Chronic immune-mediated diseases are rapidly expanding and notoriously difficult to cure. Altered relatively stable intestinal microbiota configurations are associated with several of these diseases, and with a possible pre-disease condition (more susceptible to disease development) of the host-microbiota ecosystem. These observations are reminiscent of the behavior of an ecosystem with alternative stable states (different stable configurations that can exist under identical external conditions), and we recently postulated that health, pre-disease and disease represent such alternative states. Here, our aim was to examine if alternative stable states indeed exist in the intestinal ecosystem. Rats were exposed to varying concentrations of DSS in order to create a wide range of mildly inflammatory conditions, in a context of diet-induced low microbiota diversity. The consequences for the intestinal microbiota were traced by 16S rRNA gene profiling over time, and inflammation of the distal colon was evaluated at sacrifice, 45 days after the last DSS treatment. The results provide the first formal experimental proof for the existence of alternative stable states in the rat intestinal ecosystem, taking both microbiota and host inflammatory status into consideration. The alternative states are host-microbiota ecosystem states rather than independent and dissociated microbiota and host states, and inflammation can prompt stable state-transition. Based on these results, we propose a conceptual model providing new insights in the interplay between host inflammatory status and microbiota status. These new insights call for innovative therapeutic strategies to cure (pre-)disease. We provide proof of concept showing the existence of alternative stable states in the rat intestinal ecosystem. We further propose a model which, if validated in humans, will support innovative diagnosis, therapeutic strategy, and monitoring in the treatment of chronic inflammatory conditions. This model provides a strong rationale for the application of combinatorial therapeutic strategies, targeting host and microbiota rather than only one of the two in chronic immune-mediated diseases.

中文翻译：

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肠道生态系统中的其他稳定状态：大鼠模型中的概念证明和治疗意义的观点

慢性免疫介导的疾病正在迅速蔓延，众所周知难以治愈。相对稳定的肠道菌群结构发生改变与其中几种疾病以及宿主菌群生态系统可能的疾病前期状况（对疾病发展更敏感）有关。这些观察使人联想到具有替代稳定状态（在相同外部条件下可能存在的不同稳定配置）的生态系统的行为，我们最近推测健康，疾病前期和疾病代表了这些替代状态。在这里，我们的目的是检查肠道生态系统中是否确实存在其他稳定状态。将大鼠暴露于不同浓度的DSS中，以产生各种轻度炎症性疾病，在饮食引起的低菌群多样性的背景下。肠道菌群的后果可通过16S rRNA基因随时间推移进行分析，并在最后一次DSS处理后45天处死时评估远端结肠的炎症。该结果提供了第一个正式的实验证明，考虑到微生物群和宿主的炎症状态，大鼠肠道生态系统中存在其他稳定状态。替代状态是宿主微生物区系生态系统状态，而不是独立的和分离的微生物区系和宿主状态，炎症可以促进稳定的状态转换。基于这些结果，我们提出了一个概念模型，为宿主炎症状态和微生物群状态之间的相互作用提供了新的见解。这些新见解要求创新的治疗策略来治愈（疾病前）疾病。我们提供了概念证明，证明了大鼠肠道生态系统中存在其他稳定状态。我们进一步提出了一种模型，该模型如果在人类中得到验证，将支持创新的诊断，治疗策略以及对慢性炎症状况的监测。该模型为针对宿主和微生物群的组合治疗策略的应用提供了强大的理论依据，而不仅仅是针对慢性免疫介导疾病中的两者之一。和监测慢性炎性疾病的治疗。该模型为针对宿主和微生物群的组合治疗策略的应用提供了强大的理论依据，而不仅仅是针对慢性免疫介导疾病中的两者之一。和监测慢性炎性疾病的治疗。该模型为针对宿主和微生物群的组合治疗策略的应用提供了强大的理论依据，而不仅仅是针对慢性免疫介导疾病中的两者之一。