Клинико-диагностическое значение короткоцепочечных жирных кислот у больных язвенным колитом тема диссертации и автореферата по ВАК РФ 14.00.47, кандидат медицинских наук Косачева, Татьяна Александровна

• Косачева, Татьяна Александровна
• кандидат медицинских наук
• 2006

Оглавление диссертации кандидат медицинских наук Косачева, Татьяна Александровна

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Введение

Глава 1 Обзор литературы Роль короткоцепочечных жирных кислот в патогенезе и терапии язвенного колита

1.1 Физиологическое значение короткоцепочечных жирных кислот

1.2 Клиническое значение короткоцепочечных жирных кислот при некоторых заболеваниях кишечника

1.3 Короткоцепочечные жирные кислоты при язвенном колите

Глава 2 Характеристика больных и методов исследования

2.1 Характеристика больных

2.2 Методы и объем исследований

Глава 3 Изменение профиля и концентрации короткоцепочечных жирных кислот в фекалиях у больных язвенным колитом в зависимости от распространенности, активности и тяжести заболевания

Глава 4 Уровень короткоцепочечных жирных кислот в фекалиях в фазе индукции и поддержания ремиссии язвенного колита

Введение диссертации (часть автореферата) на тему «Клинико-диагностическое значение короткоцепочечных жирных кислот у больных язвенным колитом»

Микробное сообщество, заселяющее пищеварительный тракт человека, отличается видовым разнообразием, сложностью инфраструктуры и многофункциональным действием. Особая роль принадлежит короткоцепочечным жирным кислотам (КЖК), продуцируемым анаэробными микроорганизмами и участвующими в энергообеспечении эпителия толстой кишки, регуляции его обновления и дифференцировки, поддержании ионного обмена и целостности эпителиального барьера (Дубинин A.B. с соавт., 1991; Бабин В.Н. с соавт., 1994; Ардатская М.Д. с соавт., 2001; Roediger, 1994; Cummings, 1995: Velazques et al., 1997; Dudeja et al., 2003).

Клинические и экспериментальные исследования дают веские основания считать, что язвенный колит возникает из-за дефицита энергии в слизистой толстой кишки, а именно - нарушенного синтеза, поглощения и утилизации КЖК (Ireland & Jewell, 1990; Shapman et al., 1991; Williams et al., 1992; Hendson et al., 1993; Roediger, 1994). Эта гипотеза послужила отправной точкой для нового направления в терапии язвенного колита, заключающейся попытках преодоления блока окисления КЖК за счет непосредственной их доставки в пораженные отделы кишечника. Эффективность клизм и свечей КЖК в активную фазу язвенного колита уступала действию традиционных противовоспалительных препаратов (Senagore et al., 1992; Scheppach et al., 1992; Vernia et al., 1995; Ratz et al., 1996; Steinhart et al., 1996; Breuer et al., 1997). Однако это не исключало полезности заместительной терапии КЖК у отдельных групп больных с активным заболеванием и, особенно, в периоде ремиссии (Rhodes & Tomas, 2001). Были обнаружены уникальные свойства масляной кислоты, ставящие ее в ряд наиболее перспективных средств для предупреждения реактивации язвенного колита. Это способность ингибировать NFkB (Inan et al., 2000; Lawrence et al., 2001; Luhrs et al., 2001) и снижать численность ТоН-рецепторов на эпителии (Isono et al., 2004). Данные мишени по современных представлениям являются ключевыми в терапии воспалительных заболеваний кишечника. Внимание исследователей сконцентрировалось на регуляции эндогенного синтеза КЖК как метода профилактики обострений. Наиболее живой интерес в этом отношении возбуждают пребиотики — диетические субстанции, способствующие росту и метаболической активности «полезных» кишечных бактерий (Jacobasch et al., 1999; Bird et al., 2000; Sartor, 2004). Эти субстанции повышают концентрацию комменсальных пробиотических бактерий, снижают внутрипросветную рН и повышают продукцию КЖК. В эксперименте и клинике было показано, что пребиотики способны купировать активность воспаления, предупреждать развитие колита (Madsen et al., 1999; Araki et al., 2000; Videla et al., 2001; Fukuda et al., 2002). Более того, в контролируемых исследованиях пребиотики демонстрировали эффективность равноценную месалазину в поддержании ремиссии язвенного колита (Fernandez-Banares et al., 1999; Kanauchi et al., 2003). Конечно, небольшая продолжительность терапии, малочисленные выборки и эффект-плацебо (Ilnyckyi et al., 1997) не позволяют высказать категорическое суждение о роли КЖК в поддерживающем лечении язвенного колита. Однако, учитывая физиологическое значение пребиотиков, идея использования диетических воловокон высказывается многими исследователями (Macfarlane & Cummings, 1999: Rfau & Rombeau, 2000). Требуются дополнительные клинические испытания, оценивающие эффект повышения уровня масляной кислоты для пролонгирования ремиссии.

Различно оцениваются изменения КЖК в фекалиях у больных активным язвенным колитом. По данным одних исследований уровень КЖК снижается пропорционально протяженности и активности заболевания (Breuer et al., 1997), но нередко средние значения не выходят за пределы нормы или оказываются повышенными (Ерошкина Т.Д. с соавт., 1985; Семенова Э.Э., 2002; Ардатская М.Д., 2003; Hallert et al., 2003). Неоднозначно интерпретируется и прогностическая ценность определения КЖК. Низкие значения согласно одним исследователям коррелируют с положительным эффектом противовоспалительной терапии у больных активным язвенным колитом, в других - нет (Steinhart et al., 1994). Более того, низкий уровень метаболизма масляной кислоты в фазе ремиссии язвенного колита рассматривается как предвестник скорого обострения (den Hond et al., 1998).

На основании выше изложенного представляется перспективным изучить клиническое значение исследования профиля КЖК в фекалиях как маркера активности и прогноза язвенного колита, а также возможности профилактики обострений путем регуляции уровня КЖК про- и пребиотиками.

Цель исследования;

Определение роли КЖК в становлении и поддержании ремиссии язвенного колита.

Задачи исследования:

1. Определить экскрецию и профиль КЖК в фекалиях в периоде обострения язвенного колита в зависимости от локализации, протяженности поражения и тяжести атаки.

2. Оценить характер изменений метаболитов кишечной микрофлоры на фоне противовоспалительной терапии в фазе стихания активности язвенного колита и в периоде ремиссии.

3. Установить возможность использования параметров кишечного гомеостаза для прогнозирования эффективности лечения и сроков возникновения обострения.

4. Сравнить динамику экскреции КЖК на фоне профилактического лечения аминосалицилатами, про- и пребиотиками.

Научная новизна:

В результате проведенных исследований установлено, что качественные показатели КЖК характеризуются постоянством, являясь важным параметром кишечного гомеостаза. Уровень КЖК при активном язвенном колите определяется их синтезом в правых отделах ободочной кишки и абсорбцией в пораженных сегментах. Он может быть в пределах нормальных значений или возрастать при дистальном и левостороннем поражении. Для резкого снижения синтеза и экскреции КЖК при тотальном колите необходимо выраженное воспаление в слепой и восходящей кишке с разрушением пристеночного слоя слизи, где обнаруживается основная синтезирующая анаэробная флора.

На фоне противовоспалительного лечения в периоде стихания активности заболевания и в фазе ремиссии наблюдается достоверное повышение уровня КЖК. Таким образом, впервые выявлена важная закономерность, свидетельствующая о том, что повышенный синтез КЖК способствует саногенезу язвенного колита, его репаративной фазе.

Практическая ценность работы:

Впервые подтверждена целесообразность применения пребиотических препаратов (микрокристаллическая целлюлоза, мукофальк) при стихании активности язвенного колита с целью установления и поддержания ремиссии.

Внедрение пребиотиков в поддерживающую терапию больных язвенным колитом позволит сократить объем противовоспалительного лечения и уменьшит побочные явления, связанные с приемом медикаментозных препаратов.

Апробация работы

Результаты работы доложены и обсуждены на 7-ом Славяно-Балтийском форуме в г.Санкт-Петербурге, 6-ом Съезде НОГ России в г.Москве. По материалам исследования опубликовано 5 научных работ.

Объем и структура диссертации

Диссертация состоит из введения, обзора литературы, описания материала и методов исследования, изложения результатов собственных исследований, заключения.

Заключение диссертации по теме «Гастроэнтэрология», Косачева, Татьяна Александровна

ВЫВОДЫ:

1. У больных язвенным колитом отмечаются изменения количества экскретируемых короткоцепочечных жирных кислот, при стабильных соотношениях их в спектре, что является одним из важных параметров кишечного гомеостаза.

2. Экскреция короткоцепочечных жирных кислот в фекалиях у больных язвенным колитом возрастает по мере увеличения протяженности и активности воспалительного процесса. Истинный дефицит короткоцепочечных жирных кислот отмечается при тяжелом тотальном колите из-за приостановки их синтеза.

3. Усиленная продукция короткоцепочечных жирных кислот в периоде становления и поддержания ремиссии способствует саногенезу язвенного колита.

4. Абсолютные концентрации короткоцепочечных жирных кислот отражают тяжесть заболевания и, наряду с другими показателями, могут использоваться в качестве маркера прогноза ответа на противовоспалительное лечение.

5. Для интенсификации репаративно-восстановительных процессов у больных язвенным колитом могут применяться пребиотические препараты, способствующие повышенной продукции бактериальных метаболитов.

ПРАКТИЧЕСКИЕ РЕКОМЕНДАЦИИ

1. Повышенный синтез и экскреция КЖК с фекалиями у больных язвенным колитом при низком клиническом индексе активности отражает начало восстановительно-репаративных процессов в кишечнике.

2. Как показатель, отражающий тяжесть язвенного колита, уровень КЖК может использоваться для прогнозирования ответа на проводимую противовоспалительную терапию.

3. Для усиления синтеза КЖК при стихании активности язвенного колита следует применять пребиотики - метилцеллюлозу и мукофальк с целью установления и поддержания ремиссии. Прием препаратов бифидумбактерий без пребиотиков, согласно нашим данным, не способствует росту количества КЖК.

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