Chronic neurodegenerative disorders including dementias, as Alzheimer's disease (AD) and movement disorders, as Parkinson's disease (PD) are strongly increasing worldwide. Up to now, very little is known about their biochemical mechanism and no effective therapeutic strategies are available to face brain functionality deterioration. A very intriguing hypothesis actively under investigation is referred as "microbiota-gut-brain axis". It suggests that human gut microbial community might impact central nervous system functionality through a bidirectional interaction that potentially might play also a key role in neurodegenerative disorders. Here we present a novel technological project, named MINERVA supported by the European Research Council (ERC) Programme, that aims, by using an innovative bioengineering approach, at evaluating microbiota impact on brain functionality. MINERVA goal is to develop a cutting edge technological platform, based on organ on chip microfluidic device, to model the main players of the microbiota-gut-brain axis. The final aim of MINERVA is to investigate the role of microbiota on brain functionality in physiological but also in pathological neurodegenerative conditions in order to improve the knowledge in the field and open the way to potential novel therapeutic microbiota-based approach for neurodegenerative disorders

Albani, Diego

Giordano, Carmen

Archivio istituzionale della ricerca - Politecnico di Milano

48 Agro FOOD Industry Hi Tech - vol. 28(6) - November/December 2017ELDERLY NUTRITIONDIEGO ALBANI1, CARMEN GIORDANO2**Corresponding author1. Department of Neuroscience, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy2. Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico, Milan, ItalyKEYWORDS: Intestinal microflora, neurodegeneration, microbiota- gut-brain axis.Abstract Chronic neurodegenerative disorders including dementias, as Alzheimer’s disease (AD) and movement disorders, as Parkinson’s disease (PD) are strongly increasing worldwide. Up to now, very little is known about their biochemical mechanism and no effective therapeutic strategies are available to face brain functionality deterioration.A very intriguing hypothesis actively under investigation is referred as “microbiota-gut-brain axis”. It suggests that human gut microbial community might impact central nervous system functionality through a bidirectional interaction that potentially might play also a key role in neurodegenerative disorders. Here we present a novel technological project, named MINERVA supported by the European Research Council (ERC) Programme, that aims, by using an innovative bioengineering approach, at evaluating microbiota impact on brain functionality. MINERVA goal is to develop a cutting edge technological platform, based on organ on chip microfluidic device, to model the main players of the microbiota-gut-brain axis. The final aim of MINERVA is to investigate the role of microbiota on brain functionality in physiological but also in pathological neurodegenerative conditions in order to improve the knowledge in the field and open the way to potential novel therapeutic microbiota-based approach for neurodegenerative disorders. MINERVA: the technological project to boost research on the microbiota-gut-brain axis in chronic neurodegenerative disordersMICROBIOTA-GUT-BRAIN AXIS: A FOCUSED OVERVIEW Alzheimer’s (AD) and Parkinson’s (PD) disease are severe chronic neurodegenerative pathologies. ADfeatures memory loss, followed by behavioral changes and impairment in everyday life. PD is characterized by movement disturbances, but it is not unusual the presence of dementia (1). An extremely interesting hypothesis is that the intestinal microfl ora (collectively named “microbiota”) is a key player in chronic neurodegeneration. A relation between gut microbiota and brain, referred to as “microbiota-gut-brain axis”, was fi rstly hypothesized more than 100 years ago by the Russian embryologist Elie Metchnikoff: he surmised that a healthy microbiota could help counteracting aging and that some bacterial strains (what we call today “probiotics”) found in sour milk and yogurt would increase longevity (2). Literature shows that Metchnikoff’s fi ndings have been recently re-evaluated, becoming a new, exciting hypothesis in neuroscience: up to now, the papers on a possible role of gut microbiota on brain or AD/PD increased impressively, going from 8 in 2008 to 842 in September 2017, with 258 articles published in 2016 only (Table 1; source: PubMed).  Many proposals dealing with the microbiota have been granted in the last 6 years: in 2011 and in 2012, the Michael J. Fox Foundation (USA) funded two grants on gut microbiota effect on PD, while “MYNEWGUT” was fi nanced in Europe and it deals with diet, microbiota and its impact on brain development. The Human Microbiome Project-HMP (USA) was designed to sample, determine and quantify all human-associated microbiota; MetaHIT in Europe, is focused on intestinal microbiota; Eldermet in Ireland, is a national project associated with the large European project “NU-AGE” (the latter centered on the elderly) aimed at assessing the association between gut microbiota, food and health in the elderly. Very recently, the H2020 EU Programme granted the “AD-GUT” project, where for the fi rsttime microbiota composition will be manipulated in AD patients to evaluate how this affect the diagnosis and progression of the disease. Table 1. Number of published articles on the microbiota-gut-brain axis in the last 10 years, with a focus on Alzheimer’s disease and Parkinson’s disease. (source: PubMed;  keywords: “microbiota gut brain”; “microbiota gut brain Alzheimer’s disease”; “microbiota gut brain Parkinson’s disease”.Note: the sum of published article/year exceeds the single search from 2008 to 2017 (842, 37 and 38, respectively) as some papers in the single year search are counted twice (year of e-pub and printed version).49Agro FOOD Industry Hi Tech - vol. 28(6) - November/December 2017but they are performed with standard techniques that rely on 2D static immortalized cell models and their treatment with bacterial-derived molecules, a model that is very far from the real in vivo situation. In this setting, the availability of valuable innovative technological tools to consolidate the potential mechanisms by which the microbiota impacts the brain functionality might greatly help in overcoming the current limitations of in vitro and in vivo tools (16). Actually, some interesting dynamic digestion model that involves microbiota component and reliably reproduce some key features of the human digestive tract are available, in particular: the Simulator of Human Intestinal Microbial Ecosystem (SHIME™ and M-SHIME™) (17); the TNO Gastro-Intestinal Model (TIM) (18); HUMIX (19). However, the study of the impact of gut microbiota modifications on brain functionality is far from being their aim.MINERVA: AN ERC TECHNOLOGICAL PROJECT TO EVALUATE MICROBIOTA IMPACT ON BRAIN FUNCTIONALITYRecently, an ERC Consolidator project named “Microbiota-Gut-Brain engineered axis to evaluate microbiota impact on brain functionality” (acronym: MINERVA, ERC-CoG-2016 - Proposal 724734), was funded and aims at designing the first complete “microbiota-gut-brain” axis physical model by using a bioengineering approach. This innovative platform relies on three compartments, based on state-of-the-art miniaturized, optically accessible microfluidic devices, hydraulically connected to reproduce in vitro the microbiota-gut-brain axis connection (Figure 1). In the MINERVA platform, human microbiota will be cultured in the “Microbiota-compartment” and the secreted molecules (the so called “secretome”) transported to the “Gut-compartment” where gut epithelial cells and cells from the immune system will metabolize them as occurs in vivo. The resulting modified secretome will reach the “Brain-compartment”, built up by a complete blood-brain barrier in vitro model followed by two exhaustive 3D human brain cell models, featuring the three main populations of brain cells: neurons, astrocytes and microglia. In the first model, the cells will be co-cultured, to recapitulate brain cell-to-cell contacts; in the second model, NEURODEGENERATIVE DISORDERS AND MICROBIOTA IN LITERATUREWe have already several studies addressing the role of gut microbiota in (AD) or (PD) disease. For example, Bhattacharjee et al that described a number of evidences supporting microbiota-AD relationship (3). In addition, Wang et al reported a role of the intestinal microbiota in the protective activities of polyphenols in AD (4), and a similar conclusion was drawn in a mouse model of  neurodegeneration (SAMP8 mice) (5). A direct action of microbiota on mechanisms involved in AD was reported by Minter et al, that suggested in mice  a regulation by the gut microbiota community of host innate immunity mechanisms, with an impact on inflammation and amyloidosis (6). Many other researchers reported a link between gut microbiota and AD in animal models (7-10). A very important finding came from a seminal work in human patients, where it was reported an increase of a pro-inflammatory microbiota in patients with cognitive impairment and brain amyloidosis (11). As for PD, researchers have already found a different microbiota composition in PD patients in comparison to controls, (12-14), while PD animal models point to a role of microbiota in clinical signs, as reported by Sampson et al, whose findings suggested that gut bacteria regulate movement disorders (15).CURRENT AND INNOVATIVE MODELS TO STUDY THE IMPACT OF MICROBIOTA ON BRAINCurrently the main experimental findings on microbiota-gut-brain axis impact on brain functionality, and in particular on AD/PD, rely mostly on in vivo assessments in rodent models, that allow to investigate the whole-body response to selected stimuli. Some of them have been used in particular to asses microbiota role in neurodegenerative disorders such as AD and PD (Table 2). However, they have several limitations: (a) rodent’s microbiota is very different from the human one, (b) even if we transplant human microbiota in rodents, residual murine or environmental contamination is a major issue, and (c) they are expensive, lab-intensive and do not allow a strict control on microbiota composition once inoculated. Many papers are also based on in vitro studies, Figure 1. MINERVA platform: it is based on three main compartments, representing the microbiota, the gut, and the brain that hosts five optically accessible, organ-on-chip microfluidic devices. Each device hosts advanced in vitro cell models to model the main players of the microbiota-gut-brain axis: the microbiota; the gut epithelium; the immune system; the blood brain barrier; the brain.Table 2. Examples of current models to address the role of gut microbiota in Alzheimer’s and Parkinson’s neurodegenerative disease.6. Minter MR, Zhang C, Leone V, et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep. 2016;6:30028. 7. Shen L, Liu L, Ji HF. Alzheimer’s Disease histological and behavioral manifestations in transgenic mice correlate with specific gut microbiome state. J Alzheimers Dis. 2017;56:385-390. 8. Harach T, Marungruang N, Duthilleul N, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802.9. Wu SC, Cao ZS, Chang KM, et al. Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila. Nat Commun. 2017;8:24. 10. Bonfili L, Cecarini V, Berardi S, et al.  Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels. Sci Rep. 2017;72426. 11. Cattaneo A, Cattane N, Galluzzi S, et al.  Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60-68. 12. Petrov VA, Saltykova IV, Zhukova IA, et al.  Analysis of gut microbiota in patients with Parkinson’s Disease. Bull Exp Biol Med. 2017;162:734-737. 13. Unger MM, Spiegel J, Dillmann KU, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66-72. 14. Scheperjans F, Aho V, Pereira PA, et al.  Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015;30:350-358. 15. Sampson TR, Debelius JW, Thron T, et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell. 2016;167:1469-1480.16. Fritz JV, Desai MS, Shah P et al. Microbiome from meta-omics to causality: experimental models for human microbiome research. Microbiome 2013;1:14.17. Marzorati M, Pinheiro I, Van den Abbeele P et al. An in vitro technology platform to assess host-microbiota interactions in the gastrointestinal tract. Agro FOOD Industry Hi-Tech 2012;23: 8-11. 18. Minekus M, in: The Impact of Food Bioactives on Health-in vitro and ex vivo models, Editors: Kitty Verhoeckx, Paul Cotter, Iván López-Expósito, Charlotte Kleiveland, Tor Lea, Alan Mackie, Teresa Requena, Dominika Swiatecka, Harry Wichers, ISBN: 978-3-319-15791-7 (Print) 978-3-319-16104-4 (Online), pag: 37-46.19. Shah P, Fritz JV, Glaab E, et al. A microfluidics-based in vitro model of the gastrointestinal human–microbe interface. Nature Communications 7:11535.each cell type will be cultured individually to let explore the microbiota’s effect on each cell type. MINERVA platform will be functionally and biologically validated using an approach at increasing complexity, to finally assess neural cell response once exposed to human complete microbiota from (a) healthy donors, and (b) Alzheimer’s disease (AD) patients. MINERVA has the potential to fill the gap existing in current tools in the field of microbiota-gut-brain axis at the boundaries between in vitro and in vivo models, to deep our knowledge in the field and suggest innovative strategies to be tested after the approval of clinical studies enrolling AD/PD cases that ultimately will demonstrated the impact of microbiota control in neurodegeneration. CONCLUSIONSThe fundamental concept of an interaction of gut microbiota with the nervous system has been revisiting in recent years: the main novelty is the search for a causal link between microbiota composition or metabolism and the molecular determinants of pathologies as Alzheimer’s or Parkinson’s disease, mostly considered up to now as based on brain autonomous mechanisms. We have very limited knowledge in this field but studies and models are under development. This hopefully will boost the perspective of a clinical translation, as the microbiota-brain relation would represent a breakthrough also from the therapeutic point of view: human microbiota composition is dynamic and tunable by diet and probiotics, a very common tool in medicine, for instance in association with antibiotics therapy.It is out of doubt that the challenge is complex and only a multidisciplinary approach based on fruitful discussion among neuroscience, immunology, gastroenterology and bioengineering will be successful and MINERVA might represent a first challenge on this way.ACKNOWLEDGEMENTS“MINERVA project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 724734)”.REFERENCES AND NOTES1. Jellinger K. Neuropathological substrates of Alzheimer’s disease and Parkinson’s disease. J Neural Transm Suppl. 1987;24:109-129.2. Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part I – autointoxication revisited. Gut Pathogens 2013;5:5. 3. Bhattacharjee S, Lukiw WJ. Alzheimer’s disease and the microbiome. Front Cell Neurosci. 2013;7:153. 4. Wang D, Ho L, Faith J, et al. Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer’s disease β-amyloid oligomerization. Mol Nutr Food Res. 2015; 59:1025-1040. 5. Wang J, Ye F, Cheng X, et al. The effects of LW-AFC on intestinal microbiome in senescence-accelerated mouse prone 8 strain, a mouse model of Alzheimer’s Disease. J Alzheimers Dis. 2016;53:907-919.Carmen Giordano was born in Naples in 1971. She graduated in Chemistry in 1998 and gained a PhD in Biomaterials in 2002 at Università degli Studi di Napoli “Federico II”. During her research activity, she joined the International Institute of Genetic and Biophisic (CNR, Naples) and the University College London (UK). Since 2015, she is associate professor at Politecnico di Milano.About  the author50 Agro FOOD Industry Hi Tech - vol. 28(6) - November/December 2017

MINERVA: The technological project to boost research on the microbiota-gut-brain axis in chronic neurodegenerative disorders

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MINERVA: The technological project to boost research on the microbiota-gut-brain axis in chronic neurodegenerative disorders

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Archivio istituzionale della ricerca - Politecnico di Milano