Microbiota intestinal e saúde

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<p>Gastroenterologia e Hepatologia 44 (2021) 519--535</p><p>Gastroenterologia e Hepatologia</p><p>www.elsevier.en/gastroenterologia</p><p>ANÁLISE</p><p>Microbiota intestinal e saúde</p><p>Júlia Álvareza, 1999.b, José Manuel Fernández Realc, 1999.d, Francisco Garnerdizer, 1999.∗,</p><p>Michael Guemondf, João Miguel Rodríguezg, Michael Saenz de Pipaónh, 1999.dela</p><p>e Yolanda Sanzj</p><p>aServiço de Endocrinologia e Nutrição, Hospital Universitário Príncipe das Astúrias, Meco, Madrid, Espanha</p><p>bDepartamento de Ciências da Saúde, Universidade de Alcala, Alcala de Henares, Madrid, Espanha</p><p>cUnidade de Diabetes, Endocrinologia e Nutrição, Dr. Josep Trueta, Universidade de Girona, Girona, Espanha</p><p>dCIBERobn Fisiopatologia e Nutrição da Obesidade, Espanha</p><p>dizerUnidade de Pesquisa do Aparelho Digestivo, Vall d'Hebron Institut de Recerca, Barcelona, Espanha</p><p>fDepartamento de Microbiologia e Bioquímica de Produtos Lácteos, IPLA-CSIC, Villaviciosa, Astúrias, Espanha</p><p>gDepartamento de Nutrição e Ciência Alimentar, Universidade Complutense de Madrid, Madrid, Espanha</p><p>hServiço de Neonatologia, Hospital Universitário La Paz, Madrid, Espanha</p><p>delaDepartamento de Pediatria, Universidade Autônoma de Madrid, Madrid, Espanha</p><p>jEcologia Microbiana, Nutrição e Saúde, Instituto de Agroquímica e Tecnologia Alimentar, Conselho Superior de Investigação</p><p>Científica (IATA-CSIC), Valência, Espanha</p><p>Recebido em 19 de novembro de 2020; aceito em 24 de janeiro de 2021</p><p>Disponível on-line em 27 de fevereiro de 2021</p><p>PALAVRAS-CHAVE ResumoO corpo humano é povoado por miríades de microrganismos em toda a sua superfície</p><p>e nas cavidades ligadas ao exterior. Os colonizadores microbianos do intestino (microbiota) são</p><p>uma parte funcional e não essencial do organismo humano: contribuem com genes</p><p>(microbioma) e funções adicionais para os recursos da nossa espécie e participam em múltiplos</p><p>processos fisiológicos (desenvolvimento somático, nutrição, imunidade , etc.); . . . . Algumas</p><p>doenças crónicas não transmissíveis da sociedade desenvolvida (atopias, síndrome metabólica,</p><p>doenças inflamatórias, cancro e alguns distúrbios comportamentais) estão associadas à</p><p>disbiose: perda de riqueza de espécies na microbiota intestinal e desvio do ambiente</p><p>microbiano ancestral. As alterações na transmissão vertical do microbioma, o uso de</p><p>antissépticos e antibióticos e os hábitos alimentares da sociedade industrializada parecem estar</p><p>na origem da disbiose. Gerar e manter a diversidade na microbiota é um novo objetivo clínico</p><p>para a promoção da saúde e prevenção de doenças.</p><p>© 2021 O(s) Autor(es). Publicado por Elsevier España, SLU Este é um artigo de acesso aberto sob</p><p>a licença CC BY (http://creativecommons.org/licenses/by/4.0/).</p><p>Disbiose;</p><p>Eubiose;</p><p>Simbiose;</p><p>Doenças</p><p>crônicas</p><p>intransmissível;</p><p>Industrialização;</p><p>Antibióticos;</p><p>Dieta;</p><p>Probióticos</p><p>∗Autor para correspondência.</p><p>E-mail:fguarner@telefonica.net (F. Guarner).</p><p>https://doi.org/10.1016/j.gastrohep.2021.01.009</p><p>0210-5705/© 2021 O(s) Autor(es). Publicado por Elsevier España, SLU Este é um artigo de acesso aberto sob a licença CC BY (http://</p><p>creativecommons.org/licenses/by/4.0/).</p><p>https://doi.org/10.1016/j.gastrohep.2021.01.009</p><p>http://www.elsevier.es/gastroenterologia</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/j.gastrohep.2021.01.009&domain=pdf</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>mailto:fguarner@telefonica.net</p><p>https://doi.org/10.1016/j.gastrohep.2021.01.009</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>Alvarez J, Fernandez Real JM, Guarner F et al.</p><p>PALAVRAS-CHAVE Micróbios intestinais e saúde</p><p>Disbiose;</p><p>Eubiose;</p><p>Simbiose;</p><p>Crônica</p><p>não comunicável</p><p>doenças;</p><p>Industrialização;</p><p>Antibióticos;</p><p>Dieta;</p><p>Probióticos</p><p>AbstratoO corpo humano é povoado por miríades de microrganismos em toda a sua superfície</p><p>e nas cavidades ligadas ao exterior. Os colonizadores microbianos do intestino (microbiota)</p><p>fornecem genes e funções adicionais aos recursos da nossa espécie e participam em múltiplos</p><p>processos fisiológicos (desenvolvimento somático, nutrição, imunidade)., etc.). Algumas</p><p>doenças crónicas não transmissíveis da sociedade desenvolvida (atopias, síndrome metabólica,</p><p>doenças inflamatórias, cancro e alguns distúrbios de comportamento) estão associadas à</p><p>disbiose: perda de riqueza de espécies na microbiota intestinal e desvio do ambiente</p><p>microbiano ancestral. As alterações na transmissão vertical do microbioma, o uso de</p><p>antissépticos e antibióticos e os hábitos alimentares na sociedade industrializada parecem estar</p><p>na origem da disbiose. Gerar e manter a diversidade na microbiota é um novo alvo clínico para</p><p>a promoção da saúde e prevenção de doenças.</p><p>© 2021 O(s) Autor(es). Publicado por Elsevier España, SLU Este artigo foi publicado sob a licença</p><p>CC BY (http://creativecommons.org/licenses/by/4.0/).</p><p>Introdução por parto vaginal têm uma microbiota inicial que se</p><p>assemelha à da vagina materna, enquanto aqueles nascidos</p><p>por cesariana apresentam perfis cutâneos ou ambientais</p><p>únicos6. . . . Recém-nascidos prematuros apresentam níveis</p><p>reduzidos de anaeróbios, por exemploBifidobactériaó</p><p>Bacteroides, e níveis mais elevados de enterobactérias, que</p><p>incluem patógenos potenciais (Escherichia colióKlebsiella</p><p>pneumoniae)7. . . . Os antibióticos, mesmo aqueles</p><p>administrados à mãe como profilaxia, alteram a aquisição</p><p>da microbiota intestinal8. . . .</p><p>A microbiota de bebês amamentados exclusivamente</p><p>mostra predominância de microrganismos benéficos, como as</p><p>bifidobactérias, em comparação com bebês alimentados com</p><p>fórmula9. . . . Outros fatores como a presença de irmãos mais</p><p>velhos, animais de estimação ou o ambiente rural ou urbano</p><p>também influenciam5. . . . Com a introdução da alimentação</p><p>sólida e a retirada do aleitamento materno ocorrem mudanças</p><p>importantes e acentuadasBacteroideságuaFirmicuteseles são</p><p>dominantes pelo resto da vida. Aumenta progressivamente a</p><p>diversidade microbiana, a capacidade de degradar carboidratos</p><p>complexos e xenobióticos e de produzir vitaminas. Aos 3 anos,</p><p>a microbiota se assemelha à de um adulto5, embora alguns</p><p>grupos microbianos atinjam seus níveis definitivos na</p><p>adolescência10. . . .</p><p>No adulto, 90% das bactérias intestinais pertencem a 2</p><p>cepas:BacteroideságuaFirmicutes. . . . As Proteobacteria,</p><p>Actinobacteria, Fusobacteria e Verrucomicrobia completam os</p><p>10% restantes juntamente com poucas espécies do domínio</p><p>Archaea11. . . . A microbiota intestinal humana também inclui</p><p>leveduras, fagos e protistas. O componente viral é dominado</p><p>por bacteriófagos. Sabe-se que desempenham um papel crucial</p><p>na configuração do ecossistema, através do controlo da</p><p>proliferação de espécies dominantes e da transferência</p><p>horizontal de genes, mas a grande maioria das sequências</p><p>virais partilha pouca ou nenhuma homologia com bases de</p><p>dados de referência.12. . . . As leveduras formam uma</p><p>comunidade relativamente pouco diversificada, menos de 20</p><p>espécies são identificadas no intestino do adulto saudável, a</p><p>sua abundância relativa é 4 a 5 ordens de grandeza inferior à</p><p>das bactérias, mas têm tamanho de células e genoma</p><p>A saúde de um indivíduo depende de sua biologia (genética,</p><p>desenvolvimento, envelhecimento), estilo de vida</p><p>(alimentação, exercício, consumo de drogas, hábitos</p><p>tóxicos, etc.), ambiente (fatores externos físicos, químicos,</p><p>biológicos, psicossociais, socioculturais)., etc. .) e do sistema</p><p>de saúde que o serve (utilização dos serviços, eficácia,</p><p>eficiência, etc.). 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p><p>está implicada, de</p><p>uma forma ou de outra, em muitas dessas variáveis.</p><p>Especificamente, a investigação experimental e clínica ao</p><p>longo da última década sublinhou o impacto funcional das</p><p>comunidades microbianas que habitam o intestino dos</p><p>animais, incluindo os seres humanos. A microbiota</p><p>intestinal desempenha um papel relevante na saúde e na</p><p>doença. Embora ainda não tenhamos respostas definitivas</p><p>para descrever a simbiose ideal entre microrganismos e</p><p>hospedeiro, ou qual proporção ou combinação de</p><p>microrganismos é mais apropriada para cada indivíduo,</p><p>existem evidências científicas básicas que o médico deve</p><p>conhecer e aplicar na prática clínica.</p><p>Composição e funções da microbiota</p><p>intestinal</p><p>A colonização microbiana e o desenvolvimento de uma</p><p>microbiota intestinal adequada começam no parto, mesmo</p><p>quando pode existir exposição limitada a microrganismos</p><p>durante a fase fetal1. . . . A microbiota intestinal é fundamental</p><p>para o desenvolvimento do sistema imunológico e da</p><p>homeostase do indivíduo2, e as primeiras fases da colonização</p><p>são cruciais. Experimentos em animais livres de germes</p><p>demonstram que a colonização microbiana nos primeiros</p><p>estágios da vida induz funções tróficas e imunológicas, mas isso</p><p>não ocorre mais se a colonização for retardada até a idade</p><p>adulta3,4. . . .</p><p>A aquisição da microbiota é influenciada por numerosos</p><p>fatores5: tipo de parto, idade gestacional, alimentação</p><p>inicial, exposição a antibióticos, etc. Os bebês nascidos</p><p>520</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>Gastroenterologia e Hepatologia 44 (2021) 519--535</p><p>muito maior, contribuindo com recursos funcionais integrados</p><p>ao ecossistema13. . . .</p><p>Os principais gêneros bacterianos são mostrados na figura</p><p>. . . . Ao nível da estirpe, cada indivíduo abriga um padrão</p><p>distinto de comunidades microbianas com muitas estirpes</p><p>únicas não encontradas noutros indivíduos. Existem diferenças</p><p>entre diferentes seções do tubo digestivo e também entre as</p><p>fezes e a mucosa intestinal do mesmo indivíduo, embora as</p><p>mesmas cepas sejam geralmente detectadas em proporções</p><p>variadas. Estudos longitudinais demonstram que fatores como</p><p>dieta, ingestão de medicamentos, viagens ou tempo de trânsito</p><p>colônico geram variabilidade na composição microbiana de</p><p>amostras fecais de um mesmo indivíduo, mas as diferenças</p><p>entre diferentes indivíduos são muito maiores do que as</p><p>variações intraindividuais. Estas flutuações podem ser</p><p>perceptíveis, mas o ecossistema microbiano tende a regressar</p><p>ao seu padrão típico. A resiliência é uma característica</p><p>importante de um ecossistema microbiano intestinal saudável e</p><p>consiste na capacidade de retornar ao estado anterior à</p><p>perturbação, por exemplo, após um episódio de diarreia aguda</p><p>ou após tratamento com antibióticos.14. . . .</p><p>Embora cada indivíduo possua uma composição distinta,</p><p>a estrutura geral obedece a padrões que se repetem em</p><p>diferentes indivíduos e foram definidos como enterótipos. O</p><p>conceito de enterótipo sugere que o ecossistema</p><p>microbiano no intestino humano está em conformidade</p><p>com estados internos de simbiose entre os vários membros</p><p>da comunidade microbiana, provavelmente determinados</p><p>pelas próprias redes metabólicas ou sociais nas quais estão</p><p>integrados. Estas interações explicam a estabilidade e</p><p>resiliência de um ecossistema sujeito a flutuações.</p><p>Indivíduos do enterótipo 1 são caracterizados pela</p><p>dominância deBacteroides,aqueles do enterótipo 2 pelos de</p><p>Prevotellae os do enterótipo 3 pelos deRuminococo ó</p><p>Bifidobactéria11. . . . A dieta é um dos principais</p><p>condicionantes dos enterótipos (seção 5.1).</p><p>Com a chegada da senescência inicia-se um novo</p><p>período de instabilidade. O envelhecimento está associado</p><p>à perda da diversidade microbiana e a alterações nos níveis</p><p>de alguns microrganismos15,1. . . . As alterações se</p><p>correlacionam com uma disfunção imunológica que foi</p><p>denominada «inflamação», com incremento do estado</p><p>inflamatório e em detrimento da capacidade de gerar</p><p>respostas imunes adaptativas. Os níveis de microrganismos</p><p>com capacidade anti-inflamatória, por ex.Faecalibacterium</p><p>prausnitziie outros microrganismos benéficos, como as</p><p>bifidobactérias, diminuem17. . . . A modulação do</p><p>microbioma ou a administração de alguns destes</p><p>microrganismos poderia contribuir para travar o declínio</p><p>fisiológico relacionado com o envelhecimento. Na verdade,</p><p>a administraçãoAckermansia muciniphilaé capaz de reduzir</p><p>sintomas degenerativos e prolongar a vida em um modelo</p><p>de progéria18. . . .</p><p>onde existe uma alta densidade de microrganismos com</p><p>recursos metabólicos adicionais. O processo mais comum é a</p><p>fermentação de carboidratos complexos, que geram ácidos</p><p>graxos de cadeia curta (AGCCs), principalmente ácido acético,</p><p>propiônico e butírico, que são utilizados pelos enterócitos como</p><p>fonte de energia ou passam para a torrente circulatória</p><p>atingindo órgãos distais e exercitando funções importantes19</p><p>. . . . Também é importante a produção de</p><p>compostos bioativos, como vitaminas do grupo B ou vitamina K</p><p>20.21. . . .</p><p>A microbiota intestinal transforma compostos dietéticos</p><p>inativos em moléculas bioativas. Um exemplo é a</p><p>transformação de algumas isoflavonas da soja em</p><p>compostos com atividade estrogênica como o equol22. . . . A</p><p>microbiota também pode gerar compostos potencialmente</p><p>tóxicos, como a formação de trimetilamina a partir da colina</p><p>e da carnitina presentes na dieta23. . . . A trimetilamina, que</p><p>é absorvida e transformada em óxido de trimetilamina</p><p>(TMAO) no fígado, é fator de risco para doenças</p><p>cardiovasculares24. . . .</p><p>A extração microbiana de energia de um alimento é variável</p><p>e depende da composição microbiana. A microbiota também</p><p>regula o armazenamento de lípidos, pelo que o seu papel na</p><p>obesidade e na síndrome metabólica está a ser investigado25</p><p>. . . . O transplante fecal de camundongos obesos para</p><p>camundongos com peso normal é capaz de transferir o</p><p>fenótipo, fazendo com que estes últimos ganhem mais peso e</p><p>armazenem mais gordura26. . . . Portanto, a microbiota</p><p>intestinal desempenha um papel regulador relevante para a</p><p>homeostase metabólica do indivíduo.</p><p>Maturação e regulação da barreira e função do</p><p>sistema imunológico</p><p>O trato gastrointestinal (TAG) desenvolveu mecanismos de</p><p>defesa contra agentes ambientais adversos aos quais está</p><p>exposto por via oral (alérgenos, contaminantes, patógenos,</p><p>etc.), mantendo, ao mesmo tempo, tolerância à microbiota</p><p>comensal residente ou às proteínas da dieta. . Os</p><p>microrganismos intestinais influenciam o desenvolvimento</p><p>e a função do sistema imunitário, e a quebra deste</p><p>equilíbrio com o seu hospedeiro pode levar à desregulação</p><p>imunitária e contribuir para o surgimento de doenças</p><p>inflamatórias crónicas e autoimunes.27. . . .</p><p>O TGI é uma barreira seletiva constituída por células</p><p>epiteliais, que limitam o contato direto de microrganismos,</p><p>residentes ou transitórios, com células imunes</p><p>especializadas da própria lâmina, e sua disseminação</p><p>sistêmica, contribuindo para a homeostase imunológica (</p><p>Figo. 2). Esta barreira inclui enterócitos (90-95%), células</p><p>enteroendócrinas, células caliciformes(cálice)Células M</p><p>envolvidas na captura de antígeno e células de Paneth. As</p><p>células caliciformes secretam glicoproteínas mucinas, que</p><p>no intestino grosso se acumulam gerando 2 camadas de</p><p>muco e, pela mais externa, aprisionam grande número de</p><p>micróbios, impedindo seu acesso ao epitélio e facilitando</p><p>sua eliminação nas fezes28. . . . No intestino delgado estão</p><p>localizadas as células de Paneth responsáveis pela</p><p>secreção de peptídeos antimicrobianos (defensinas, Reg</p><p>-gama, etc.), que inibem o crescimento de certas bactérias</p><p>Digestão e metabolismo</p><p>A microbiota intestinal desempenha um papel</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0795</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0800</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0805</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0810</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3/sbref0810</p><p>http://refhub.elsevier.com/S0210-5705(21)00058-3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no</p><p>processo digestivo e na regulação metabólica do hospedeiro. Parte</p><p>dos alimentos não é completamente degradada pelas enzimas</p><p>humanas e os resíduos que não são absorvidos chegam ao cólon</p><p>521</p><p>Alvarez J, Fernandez Real JM, Guarner F et al.</p><p>Figura</p><p>sequenciamento massivo de DNA extraído de amostras fecais de indivíduos espanhóis e dinamarqueses da coorte MetaHIT (dados</p><p>publicados na referência Arumugam et al.11).</p><p>Composição bacteriana da microbiota intestinal em nível de gênero, filo ou classe, obtida por</p><p>Figura</p><p>os sistemas imunológico e neuroendócrino (projeto original de Yolanda Sanz).</p><p>Representação esquemática da influência da microbiota e dos seus metabolitos na função de barreira do intestino e</p><p>e evitar seu contato direto com o epitélio29. . . . Por sua vez, as</p><p>bactérias comensais regulam a expressão de genes que</p><p>codificam mucina(MUC-2, MUC-3)e modificar seu padrão de</p><p>glicosilação, bem como a produção de peptídeos</p><p>antimicrobianos, contribuindo para regular a adesão,</p><p>colonização e invasão microbiana27.29. . . .</p><p>A microbiota comensal também tem efeito trófico,</p><p>influenciando a proliferação de células epiteliais e a</p><p>manutenção de junções intercelulares próximas e, desta</p><p>forma, contribui para fortalecer a função do epitélio como</p><p>barreira física contra a entrada de agentes exógenos30. . . . A</p><p>produção de imunoglobulina A secretora</p><p>522</p><p>Gastroenterologia e Hepatologia 44 (2021) 519--535</p><p>(IgAs) constitui outro mecanismo de defesa que limita o acesso</p><p>bacteriano à mucosa. As células dendríticas reconhecem e</p><p>capturam pequenas quantidades de bactérias e interagem com</p><p>as células B e T das placas de Peyer, ativando a produção de IgA</p><p>específica. Estas IgAs são transportadas através do epitélio e,</p><p>uma vez expostas à luz, ligam-se às bactérias intestinais</p><p>contribuindo para o controlo dos agentes patogénicos,</p><p>neutralizando as toxinas e favorecendo a sua eliminação.31. . . .</p><p>Na lâmina propriamente dita, os macrófagos fagocitam e</p><p>eliminam microrganismos que teriam penetrado no epitélio</p><p>intestinal. As células dendríticas parecem estar ainda mais</p><p>envolvidas na coordenação entre a imunidade inata e</p><p>adaptativa. Bactérias ou outros antígenos capturados pelas</p><p>células dendríticas são transportados para os linfonodos</p><p>mesentéricos, onde podem influenciar a diferenciação dos</p><p>linfócitos T em células efetoras ou reguladoras,</p><p>dependendo do tipo de estímulo antigênico e do tônus</p><p>inflamatório. A homeostase intestinal é mantida através de</p><p>um sistema de verificações e equilíbrios entre células T</p><p>efetoras inflamatórias, que incluem células Th1 (CD4).+e CD8</p><p>+que migram para o epitélio tornando-se linfócitos</p><p>intraepiteliais), células Th17 e células T reguladoras Foxp3+</p><p>antiinflamatório (Tregs) envolvido no desenvolvimento da</p><p>tolerância. As bactérias comensais estão implicadas no</p><p>desenvolvimento das células Tregs, na ausência de resposta</p><p>das células T efetoras e na indução de apoptose ou anergia</p><p>das células T, evitando inflamação crônica e fenômenos</p><p>autoimunes. Além disso, as células dendríticas ativadas</p><p>interagem com as células B e T das placas de Peyer,</p><p>induzindo a produção de imunoblogulinas, tanto secretoras</p><p>quanto aquelas que exercem proteção sistêmica.27. . . .</p><p>As células linfóides inatas (ILCs) localizam-se no epitélio</p><p>intestinal e na lâmina própria32, e estão envolvidos na</p><p>manutenção de respostas imunes adequadas a vários</p><p>microrganismos, potencializando a imunidade adaptativa e</p><p>regulando a inflamação e o reparo tecidual na mucosa</p><p>intestinal. As funções dos CLIs também são reguladas pela</p><p>microbiota comensal.</p><p>As interações entre a microbiota e as células do sistema imune</p><p>inato ocorrem através de receptores de reconhecimento de padrões</p><p>moleculares microbianos (TLR, NODs, inflamassomas, etc.) ou de</p><p>metabólitos (triptofano, indóis, butirato) produzidos pela microbiota</p><p>(receptor de hidrocarbonetos de arila [ AhR], receptores acoplados à</p><p>proteína G [GPRs]). Esses estímulos ativam tanto as funções de</p><p>barreira descritas anteriormente, quanto a síntese de outros</p><p>mediadores (citocinas, moléculas coestimuladoras, etc.) que</p><p>regulam a resposta das células imunes do tecido linfóide</p><p>especializado associado ao intestino, coordenando suas ações para</p><p>prevenir a invasão de patógenos e favorecem o desenvolvimento de</p><p>tolerância a antígenos inócuos. Por exemplo, a ativação de TLR2 por</p><p>ácidos lipoteicóicos de bactérias Gram-positivas regula junções</p><p>estreitas entre enterócitos e contribui para prevenir aumentos na</p><p>permeabilidade paracelular, o que poderia provocar ativação</p><p>imunológica excessiva e inflamação sistêmica. Os clostrídios dos</p><p>grupos IV e XIVa induzem a expansão de células T reguladoras na</p><p>lâmina própria já no nível sistêmico, presumivelmente através da</p><p>produção de AGCC, que atuam em receptores acoplados à proteína</p><p>G, modulando a função das células imunológicas33. . . .</p><p>Influência no sistema neuroendócrino</p><p>A microbiota e os metabólitos gerados no intestino pela</p><p>dieta configuram sinais neurais e endócrinos que</p><p>influenciam órgãos e tecidos distantes. Desta forma, a</p><p>microbiota contribui para funções tão diversas como a</p><p>regulação do balanço energético (ingestão, gasto</p><p>energético, metabolismo da glicose, etc.), bem como outras</p><p>que dependem do sistema nervoso, incluindo funções</p><p>cognitivas, humor e comportamento ( eixo microbiota-</p><p>intestino-cérebro).</p><p>A microbiota comensal, por meio da geração de AGCC,</p><p>exerce efeitos tróficos na mucosa intestinal e ativa diversos</p><p>receptores (GPR41 e GPR43), que estimulam a produção de</p><p>hormônios enteroendócrinos pelas células L, como o</p><p>peptídeo semelhante ao glucagon (GLP-1) ou o peptídeo</p><p>tirosina-tirosina (PYY). AGCCs e peptídeos enteroendócrinos</p><p>contribuem para regular a homeostase energética,</p><p>modulando aspectos como metabolismo da glicose,</p><p>sensibilidade à insulina, termogênese e apetite, através de</p><p>efeitos endócrinos em órgãos periféricos (fígado e tecido</p><p>adiposo branco e marrom), e através de vias de sinalização</p><p>neural (nervosa entérica e autonômica). sistemas) que</p><p>chegam ao sistema nervoso central, onde se integram os</p><p>sinais que regulam o equilíbrio energético de curto prazo</p><p>(GLP-1) e longo prazo (insulina, leptina);34. . . . Mais</p><p>recentemente foi sugerido que outros metabólitos</p><p>resultantes da atividade metabólica da microbiota na dieta,</p><p>como os indóis, podem aumentar a sensibilidade dos</p><p>neurônios aferentes do cólon ao GLP-1, contribuindo para</p><p>os efeitos desse hormônio na homeostase energética34. . . .</p><p>Além disso, a microbiota intestinal participa do</p><p>metabolismo e da circulação entero-hepática dos sais</p><p>biliares e contribui para a geração de ácidos biliares</p><p>secundários, que interagem com o receptor TGR5,</p><p>induzindo a diferenciação e aumento das células L e a</p><p>secreção de GLP-1.1 , o que também influencia</p><p>beneficamente a tolerância oral à glicose35. . . .</p><p>As células epiteliais também estão implicadas na síntese</p><p>de glicocorticóides, que desempenham uma função anti-</p><p>inflamatória e endócrina, e tanto a sua síntese como a</p><p>expressão dos seus receptores podem ser modificadas pela</p><p>composição da microbiota intestinal.36. . . . As bactérias</p><p>comensais participam da regulação circadiana dos</p><p>glicocorticóides de maneira dependente do eixo</p><p>hipotálamo-hipófise-adrenal. A depleção da microbiota</p><p>intestinal perturba a expressão de genes envolvidos nos</p><p>ritmos de produção de corticosterona no íleo e isso acarreta</p><p>alterações importantes, como hipersecreção sustentada de</p><p>corticosterona em nível sistêmico e, por sua vez, um estado</p><p>de hiperglicemia, resistência à insulina e</p><p>hipertrigliceridemia37. . . .</p><p>A microbiota também está direta ou indiretamente</p><p>envolvida na síntese de compostos neuroativos, incluindo</p><p>vários neurotransmissores (serotonina, dopamina, ácido</p><p>aminobutírico [GABA], etc.) que influenciam as funções</p><p>cerebrais, o comportamento, o metabolismo e a imunidade.</p><p>A influência da microbiota na síntese da serotonina parece</p><p>particularmente relevante, uma vez que até 90% 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exerce funções essenciais a níveis</p><p>central e periférico, é sintetizado no intestino. A</p><p>523</p><p>Alvarez J, Fernandez Real JM, Guarner F et al.</p><p>ao nível do sistema nervoso central, a serotonina é</p><p>fundamental na regulação do humor, do apetite e das</p><p>funções cognitivas e ao nível do intestino regula a</p><p>inflamação e a motilidade38. . . . A microbiota intestinal pode</p><p>estar envolvida tanto na redução dos níveis de serotonina</p><p>(devido à sua capacidade de metabolizar o triptofano</p><p>atuando como precursor), como na sua produção,</p><p>estimulando a expressão de genes hospedeiros (triptofano</p><p>1 hidroxilase) implicados na sua síntese, possivelmente</p><p>através do estímulo efeito dos AGCCs39. . . . A desregulação</p><p>do sistema serotoninérgico também está relacionada a</p><p>doenças inflamatórias crônicas e à obesidade induzida por</p><p>dieta. A modulação microbiana da biossíntese da serotonina</p><p>e da expressão dos seus receptores atenua a inflamação</p><p>intestinal e os sintomas depressivos38. . . .</p><p>Várias bactérias intestinais codificam tirosinases capazes</p><p>de transformar a tirosina em L-dihidroxifenilalanina (L-</p><p>DOPA), o que por sua vez levaria à síntese de catecolaminas,</p><p>como dopamina, norepinefrina e epinefrina. A dopamina</p><p>tem importante função no sistema de recompensa,</p><p>implicada na regulação do comportamento alimentar e</p><p>também no humor. Por outro lado, a microbiota de alguns</p><p>indivíduos pode degradar o medicamento L-DOPA</p><p>reduzindo a sua biodisponibilidade e a eficácia da sua</p><p>utilização no tratamento da doença de Parkinson.40. . . .</p><p>O GABA é produzido por diversas bactérias intestinais</p><p>através da descarboxilação do glutamato pela ação da</p><p>enzima glutamato descarboxilase, implicada na tolerância</p><p>ao pH ácido e na manutenção da homeostase intracelular</p><p>bacteriana. O GABA é um importante neurotransmissor com</p><p>efeitos inibitórios no cérebro e sua disfunção está implicada</p><p>em doenças como autismo e esquizofrenia. Estudos pré-</p><p>clínicos indicam que a administração de certas bactérias</p><p>probióticas ou prebióticas pode aumentar as concentrações</p><p>de GABA ou dos seus receptores no cérebro, possivelmente</p><p>contribuindo para a melhoria destas doenças.41. . . .</p><p>microbiota, ou perda ou ganho de espécies concretas. Por</p><p>exemplo, nas doenças inflamatórias intestinais, geralmente</p><p>é observada uma perda de bactérias produtoras de</p><p>butirato.(Faecalibacterium, Roseburia, Eubacterium)43que,</p><p>no caso da diarreia associada a antibióticos, coincide com o</p><p>crescimento excessivo de espécies oportunistas, por ex.</p><p>Clostridioides difficilena colite pseudomembranosa44. . . . No</p><p>câncer colorretal é frequente o aumento da abundância</p><p>relativa deFusobactérianas fezes, um gênero próprio da</p><p>microbiota bucal45. . . .</p><p>Múltiplos fatores, como o uso de antibióticos e outros</p><p>medicamentos, estresse, fatores genéticos, dieta, estilo de</p><p>vida, etc., têm sido implicados na origem da disbiose. Se o</p><p>fator desencadeante for intenso ou persistente ao longo do</p><p>tempo, o processo pode levar à doença, geralmente de tipo</p><p>crônico ou recorrente e de padrão inflamatório. Durante os</p><p>primeiros anos de vida, a disbiose materna pode levar a</p><p>alterações na transferência vertical e afetar a aquisição</p><p>inicial da microbiota intestinal, com possíveis consequências</p><p>a curto e longo prazo5. . . .</p><p>Evolução da microbiota intestinal humana</p><p>Avanços recentes na ecologia microbiana e na genómica</p><p>mostram que as principais perturbações das populações</p><p>microbianas humanas correspondem estreitamente às</p><p>principais fases do antropoceno: a) o «paleoantropoceno»</p><p>que começou com o surgimento da agricultura e da</p><p>pecuária no Neolítico; (b) a revolução industrial, no final do</p><p>século XVIII, ec) a “grande aceleração” da década de 1950</p><p>até o presente46,47(Figo. 3).</p><p>O Neolítico foi um processo gradual no qual a humanidade</p><p>estava em transição de uma economia de caçadores-coletores</p><p>para sistemas planejados de produção de alimentos através da</p><p>domesticação de espécies vegetais, animais e microbianas. A</p><p>garantia de um abastecimento alimentar mais contínuo e</p><p>estável reduziu a diversidade da dieta neolítica e também da</p><p>microbiota intestinal. A análise do microbioma preservado em</p><p>coprólitos confirmou que a dieta afetou drasticamente a</p><p>composição do microbioma, uma vez que os microbiomas</p><p>«neolíticos» são semelhantes aos das comunidades rurais</p><p>modernas, preservando dietas ricas em fibras e polissacarídeos</p><p>48--5, mas distintos daqueles das tribos de caçadores-coletores</p><p>que perduraram até os nossos dias51. . . .</p><p>A revolução industrial provocou a segunda grande mudança</p><p>na colonização microbiana dos seres humanos ao passar de</p><p>uma economia rural para uma de caráter urbano,</p><p>industrializado e mecanizado. O êxodo para a cidade gerou</p><p>favelas sem infraestrutura básica de saúde, densamente</p><p>povoadas por pessoas com pouco acesso a alimentos frescos. A</p><p>tuberculose, a difteria, a tosse convulsa, o sarampo, a varíola, a</p><p>cólera, a febre tifóide e muitas outras doenças infecciosas</p><p>espalham-se facilmente, causando elevadas taxas de</p><p>mortalidade.</p><p>Pasteur e Koch demonstraram que as infecções eram</p><p>causadas por microrganismos, e Joseph Lister e outros</p><p>generalizaram o uso de métodos de assepsia e antissepsia em</p><p>cirurgia e medicina. Os avanços médicos e farmacológicos</p><p>(antibióticos) e as medidas de saúde pública para fornecer água</p><p>potável, prevenir a contaminação dos alimentos, etc.,</p><p>Eubiose e disbiose</p><p>As comunidades microbianas que habitam estavelmente</p><p>um nicho vivem num estado de equilíbrio caracterizado pela</p><p>abundância de espécies que têm uma relação de</p><p>comensalismo e mutualismo com o hospedeiro, de modo</p><p>que tanto o hospedeiro como os seus hóspedes beneficiam</p><p>da simbiose. Esta situação é conhecida como “eubiose”. Em</p><p>contraste, o termo “disbiose” define um desequilíbrio que</p><p>envolve perturbação do estado simbiótico e é reconhecido</p><p>por alterações qualitativas e/ou quantitativas na</p><p>composição e funções da microbiota. Contudo, determinar</p><p>o que é uma microbiota “normal”, tanto em composição</p><p>como em funções, não é uma tarefa fácil devido aos</p><p>múltiplos fatores que influenciam a sua configuração, tais</p><p>como comentados anteriormente, e devido à grande inter e</p><p>intravariabilidade individual. condições fisiológicas42. . . .</p><p>Os estados de disbiose são geralmente caracterizados pela</p><p>perda ou representação insuficiente de espécies benéficas que</p><p>geralmente são dominantes, já por um aumento na abundância</p><p>de espécies minoritárias que, muitas vezes, incluem</p><p>patobiontes ou patógenos oportunistas. As mudanças podem</p><p>ser específicas de cada nicho e de cada doença, e podem</p><p>implicar alteração global da estrutura do</p><p>524</p><p>Gastroenterologia e Hepatologia 44 (2021) 519--535</p><p>Figura</p><p>vertical de pais para filhos. O esquema cronológico mostra as etapas sucessivas, os principais fatores e as consequências</p><p>potencialmente derivadas das mudanças. 1: Taxa de doenças infecciosas: 2: Taxa de doenças alérgicas e autoimunes; 3:</p><p>Pasteurização e novos sistemas de conservação de alimentos; 4: Uso de antibióticos; 5: Atividade física; 6: Uso de fórmulas infantis;</p><p>7: Consumo de alimentos processados e/ou ricos em gorduras, açúcar e/ou sal; 8: Taxa de cesárea; 9: Diversidade da microbiota</p><p>associada ao corpo humano. As estrelas indicam grandes mudanças na composição da microbiota intestinal, maiores quanto maior</p><p>for o tamanho da estrela (desenho original de Juan Miguel Rodriguez).</p><p>A microbiota associada ancestralmente a todosHomo sapiensvem mudando ao longo do tempo, bem como sua transmissão</p><p>conseguimos controlar as grandes pragas infecciosas que</p><p>assolaram os nossos antepassados há apenas uma década.</p><p>Mas as novas medidas sanitárias provocaram a terceira grande</p><p>mudança, talvez irreversível, na colonização microbiana do</p><p>homem moderno52. . . . As suas consequências prendem-se com</p><p>o aumento da incidência das novas pragas: as doenças crónicas</p><p>não transmissíveis52. . . .</p><p>resultando em um aumento na atividade das células Th2,</p><p>uma característica dos distúrbios alérgicos.</p><p>Hipótese de velhos 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intestinal y salud</p><p>Introducción</p><p>Composición y funciones de la microbiota intestinal</p><p>Digestión y metabolismo</p><p>Maduración y regulación de la función de barrera y del sistema inmunitario</p><p>Influencia sobre el sistema neuroendocrino</p><p>Eubiosis y disbiosis</p><p>Evolución de la microbiota intestinal humana</p><p>Hipótesis de la higiene</p><p>Hipótesis de los viejos amigos</p><p>Enfermedades asociadas a disbiosis intestinal</p><p>Enterocolitis necrosante</p><p>Sepsis neonatal</p><p>Desnutrición proteica</p><p>Enfermedades atópicas</p><p>Enfermedad metabólica prevalente y deterioro cognitivo</p><p>Diabetes mellitus</p><p>Enfermedad inflamatoria intestinal</p><p>Trastornos funcionales digestivos</p><p>Inmunosenescencia y fragilidad</p><p>Enfermedad injerto contra receptor</p><p>Modulación e intervención funcional</p><p>Dieta</p><p>Prebióticos</p><p>Probióticos</p><p>Simbióticos</p><p>Transmisión de microbiota fecal</p><p>Financiación</p><p>Conflicto de intereses</p><p>Bibliografía</p><p>estudos epidemiológicos começaram a quebrar a</p><p>presumível ligação entre as infecções e a redução do risco</p><p>de alergia: o sarampo e outras infecções que afectam a</p><p>mucosa respiratória não só não protegem contra doenças</p><p>alérgicas, mas, em muitos casos, aumentam o risco55. . . .</p><p>Negligenciar a higiene pessoal não teria impacto relevante</p><p>na incidência de doenças inflamatórias e alérgicas crónicas,</p><p>mas aumentaria as infecções. Evidências epidemiológicas e</p><p>experimentais apoiam uma hipótese diferente, a dos</p><p>«velhos amigos»56. . . . De acordo com esta hipótese, o que</p><p>conduz ao correcto desenvolvimento do sistema imunitário</p><p>não são as infecções por agentes patogénicos na primeira</p><p>infância, mas a exposição precoce e regular a uma vasta</p><p>gama de micróbios inofensivos ou «velhos amigos»,</p><p>presentes ao longo da evolução humana e reconhecidos por</p><p>o sistema imunológico, que o treina para reagir</p><p>adequadamente diante de diversos estímulos ou ameaças.</p><p>As melhorias sanitárias introduzidas gradualmente a partir</p><p>do século XIX teriam implicado uma redução</p><p>Hipótese de higiene</p><p>A hipótese foi proposta por Strachan em 1989, quando</p><p>observou uma correlação inversa entre a febre do feno e o</p><p>número de irmãos mais velhos em uma população de 17.000</p><p>crianças britânicas nascidas em 1958.53. . . . Assumindo que</p><p>mais crianças num agregado familiar significavam mais</p><p>«germes» partilhados, Strachan sugeriu que as infecções na</p><p>primeira infância protegiam contra doenças alérgicas. A palavra</p><p>«higiene» apareceu apenas no título do seu artigo, mas foi o</p><p>suficiente para cunhar o nome de uma hipótese.</p><p>Posteriormente, Bach54propuseram que era possível estender a</p><p>hipótese do campo da alergia para o das doenças autoimunes.</p><p>Até uma explicação científica foi encontrada para apoiar a</p><p>hipótese da higiene: a perda ou redução do contato com</p><p>agentes infecciosos reduz a atividade Th1 (relacionada à</p><p>resposta a infecções bacterianas),</p><p>525</p><p>Alvarez J, Fernandez Real JM, Guarner F et al.</p><p>da nossa exposição aos micróbios que viveram</p><p>ancestralmente em simbiose com o ser humano (Figo. 3).</p><p>Globalmente, as alterações na microbiota dos indivíduos</p><p>nos países industrializados são o resultado de múltiplos</p><p>factores entre os quais a dieta habitual e o uso excessivo de</p><p>antibióticos merecem especial atenção, pois oferecem</p><p>oportunidades para melhorar o curso dos acontecimentos.</p><p>Apesar do grande sucesso dos antibióticos no combate às</p><p>infecções, o seu uso intensivo tem causado dois grandes</p><p>problemas: a) a propagação de bactérias multirresistentes,</p><p>especialmente a partir da década de 80, que é atualmente</p><p>considerada uma das ameaças mais graves à saúde pública</p><p>57, eb) seu impacto negativo e indiscriminado no</p><p>microbioma57, 1999.58. . . . Muitos aspectos da fisiologia</p><p>humana, desde a defesa imunitária ou metabolismo até ao</p><p>comportamento, parecem ser alterados na ausência de uma</p><p>infinidade de genes microbianos. Estudos epidemiológicos e</p><p>experimentais têm demonstrado uma correlação positiva</p><p>entre a exposição a antibióticos e o desenvolvimento de</p><p>praticamente todas as “pragas modernas”, cujo início</p><p>epidêmico remonta à década de 1940, ou seja, à época em</p><p>que começou o uso generalizado dos antibióticos.58. . . . É</p><p>conveniente lembrar que os primeiros 2 anos de vida são o</p><p>período em que o uso per capita de antibióticos é maior59</p><p>. . . .</p><p>A comunidade microbiana nas fezes de recém-nascidos de</p><p>muito baixo peso ao nascer difere significativamente entre</p><p>aqueles que eventualmente desenvolverão NE e aqueles que</p><p>não desenvolverão, especialmente entre aqueles nascidos com</p><p>menos de 27 semanas de gestação62. . . . As diferenças são</p><p>evidentes um mês após o nascimento e precedem o início da</p><p>doença. O aumento de proteobactérias gama causadoras de</p><p>inflamação (enterobactérias) e a diminuição de anaeróbios</p><p>produtores de AGCC parecem ser a assinatura microbiana que</p><p>precede a EN.</p><p>As causas ainda são desconhecidas e cepas de</p><p>proteobactérias gama de bebês que desenvolvem a doença</p><p>estão sendo investigadas. A abundância deBifidobactériaágua</p><p>Lactobacilosparece ser fundamental para a proteção do</p><p>intestino do recém-nascido. A NE pode ser consequência da</p><p>resposta inflamatória secundária ao excesso de</p><p>enterobactérias. A modulação da microbiota intestinal de bebês</p><p>prematuros por meio da alimentação com leite materno e</p><p>suplementos dietéticos diminui o risco de NE. Mais estudos são</p><p>necessários para identificar a composição microbiana ideal e a</p><p>combinação mais eficaz de suplementos63. . . .</p><p>Sepse neonatal</p><p>A microbiota intestinal neonatal sofre mudanças dinâmicas</p><p>em resposta a muitas variáveis nutricionais e ambientais. A</p><p>infecção neonatal é uma causa comum de mortalidade</p><p>infantil em todo o mundo, particularmente em bebês muito</p><p>prematuros. A sepse é definida como uma disfunção</p><p>orgânica potencialmente letal causada por uma resposta</p><p>desregulada do hospedeiro à infecção microbiana. Bebês</p><p>prematuros frequentemente apresentam disbiose neonatal,</p><p>geralmente caracterizada pelo crescimento excessivo de</p><p>uma única espécie das famílias anaeróbias facultativas.</p><p>Enterococcaceae, StaphylococciaeóEnterobactérias). A</p><p>doença surge como consequência da disseminação</p><p>sistêmica de microrganismos intestinais.</p><p>O uso prolongado de antibióticos de amplo espectro em</p><p>recém-nascidos prematuros tem sido associado a um risco</p><p>aumentado de sepse. Um estudo experimental64revisamos</p><p>mecanismos para prevenir a expansão de patobiontes,</p><p>comensais que podem se disseminar sistemicamente, como o</p><p>Klebsiella pneumoniae. . . . No modelo murino, a exposição</p><p>materna a vários antibióticos que erradicam ou enriquecem a</p><p>população deLactobacillus murinusexacerba ou previne a</p><p>sepse, respectivamente, e a administração profilática de alguns,</p><p>mas não todos, lactobacilos previne a sepse. A administração</p><p>também foi eficazE. coli, pela competição nutricional com</p><p>Klebsiella. . . . O nível de oxigênio intestinal parece ser</p><p>determinante na dinâmica da colonização, favorecendo a</p><p>disbiose e a sepse. As vias que restringem o oxigênio luminal</p><p>em adultos não funcionam em recém-nascidos.</p><p>Doenças associadas à disbiose intestinal</p><p>A disbiose da microbiota intestinal tem sido associada a</p><p>uma ampla lista de doenças inflamatórias, autoimunes,</p><p>metabólicas e neoplásicas, e a alguns distúrbios</p><p>comportamentais. O banco de dados Disbiome®</p><p>(https://disbiome.week.be)60, reúne estudos sobre a relação</p><p>microbiota-doença para mais de 300 doenças diferentes (</p><p>Figo. 4). Na maioria deles, a evidência científica revela-se</p><p>insuficiente para distinguir se a disbiose precede a doença</p><p>ou se a própria doença e o seu tratamento levam à disbiose.</p><p>42. . . . No entanto, modelos experimentais de transmissão</p><p>da microbiota fecal (FMT) sugerem que existe uma certa</p><p>relação de causalidade entre a comunidade microbiana</p><p>alterada e algumas doenças26. . . . Esta seção analisa</p><p>doenças com evidência de disbiose intestinal.</p><p>Enterocolite necrosante</p><p>Apesar das melhorias nos cuidados intensivos neonatais, o</p><p>número de crianças que sofrem de enterocolite necrosante (EN)</p><p>está a aumentar devido ao aumento da sobrevivência de</p><p>recém-nascidos de muito baixo peso ao nascer. Na maioria das</p><p>vezes a doença apresenta-se sem aviso prévio e permanece</p><p>devastadora, com altas taxas de mortalidade e complicações.</p><p>Nos sobreviventes, a síndrome do intestino curto pós-cirúrgico</p><p>acarreta morbidade importante: dependência de nutrição</p><p>parenteral, infecções recorrentes, comprometimento do</p><p>crescimento, insuficiência hepática, hospitalizações</p><p>prolongadas e distúrbios de longo prazo do desenvolvimento</p><p>neurológico.</p><p>A prematuridade é o principal fator de risco. A implantação</p><p>deficiente da microbiota intestinal desempenha um papel</p><p>fundamental na sua patogênese61. . . . A estrutura do</p><p>Desnutrição proteica</p><p>A desnutrição afeta mais de um bilhão de pessoas em todo o</p><p>mundo e é uma importante causa de mortalidade. Em muitos casos,</p><p>a desnutrição está associada a diarreia e inflamação intestinal</p><p>(colite), o que contribui para</p><p>o aumento da morbilidade e</p><p>mortalidade. Nos últimos anos, tornou-se evidente que a microbiota</p><p>intestinal pode desempenhar um papel</p><p>526</p><p>Gastroenterologia e Hepatologia 44 (2021) 519--535</p><p>Figura</p><p>microbiota com doenças humanas (https://disbiome.week; referência Janssens et al.60).</p><p>Gráficos estatísticos da web Disbiome®em publicações e estudos que associam mudanças na composição do</p><p>papel modulador neste processo. Na verdade, a desnutrição</p><p>e a deficiência de triptofano parecem ter uma influência</p><p>causal no desenvolvimento de diarreia e colite. O triptofano</p><p>na dieta é absorvido principalmente através da via de</p><p>transporte B0AT1/ACE2 na superfície luminal das células</p><p>epiteliais do intestino delgado. Isto resulta na ativação do</p><p>mTOR (um fator que regula a expressão de peptídeos</p><p>antimicrobianos) diretamente através da detecção de</p><p>nutrientes ou através da via da triptofanicotinamida, que</p><p>afeta notavelmente a composição da microbiota65. . . . Em</p><p>condições de lesão intestinal, um microbioma alterado</p><p>contribui para a gravidade da colite.</p><p>carece de genes que codificam enzimas essenciais para o</p><p>metabolismo de carboidratos e produção de butirato70. . . .</p><p>Doença metabólica prevalente e comprometimento</p><p>cognitivo</p><p>Indivíduos com obesidade e/ou diabetes mellitus tipo 2 (DM2)</p><p>desenvolvem comprometimento cognitivo71, 1999.72. . . . Uma</p><p>meta-análise destacou que a obesidade produz um aumento</p><p>significativo no risco de déficit cognitivo em adultos73. . . . As</p><p>taxas de comprometimento cognitivo em pacientes com DM2</p><p>aumentam entre 1,5 e 2 vezes em comparação com pacientes</p><p>sem DM2. Tanto o aumento da adiposidade quanto a disfunção</p><p>metabólica (alteração da tolerância à glicose e resistência à</p><p>insulina) associadas à obesidade podem afetar o modo</p><p>independente de cognição74. . . .</p><p>Pessoas com obesidade, com DM2 ou com déficits</p><p>cognitivos estabelecidos compartilham mecanismos</p><p>patogênicos semelhantes: inflamação sistêmica de baixo grau,</p><p>resistência à insulina, aumento das reservas corporais de ferro,</p><p>estresse oxidativo, disfunção mitocondrial, alterações</p><p>vasculares (aumento da pressão arterial) e apneia do sono, que</p><p>podem afetar a cognição75. . . . Há evidências de que a</p><p>inflamação crónica de baixo grau danifica diretamente os</p><p>neurónios (diminuição da neurogénese), independentemente</p><p>dos seus efeitos no metabolismo.76, resultando em pior</p><p>desempenho em testes de memória e função executiva,</p><p>redução no volume de massa cinzenta e de massa branca,</p><p>todos diretamente relacionados à adiposidade corporal77. . . .</p><p>Na verdade, algumas meta-análises descobriram que adultos</p><p>com DM2 apresentam alterações negativas claras na função</p><p>motora, função executiva, velocidade de processamento,</p><p>memória verbal e memória visual.78. . . . A memória, função</p><p>executiva e</p><p>Doenças atópicas</p><p>Asma e atopia, classicamente associadas à hiperativação da</p><p>imunidade adaptativa T helper 2 (Th2), são doenças crônicas</p><p>frequentes. A asma afeta mais de 235 milhões de pessoas em</p><p>todo o mundo66. . . . Evidências recentes relacionam atopia e</p><p>asma à composição e função do microbioma. Há menos</p><p>diversidade da microbiota intestinal em bebês de 6 meses de</p><p>idade que desenvolvem sensibilização alimentar até o ano67e</p><p>chiado aos 5 anos68. . . . A abundância de clostridiums e outros</p><p>gêneros do filoFirmicutesdurante a primeira infância está</p><p>associada a uma maior probabilidade de remissão da alergia à</p><p>proteína do leite antes dos 8 anos de idade67. . . . O</p><p>desenvolvimento de alergias, particularmente alergias</p><p>respiratórias, está associado ao aumento da abundância fecal</p><p>deRuminococcus gnavus, que tende a ser baixo em indivíduos</p><p>não alérgicos. Aumento é observadoR.gnavusantes do</p><p>aparecimento de alergias respiratórias coexistindo com eczema</p><p>atópico69. . . . Os AGCCs, e particularmente o butirato, podem</p><p>promover a tolerância. O microbioma de bebês que</p><p>desenvolvem sensibilização alérgica na infância</p><p>527</p><p>https://disbiome.ugent.be/</p><p>Alvarez J, Fernandez Real JM, Guarner F et al.</p><p>estruturas do lobo temporal medial também parecem</p><p>particularmente afetadas em pacientes obesos74. . . . O</p><p>acúmulo de ferro durante o envelhecimento normal do</p><p>cérebro é um achado comum associado ao</p><p>comprometimento cognitivo79, 1999.80, um processo que é</p><p>amplificado na obesidade, especialmente no lobo temporal</p><p>medial e no hipocampo80,81. . . .</p><p>A composição alterada da microbiota intestinal pode</p><p>desempenhar um papel importante como desencadeador</p><p>de inflamação metabólica, resistência à insulina, DM2 e</p><p>cognição alterada82,83. . . . Em modelos de mouse axênico(</p><p>livre de germes),a ausência de micróbios intestinais confere</p><p>proteção contra o desenvolvimento da obesidade e de</p><p>défices cognitivos na aprendizagem e na memória, o que</p><p>apoia o papel da microbiota nas funções cerebrais</p><p>superiores83--8. . . . Um estudo evidenciou que alterações</p><p>recentes de memória em indivíduos obesos estão</p><p>relacionadas ao metabolismo de aminoácidos aromáticos</p><p>pela microbiota intestinal86. . . .</p><p>Distúrbios funcionais digestivos</p><p>A síndrome do intestino irritável é o distúrbio funcional mais</p><p>frequente e caracteriza-se pela presença de dor abdominal</p><p>recorrente associada a alterações no ritmo de deposição,</p><p>seja na forma de constipação ou diarreia. Os pacientes</p><p>apresentam alterações quantitativas nas espécies</p><p>bacterianas intestinais em comparação com a população</p><p>saudável. Os produtores de butirato, por ex.F. prausnitzi, e a</p><p>diversidade microbiana é reduzida em pacientes com</p><p>predominância de diarreia, enquanto os metanógenos são</p><p>aumentados em pacientes com constipação93. . . .</p><p>Em indivíduos com distúrbios funcionais devido ao excesso</p><p>de gases, os sintomas induzidos pelos alimentos, como inchaço,</p><p>distensão e dor, foram relacionados à instabilidade microbiana.</p><p>A dieta rica em vegetais fermentáveis induz sintomas nos</p><p>pacientes e a composição da microbiota intestinal apresenta</p><p>mudanças abruptas nos principais filos e gêneros</p><p>paralelamente ao início dos sintomas. Indivíduos saudáveis</p><p>não manifestam sintomas e a sua microbiota intestinal</p><p>permanece estável94. . . . Estes dados sugerem que a</p><p>competência funcional da microbiota intestinal confere</p><p>estabilidade e previne a ocorrência de sintomas abdominais</p><p>pós-prandiais.</p><p>Diabetes mellitus</p><p>A dieta é um fator importante no perfil da microbiota intestinal,</p><p>com reconhecimento crescente de como vários metabólitos</p><p>microbianos derivados da dieta estão associados à secreção de</p><p>insulina, à sensibilidade à insulina e à incidência de diabetes</p><p>tipo 287. . . . A título de exemplo, o butirato é produzido por</p><p>bactérias específicas que fermentam a fibra alimentar. A perda</p><p>relativa dessas bactérias tem sido objetivada de forma</p><p>consistente tanto no pré-diabetes quanto no diabetes tipo 2 em</p><p>diferentes coortes e diferentes grupos étnicos88. . . . Na</p><p>verdade, a resposta glicémica a uma refeição é determinada</p><p>tanto pela fisiologia do hospedeiro como pela composição da</p><p>microbiota intestinal.89. . . .</p><p>Imunossenescência e fragilidade</p><p>O termo «imunosenescência» aplica-se a alterações no sistema</p><p>imunitário relacionadas com a idade avançada. Consistem</p><p>basicamente na exacerbação progressiva do tônus</p><p>inflamatório e na redução da capacidade de gerar respostas</p><p>adaptativas diante de novos antígenos. Foi observado que o</p><p>aumento dos marcadores inflamatórios séricos (TNF--, IL-6, IL-8,</p><p>PCR) e a deterioração dos índices de fragilidade e comorbidade</p><p>se correlacionam com a diminuição progressiva da riqueza e</p><p>diversidade da microbiota intestinal durante o processo de</p><p>envelhecimento.15. . . . A diminuição da diversidade microbiana</p><p>intestinal é caracterizada por uma redução nas espécies</p><p>produtoras de butirato e um aumento relativo nas</p><p>proteobactérias com potencial inflamatório. Ingestão</p><p>insuficiente de frutas e vegetais pode explicar as mudanças15, já</p><p>que um estudo de intervenção com dieta mediterrânea</p><p>conseguiu melhorar a microbiota intestinal, reverter alterações</p><p>inflamatórias e reduzir índices de fragilidade95. .</p><p>. .</p><p>Doença inflamatória intestinal</p><p>A colite ulcerativa e a doença de Crohn são caracterizadas por</p><p>respostas imunoinflamatórias exageradas contra</p><p>microrganismos não patogênicos da microbiota intestinal,</p><p>gerando lesões ulcerativas que evoluem para cronicidade.</p><p>Numerosos estudos encontraram defeitos marcantes na</p><p>composição da microbiota fecal e associada à mucosa90,91. . . .</p><p>Os pacientes apresentam perda de riqueza e diversidade</p><p>microbiana em comparação com controles saudáveis, com</p><p>produtores reduzidos de butirato (Faecalibacterium, Roseburia,</p><p>Coprococcus, Lachnospira,etc.) e de Ackermansia muciniphila,</p><p>que é colonizador habitual do muco intestinal e com</p><p>crescimento excessivo de proteobactérias, fusobactérias e</p><p>estreptococos. A perda de diversidade é especialmente</p><p>manifesta durante e após surtos de atividade91. . . . A quebra do</p><p>equilíbrio simbiótico devido à incompatibilidade no controle</p><p>imunológico-inflamatório da população microbiana intestinal</p><p>leva à seleção de espécies resistentes ao oxigênio com</p><p>potencial inflamatório.</p><p>Pacientes com colite ulcerosa ou doença de Crohn não</p><p>recuperam um ecossistema microbiano equilibrado durante os</p><p>períodos de remissão, e foi demonstrada variabilidade na</p><p>composição microbiana devido à instabilidade do ecossistema.</p><p>Quanto maior a instabilidade microbiana, maior o risco de novo</p><p>surto92. . . .</p><p>Enxerto de doença contra receptor</p><p>O transplante de progenitores hematopoiéticos é</p><p>tratamento de escolha em diversas doenças, principalmente</p><p>nas hemopatias malignas e não malignas. Sua eficácia é</p><p>limitada por complicações graves e potencialmente fatais,</p><p>como a incidência de infecções intratáveis durante a</p><p>depressão imunológica e a doença do enxerto contra o</p><p>hospedeiro, também chamada de doença do enxerto contra</p><p>o hospedeiro. Está a ser estudado o papel da microbiota</p><p>intestinal no contexto do “reboot” do sistema imunitário</p><p>que supõe o transplante de progenitores hematopoiéticos,</p><p>e o seu possível impacto na apresentação de complicações.</p><p>528</p><p>Gastroenterologia e Hepatologia 44 (2021) 519--535</p><p>A baixa diversidade da microbiota fecal tem sido associada</p><p>ao aumento significativo da mortalidade (52%) em comparação</p><p>com a alta diversidade (8%) e à abundância de enterobactérias (</p><p>Escherichia, Proteus, Klebsiella, etc.) se correlaciona com maior</p><p>incidência de bacteremia e menor sobrevida global96. . . . A</p><p>baixa diversidade bacteriana nas fezes também é preditiva de</p><p>evolução fatal da doença do enxerto versus receptor96. . . . Os</p><p>antibióticos reduzem consideravelmente a diversidade da</p><p>microbiota intestinal e os receptores de transplantes são</p><p>geralmente submetidos a múltiplos tratamentos com</p><p>antibióticos. Observou-se que o uso de antibióticos versus</p><p>anaeróbios ou colonização por bactérias multirresistentes,</p><p>sugerindo exposição frequente ou prolongada a antibióticos,</p><p>está associado a maior incidência de doença do enxerto contra</p><p>receptores96. . . .</p><p>Estas observações abrem a possibilidade de intervir na</p><p>microbiota intestinal do transplantado com o objetivo de</p><p>evitar ou mitigar complicações e melhorar a sua</p><p>sobrevivência. Uma série não controlada em pacientes</p><p>portadores de bactérias multirresistentes demonstrou que</p><p>o TMF, antes ou depois do transplante de células</p><p>progenitoras hematopoiéticas, é uma estratégia eficaz e</p><p>segura para a descolonização de bactérias multirresistentes</p><p>97. . . . Obviamente, mais estudos são necessários para</p><p>confirmar a eficácia do TMF na prevenção de complicações</p><p>em transplantados, mas é certamente uma estratégia</p><p>terapêutica promissora.</p><p>Os enterótipos parecem ser influenciados pelo padrão</p><p>alimentar habitual99. . . . O enterótipoBacteroidesé a mais</p><p>frequente nos países industrializados e está associada a hábitos</p><p>alimentares peculiares à vida urbana. O enterótipoPrevotellaé</p><p>mais frequente em áreas de cultura agrária, com dietas ricas</p><p>em fibras e pobres em proteínas e gordura animal48.100. . . .</p><p>Outros estudos101.102detectaram modificações na microbiota de</p><p>acordo com o período sazonal, notando mudanças em relação</p><p>ao consumo de vegetais e frutas frescas no verão, versus</p><p>alimentos congelados ou enlatados durante o inverno. As</p><p>diferenças dietéticas entre diferentes populações podem ser</p><p>responsáveis pela variabilidade taxonómica do ecossistema</p><p>microbiano intestinal.</p><p>Intervenções dietéticas de curto prazo podem induzir</p><p>mudanças rápidas na composição da microbiota associadas</p><p>a variações drásticas na quantidade de fibra alimentar. A</p><p>magnitude dos efeitos é relativamente modesta em</p><p>comparação com a variabilidade interindividual na</p><p>taxonomia microbiana e as mudanças não são consistentes</p><p>entre diferentes indivíduos, ou seja, cada um muda, mas de</p><p>uma forma diferente103. . . . Observou-se que o incremento</p><p>de proteína e gordura animal juntamente com a ausência</p><p>de fibra alimentar aumenta a abundância de</p><p>microrganismos tolerantes aos sais biliares.(Alótipos,</p><p>Bilophila)e diminui os níveis deFirmicutesque metabolizam</p><p>polissacarídeos complexos vegetais (Roseburia,</p><p>Eubacteriumágua Ruminococo). Por outro lado, o consumo</p><p>abundante de fibra alimentar, frutas, vegetais e outros</p><p>vegetais está associado a incrementos importantes e</p><p>significativos nas espécies fermentativas. Em estudos</p><p>controlados observou-se que o consumo de amido</p><p>resistente ou outros polissacarídeos não digeríveis aumenta</p><p>a abundância de espécies fermentativas como</p><p>Ruminococcus bromii e Eubacterium retal104. . . .</p><p>Em modelos experimentais, um consumo elevado de</p><p>gorduras pode traduzir-se num desequilíbrio do ecossistema</p><p>intestinal que contribui para o desenvolvimento de processos</p><p>inflamatórios. O mecanismo parece ser mediado pelo aumento</p><p>da captação de lipopolissacarídeos, endotoxemia subclínica e</p><p>ativação de TLR4. Este mesmo mecanismo parece contribuir</p><p>para o desenvolvimento de doenças cardiovasculares e</p><p>metabólicas105. . . . Além disso, a microbiota pode contribuir</p><p>para a regulação do metabolismo lipídico e da glicose através</p><p>da interação dos ácidos biliares no íleo terminal e da</p><p>modulação do receptor de ácidos biliares acoplado à proteína</p><p>G1 (TGR5). Esta evidência abre uma linha de investigação sobre</p><p>o envolvimento da microbiota na eficácia e segurança individual</p><p>de alguns dos tratamentos testados com ácidos biliares na</p><p>obesidade106. . . .</p><p>As proteínas também modulam a composição da</p><p>microbiota e a produção de metabólitos. O catabolismo</p><p>microbiano de aminoácidos gera indóis, fenóis, amônia e</p><p>aminas, que podem se combinar com o óxido nítrico para</p><p>formar compostos nitrosos genotóxicos relacionados à</p><p>carcinogênese colorretal.107. . . . Por outro lado, o ácido</p><p>indolepropiônico e o indol-3-acetato resultantes do</p><p>metabolismo microbiano do triptofano mantêm a</p><p>homeostase intestinal, protegem contra a colite</p><p>experimental e/ou reduzem a inflamação dos hepatócitos106</p><p>. . . . A contribuição microbiana para a geração de TMAO</p><p>(um fator de risco cardiovascular23.24) da carnitina e da</p><p>fosfatidilcolina já foi comentado anteriormente.</p><p>Modulação e intervenção funcional</p><p>Modular a microbiota intestinal para melhorar a saúde</p><p>humana é hoje o objectivo de investigação intensiva e</p><p>extensa que testa estratégias como a intervenção dietética</p><p>com vários nutrientes, incluindo prebióticos, probióticos,</p><p>simbióticos e outras estratégias relacionadas (posbióticos,</p><p>paraprobióticos), ou TMF. Muito provavelmente, o</p><p>conhecimento da composição individual da microbiota</p><p>intestinal facilitará futuros protocolos nutricionais</p><p>personalizados para otimizar a saúde. Atualmente, os</p><p>principais objetivos consistem em aumentar a diversidade</p><p>microbiana e fortalecer a capacidade funcional de gerar</p><p>AGCC, especialmente butirato.</p><p>Dieta</p><p>Os nutrientes não são apenas essenciais para a saúde</p><p>humana, mas também para a saúde da microbiota</p><p>intestinal. As funções metabólicas da microbiota intestinal</p><p>estão ligadas à digestão de polissacarídeos complexos, à</p><p>produção de AGCC, ao metabolismo dos ácidos biliares, à</p><p>produção de vitaminas, etc., com os</p><p>consequentes efeitos</p><p>tróficos na barreira intestinal e no sistema imunitário.</p><p>Assim, a alimentação acaba por ser um elemento</p><p>fundamental na simbiose entre a microbiota e o</p><p>hospedeiro, condicionando e modulando o estabelecimento</p><p>da microbiota intestinal na criança, e a sua estrutura e</p><p>funcionalidade no adulto. Além da dieta (componentes</p><p>alimentares, nutrientes, padrões alimentares etc.), outros</p><p>fatores relevantes são medicamentos, condições de higiene,</p><p>ritmo circadiano, jejum intermitente, mudanças sazonais,</p><p>industrialização, etc.98. . . .</p><p>529</p><p>Alvarez J, Fernandez Real JM, Guarner F et al.</p><p>O impacto dos aditivos alimentares na microbiota intestinal</p><p>e na homeostase é uma área pouco estudada, embora se saiba</p><p>que alguns emulsionantes dietéticos, como o polissorbato-80</p><p>ou a carboximetilcelulose, condicionam alterações metabólicas</p><p>em ratos obesos. Da mesma forma, os adoçantes não calóricos</p><p>podem induzir intolerância aos hidrocarbonetos através das</p><p>suas interações com a microbiota, tanto em animais</p><p>experimentais como em humanos.106. . . .</p><p>As dietas vegetarianas ou veganas são ricas em hidratos</p><p>de carbono complexos, pelo que seria de esperar o seu</p><p>impacto benéfico na microbiota intestinal. Alguns estudos</p><p>transversais e de intervenção evidenciaram que as</p><p>mudanças ocorrem ao nível dos diferentes táxons, mas não</p><p>tanto ao nível da riqueza e da diversidade. Estas mudanças</p><p>mínimas podem ser suficientes para justificar os benefícios</p><p>na produção de AGCC que aumentam na população</p><p>vegetariana. É também provável que os benefícios das</p><p>dietas vegetarianas derivem da presença de produtos</p><p>fitoquímicos, como as já mencionadas isoflavonas e outros.</p><p>106. . . .</p><p>A dieta mediterrânica tem demonstrado vastos</p><p>benefícios na saúde da população, reduzindo o risco de</p><p>mortalidade e de muitas doenças crónicas108.109. . . . Estudos</p><p>sugerem que na intervenção dietética a inclusão de</p><p>quantidade e variedade de alimentos vegetais deve ser</p><p>priorizada em detrimento da exclusão de alimentos de</p><p>origem animal, apoiando o conceito de que a diversidade da</p><p>dieta favorece a estabilidade da microbiota.</p><p>comoEubactériaáguaRosebúria.Embora a maioria dos</p><p>prebióticos sejam administrados por via oral, o painel admite</p><p>que também podem ser administrados a outras áreas do corpo</p><p>colonizadas por microrganismos, como a pele ou o trato</p><p>vaginal.</p><p>Menção especial merecem os oligossacarídeos do leite</p><p>materno (HMO), uma mistura de extraordinária</p><p>complexidade com mais de 1.000 estruturas químicas</p><p>descritas que atuam além de meros substratos para a</p><p>microbiota intestinal e influenciam inúmeras funções</p><p>benéficas para a saúde local e sistêmica da lactante.5. . . .</p><p>Seu potencial uso terapêutico na obesidade, resistência à</p><p>insulina, esteatose hepática, ansiedade ou depressão é objeto</p><p>de investigação. As evidências geradas em diversas doenças</p><p>endossam a possibilidade de os prebióticos terem um papel</p><p>promotor da saúde em populações saudáveis, o que pode ser</p><p>detectado através de extensos estudos observacionais111. . . . Os</p><p>prebióticos emergentes em fase de estudo são amido</p><p>resistente e prebióticos sem carboidratos.</p><p>Probióticos</p><p>Os alimentos fermentados por microrganismos como o pão,</p><p>a cerveja, o vinho, o kefir, o iogurte, o kumis ou o queijo</p><p>fazem parte da dieta humana desde o Neolítico, e não</p><p>apenas para fins nutricionais, mas também terapêuticos.</p><p>Uma comissão de especialistas reunida em 2001 pela FAO e</p><p>pela OMS definiu os probióticos como «microrganismos</p><p>vivos que, quando administrados em quantidades</p><p>adequadas, conferem benefício à saúde do hospedeiro»112</p><p>. . . . Esta definição foi amplamente aceita pela comunidade</p><p>científica global e foi coletada no consenso da Sociedade</p><p>Espanhola de Microbiota, Probióticos e Prebióticos</p><p>(SEMIPyP)113e do ISAPP114. . . . Ocasionalmente, o termo</p><p>«probióticos de nova geração» é utilizado para se referir às</p><p>espécies benéficas que fazem parte da microbiota intestinal</p><p>humana (Faecalibacterium prausnitziióRoseburia intestinalis</p><p>). Além disso, outros termos têm sido propostos para</p><p>designar probióticos com indicações em áreas específicas,</p><p>como “psicobióticos” ou “oncobióticos”. A definição de</p><p>probióticos exclui microrganismos mortos e componentes</p><p>ou substâncias produzidas por microrganismos, mesmo</p><p>que demonstrem efeitos biológicos saudáveis. Eles são</p><p>chamados de “paraprobióticos” ou “pós-bióticos”,</p><p>respectivamente.</p><p>Nos consensos SEMIPyP e ISAPP enfatiza-se que os</p><p>probióticos devem ser perfeitamente caracterizados ao nível da</p><p>cepa, e sua viabilidade deve ser mantida durante toda a vida útil</p><p>dos produtos nos quais serão fornecidos. Devem ser</p><p>implementados sistemas de qualidade rigorosos que garantam</p><p>a sua taxonomia e a presença de quantidades suficientes de</p><p>microrganismos viáveis.</p><p>Os microrganismos comercializados como probióticos</p><p>incluem leveduras(Saccharomyces, Kluyveromyces)e bactérias</p><p>de diferentes gêneros(Lactobacillus, Streptococcus,</p><p>Enterococcus, Pediococcus, Bifidobacterium,</p><p>Propionibacterium, Bacillus, Escherichia).A perfeita</p><p>caracterização taxonômica do microrganismo é essencial para</p><p>avaliar sua segurança. Além disso, o conceito probiótico só se</p><p>aplica a estirpes que foram avaliadas em conformidade</p><p>Prebióticos</p><p>Enquanto em meados do século XX a existência de um fator</p><p>bifidogênico presente no leite materno foi reconhecida como</p><p>responsável pelo incremento de bifidobactérias em lactentes, o</p><p>termo prebiótico aparece publicado pela primeira vez em 1995</p><p>110. . . . Gibson e Roberfroid definiram o conceito como «</p><p>ingrediente alimentar não digerível que beneficia o hospedeiro</p><p>ao estimular seletivamente o crescimento e/ou atividade de um</p><p>número limitado de bactérias no cólon, melhorando a saúde do</p><p>hospedeiro». Atendendo a esta definição, apenas alguns</p><p>carboidratos como galacto-oligossacarídeos (GOS), lactulose,</p><p>inulina e fruto-oligossacarídeos (FOS) atendem aos critérios.</p><p>Outros compostos que têm possibilidades de atender a esses</p><p>critérios são isomalte-oligossacarídeos (IMO), xilo-</p><p>oligossacarídeos (XOS), transgalacto-oligossacarídeos (TOS) e</p><p>oligossacarídeos de soja (SBOS). Estão presentes no leite,</p><p>verduras, frutas, legumes, cereais, legumes e frutas secas99. . . .</p><p>Em 2017, o ISAPP revisou o conceito e propôs que um</p><p>prebiótico «um substrato que é utilizado seletivamente por</p><p>microrganismos hospedeiros e confere benefícios à saúde»</p><p>111. . . . O novo conceito seria aplicável a diferentes</p><p>substâncias, incluindo carboidratos, polifenóis, ácidos</p><p>graxos poliinsaturados, etc.</p><p>O consenso mantém a exigência do caráter seletivo desses</p><p>compostos sobre a microbiota e que os benefícios à saúde</p><p>sejam demonstrados por meio de ensaios clínicos bem</p><p>elaborados. Os avanços científicos e clínicos, associados ao</p><p>desenvolvimento de técnicas moleculares, estão evidenciando</p><p>que o uso seletivo de prebióticos não é exclusivo de lactobacilos</p><p>e bifidobactérias, estendendo-se a tais gêneros</p><p>530</p><p>Gastroenterologia e Hepatologia 44 (2021) 519--535</p><p>Figura As diretrizes da FAO/OMS para a avaliação de um microrganismo como probiótico (referência Roberfroid et al.110).</p><p>as diretrizes da FAO/OMS (Figo. 5)112. . . . Todo probiótico deve</p><p>ser identificado por seu gênero, espécie, subespécie (se</p><p>aplicável) e uma designação alfanumérica própria da cepa. O</p><p>benefício para a saúde deve ser demonstrado através de</p><p>ensaios clínicos randomizados e controlados. Além disso, o</p><p>benefício demonstrado para uma condição de saúde concreta</p><p>(por exemplo, diarreia aguda) não é extrapolável para outras</p><p>indicações (por exemplo, alergia).</p><p>Numerosos ensaios clínicos avaliaram a eficácia e</p><p>segurança de vários probióticos para diversas indicações,</p><p>incluindo prevenção ou tratamento de diarreia aguda,</p><p>diarreia associada a antibióticos, sintomas funcionais</p><p>digestivos ligeiros ou moderados, má digestão de lactose,</p><p>cólicas em lactação, etc. A Organização Mundial de</p><p>Gastroenterologia (WGO) publica documento de acesso</p><p>gratuito com informações sobre cepas, posologia e</p><p>nível de evidência</p><p>para diversas aplicações no campo</p><p>gastrointestinal115. . . . O potencial uso terapêutico de</p><p>probióticos em outras doenças (por exemplo, obesidade,</p><p>resistência à insulina, esteatose hepática, ansiedade ou</p><p>depressão) é objeto de estudo e deve ser considerado com</p><p>cautela. Os probióticos podem ter um papel de promoção</p><p>da saúde na população saudável114.116. . . .</p><p>Simbiótico</p><p>Um simbiótico é um produto que combina pelo menos um</p><p>probiótico e um prebiótico. Um produto só pode ser</p><p>denominado simbiótico se estiver perfeitamente</p><p>caracterizado e tiver demonstrado induzir efeito benéfico</p><p>superior à soma daqueles gerados separadamente,</p><p>531</p><p>Alvarez J, Fernandez Real JM, Guarner F et al.</p><p>pelos seus constituintes117. . . . Um exemplo bastante</p><p>popular deste tipo de produtos é a combinação de</p><p>microrganismos do gêneroBifidobactériaóLactobaciloscom</p><p>frutooligossacarídeos116. . . .</p><p>Moldar futuras respostas imunológicas do hospedeiro. PLoS Um.</p><p>2012;7:e34043.</p><p>4.Gensollen T, Anos SS, Kasper DL, Blumberg RS. Como a colonização pela</p><p>microbiota no início da vida molda o sistema imunológico. Ciência.</p><p>2016;352:539–44.</p><p>5.Milani C, Duranti S, Bottacini F, Casey E, Turroni F, Mahony J, et</p><p>al. Os primeiros colonizadores microbianos do intestino</p><p>humano: composição, atividades e implicações para a saúde</p><p>da microbiota intestinal infantil. Rev. 2017;81:e00036.</p><p>6.Arboleya S, Suarez M, Fernandez N, Mantecon L, Solis G,</p><p>Gueimonde M, et al. Cesárea e aquisição do microbioma</p><p>intestinal neonatal: consequências para a saúde futura. Ann</p><p>Nutr Metab. 2018;73:17--2</p><p>7.Árvore S, Sanchez B, Milani C, Duranti S, Solis G, Fernandez N, et</p><p>al. Desenvolvimento da microbiota intestinal em neonatos</p><p>prematuros e efeito dos antibióticos perinatais. J Pediatr.</p><p>2015;166:538–44.</p><p>8.Zimmermann P, Curtis N. Efeito dos antibióticos intraparto na</p><p>microbiota intestinal de bebês: uma revisão sistemática. Arch Dis</p><p>Criança Fetal Neonatal Ed. 2020;105:201--8</p><p>9.Backhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P,</p><p>et al. Dinâmica e estabilização do microbioma intestinal humano</p><p>durante o primeiro ano de vida. Micróbio hospedeiro celular.</p><p>2015;17:852.</p><p>10.[PubMed] Cheng J, Ringel-Kulka T, Heikamp-de Jong I, Ringel Y, Carroll</p><p>Eu, de Vos WM, et al. Desenvolvimento temporal discordante de</p><p>filos bacterianos e surgimento de núcleo na microbiota fecal de</p><p>crianças pequenas. ISME J. 2016;10:1002--14.</p><p>11.Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR,</p><p>et al. Enterótipos do microbioma intestinal humano. Natureza.</p><p>2011;473:174–80.</p><p>12.Sutton TDS, Hill C. Bacteriófago intestinal: compreensão e</p><p>desafios atuais. Frente Endocrinol (Lausanne). 2019; 10:784.</p><p>13.Richard ML, Sokol H. A micobiota intestinal: insights sobre análise,</p><p>interações ambientais e papel nas doenças gastrointestinais. Nat</p><p>Rev Gastroenterol Hepatol. 2019;16:331--4</p><p>14.Fragiadakis GK, Wastyk HC, Robinson JL, Sonnenburg ED,</p><p>Sonnenburg JL, Gardner CD. A intervenção dietética a longo prazo</p><p>revela a resiliência da microbiota intestinal, apesar das mudanças</p><p>na dieta e no peso. Sou J Clin Nutr. 2020;111:1127--3</p><p>15.Claesson MJ, Jeffery IB, Count S, Power SE, O'Connor EM, Cusack</p><p>S, et al. A composição da microbiota intestinal está</p><p>correlacionada com a dieta e a saúde dos idosos. Natureza.</p><p>2012;488:178–84.</p><p>16.Salazar N, Arboleya S, Fernandez-Navarro T, de los Reyes-Gavilán CG,</p><p>Gonzalez S, Gueimonde M. Mudanças associadas à idade na</p><p>microbiota intestinal e componentes dietéticos relacionados ao</p><p>sistema imunológico na idade adulta e na velhice: um estudo</p><p>transversal . . . . 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As</p><p>concentrações fecais de formas de vitamina K derivadas de bactérias estão</p><p>associadas à composição da microbiota intestinal, mas não às concentrações</p><p>plasmáticas ou de citocinas fecais em adultos saudáveis. Sou</p><p>J Clin Nutr. 2017;106:1052--6</p><p>Transmissão da microbiota fecal</p><p>A transmissão da microbiota fecal (FMT) é um método</p><p>definido para alterar a microbiota intestinal de um paciente,</p><p>a fim de normalizar a sua composição e obter um benefício</p><p>terapêutico. Consiste na infusão de uma suspensão de fezes</p><p>provenientes de indivíduo saudável no tubo digestivo do</p><p>paciente receptor. Refere-se a uma técnica já utilizada na</p><p>China no século IV que ao longo da história teve poucas</p><p>dificuldades até que em 2013 demonstrou a sua</p><p>extraordinária eficácia no tratamento da diarreia refratária</p><p>e recorrente devido ao crescimento excessivo de</p><p>Clostridioides difficile, com taxas de resolução superiores a</p><p>90%118. . . .</p><p>A seleção dos doadores deve ser rigorosa para evitar</p><p>efeitos adversos, como a transferência inadvertida de</p><p>bactérias multirresistentes. A experiência atual considera</p><p>que o procedimento é livre de efeitos colaterais importantes</p><p>quando realizado de acordo com protocolos de consenso,</p><p>como o protocolo europeu119e a da Sociedade Catalã de</p><p>Digestologia e da Sociedade Catalã de Doenças Infecciosas</p><p>e Microbiologia Clínica, mais atualizada120. . . . Nos últimos</p><p>anos está a ser investigada a sua aplicabilidade noutras</p><p>doenças, como doenças inflamatórias intestinais, síndrome</p><p>metabólica ou transplante de progenitores</p><p>hematopoiéticos.121. . . . Fora da indicação acima</p><p>mencionada para resolução de diarreia recorrente por</p><p>Clostridioides difficile, essa técnica só é utilizada em</p><p>protocolos de pesquisa aprovados por comitê de ética. É</p><p>essencial otimizar procedimentos (especialmente no</p><p>contexto atual da pandemia do coronavírus), definir melhor</p><p>as deficiências e selecionar os microrganismos ativos que</p><p>permitem aplicar abordagens personalizadas para tratar</p><p>doenças específicas.</p><p>Financiamento</p><p>A elaboração do artigo foi financiada pelo Instituto Danone</p><p>(Barcelona).</p><p>Conflito de interesses</p><p>JA, FG e MSP fazem parte do conselho científico do Instituto</p><p>Danone.</p><p>Bibliografia</p><p>1.Perez-Muñoz ME, Arrieta MC, Ramer-Tait AE, Walter J. Uma</p><p>avaliação crítica das hipóteses de “útero estéril” e “colonização</p><p>in utero”: Implicações para a pesquisa sobre o microbioma</p><p>infantil pioneiro. Microbioma. 2017;5:4</p><p>2.Sommer F, Bäckhed F. A microbiota intestinal. Nat Rev</p><p>Microbiol. 2013;11:227--3</p><p>3.Hansen CHF, Nielsen DS, Kverka M, Zakostelska Z, Klimesova K,</p><p>Hudcovic T, et al. 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