년중반부터본격적으로인간과세균총에대한많은연구가진행되고있다. 이미많은연구들이진행되고있는하부위장관세균총과는달리, 세균이살기힘든환경을가진위장 이라는오래된관념이깨지고한참을지난뒤에야위장세균총에대한연구가활발해진것은세균총연구의방법론적인어려움뿐만아니라, 위산의존재와높은헬리코박터유병률이라는특수한상황이복잡하게엮여있기때문이라고생각된다. 하부위장관세균총의첫관문인위장세균총은하부위장관세균총에많은영향을미칠것으로생각되나아직밝혀져야할것들이많은분야이다. 그중위장세균총에영향을미치는요인들은아직까지연구가거의없는상황이다. 향후위장세균총에대한지식이쌓여서이들의영향과역할, 인간세포와의상호작용기전등이더명확해지면이를이용한치료까지가능하리라기대해본다. REFERENCES 1. Wu WM, Yang YS, Peng LH. Microbiota in the stomach: new insights. J Dig Dis 2014;15: Anderson CM, Langford RF. Bacterial content of small intestine of children in health, in coeliac disease, and in fibrocystic disease of pancreas. Br Med J 1958;1: Gray JD, Shiner M. Influence of gastric ph on gastric and jejunal flora. Gut 1967;8: Yang I, Nell S, Suerbaum S. Survival in hostile territory: the microbiota of the stomach. FEMS Microbiol Rev 2013;37: 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: Azcárate-Peril MA, Sikes M, Bruno-Bárcena JM. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol 2011;301: G401-G Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011;108 Suppl 1: Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature 2011;473: 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: Kazor CE, Mitchell PM, Lee AM, et al. Diversity of bacterial populations on the tongue dorsa of patients with halitosis and healthy patients. J Clin Microbiol 2003;41:

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<30312DC1A4BAB8C5EBBDC5C7E0C1A4B9D7C1A4C3A52DC1A4BFB5C3B62E687770> Journal of the Korea Institute of Information and Communication Engineering 한국정보통신학회논문지(J. Korea Inst. Inf. Commun. Eng.) Vol. 19, No. 2 : 258~264 Feb. 2015 ID3 알고리즘 기반의 귀납적 추론을 활용한 모바일 OS의 성공과 실패에 대한