Periodic Reporting for period 4 - Homo.symbiosus (Assessing, preserving and restoring man-microbes symbiosis)
Okres sprawozdawczy: 2023-07-01 do 2024-12-31
Derived from a long co-evolution, man-microbes inter-relation has been challenged by modern lifestyles, changes in birth modalities, nutritional transition and therapeutic attitudes. Altered interactions between microbiomes and human host features with auto-aggravating signals result is increased incidence of incurable immune-mediated diseases that affect a third the human population on earth today.
The Homo symbiosus ERC project was geared to open a new era of individualized preventive care and novel gut ecology-based therapeutic approaches. The project assembled insights and contributions from theoretical to experimental ecology, quantitative and functional microbiomics, preclinical work, cohort studies and clinical trials, so as to:
• Validate the concept of critical transition and alternative stable states as it applies to a shift from human-microbes symbiosis to disease-prone human-microbes dysbiosis
• Assess the potential of diet alone to promote such a shift.
• Model the symbiosis-to-dysbiosis transitions and derive predictors of tipping points.
• Propose counter-measures that may allow to break vicious circles and restore a balanced, health-prone, human-microbes symbiosis by concomitantly acting upon microbiome and host features.
• Validate strategies to reinforce ecological robustness and restore human-microbes symbiosis.
Based on a paradigm shift, the proposed work did set the grounds for future personalized preventive nutrition and clinical management considering human as true holobionts.
The Homo symbiosus ERC project was geared to open a new era of individualized preventive care and novel gut ecology-based therapeutic approaches. The project assembled insights and contributions from theoretical to experimental ecology, quantitative and functional microbiomics, preclinical work, cohort studies and clinical trials, so as to:
• Validate the concept of critical transition and alternative stable states as it applies to a shift from human-microbes symbiosis to disease-prone human-microbes dysbiosis
• Assess the potential of diet alone to promote such a shift.
• Model the symbiosis-to-dysbiosis transitions and derive predictors of tipping points.
• Propose counter-measures that may allow to break vicious circles and restore a balanced, health-prone, human-microbes symbiosis by concomitantly acting upon microbiome and host features.
• Validate strategies to reinforce ecological robustness and restore human-microbes symbiosis.
Based on a paradigm shift, the proposed work did set the grounds for future personalized preventive nutrition and clinical management considering human as true holobionts.
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]).
• 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]).
The five most significant achievements of the Homo symbiosus ERC project are:
1. The proof of concept of critical transition and alternative stable states as they apply to host-microbes symbiosis (van de Guchte et al. 2020 Microbiome, Droga et al. 2020 Frontiers in Microbiology, Malard et al. 2020 Mucosal Immunology, van de Guchte et al. 2021 Gastroenterology, Doré & Ortega-Ugalde 2023 Frontiers in Astronomy and Space Sciences, Rous et al. 2025 Microbiology Spectrum, Komati et al. 2025 Eur J Nutr).
2. Mathematical modelling delivering the first digital twin of human-microbes symbiosis with perspectives of application in diagnostics and for the design of innovative prevention and therapeutic strategies in chronic conditions and their treatment (Haghebaert et al. 2024. Journal of the Royal Society Interface).
3. The demonstration of potential applications in prevention of diseases by the preservation of integrity of human-microbes symbiosis (Faucher et al. 2022 Beneficial Microbes, Ranaivo et al. 2022 Gut Microbes ; see clinical trials above (Malard et al. Nature Com 2021, Malard et al. Blood 2023)
4. The demonstration of potential applications in beneficial modulation of current therapies by the restoration of a functional human-microbes symbiosis (Malard et al. 2021 Nature Communication, Malard et al. 2023 eClinicalMedicine). The positive Phase-3 ARES trial lead to an application for market access for the drug Xerviteg by MaaT Pharma.
5. The launch of 3 major initiatives aiming to structure the microbiome field : i) at national level the priority program PEPR SAMS, € 60 million(odnośnik otworzy się w nowym oknie) ; ii) at European level, the launch of the European Microbiome Centers Consortium, gathering all stakeholders with expertise and interest in human microbiome and health ; iii) at world level, the World Microbiome Partnership (https://worldmicrobiomepartnership.org/(odnośnik otworzy się w nowym oknie)) a forum aiming to promote leveraging microbiomes to tackle major societal challenges tof the ONE Health framework.
1. The proof of concept of critical transition and alternative stable states as they apply to host-microbes symbiosis (van de Guchte et al. 2020 Microbiome, Droga et al. 2020 Frontiers in Microbiology, Malard et al. 2020 Mucosal Immunology, van de Guchte et al. 2021 Gastroenterology, Doré & Ortega-Ugalde 2023 Frontiers in Astronomy and Space Sciences, Rous et al. 2025 Microbiology Spectrum, Komati et al. 2025 Eur J Nutr).
2. Mathematical modelling delivering the first digital twin of human-microbes symbiosis with perspectives of application in diagnostics and for the design of innovative prevention and therapeutic strategies in chronic conditions and their treatment (Haghebaert et al. 2024. Journal of the Royal Society Interface).
3. The demonstration of potential applications in prevention of diseases by the preservation of integrity of human-microbes symbiosis (Faucher et al. 2022 Beneficial Microbes, Ranaivo et al. 2022 Gut Microbes ; see clinical trials above (Malard et al. Nature Com 2021, Malard et al. Blood 2023)
4. The demonstration of potential applications in beneficial modulation of current therapies by the restoration of a functional human-microbes symbiosis (Malard et al. 2021 Nature Communication, Malard et al. 2023 eClinicalMedicine). The positive Phase-3 ARES trial lead to an application for market access for the drug Xerviteg by MaaT Pharma.
5. The launch of 3 major initiatives aiming to structure the microbiome field : i) at national level the priority program PEPR SAMS, € 60 million(odnośnik otworzy się w nowym oknie) ; ii) at European level, the launch of the European Microbiome Centers Consortium, gathering all stakeholders with expertise and interest in human microbiome and health ; iii) at world level, the World Microbiome Partnership (https://worldmicrobiomepartnership.org/(odnośnik otworzy się w nowym oknie)) a forum aiming to promote leveraging microbiomes to tackle major societal challenges tof the ONE Health framework.