Маркеры дисбиоза у пациентов с язвенным колитом и болезнью Крона
Маркеры дисбиоза у пациентов с язвенным колитом и болезнью Крона
Данилова Н.А., Абдулхаков С.Р., Григорьева Т.В. и др. Маркеры дисбиоза у пациентов с язвенным колитом и болезнью Крона. Терапевтический архив. 2019; 91 (4): #–20. DOI: 10.26442/00403660.2019.04.000211
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Аннотация
Результаты современных отечественных и зарубежных исследований указывают на существенную роль кишечной микробиоты в патогенезе воспалительных заболеваний кишечника (ВЗК).
Цель исследования: оценить таксономический и функциональный состав кишечной микробиоты у пациентов с язвенным колитом (ЯК) и болезнью Крона (БК) для выявления ключевых маркеров дисбиоза при ВЗК.
Материалы и методы. Для анализа использованы образцы кала 95 пациентов с ВЗК (ЯК – 78, БК – 17) и 96 здоровых добровольцев. Подготовка библиотеки ДНК и полногеномное секвенирование проводили на платформе SOLiD 5500 W. Таксономическое профилирование осуществляли путем выравнивания ридов, не картировавшихся на hg19, на референсную базу данных маркерных бактериальных последовательностей MetaPhlAn2. Для оценки представленности микробных метаболических путей риды картированы с помощью алгоритма HUNAnN2 на базу данных ChocoPhlAn. Определение уровня короткоцепочечных жирных кислот (КЖК) в кале осуществляли методом газожидкостного хроматографического анализа.
Результаты и обсуждение. Изменения кишечной микробиоты у пациентов с ЯК и БК характеризуются увеличением представленности бактерий фил Proteobacteria и Bacteroidetes на фоне снижения относительного количества бактерий филы Firmicutes и архей филы Euryarchaeota; снижением индекса альфа-разнообразия бактерий, уменьшением представленности бутират-продуцирующих, водород-утилизирующих бактерий, Methanobrevibacter smithii, увеличением представленности Ruminococcus gnavus у пациентов с БК и ЯК и Akkermansia muciniphila у пациентов с БК. Снижение относительной представленности гена Butyryl-CoA: acetate CoA transferase у пациентов с БК, уменьшение абсолютного содержания как отдельных КЖК, так и их суммарного количества, а также изменение соотношения основных КЖК у пациентов с ВЗК могут свидетельствовать об угнетении функциональной активности и количества анаэробной микрофлоры и/или изменении утилизации КЖК колоноцитами.
Заключение. Выявленные изменения можно рассматривать в качестве характерных признаков дисбиоза у пациентов с ВЗК и потенциальных мишеней при подборе персонифицированной терапии.
Ключевые слова: микробиота кишечника, полногеномное секвенирование, дисбиоз, короткоцепочечные жирные кислоты, язвенный колит, болезнь Крона.
The aim of the study was to study the taxonomic and functional composition of the gut microbiota in ulcerative colitis (UC) and Crohn's disease (CD) patients to identify key markers of dysbiosis in IBD.
Materials and methods. Fecal samples obtained from 95 IBD patients (78 UC and 17 CD) as well as 96 healthy volunteers were used for whole-genome sequencing carried out on the SOLiD 5500 W platform. Taxonomic profiling was performed by aligning the reeds, not maped on hg19, on MetaPhlAn2 reference database. Reeds were mapped using the HUNAnN2 algorithm to the ChocoPhlAn database to assess the representation of microbial metabolic pathways. Short-chain fatty acids (SCFA) level were measured in fecal samples by gas-liquid chromatographic analysis.
Results and discussion. Changes in IBD patients gut microbiota were characterized by an increase in the representation of Proteobacteria and Bacteroidetes phyla bacteria and decrease in the number of Firmicutes phylum bacteria and Euryarchaeota phylum archaea; a decrease in the alpha-diversity index, relative representation of butyrate-producing, hydrogen-utilizing bacteria, and Methanobrevibacter smithii; increase in the relative representation of Ruminococcus gnavus in UC and CD patients and Akkermansia muciniphila in CD patients. Reduction of Butyryl-CoA: acetate CoA transferase gene relative representation in CD patients, decrease of absolute content of SCFA total number as well as particular SCFAs and main SCFAs ratio in IBD patients may indicate inhibition of functional activity and number of anaerobic microflora and/or an change in SCFA utilization by colonocytes.
Conclusion: the revealed changes can be considered as typical signs of dysbiosis in IBD patients and can be used as potential targets for IBD patients personalized treatment development.
Key words: gut microbiota, whole-genome sequencing, dysbiosis, short-chain fatty acids, ulcerative colitis, Crohn's disease.
Цель исследования: оценить таксономический и функциональный состав кишечной микробиоты у пациентов с язвенным колитом (ЯК) и болезнью Крона (БК) для выявления ключевых маркеров дисбиоза при ВЗК.
Материалы и методы. Для анализа использованы образцы кала 95 пациентов с ВЗК (ЯК – 78, БК – 17) и 96 здоровых добровольцев. Подготовка библиотеки ДНК и полногеномное секвенирование проводили на платформе SOLiD 5500 W. Таксономическое профилирование осуществляли путем выравнивания ридов, не картировавшихся на hg19, на референсную базу данных маркерных бактериальных последовательностей MetaPhlAn2. Для оценки представленности микробных метаболических путей риды картированы с помощью алгоритма HUNAnN2 на базу данных ChocoPhlAn. Определение уровня короткоцепочечных жирных кислот (КЖК) в кале осуществляли методом газожидкостного хроматографического анализа.
Результаты и обсуждение. Изменения кишечной микробиоты у пациентов с ЯК и БК характеризуются увеличением представленности бактерий фил Proteobacteria и Bacteroidetes на фоне снижения относительного количества бактерий филы Firmicutes и архей филы Euryarchaeota; снижением индекса альфа-разнообразия бактерий, уменьшением представленности бутират-продуцирующих, водород-утилизирующих бактерий, Methanobrevibacter smithii, увеличением представленности Ruminococcus gnavus у пациентов с БК и ЯК и Akkermansia muciniphila у пациентов с БК. Снижение относительной представленности гена Butyryl-CoA: acetate CoA transferase у пациентов с БК, уменьшение абсолютного содержания как отдельных КЖК, так и их суммарного количества, а также изменение соотношения основных КЖК у пациентов с ВЗК могут свидетельствовать об угнетении функциональной активности и количества анаэробной микрофлоры и/или изменении утилизации КЖК колоноцитами.
Заключение. Выявленные изменения можно рассматривать в качестве характерных признаков дисбиоза у пациентов с ВЗК и потенциальных мишеней при подборе персонифицированной терапии.
Ключевые слова: микробиота кишечника, полногеномное секвенирование, дисбиоз, короткоцепочечные жирные кислоты, язвенный колит, болезнь Крона.
________________________________________________
The aim of the study was to study the taxonomic and functional composition of the gut microbiota in ulcerative colitis (UC) and Crohn's disease (CD) patients to identify key markers of dysbiosis in IBD.
Materials and methods. Fecal samples obtained from 95 IBD patients (78 UC and 17 CD) as well as 96 healthy volunteers were used for whole-genome sequencing carried out on the SOLiD 5500 W platform. Taxonomic profiling was performed by aligning the reeds, not maped on hg19, on MetaPhlAn2 reference database. Reeds were mapped using the HUNAnN2 algorithm to the ChocoPhlAn database to assess the representation of microbial metabolic pathways. Short-chain fatty acids (SCFA) level were measured in fecal samples by gas-liquid chromatographic analysis.
Results and discussion. Changes in IBD patients gut microbiota were characterized by an increase in the representation of Proteobacteria and Bacteroidetes phyla bacteria and decrease in the number of Firmicutes phylum bacteria and Euryarchaeota phylum archaea; a decrease in the alpha-diversity index, relative representation of butyrate-producing, hydrogen-utilizing bacteria, and Methanobrevibacter smithii; increase in the relative representation of Ruminococcus gnavus in UC and CD patients and Akkermansia muciniphila in CD patients. Reduction of Butyryl-CoA: acetate CoA transferase gene relative representation in CD patients, decrease of absolute content of SCFA total number as well as particular SCFAs and main SCFAs ratio in IBD patients may indicate inhibition of functional activity and number of anaerobic microflora and/or an change in SCFA utilization by colonocytes.
Conclusion: the revealed changes can be considered as typical signs of dysbiosis in IBD patients and can be used as potential targets for IBD patients personalized treatment development.
Key words: gut microbiota, whole-genome sequencing, dysbiosis, short-chain fatty acids, ulcerative colitis, Crohn's disease.
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10. Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Semin Immunopathol. 2015;37:47-55. doi: 10.1007/s00281-014-0454-4
11. Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE. Metagenomic analysis of the human distal gut microbiome. Science. 2006;5778:1355-9. doi: 10.1126/science.1124234
12. Tap J, Mondot S, Levenez F, Pelletier E, Caron C, Furet JP, Ugarte E, Muñoz-Tamayo R, Paslier DL, Nalin R, Dore J, Leclerc M. Towards the human intestinal microbiota phylogenetic core. Environ Microbiol. 2009;11(10):2574-84. doi: 10.1111/j.1462-2920.2009.01982.x
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16. Truong DT, Franzosa EA, Tickle TL, Scholz M, Weingart G, Pasolli E, Tett A, Huttenhower C, Segata N. MetaPhlAn2 for enhanced metagenomic taxonomic profiling. Nat Methods. 2015;12:902-3. doi: 10.1038/nmeth.3589
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18. Andoh A, Kuzuoka H, Tsujikawa T, Nakamura S, Hirai F, Suzuki Y, Matsui T, Fujiyama Y, Matsumoto T. Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn’s disease. J Gastroenterol. 2012;47:1298-307. doi: 10.1007/s00535-012-0605-0
19. Ohkusa T, Sato N, Ogihara T, Morita K, Ogawa M, Okayasu I. Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody. J Gastroenterol Hepatol. 2002;17(8):849-53.
20. Ott SJ, Musfeldt M, Wenderoth DF, Hampe J, Brant O, Fölsch UR, Timmis KN, Schreiber S. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut. 2004;53:685-93. doi: 10.1136/gut.2003.025403
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Авторы
Н.А. Данилова 1, С.Р. Абдулхаков 1,2, Т.В. Григорьева 1, М.И. Маркелова 1, И.Ю. Васильев 1, Е.А. Булыгина 1, М.Д. Ардатская 3, А.В. Павленко 4, А.В. Тяхт 5, А.Х. Одинцова 6, Р.А. Абдулхаков 2
1 ФГАОУ ВО «Казанский (Приволжский) федеральный университет», Казань, Россия;
2 ФГБОУ ВО «Казанский государственный медицинский университет» Минздрава России, Казань, Россия;
3 ФГБУ ДПО «Центральная государственная медицинская академия» Управления делами Президента РФ, Москва, Россия;
4 ФГБУ «Федеральный научно-клинический центр физико-химической медицины» Федерального медико-биологического агентства России, Москва, Россия;
5 Институт биологии гена РАН, Москва, Россия;
6 Республиканская клиническая больница Минздрава Республики Татарстан, Казань, Россия
The aim of the study was to study the taxonomic and functional composition of the gut microbiota in ulcerative colitis (UC) and Crohn's disease (CD) patients to identify key markers of dysbiosis in IBD.
Materials and methods. Fecal samples obtained from 95 IBD patients (78 UC and 17 CD) as well as 96 healthy volunteers were used for whole-genome sequencing carried out on the SOLiD 5500 W platform. Taxonomic profiling was performed by aligning the reeds, not maped on hg19, on MetaPhlAn2 reference database. Reeds were mapped using the HUNAnN2 algorithm to the ChocoPhlAn database to assess the representation of microbial metabolic pathways. Short-chain fatty acids (SCFA) level were measured in fecal samples by gas-liquid chromatographic analysis.
Results and discussion. Changes in IBD patients gut microbiota were characterized by an increase in the representation of Proteobacteria and Bacteroidetes phyla bacteria and decrease in the number of Firmicutes phylum bacteria and Euryarchaeota phylum archaea; a decrease in the alpha-diversity index, relative representation of butyrate-producing, hydrogen-utilizing bacteria, and Methanobrevibacter smithii; increase in the relative representation of Ruminococcus gnavus in UC and CD patients and Akkermansia muciniphila in CD patients. Reduction of Butyryl-CoA: acetate CoA transferase gene relative representation in CD patients, decrease of absolute content of SCFA total number as well as particular SCFAs and main SCFAs ratio in IBD patients may indicate inhibition of functional activity and number of anaerobic microflora and/or an change in SCFA utilization by colonocytes.
Conclusion: the revealed changes can be considered as typical signs of dysbiosis in IBD patients and can be used as potential targets for IBD patients personalized treatment development.
Key words: gut microbiota, whole-genome sequencing, dysbiosis, short-chain fatty acids, ulcerative colitis, Crohn's disease.
1 ФГАОУ ВО «Казанский (Приволжский) федеральный университет», Казань, Россия;
2 ФГБОУ ВО «Казанский государственный медицинский университет» Минздрава России, Казань, Россия;
3 ФГБУ ДПО «Центральная государственная медицинская академия» Управления делами Президента РФ, Москва, Россия;
4 ФГБУ «Федеральный научно-клинический центр физико-химической медицины» Федерального медико-биологического агентства России, Москва, Россия;
5 Институт биологии гена РАН, Москва, Россия;
6 Республиканская клиническая больница Минздрава Республики Татарстан, Казань, Россия
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The aim of the study was to study the taxonomic and functional composition of the gut microbiota in ulcerative colitis (UC) and Crohn's disease (CD) patients to identify key markers of dysbiosis in IBD.
Materials and methods. Fecal samples obtained from 95 IBD patients (78 UC and 17 CD) as well as 96 healthy volunteers were used for whole-genome sequencing carried out on the SOLiD 5500 W platform. Taxonomic profiling was performed by aligning the reeds, not maped on hg19, on MetaPhlAn2 reference database. Reeds were mapped using the HUNAnN2 algorithm to the ChocoPhlAn database to assess the representation of microbial metabolic pathways. Short-chain fatty acids (SCFA) level were measured in fecal samples by gas-liquid chromatographic analysis.
Results and discussion. Changes in IBD patients gut microbiota were characterized by an increase in the representation of Proteobacteria and Bacteroidetes phyla bacteria and decrease in the number of Firmicutes phylum bacteria and Euryarchaeota phylum archaea; a decrease in the alpha-diversity index, relative representation of butyrate-producing, hydrogen-utilizing bacteria, and Methanobrevibacter smithii; increase in the relative representation of Ruminococcus gnavus in UC and CD patients and Akkermansia muciniphila in CD patients. Reduction of Butyryl-CoA: acetate CoA transferase gene relative representation in CD patients, decrease of absolute content of SCFA total number as well as particular SCFAs and main SCFAs ratio in IBD patients may indicate inhibition of functional activity and number of anaerobic microflora and/or an change in SCFA utilization by colonocytes.
Conclusion: the revealed changes can be considered as typical signs of dysbiosis in IBD patients and can be used as potential targets for IBD patients personalized treatment development.
Key words: gut microbiota, whole-genome sequencing, dysbiosis, short-chain fatty acids, ulcerative colitis, Crohn's disease.
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