Periodic Reporting for period 3 - Homo.symbiosus (Assessing, preserving and restoring man-microbes symbiosis)
Okres sprawozdawczy: 2022-01-01 do 2023-06-30
The importance of man-microbes symbiosis in health and disease has emerged as a central paradigm. Derived from a long co-evolution, man-microbes inter-relation has been challenged by numerous environmental triggers, modern lifestyles, changes in birth modalities, nutritional transition and therapeutic attitudes. A large fraction of the human population has tentatively entered a man-microbes dysbiotic state characterized by altered interactions between microbiome and host features with auto-aggravating crosstalk signals. The result is increased incidence of incurable immune-mediated diseases of modern societies that affect a third the human population on earth today and for which current therapeutics only address symptoms alleviation, rather than considering man as a holobiont.
In this context and its resulting threat for the human species, the Homo symbiosus ERC project is geared to open a new era of individualized preventive care and novel gut ecology-based therapeutic approaches. The project will assemble 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 state as it applies to a shift from man-microbes symbiosis to disease-prone man-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, man-microbes symbiosis by concomitantly acting upon microbiome and host features
• Validate strategies to reinforce ecological robustness and restore man-microbes symbiosis
Based on a paradigm shift, the proposed work will set the grounds for future personalized preventive nutrition and clinical management considering man as a true holobiont.
In this context and its resulting threat for the human species, the Homo symbiosus ERC project is geared to open a new era of individualized preventive care and novel gut ecology-based therapeutic approaches. The project will assemble 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 state as it applies to a shift from man-microbes symbiosis to disease-prone man-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, man-microbes symbiosis by concomitantly acting upon microbiome and host features
• Validate strategies to reinforce ecological robustness and restore man-microbes symbiosis
Based on a paradigm shift, the proposed work will set the grounds for future personalized preventive nutrition and clinical management considering man as a true holobiont.
We herein present the progress update with emphasis on mitigating delays imposed by the Covid pandemics.
A study providing the first animal model ever established that demonstrates the existence of alternative stable states of host-microbes symbiosis was published in the journal Microbiome. The reproducibility of our model of altered host-microbe symbiosis in rats was validated (publication in writing).
A pilot trial was implemented and confirmed that a dietary intervention may alter different aspects of host-microbes symbiosis (gut microbiota diversity/richness and overall ecology, gut barrier integrity).
A full trial with assessment of durable host-microbes symbiosis alteration upon dietary intervention is ongoing (august 2021 to January 2022).
As for relevance to humans, published data for pediatric patients treated for an ulcerative colitis and followed over one-year, was analyzed using our bio-analysis modeling tools and we gave the first evidence of the existence of alternative stable states in humans. Several stable states of symbiosis were observed, only one being associated with health. As only 36% of the patients could revert to this non-pathological state after one year of treatment with anti-inflammatory drugs, our analysis suggests that inflammation and microbiome should be combined targets for symbiosis monitoring and for treatment.
A study involving volunteers of the French NutriNet cohort is ongoing. As of aug 31, 2021, 195 first- and 149 second time-points have been collected for our target of 200 subjects (50 no diabetic relative controls, 51 one diabetic relative (father or mother), 50 both father & mother diabetics, and 45 diabetic volunteers. Samples are subjected to DNA extraction and metagenomic sequencing in batches of 96 as they become available.
For mathematical modelling task, we have initiated a collaboration with a program centered on immunome-microbiome interplay. A PhD student, is performing data analysis aligned with the Homo.symbiosus paradigm. The intermediate results so-far have led to optimize bioinformatics tools and gene catalogs for the metagenomic studies, recover and prepare clinical datasets for public/internal cohort, generate metagenomics sequence profiles for 616 samples, assess the impact of autoimmune diseases on the richness/composition of the microbiota for multi auto-immune diseases, with significant enrichment in oral species, and assess the potential association between microbiota composition and disease severity scores.
Another PhD trainee is currently working on mathematical modeling of symbiosis dynamics using available datasets.
A study providing the first animal model ever established that demonstrates the existence of alternative stable states of host-microbes symbiosis was published in the journal Microbiome. The reproducibility of our model of altered host-microbe symbiosis in rats was validated (publication in writing).
A pilot trial was implemented and confirmed that a dietary intervention may alter different aspects of host-microbes symbiosis (gut microbiota diversity/richness and overall ecology, gut barrier integrity).
A full trial with assessment of durable host-microbes symbiosis alteration upon dietary intervention is ongoing (august 2021 to January 2022).
As for relevance to humans, published data for pediatric patients treated for an ulcerative colitis and followed over one-year, was analyzed using our bio-analysis modeling tools and we gave the first evidence of the existence of alternative stable states in humans. Several stable states of symbiosis were observed, only one being associated with health. As only 36% of the patients could revert to this non-pathological state after one year of treatment with anti-inflammatory drugs, our analysis suggests that inflammation and microbiome should be combined targets for symbiosis monitoring and for treatment.
A study involving volunteers of the French NutriNet cohort is ongoing. As of aug 31, 2021, 195 first- and 149 second time-points have been collected for our target of 200 subjects (50 no diabetic relative controls, 51 one diabetic relative (father or mother), 50 both father & mother diabetics, and 45 diabetic volunteers. Samples are subjected to DNA extraction and metagenomic sequencing in batches of 96 as they become available.
For mathematical modelling task, we have initiated a collaboration with a program centered on immunome-microbiome interplay. A PhD student, is performing data analysis aligned with the Homo.symbiosus paradigm. The intermediate results so-far have led to optimize bioinformatics tools and gene catalogs for the metagenomic studies, recover and prepare clinical datasets for public/internal cohort, generate metagenomics sequence profiles for 616 samples, assess the impact of autoimmune diseases on the richness/composition of the microbiota for multi auto-immune diseases, with significant enrichment in oral species, and assess the potential association between microbiota composition and disease severity scores.
Another PhD trainee is currently working on mathematical modeling of symbiosis dynamics using available datasets.
Future animal work will involve either our chemical or our nutritional induction model of altered symbiosis. We intend to asses mother-to-pups transferability and the impact of durably altered symbiosis on animal longevity, as well as preventive or curative interventions.
Owing to regulatory restrictions, we will not be able to perform the ‘curative restoration’ by fecal microbiota transfer in human patients as anticipated. Instead, we selected a clinical context relevant to the proposal (extreme obesity requiring bariatric surgery) for which our preliminary data suggests it is a most appropriate setting to test a dietary intervention that could restore host-microbes homeostasis and in doing so possibly avoid the need for a surgical intervention.
Two sets of results of Homo symbiosus will be advancing the research field
• a model of the dynamics of man-microbes symbiosis and symbiosis-to-dysbiosis transition in order to assess the respective weight of various stress factors and to predict the impact of preventive or curative interventions.
• preclinical (animal model) validation of the potential for preventive or curative mitigation of altered host-microbes symbiosis.
Three sets of results may be considered as breakthroughs with a potential impact on the current standard of care. Our recent publication [Van de Guchte et al, Gastroenterology 2021, online sept 8] strongly supports this.
• preclinical (animal model) validation of the central paradigm that dysbiosis is a stable state of altered host-microbes symbiosis and thereby a breach in the natural course of man-microbes co-evolution.
• clinical validation of the central paradigm in humans (patients) suggesting the relevance of a revision of standard of care towards a clinical management combining modulation of microbiome and host parameters (i.e. inflammation).
• clinical validation of the potential for preventive or curative mitigation of altered host-microbes symbiosis demonstrating the relevance of a revision of standard of care in patients.
Owing to regulatory restrictions, we will not be able to perform the ‘curative restoration’ by fecal microbiota transfer in human patients as anticipated. Instead, we selected a clinical context relevant to the proposal (extreme obesity requiring bariatric surgery) for which our preliminary data suggests it is a most appropriate setting to test a dietary intervention that could restore host-microbes homeostasis and in doing so possibly avoid the need for a surgical intervention.
Two sets of results of Homo symbiosus will be advancing the research field
• a model of the dynamics of man-microbes symbiosis and symbiosis-to-dysbiosis transition in order to assess the respective weight of various stress factors and to predict the impact of preventive or curative interventions.
• preclinical (animal model) validation of the potential for preventive or curative mitigation of altered host-microbes symbiosis.
Three sets of results may be considered as breakthroughs with a potential impact on the current standard of care. Our recent publication [Van de Guchte et al, Gastroenterology 2021, online sept 8] strongly supports this.
• preclinical (animal model) validation of the central paradigm that dysbiosis is a stable state of altered host-microbes symbiosis and thereby a breach in the natural course of man-microbes co-evolution.
• clinical validation of the central paradigm in humans (patients) suggesting the relevance of a revision of standard of care towards a clinical management combining modulation of microbiome and host parameters (i.e. inflammation).
• clinical validation of the potential for preventive or curative mitigation of altered host-microbes symbiosis demonstrating the relevance of a revision of standard of care in patients.