Alternative stable states in the intestinal ecosystem: proof of concept in a rat model and a perspective of therapeutic implications

Joël Doré,Stanislas Mondot,Hervé M. Blottière,Jiangbo Wu,Maarten Van de Guchte,Sebastian D. Burz,Julie Cadiou

doi:10.1186/s40168-020-00933-7

Abstract

BackgroundChronic 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.ResultsRats 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.ConclusionsWe 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.1Cq2U_E-ane_XBWK_L-CzoVideo

Highlights

Chronic immune-mediated diseases are rapidly expanding and notoriously difficult to cure
Diet shift leads to a marked change in gut microbiota diversity We hypothesize that low microbiota diversity and inflammation due to intestinal barrier failure, both of which can be brought about by Western dietary habits or other risk factors, can push the ecosystem beyond a tipping point (Fig. 1a, subpanel II) and induce a selfenhancing process of alteration of the intestinal ecosystem, resulting in a transition to an alternative stable state (Additional Fig. 1) [15]
The present study examines if proof of concept can be obtained for the existence of alternative stable states and state-transition in the intestinal ecosystem

Summary

Introduction

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 predisease 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. More specific atypical microbiota compositions are associated with an ever-growing number of chronic inflammatory diseases These may be characterized by (among other changes) bacterial species with modified abundance (e.g., [11,12,13]), or by the alteration of a set of bacterial species that can together serve as a biomarker with high predictive value (e.g., [10])

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