RESUMO
Early-life stress is a determinant of vulnerability to a variety of disorders that include dysfunction of the brain and gut. Here we exploit a model of early-life stress, maternal separation (MS) in mice, to investigate the role of the intestinal microbiota in the development of impaired gut function and altered behaviour later in life. Using germ-free and specific pathogen-free mice, we demonstrate that MS alters the hypothalamic-pituitary-adrenal axis and colonic cholinergic neural regulation in a microbiota-independent fashion. However, microbiota is required for the induction of anxiety-like behaviour and behavioural despair. Colonization of adult germ-free MS and control mice with the same microbiota produces distinct microbial profiles, which are associated with altered behaviour in MS, but not in control mice. These results indicate that MS-induced changes in host physiology lead to intestinal dysbiosis, which is a critical determinant of the abnormal behaviour that characterizes this model of early-life stress.
Assuntos
Ansiedade/microbiologia , Comportamento Animal , Colo/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal , Privação Materna , Estresse Psicológico/microbiologia , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/psicologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína C-Reativa/metabolismo , Colo/inervação , Corticosterona/metabolismo , Dopamina/metabolismo , Disbiose/metabolismo , Disbiose/psicologia , Microbioma Gastrointestinal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Camundongos , Modelos Animais , Plexo Mientérico , Norepinefrina/metabolismo , Peroxidase/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , RNA Ribossômico 16S/genética , Serotonina/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologiaRESUMO
The irritable bowel syndrome (IBS) is a chronic abdominal symptom complex that is heterogeneous in terms of its clinical presentation and underlying pathophysiology and pathogenesis. It is now established that enteric infection can trigger the syndrome in at least a subset of patients. In addition, there is growing evidence of low grade inflammation and immune activation in the distal bowel of some IBS patients. These observations now prompt the question as to what maintains gut dysfunction in these patients. The intestinal microbiota influences a broad array of host organs that include the gut and the brain, and is an important determinant of normal function in these systems. Disruption of the delicate balance between the host and its intestinal microbiota (termed dysbiosis) results in changes in the mucosal immune system that range from overt inflammation as seen in Crohn's Disease, to low grade inflammation without tissue injury, as seen in a subset of IBS patients. Under experimental conditions, disruption of the microbiota also produces changes in gut sensory-motor function and immune activity. Thus, dysbiosis induced by infection, dietary change or drugs such as antibiotics could produce low grade inflammation and chronic gut dysfunction, reminiscent of that seen in IBS. Fluctuations in gut physiology destabilize the habitat of commensal bacteria and provide a basis for chronic dysbiosis. Recent observations in animal models that changes in gut flora influence behavior provide a basis for a novel unifying hypothesis that accommodates both gut dysfunction and behavioral changes that characterize many IBS patients. This hypothesis states that dysbiosis exists in at least a subset of IBS patients, as a result of infection, dietary change or drugs and contributes to gut inflammatory and functional change in addition to psychiatric co-morbidity.