Periodic Reporting for period 1 - BRAINeSs (Short-chain fatty acids in brain neuroinflammation: modulators of immunity and neural stemness)
Reporting period: 2021-06-01 to 2023-05-31
The BRAINeSs project arose from the scientific and clinical necessity to clarify the role of the microbiota-gut-brain axis in neuroinflammatory diseases, considering both the molecular and cellular points of view.
Recent studies pointed out that gut microbiota dysbiosis is a triggering event in a plethora of intestinal and extra-intestinal diseases, among them the outcome of autoimmune diseases such as multiple sclerosis (MS).
The microbiota communicates with the host mainly through the synthesis and secretion of specific metabolites that cannot be produced by host cells but are fundamental for their function. Among these metabolites, there are the short-chain fatty acids (SCFAs), molecules that regulate multiple functions, among them stemness, tissue integrity, gene expression, and induction of pro-tolerogenic immune response.
SCFAs supplementation has been proven beneficial in both the experimental autoimmune encephalomyelitis (EAE) model of MS and MS patients. In both cases, the authors analyze mainly their pro-tolerogenic role on the immune system, overlooking their impact on the nervous tissue, the primary disease target.
With the BRAINeSs project, I proposed a ground-breaking research that will establish novel regulatory mechanisms by which SCFAs modulate the pathogenesis of MS directly at the central nervous system (CNS), by deciphering three main research questions or specific objectives: 1. SCFAs and NPCs: How do SCFAs influence NPC's self-renewal and differentiation? 2. SCFAs and immunity. 3. SCFAs and neuronal/glial cells: How do SCFAs influence the physiology of mature neuronal & glial cells and their mutual communication?
Answering these questions is important for society since my finalized results could be easily translated into clinical practice, especially for patients with neuroinflammatory/neurodegenerative disorders (MS, Alzheimer’s, Parkinson’s, etc.), but also to prevent these disorders in high-risk subjects (e.g. dysbiotic subjects or individuals with genetic predisposition), with an impact on EU public health and economy.
Conclusions: The BRAINeSs project shed light on the importance of SCFAs for the physiology of the CNS. In particular, I found that SCFAs have a strong protective effect in the case of oxidative stress and are modulated not only in the gut but on a whole body scale in the frame of MS, both in the mouse model and in patients. With the BRAINeSs project, I show that SCFAs modulate not only the systemic and brain immune system but also the nervous system.
Recent studies pointed out that gut microbiota dysbiosis is a triggering event in a plethora of intestinal and extra-intestinal diseases, among them the outcome of autoimmune diseases such as multiple sclerosis (MS).
The microbiota communicates with the host mainly through the synthesis and secretion of specific metabolites that cannot be produced by host cells but are fundamental for their function. Among these metabolites, there are the short-chain fatty acids (SCFAs), molecules that regulate multiple functions, among them stemness, tissue integrity, gene expression, and induction of pro-tolerogenic immune response.
SCFAs supplementation has been proven beneficial in both the experimental autoimmune encephalomyelitis (EAE) model of MS and MS patients. In both cases, the authors analyze mainly their pro-tolerogenic role on the immune system, overlooking their impact on the nervous tissue, the primary disease target.
With the BRAINeSs project, I proposed a ground-breaking research that will establish novel regulatory mechanisms by which SCFAs modulate the pathogenesis of MS directly at the central nervous system (CNS), by deciphering three main research questions or specific objectives: 1. SCFAs and NPCs: How do SCFAs influence NPC's self-renewal and differentiation? 2. SCFAs and immunity. 3. SCFAs and neuronal/glial cells: How do SCFAs influence the physiology of mature neuronal & glial cells and their mutual communication?
Answering these questions is important for society since my finalized results could be easily translated into clinical practice, especially for patients with neuroinflammatory/neurodegenerative disorders (MS, Alzheimer’s, Parkinson’s, etc.), but also to prevent these disorders in high-risk subjects (e.g. dysbiotic subjects or individuals with genetic predisposition), with an impact on EU public health and economy.
Conclusions: The BRAINeSs project shed light on the importance of SCFAs for the physiology of the CNS. In particular, I found that SCFAs have a strong protective effect in the case of oxidative stress and are modulated not only in the gut but on a whole body scale in the frame of MS, both in the mouse model and in patients. With the BRAINeSs project, I show that SCFAs modulate not only the systemic and brain immune system but also the nervous system.
The main work performed during the period of the fellowship comprises:
the characterization of the biodistribution of SCFAs in multiple human biofluids and mouse tissues;
the untargeted brain metabolomics after SCFAs treatment.
the characterization of human blood circulating immunophenotyping of MS patients compared to healthy controls and the tissue immunophenotyping of EAE mice with and without sCFAs treatment;
the scRNAseq analysis on human brain organoids treated with SCFAs;
the fate mapping on healthy controls and EAE mice treated with SCFAs;
the spatial transcriptomics analysis on mouse brain after SCFAs treatment.
Main results achieved so far: I substantially contributed to filling the knowledge gap about:
- the biodistribution of SCFAs in MS patients versus healthy controls; the biodistribution of SCFAs in the EAE mouse model; establish, characterize, and test SCFAs in human brain organoids, a proxy for in vivo action of SCFAs in the human CNS; NPCs tracking and fate mapping elucidating the effects of SCFAs in vivo.
- the immune consequences of an altered SCFAs biodistribution in MS patients versus healthy controls; the organ-specific immune effects of SCFAs in the EAE mouse model, beyond the already documented phenotype on CD4+ T cells, further elucidating the effects of SCFAs in vivo.
- the influence of SCFAs on mature neuronal, astrocytes, and oligodendrocytes, both in a human and a mouse setting. Furthermore, I unraveled the impact of EAE pathogenesis and SCFAs oral supplementation on general metabolomic profile in multiple organs and biological samples, including the CNS, further elucidating the effects of SCFAs in vivo.
Overview of the results and their exploitation and dissemination:
The BRAINeSs project allowed me to clarify mainly: (a) The biodistribution of SCFAs in newly diagnosed not yet treated MS patients compared to healthy volunteers, correlated with the immunophenotypic profiling and the microbial profiling. (b) The biodistribution of SCFAs in EAE mice compared to healthy control mice, in the presence or absence of a preventive SCFAs treatment, correlated with the immunophenotypic profiling and the microbial profiling. (c) The protective role of SCFAs toward neuronal axonal damage induced by oxidative stress and how SCFAs favor neuronal plasticity.
Exploitation of the results:
I am preparing the manuscript for publication, which will follow the open-access criteria and specify the reference to the EU funding. After publication, data will be openly available to the scientific community through open-access repositories.
Dissemination of the results:
The results of the project have been periodically reported inside and outside my institution.
Internal dissemination:
I had regular scientific talks within my department, the Institute of Experimental Neurology, and a yearly poster presentation at the institutional retreat.
External dissemination:
During the two years, I took part in a total of 8 conferences and I am part of the organizing committee of 2 scientific events.
I took part in a short video interview during the Mind, Mood and Microbes congress in Amsterdam. The interview is available online on Twitter and Instagram @mymindmicrobes. I have been yearly invited to teach a lesson about gut microbiota and animal experimentation to the students of University Vita-Salute San Raffaele and I took advantage of the occasion to talk about my research and science.
I daily use my Twitter account to spread news about our research and discoveries in the field. I also personally created a new laboratory website that is currently undergoing a formal check from our institution and will be available online soon. I created it with special attention for both scientists and the general public/MS patients.
the characterization of the biodistribution of SCFAs in multiple human biofluids and mouse tissues;
the untargeted brain metabolomics after SCFAs treatment.
the characterization of human blood circulating immunophenotyping of MS patients compared to healthy controls and the tissue immunophenotyping of EAE mice with and without sCFAs treatment;
the scRNAseq analysis on human brain organoids treated with SCFAs;
the fate mapping on healthy controls and EAE mice treated with SCFAs;
the spatial transcriptomics analysis on mouse brain after SCFAs treatment.
Main results achieved so far: I substantially contributed to filling the knowledge gap about:
- the biodistribution of SCFAs in MS patients versus healthy controls; the biodistribution of SCFAs in the EAE mouse model; establish, characterize, and test SCFAs in human brain organoids, a proxy for in vivo action of SCFAs in the human CNS; NPCs tracking and fate mapping elucidating the effects of SCFAs in vivo.
- the immune consequences of an altered SCFAs biodistribution in MS patients versus healthy controls; the organ-specific immune effects of SCFAs in the EAE mouse model, beyond the already documented phenotype on CD4+ T cells, further elucidating the effects of SCFAs in vivo.
- the influence of SCFAs on mature neuronal, astrocytes, and oligodendrocytes, both in a human and a mouse setting. Furthermore, I unraveled the impact of EAE pathogenesis and SCFAs oral supplementation on general metabolomic profile in multiple organs and biological samples, including the CNS, further elucidating the effects of SCFAs in vivo.
Overview of the results and their exploitation and dissemination:
The BRAINeSs project allowed me to clarify mainly: (a) The biodistribution of SCFAs in newly diagnosed not yet treated MS patients compared to healthy volunteers, correlated with the immunophenotypic profiling and the microbial profiling. (b) The biodistribution of SCFAs in EAE mice compared to healthy control mice, in the presence or absence of a preventive SCFAs treatment, correlated with the immunophenotypic profiling and the microbial profiling. (c) The protective role of SCFAs toward neuronal axonal damage induced by oxidative stress and how SCFAs favor neuronal plasticity.
Exploitation of the results:
I am preparing the manuscript for publication, which will follow the open-access criteria and specify the reference to the EU funding. After publication, data will be openly available to the scientific community through open-access repositories.
Dissemination of the results:
The results of the project have been periodically reported inside and outside my institution.
Internal dissemination:
I had regular scientific talks within my department, the Institute of Experimental Neurology, and a yearly poster presentation at the institutional retreat.
External dissemination:
During the two years, I took part in a total of 8 conferences and I am part of the organizing committee of 2 scientific events.
I took part in a short video interview during the Mind, Mood and Microbes congress in Amsterdam. The interview is available online on Twitter and Instagram @mymindmicrobes. I have been yearly invited to teach a lesson about gut microbiota and animal experimentation to the students of University Vita-Salute San Raffaele and I took advantage of the occasion to talk about my research and science.
I daily use my Twitter account to spread news about our research and discoveries in the field. I also personally created a new laboratory website that is currently undergoing a formal check from our institution and will be available online soon. I created it with special attention for both scientists and the general public/MS patients.
Beyond pure basic science, since my subject of study is highly translatable. I set up a collaboration with a company in the field of probiotics to understand the effect of specific commercially available microbiota products on the gut-brain axis and ease the translation of my findings into the clinic.
The work carried out in this project, as foreseen, addresses the third UN development goal, “good health and well-being”, and strengthens the knowledge of microbiota and neuroinflammatory conditions. I anticipate that in a short time, my finalized results will be translated into clinical practice, especially for patients with MS, but also with other neuroinflammatory/neurodegenerative disorders (Alzheimer’s, Parkinson’s, etc), and to prevent these disorders in high-risk subjects (e.g. dysbiotic subjects or individuals with genetic predisposition), with an impact on EU public health and economy.
The work carried out in this project, as foreseen, addresses the third UN development goal, “good health and well-being”, and strengthens the knowledge of microbiota and neuroinflammatory conditions. I anticipate that in a short time, my finalized results will be translated into clinical practice, especially for patients with MS, but also with other neuroinflammatory/neurodegenerative disorders (Alzheimer’s, Parkinson’s, etc), and to prevent these disorders in high-risk subjects (e.g. dysbiotic subjects or individuals with genetic predisposition), with an impact on EU public health and economy.