Almanac of Clinical MedicineAlmanac of Clinical MedicineАльманах клинической медицины2072-05052587-9294Moscow Regional Research and Clinical Institute (MONIKI)770810.18786/2072-0505-2023-51-007REVIEW ARTICLEОБЗОРReview ArticleBile acid dysmetabolism in inflammatory bowel diseasesНарушение метаболизма желчных кислот при воспалительных заболеваниях кишечникаhttps://orcid.org/0000-0001-5318-354X57211460283AAL-2712-20206110-6168KuznetsovaDaria A.КузнецоваДарья Александровна
Russian Federation

MD, PhD, Clinical Laboratory Diagnostics Doctor, Laboratory of Autoimmune Diseases Diagnostics, Center of Molecular Medicine

канд. мед. наук, врач клинической лабораторной диагностики лаборатории диагностики аутоиммунных заболеваний Научно-методического центра Минздрава России по молекулярной медицине

lariwar@mail.ruhttps://orcid.org/0000-0002-4998-36999852-7501LapinSergey V.ЛапинСергей Владимирович
Russian Federation

MD, PhD, Head of Laboratory of Autoimmune Diseases Diagnostics, Center of Molecular Medicine

канд. мед. наук, заведующий лабораторией диагностики аутоиммунных заболеваний Научно-методического центра Минздрава России по молекулярной медицине

svlapin@mail.ruhttps://orcid.org/0000-0002-6302-7767GuboninaIrina V.ГубонинаИрина Владимировна
Russian Federation

MD, PhD, Associate Professor, Chair of Therapy No. 2 (Postgraduate Training)

канд. мед. наук, доцент, доцент 2-й кафедры терапии (усовершенствования врачей)

giv70@bk.ruAcademician I.P. Pavlov First St. Petersburg State Medical UniversityФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Минздрава РоссииMilitary Medical Academy named after S.M. KirovФГБВОУ ВО «Военно-медицинская академия имени С.М. Кирова» Минобороны России100520235111130404202324042023Copyright ©; 2023, Kuznetsova D.A., Lapin S.V., Gubonina I.V.Copyright ©; 2023, Кузнецова Д.А., Лапин С.В., Губонина И.В.2023Kuznetsova D.A., Lapin S.V., Gubonina I.V.Кузнецова Д.А., Лапин С.В., Губонина И.В.https://creativecommons.org/licenses/by-nc/4.0https://almclinmed.ru/jour/article/view/7708

Aim: To summarize the state-of-the-art data on the molecular mechanisms of bile acid (BA) synthesis and absorption, their impaired absorption and receptor-dependent signaling, as well as on the effects of the gut microbiota on BA metabolism in inflammatory bowel diseases (IBD).

Key messages: BA malabsorption is one of the relevant mechanisms in the development of diarrhea in IBD. It may occur due to various disorders of the ileum, such as terminal ileitis, ileocolitis or ileocecal resection in Crohn's disease and ileoanal reservoir in ulcerative colitis. Molecular mechanisms of BA malabsorption in IBD are related to a defect in the BA uptake by the apical sodium dependent bile acid transporter (ASBT), as well as to a decrease in the expression of pregnane X receptor (PXR) and farnesoid X receptor (FXR), whose activation by glucocorticoids results in an increase in the BA reabsorption in the ileum and a decrease in hologenic diarrhea. The metabolic profile of luminal BA in IBD is characterized by an increased content of conjugated and 3-OH-sulfated BA and reduced levels of secondary BA. The decrease in the relative abundance of the Lachnospiraceae and Oscillospiraceae spp. in IBD patients leads to a decrease in the efficiency of microbial biotransformation of BA. Changes in the BA metabolic profile in IBD affect the gut microbiota, and impaired interaction with the FXR, PXR, G protein-coupled bile acid receptor (GPBAR1), retinoid-related orphan receptors (RORs) and vitamin D receptor (VDR) results in a pro-inflammatory response and increased intestinal permeability, bacterial translocation, and IBD progression. BA metabolism in IBD-associated primary sclerosing cholangitis (PSC-IBD) is characterized by a significant decrease in the luminal BA pool, and the microbiota composition is remarkable for an increase in the relative abundance of Fusobacterium and Ruminococcus spp., and a decrease in Veillonella, Dorea, Blautia, Lachnospira and Roseburia.

Conclusion: Disordered synergistic interplay of BA with intestinal microbiota results in disruption of the ligand-receptor interaction and BA metabolic transformation, which contributes to the activation of the immune system, formation of a vicious circle of chronic inflammation and IBD progression. Further studies into mutual influence of the gut microbiota, BA metabolism and receptor signaling may promote the development of new methods for the diagnosis and treatment of IBD.

Цель – обобщить современные представления о молекулярных механизмах синтеза и абсорбции желчных кислот (ЖК), нарушении их всасывания и рецептор-зависимой сигнализации, а также влиянии микробиоты кишечника на метаболизм ЖК при воспалительных заболеваниях кишечника (ВЗК).

Основные положения. Мальабсорбция ЖК – один из значимых механизмов в развитии диарейного синдрома при ВЗК. Она может быть обусловлена различной патологией подвздошной кишки: терминальным илеитом, илеоколитом или илеоцекальной резекцией при болезни Крона и илеоанальным резервуаром при язвенном колите. Молекулярные механизмы нарушения всасывания ЖК при ВЗК связаны с дефектом захвата ЖК апикальным натрий-зависимым транспортером (англ. apical sodium-dependent bile acid transporter, ASBT), а также снижением экспрессии прегнанового (англ. pregnane X receptor, PXR) и фарнезоидного (англ. farnesoid X receptor, FXR) Х рецепторов, активация глюкокортикоидами которых приводит к увеличению реабсорбции ЖК в подвздошной кишке и уменьшению хологенного компонента диареи. Метаболический профиль люминальных ЖК при ВЗК характеризуется повышенным содержанием конъюгированных и 3-ОН-сульфатированных ЖК и сниженной концентрацией вторичных ЖК. Уменьшение относительной численности семейств Lachnospiraceae и Oscillospiraceae у пациентов с ВЗК приводит к снижению эффективности микробной биотрансформации ЖК. Изменение метаболического профиля ЖК при ВЗК влияет на микробиоту кишечника, а нарушение взаимодействия с FXR, PXR, G-белок-связанным мембранным рецептором ЖК (англ. G protein-coupled bile acid receptor 1, GPBAR1), ретиноид-связанными орфанными рецепторами (англ. retinoid-related orphan receptors, RORs) и рецептором витамина D (англ. vitamin D receptor, VDR) обусловливает провоспалительный ответ и повышение проницаемости кишечника, бактериальную транслокацию и прогрессирование ВЗК. Метаболизм ЖК при первичном склерозирующем холангите (ПСХ), ассоциированном с ВЗК (ПСХ-ВЗК), характеризуется существенным снижением люминального пула ЖК, а состав микробиоты – увеличением относительного количества рода Fusobacterium и Ruminococcus, и уменьшением – Veillonella, Dorea, Blautia, Lachnospira и Roseburia.

Заключение. Нарушение синергического взаимодействия ЖК и микробиоты кишечника приводит к нарушению лиганд-рецепторного взаимодействия и метаболической трансформации ЖК, что способствует активации иммунной системы, формированию порочного круга хронического воспаления и прогрессированию ВЗК. Дальнейшее изучение взаимовлияния микробиоты кишечника, метаболизма и рецепторной сигнализации ЖК может способствовать разработке новых методов диагностики и лечения ВЗК.

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