Achievements along the Homo symbiosus ERC project led to:
• Validate the concept of critical transition and alternative stable state as it applies to a shift from man-microbes symbiosis to disease-prone man-microbes dysbiosis.
A proof of concept study provided the first animal model ever established with alternative stable states of host-microbes symbiosis [van de Guchte et al. 2020 Microbiome]. Temporary deprivation of dietary fiber alone, lasting as little as 3 weeks, could induce a transition to an alternative stable microbiota state [Rous et al. 2025 Microbiology Spectrum]. Evidence of the existence of alternative stable states in humans was provided applying modeling tools to pediatric ulcerative colitis data [van de Guchte et al. 2021 Gastroenterology].
Relevance to humans in the context of diabetes was provided by the study of 150 healthy subjects with increasing risk (none to both ascendants affected by diabetes) and 50 diabetic patients. The increasing risk was associated with a gradient in alteration of the microbiota from healthy controls to diabetics, characterized by biomarkers among bacterial species or functions [Gitton-Quent et al. 2025 Gut Microbes Reports].
• Assess the potential of diet alone to promote or prevent such a shift
Although low fibre intake had a major detrimental impact, an obesogenic diet did not induce major-durable alterations in animal models.
• Model the symbiosis-to-dysbiosis transitions and derive predictors of tipping points
Homo symbiosus delivered the first digital twin model of human-microbes symbiosis pointing at the key role of crucial factors influencing the colon environment [Haghebaert et al. 2024 J. Royal Soc. Interface]. Strategies to mitigate transition (be it preventive or curative) will require to concomitantly target altered microbiome and host symptoms.
• Propose counter-measures that may allow to break vicious circles and restore a balanced, health-prone, man-microbes symbiosis by concomitantly acting upon microbiome and host features
In animal models, preventive mitigation experiment over 15 weeks did not show the expected effect of regular diet versus reduced fibre, possibly due to resilience of symbiosis before the challenge [Rous et al. in preparation]. For curative restoration of symbiosis, allogenic FMT performed better than autologous FMT to restore a healthy microbiota following a drastic alteration with a combination of inflammatory and antibiotic stress [van de Guchte et al. submitted].
In humans, preventive mitigation of alteration of symbiosis was addressed by startup companies for which the Homo symbiosus concept was central to their innovative approaches targeting liver steatosis (ICAN trial [NCT04781933]), depression (OptiMOOD trial), complications in patients treated for blood cancer (ODYSSEE trial [NCT02928523] and PHOEBUS trial [NCT05762211], Malard et al. 2021 Nature Com, Malard et al. 2023 Blood).
• Validate strategies to reinforce ecological robustness and restore man-microbes symbiosis
The curative approach to restore symbiosis involves the ongoing trial GUTERING [NCT05832190] promoted by our associated partner AP-HP. It is a pilot open label study that aims to examine the efficacy of biotin supplementation with or without enriched soluble and insoluble fibres before bariatric surgery, compared to standard of care.
In parallel, the Homo symbiosus concept was applied in several trials in the treatment of cancer ; i.e. melanoma (PICASSO trial [NCT04988841]), corticosteroid-resistant acute GvHD (HERACLES trial [NCT03359980], Malard et al. eClinicalMedicine 2023), steroid and ruxolitinib-resistant (ARES trial [NCT04769895]).
