OVERVIEW

MicrobiotaBiofortis Newsletter

EDITOMarc BONNEVILLECSO Institut Mérieux

October 201 7 #4

Interviews of Hervé Affagard, MAAT

PHARMA and Kristin Wannerberber,

FERRING

(pages 7-8)

HIGHLIGHTS 201 7-201 8

The 3rd IMODI newsletter

Targeted metagenomic data

visualization & analysis

(poster: page 9)

Publication on the oral cavity

microbiota. Le Bars et al. 201 7

(page 9)

Biofortis participation in scientific

microbiome events in 201 7

(page 10)

The 6th Better Food for Better

Health event in 201 8

(page 10)

Development of NGS Industry

(poster page 10)

D ear readers,

As the number of studies in the microbiota fieldincreases exponential ly, we are now well aware of theprofound implications this evolving field could have onour understanding of biological, medical orenvironmental processes. I t rel ies on complex interplaysbetween tremendously diverse microbial communities.This fourth “Microbiota” letter focuses on new clinicaldevelopments that rely either on a better knowledge ofmicrobial communities that populate our organisms ordirect therapeutic use of microbiota or microbiota-derived products.

The various applications of microbiome research includenew stratification tools to better predict efficacy or sideeffects of treatments, as well as new therapeutics basedon the use of prebiotics, probiotics or fecal transplants.These are herein reviewed, as well as key industrialplayers in these areas. This letter further describesinterventional approaches using antimicrobial peptides,fecal microbiota transplantation and phagotherapy,which could represent promising alternatives toantibiotherapy.

While microbiome studies have already yieldedpromising cl inical developments, we sti l l face manychallenges. More mechanistic work to assess the causalrelationships between microbiota alterations anddiseases are needed. Additional ly, many technical andregulatory hurdles should be addressed to improvestandardization of microbiome monitoring andmicrobiota-derived therapeutic products.Thanks to its broad services offer, integrating CROactivities and microbiome analysis, Biofortis MérieuxNutriSciences contributes to the worldwide collaborativeefforts to tackle these various challenges.

HUMAN MICROBIOMETHERAPEUTICS (pages 2-6)

Our gut ecosystem, including the microbial communitynamed microbiome, has a key role in human health andrepresents a new area of innovative therapies. Twokinds of microbiome investigation areas can bedistinguished in human healthcare, the first is toward thebiomarker discovery and monitoring and the second inthe development of Human Microbiome Therapeutics(HMTs).

OBSERVATIONAL STUDIES FOR BIOMARKERDISCOVERY

Microbial population-scale studies which integratedriving factors evaluation such geography, diet andl ifestyles are strategic for patient stratification and forbiomarker discovery. These investigations require long-term clinical trials on cohorts and robust data analyses.IMODI1 , EPIPAGE2, MOMS-Pi3, Eldermet4, My New Gut5

are all examples of such initiatives. These studiescontribute to a better understanding of what is a ‘healthymicrobiome’ and what is a ‘risky microbiome’ (1 ).Microbiome-based biomarkers would be useful to predictor diagnosis patient diseases (e.g. dysbiosis, lack ofdiversity, harmful bacteria or lack of beneficial bacteria).Microbiome evaluation is also important for apprehendingthe toxicity of a treatment (e.g. dysbiosis afterchemotherapy or antibiotherapy, associated withundesirable side effects), l ikewise to inform on theseverity of the disease during the therapy. They may alsobe useful for elucidating treatment response variabil ity(responder / non-responder) toward personalizedmedicine. In such context, within the French IMODIconsortium, Biofortis Mérieux NutriSciences is studyingthe gut microbiota from cancer patients treated withchemotherapy agents. This col laborative project involvessome of the leading public Institutes and bigpharmaceutical companies to identify biomarkers inoncology (Microbiome Newsletter #1 and IMODI Flyers).Besides, some companies have a functional microbiomeplatform dedicated to microbiome biomarker discoverytoward HMTs, development for example Biospherex LLC,Enterome, Vaiomer, Second Genome.

MICROBIOME FOR NEW INNOVATIVETHERAPEUTICS

Pharmaceutical companies such as Biocodex, 4D-pharma, Vedanta Bioscience, Evelo Biosciences developmicrobiome therapeutics in human healthcare. HMTsmight improve health by i) re-balancing the microbial-host ecosystem i i ) modulating the inflammatory process,with a direct or indirect immunomodulation , i i i)enhancing the gut epithelium/barrier, iv) eradication ofa pathogen .

HMTs can either be Live Biotherapeutic Products(LBPs) defined as ‘medicinal products containing livemicro-organisms’ (probiotics, Fecal M icrobiota Transplant(FMT), bacteriophages), or microbiome-derived products(antimicrobial peptides, enzymes, metabolites, bacterial

lysates, stool fi l trates, phages-derived products).

Other health studies, outside the gut, support theimportance of gut microbiome therapies: the gutecosystem communicates with other organs via thebloodstream and enteric nervous system (using signal l ingmolecules, metabolites, derived bacterial products), andinfluence the immune responses and cognitive functions.

A first probiotic drug with a positive effect on the gutmicrobiome was Saccharomyces boulardii CNCM I-745®, developed by the pharmaceutical companyBiocodex. Since then, only a few HMTs have progressedto phase 2 clinical trials because of lack of scientificconsensus and regulatory constraints. However, severalworking group initiatives are worldwide organized todiscuss these constraints. Quorum Innovations ispioneering Probiomic™ therapeutics to treat a range ofdiseases. Evelo Biosciences HMTs are based onmonoclonal microbials and Vedanta Biosciences HMTson bacterial consortia. Rebiotix, Seres Therapeutics aredrivers in Microbiota Restoration Therapy (MRT), theyboth have a product in cl inical phase 3 (Rebiotix‘RBX2660’, Seres Therapeutics ‘SER 1 09’).

Another strategy is the development of co-treatment toprotect the microbial-host gut ecosystem. For example,the compound, FE 203799 (developed by Glypharma andgranted by Ferring), is a long-acting GLP-2 receptoragonist with intestine-protective activity fromchemotherapy-induced intestinal mucositis. AxialBiotherapeutics is a biopharmaceutical companyharnessing the l ink between the human gut microbiomeand Central Nervous System (CNS) to develop a newclass of therapeutics to improve the quality of l ife forpeople with CNS diseases and disorders.

MICROBIOME: A NEW LAND OFPROMISING HEALTH INNOVATION

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D ear readers,

As the number of studies in the microbiota fieldincreases exponential ly, we are now well aware of theprofound implications this evolving field could have onour understanding of biological, medical orenvironmental processes. I t rel ies on complex interplaysbetween tremendously diverse microbial communities.This fourth “Microbiota” letter focuses on new clinicaldevelopments that rely either on a better knowledge ofmicrobial communities that populate our organisms ordirect therapeutic use of microbiota or microbiota-derived products.

The various applications of microbiome research includenew stratification tools to better predict efficacy or sideeffects of treatments, as well as new therapeutics basedon the use of prebiotics, probiotics or fecal transplants.These are herein reviewed, as well as key industrialplayers in these areas. This letter further describesinterventional approaches using antimicrobial peptides,fecal microbiota transplantation and phagotherapy,which could represent promising alternatives toantibiotherapy.

While microbiome studies have already yieldedpromising cl inical developments, we sti l l face manychallenges. More mechanistic work to assess the causalrelationships between microbiota alterations anddiseases are needed. Additional ly, many technical andregulatory hurdles should be addressed to improvestandardization of microbiome monitoring andmicrobiota-derived therapeutic products.Thanks to its broad services offer, integrating CROactivities and microbiome analysis, Biofortis MérieuxNutriSciences contributes to the worldwide collaborativeefforts to tackle these various challenges.

1http: //www.imodi-cancer.org/, 2http: //epipage2.inserm.fr/index.php/en/, 3http: //vmc.vcu.edu/momspi, 4http: //eldermet.ucc.ie/,5http: //www.mynewgut.eu/

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Wordwilde driving forces for Human MicrobiomeTherapeutics

Multiple worldwide health organizations are driving forceto go forward with scientific and regulatory challengesfor HMTs. Especial ly, col laborative initiatives andconstructive dialogue among researchers, stakeholdersand health organizations are occurring to consider noveltherapies to counteract acute and/or chronic infections.The World Health Organization (WHO) considers thatdrug resistance is one health problem which complicatesthe fight against HIV, malaria and increases risks formedical procedures such as organ transplantation, majorsurgery, cancer chemotherapy, diabetes management(http: //www.who. int/mediacentre/factsheets/fs1 94/en/).Globally, the Organization estimates that 480 000 peopledevelop multi-drug resistant against tuberculosis eachyear. Additional ly, they stress that novel antimicrobialagents are needed in l ivestock health. Their use has beenbanned since 2006 in EU (http: //europa.eu/rapid/press-release_IP-05-1 687_en.htm) and in USA, prescriptionsrequire a FDA’s VFD (Veterinary Feed Directive) sinceJanuary 201 7(https://www.fda.gov/AnimalVeterinary/default.htm). WHOis working closely with the FAO (Food and AgricultureOrganization of the United Nations) and the OIE (TheWorld Organisation for Animal Health) in a ‘One Health

approach’ to avoid the emergence and the spread ofantibacterial resistance, including optimal use ofantibiotics in both humans and animals.Besides, major HMTs accelerating private players formicrobiome discoveries are Biocodex MicrobiotaInstitute (BMI), Second genome, 4D Pharma MicroRx (1 5development programmes in diverse therapeutic areas),the Janssen Human Microbiota Institute (JHMI),NuBiyota’s microbiome platform (Takeda and NuBiyotacollaboration for HMTs), Novartis col laborate withAnaeropharma in engineering HMTs in oncology field.

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HUMAN MICROBIOME THERAPEUTICS

AMPs (Antimicrobial peptides) are multifunctional peptides with a fundamental biological role, especial ly ineradication of pathogen micro-organisms [1 ].

FMT (Fecal Microbiota Transplantation) is the transfer of biologic material containing a minimally manipulatedcommunity of microorganisms from a human donor to a human recipient (including autologous use) with the intentof affecting the microbiota of the recipient [2]

LBP (Live Biotherapeutic Product) is a biological product that contains l ive microorganisms (e.g. bacteria or yeast).I t is applicable to the prevention, treatment or cure of a disease or condition of human beings. LBP may containone or multiple microbial strains from the same or different species of micro-organisms [3].

Phagotherapy (or bacteriophage therapy) is the therapeutic use of bacteriophages to treat pathogenic bacterialinfections. Bacteriophages are much more specific than antibiotics.

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FECAL MICROBIOTA TRANSFERAN EMERGING THERAPY

Fecal transfer is examined as a possible way toprevent or treat multiple of diseases [6]. Nowadays,FMT effectiveness is well recognized for the managementof recurrent or refractory Clostridioides difficile infection(rCDI) (not cured with antibiotic administration) [7, 8].Consistent disease resolution rates are observed in85-90% of rCDI patients after one FMT and up to 1 00%after 2 FMTs. Beyond this therapeutic indication,promising clinical improvements have been observedfor chronic gut disorders such as Irritable BowelSyndrome (IBS) [9], Crohn disease [9, 1 0], col itis [1 1 ],metabolic disorders [1 2], non-alcoholic steatohepatitis(NASH) [1 3] and autoimmune disorders [6]. In apreclinical study in oncology, it was shown that FMT mayalso l imit irradiatiation treatment toxicity by improvingthe gut integrity and functionality [1 4]. Interestingly, FMTinduced amelioration of neurologic disorders in autismchildren [1 5, 1 6], supporting the gut-brain axis hypothesis[1 7].

Nowadays, the regulatory status of FMT is inconsistent.Some health authorities agree to consider FMT as a drug

(France, USA and Canada) which require ful l investigationand authorization before marketing. However, theyacknowledge its use in specific conditions for rCDImanagement. In Europe, the situation is heterogeneousamong countries, namely on its status: is FMT a drug, atherapeutic intervention, or a human tissue? TheEuropean Medicines Agency (EMA) has not yet defined aposition and discussions are sti l l ongoing. While theregulators debate, scientists continue research to defineand characterize FMT. Recently, a European consensushas been reported by experts from 1 0 countries to providestatements on key issues for use of FMT in clinicalpractice [8]. Major topics related to regulatory,administrative and laboratory requirements. This solutionopens many promises but it is sti l l in its infancyconcerning indications, procedures and expected results.In paral lel , other methods of microbiome transfer areunder investigations: transfer of selected microorganismsconsortia (microbial ecosystem therapeutics, MET) [1 8],transfer of fecal water [1 9], or transfer of vaginalmicrobiota from mothers to newborns [20], (see ourNewsletter #3).

Microbiome Therapeutics: to manage antibiotherapy challenges

In the last decade, development of novel antimicrobial therapy was undeniably one major goal of pharmaceuticalindustries in order to develop alternative solutions to antibiotherapy [4].

Keeping the commensal microbiome at balance is crucial to fight pathogen invasion . I t is known that antibiotherapycan disrupt microbiome equil ibrium and cause gut disorders. Besides, it is a global worldwide health concern with therise of antimicrobial resistance causing acute and/or chronic infections responsible for patient morbidity or death,especial ly in developing countries, in immune-compromised or hospital ized patients, and elderly in nursing home.Microorganisms that develop antimicrobial resistance are sometimes referred to as “superbugs”. The French biotechDa Volterra developed a portfol io of unique products in the antibacterial field with research dedicated to understandingthe impact of antibiotics on the intestinal flora. Their most advanced product is DAV1 32, developed to prevent thedisruption of the intestinal microbiota and inhibit Clostridioides difficile infections associated with antibiotic use (itsperformance was already demonstrated in 2 cl inical trials, phase 2). Debiopharm International belongs to a globalbiopharmaceutical group of companiesthat develops drugs in oncology and infectious diseases. Their most advancedantimicrobial compound is afabicin (Debio 1 450), a first-in-class FabI inhibitor with targeted activity on Staphylococci. Incontrast to broad-spectrum antibiotics afabicin has been shown recently not to cause significant changes in compositionof the mouse gut microbiota. An interesting recent communication reported the beneficial effect of a combination ofprobiotic (Lactobacillus plantarum) and a prebiotics in reducing Indian neonates sepsis [5].

In the next sections, we have detailed three HMTs, which are promising alternatives to antibiotherapy: theAntimicrobial peptides (AMPs), the Fecal Microbiota Transplantation (FMT) and the Phagotherapy.

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PHAGE-DERIVED THERAPEUTICS'NATURAL PREDATION OF TARGETED BACTERIA'

Faced with antibiotic-resistant strains, or lack of drugefficacy and target specificity, one major antimicrobialtherapeutic alternative is phagotherapy. This traditionaltargeted bacterial therapy is a current practice in East-Europe, but slowed down in the western countries whenantibiotics were discovered, and is currently of re-emerging interest from drug discovery companiesand scientists. Phages are natural predators oftargeted bacteria. Most common targeted bacteria arePseunomonas aeruginosa, Staphylococcus aureus,Escherichia coli. Phage cocktails are produced underGMP conditions, in l ine with current guidelines forbiological medicinal products. Both whole phages andphage-based antibacterial therapy are subjected to thesame rigorous clinical trials process as antibiotics andare classified as ’therapeutic biological products’ [21 , 22,23]. One challenge is regulatory: phagotherapy issubmitted to drug legislation without any marketingauthorization in the EU and in the USA for the moment.Indeed, safety, pharmacokinetics and pharmacodynamicsresearch are sti l l poorly understood. For example, safetyinformation in infected patients is necessary as theadministrated phages would multiply in the presence ofthe pathogenic bacteria [24]. In the USA, the first phagephase 1 cl inical trial was approved by the FDA in 2008,but the phages are not approved to be used astherapeutics [25, 26]. In 201 5, The EMA organized aworkshop to explore all possibi l ities for using the current

regulatory framework in order to al low the authorization ofthis therapeutic approach (EMA/389257/2015). Besides,The National Agency for the Safety of Medicines andHealth Products (ANSM) designed a 'temporaryscientific committee' to evaluate each case study ofphagotherapy, in therapeutical or preventative cl inicalpractices (N° CSST201 611 01 3 –CSST Phagothérapie).

The European collaborative project PhagoBurn (7thFramework Programme, involving the French companiesPherecydes Pharma and Clean cells), was the world firstmulticenter cl inical study of phage therapy in serious burnvictims (Pseudomonas aeruginosa infection). Besides theuse of natural bacteriophages (Pherecydes Pharma,AmpliPhi), some companies develop phage-derivedtherapy: lysin, bioengineered phage, vectorsU (Eligo-Bioscience, Micreos, ContraFect, Avid Biotics, Enbiotix).Dual therapy with phage and antibiotics are alsoencouraging therapy in el iminating drug-resistantpathogens [24]. Overal l , advances were successful lyobtained for single patient therapy, to address varioussystemic or topical chronic infections (burn & skin, bone,prosthesis, urinary/genital tracts, oral/respiratory tracts,ear infectionU) and diarrhea & food poisoning [24, 25].Several placebo-control led cl inical trials havedemonstrated phage therapy to be safe.

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ANTIMICROBIAL PEPTIDES (AMPs)NATURAL DEFENSE AGAINST PATHOGEN

Natural ly occurring AMPs are key components of theinnate immune system to survey pathogen invasions inmulticel lular organisms. The health potential of AMPs islargely unexplored: more than 2500 peptides have beenidentified from multiple organisms (AMPs Databases:http: //aps.unmc.edu/AP/main.php;http: //bioinformatics.cs.ntou.edu.tw/adam/).Human defense peptides (e.g. defensin) combined withcommensal bacterial AMPs (bacteriocins and peptideantibiotics) modulate our microbiome and regulatepathogen colonization [27]. Some antimicrobial peptideskil l both bacteria and fungi. For example, humandefensins have a broad spectrum of antimicrobial activity.They are highly effective in ki l l ing Gram-negative bacterial ike Escherichia coli and Pseudomonas aeruginosa andact against Candida albicans [28]. Bacteriocins areproteins produced by non-pathogen bacteria with anactivity usually against closely related pathogen species.Nisin, produced by the bacterium Lactococcus lactis, is arare example of a ‘broad-spectrum’ bacteriocin effectiveagainst many Gram-positive organisms (lactic acidbacteria, Listeria monocytogenes, Staphylococcus aureus,Bacillus cereus, Clostridium botulinum); it is the onlybacteriocin ‘recognized as safe’ by the FDA and used as

food preservative. One specific bacteriocin can beproduced by several closely species (e.g. enterocin issynthesized by several strains of Enterococcus faecalisand Enterococcus faecium). AMPs engineering (e.g.SNAPPs, Structural ly Nanoengineered AntimicrobialPolypeptide Polymers) or stimulation of natural AMPswith cofactors (e.g. metals, amino acids, vitamin D andsunlight) are attractive strategies of ‘new antibiotics’[29]. Scientific advances have been reported for oralmucositis, lung infections associated with cystic fibrosis,skin and wound infections and cancer therapy [30]. Forexample, a lack of defensin (AMPs) has been correlatedwith Crohn disease [31 ]. One main advantage of AMPs isto counteract pathogens that are resistant toantibiotics, including pathogens within biofi lms. They actby fast elimination of several targets and they can l imittoxin production while antibiotics can increase toxinrelease. The high cost of their commercial productionand regulatory concerns are main limitations forbacteriocin market. In the next years, the optimization oftheir production and purification, the efficacy ofcombinations with other antimicrobial agents andengineered product, represent promising solutions to themarket constraints [32].

In summary, several kinds of HMTs are emerging as excellent candidates for innovative health strategies but somescientific and regulatory challenges remain. Despite no current market authorization, FMT, phagotherapy and AMPs arepositioning as forthcoming novel solutions to infectious disease. They should benefit within a short-time from multipleregulatory working groups and scientific committee initiatives. Long-term investigations with microbiome analysis andassociated cl inical parameters wil l make it possible to judge the relevance and safety of these therapeutic indications. Inthe context of this newsletter, Hervé Affagard (MaaT Pharma) and Kristin Wannerberger (Ferring Int. center S.A.)kindly accepted to discuss the historical context of their work in HMTs and their point of view on this thematic.

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HERVÉ AFFAGARD is the CEO – Co-Founder of MaaTPharma, a biotechnology company that stands forMicrobiota as a Therapy with a focus on faecalmicrobiotherapy to develop innovative solutions of cl inicalrelevance to treat unmet medical needs of dysbiosis-related diseases. Mr Affagard leads the MaaT Pharmaproject since its inception phase in 201 3. Previously, heworked as an entrepreneur in residence for venture capitalfirms in the Healthcare field; as a consultant forbiotechnology companies; as executive director leading amultidiscipl inary team at Biomnis, and he combinedexperience at Bio-Rad.

‘Today I work with a team of 20+ passionate individualsdeveloping drugs to fight iatrogenic symbiosis. There isgrowing evidence that the microorganisms living in our gutplay an important role in our health. I found HumanMicrobiome Therapeutics very interesting as anentrepreneurial adventure but mostly from a personalperspective, because my family has a history of intestinaldisorders. For me, it meant giving a new angle toanalyze diseases where drugs showed limited effects.They represent a new generation of microbiome-drugsconsidering man-microbes as a whole and thereforebring new solutions. Currently, we have 3 clinical trials inthe pipeline: Odyssee (Prevention of dysbiosiscomplications with autologous FMT in patients with AcuteMyeloid Leukemia), Ulysse (Epidemiological study toassess clinical consequences of dysbiosis in patients withAcute Myeloid Leukemia) and Osiris (A prospectiveclinical study aiming to assess the potential of gutmicrobiotherapy in patients with Bone and Joint Infectionsundergoing long term antibiotherapy). MaaT Pharma’score business focuses on the restoration of the man-microbes symbiosis. It is based on clinically validatedplatform to develop FMT-based treatment on a safe,patented, GMP end-to-end process. With 4 patents and 2trademarks, MaaT Pharma developed and recentlyannounced the CE marking of a stool collection device(gΛt RePrint ™). MaaT Pharma is also the first in Europeto enter in the clinics for complex ecosystem based drugs.We noticed an emerging need for which no solutionexisted in the market to treat the consequences of heavytreatments such as chemotherapy, antibiotics andinfectious diseases. Our goal is to become one of theleaders in development of drugs aiming at preventingand treating dysbiosis-related diseases by using theclinical promise of Fecal Microbiota Transfer (bothautologous and allogenic). MaaT Pharma is currentlypartnering with Biocodex on the industrialization anddevelopment of an oral formulation of FMT. Our market

entry strategy is a niche as we are establishing aHuman Proof of Concept in immune-compromisedpatients: Leukemia. ‘Regulatory is probably one of thebiggest challenges for developing living micro-organisms-based therapeutics. Coming back to FMT,France is ahead of the curve as the French Agency seta working group (2013) to support first hospitalphysicians and now the entire industry. The highest levelof qualification was decided in France as FMT is regulatedas a drug, as it is in the USA, UK or even Germany.However, there is lack ofharmonization as few countriesare considering it as a tissue. Basically, scientists knowthat a symbiotic microbiome has beneficial health effectsand are seeking to understand what specific playersmake you healthy. Understanding the details might helpMaaT Pharma create better treatments for a wide rangeof conditions. Multiple pharmaceutical forms (oral formwith crude, cultured or enriched microbiota) will facilitateproduct line extensions in numerous other indicationswhich are to be assessed: Autism, IBD and MetabolicDisorders5 New clinical programs are to be launchedin additional fields of Immuno-oncology and infectiousdiseases. Our goals are to reduce infections co-mortalityin Leukemia patients, reduce re-hospitalization rate andimprove response to anti-cancer treatments. Byproviding a safer and easier process, we believe thatwill help medical professionals to perform this procedureand enables universal access to FMT-based drugs.Oral form product might facilitate global spread of theCompany’s FMT solution to other indications. ’

BIOFORTISINTERVIEW SECTION

INTERVIEW WITH HERVE AFFAGARDCEO - Co-Founder of MaaT Pharma, France.

Image kindly provided by Maat Pharma.

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KRISTIN WANNERBERGER is Director All ianceManagement in R&D where she is involved in early stagedevelopment projects and working with multiple academicinstitutes and companies. Her background is a MSc inChemical Engineering with Food and Dairy Technology asspecialty as well as a PhD in Biophysical Technology. Shehas 20 years of experience working in the PharmaceuticalIndustry (Astra Zeneca and Ferring Pharmaceuticals) andin the last 1 0 years she worked in Global ProjectManagement as Global Project Director. During her carriershe was part of several product approvals both in Europeand the US.

‘My interest was always towards chemistry, nutrition andhealth and specifically fermented products. I made athesis on the effect of lipid oxidation by acidification onfish by using lactic acid bacteria instead of adding acids.This was in the 1980s. With my PhD in BiophysicalTechnology I joined Pharmaceutical Industry and gotinsight in the field of drug development. I always keptreferring back to my physicochemical background and

when the moment came to look into the human microbiotaI could see so many connections. The biggestchallenges in Human Microbiome Therapeutics areregulatory pathway and clinical development strategy,for sure.

Our business strategic positioning is very broad. We doearly-stage studies in large cohorts of subjects with theobjective to try to understand what is ‘normal’ with respectto the human microbiota. We also run several projectsincluding both bacteriophages and bacterial strains.We also naturally include any metabolites of themicrobiota in our strategy. With the growing interest fromthe world around us and more evidence that e.g. FMT hasa positive effect you could expect that the regulatoryenvironment will change. Today we divide between thedrug and the food route. Perhaps in the future thesewill merge into something in between the two. Youhave to provide clinical data and it must be relevant. Towhat extent and when is something that should bediscussed and agreed with the regulatory bodies. ’

To conclude, HMTs are still challenging but a promising alternative therapy. Guidance and safety are lacking to respectregulatory requirement for market approval. However, many clinical trials are currently underway, which may result in scientificsupport for future approvals. One other future challenge is the functional characterization of HMT and its impact on the globalmicrobial-host ecosystem.

KEY DRIVER ORGANIZATIONS FOR ‘MICROBIOME THERAPEUTICS’

ANSM (Agence National de Sécurité du Médicament et des produits de santé) is the French Health ProductsSafety Agency. They established in 201 6 a temporary scientific committee (CSST) dedicated to phagotherapies.

CBER (Center for B iologics Evaluation and Research) regulates biological products for human use underapplicable federal laws, including the Public Health Service Act within FDA. They published guidance for Industry:Early cl inical trials with LBPs (201 2 Feb).

EDQM (European D irectorate for the Quality of Medicines and HealthCare) sets the European Pharmacopoeiawhich provides a legal and scientific reference for the quality control of medicines for producers of medicinesand/or substances for pharmaceutical use.

EMA (European Medicines Agency) is responsible for the scientific evaluation, supervision and safety monitoringof medicines developed by pharmaceutical companies in European Union.

ILSI (International Life Sciences Institute) is a key health driver organization. Previous work by ILSI North Americatook on the task of defining a ’healthy microbiome’[33]. This microbiome framework is useful to assess thepotential benefit of prebiotics or probiotics.

IPA (International Probiotics Association) is an international organization with members from industry andacademia. I ts goal is to provide a unique forum for the exchange of research and the latest breakthroughs inprobiotic technology and new product development.

PRI (Pharmabiotics Research Institute) is a European non-profit organization focused on Microbiotic MedicinalProducts.

INTERVIEW WITH KRISTIN WANNERBERGERDirector R&D Alliance Management, FERRING, InternationalCenter S.A., Switzerland.

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Abstract: With the recent advances in the field of next-generation sequencing (NGS), metagenomics allow toexplore the biodiversity of microbiota. Dedicatedbioinformatic pipel ine focusing on targeted metagenomics(such as 1 6S rRNA) provides to biologists the bacterialcomposition of the samples. Faced with this large amountof data, their visual ization and appropriate statisticalanalysis are essential for scientists to adequately exploreand interpret their experiments.

In this context, Biofortis has developed an R and Shinyweb based platform called BioMAnTM (BiofortisMetagenomics Analysis) which mixes the statistical powerof dedicated R packages (metagenomeSeq, mixOmics. . . )

and a user friendly web design.This interface allows users to interactively look into theirproject by manipulating, fi l tering or gathering informationfor further interpretation or communications purposes.

BioMAnTM is deployed on a Shiny Server Pro,implemented by a secure health data hosting provideraccording to the French regulatory requirements, toprotect the confidential ity, integrity and availabi l ity ofpatient and user data.

BIOFORTISSCIENTIFIC COMMUNICATION

POSTER: JOBIM 201 7, July 3-6, Lille, France.BioMAnTM: A user friendly interface for targeted metagenomic data visualizationand analysis

Vaissié P, Camus C, Amouzou Y, Carton T, Le Fresne-Languil le S, Le Vacon F, Cazaubiel M and Leuil let S.

REVIEW:The oral cavity microbiota: between health, oral disease and cancers of theaerodigestive tract.

Le Bars P, Matamoros S, Montassier E, Le Vacon F, Potel G, Soueidan A, Jordana F, De La Cochétière MF.

Canadian Journal of Microbiology - 201 7 Jun;63(6):475-492. doi: 1 0.1 1 39/cjm-201 6-0603.

Abstract: Many studies show that the human microbiomeplays a critical role in the chronic pathologies of obesity,inflammatory bowel diseases, and diabetes. Morerecently, the interaction between cancer and themicrobiome has been highl ighted. Most studies havefocused on the gut microbiota because it represents themost extensive bacterial community, and the body ofevidence correlating it with gut syndromes is increasing.However, in the strict sense, the gastrointestinal (GI) tractbegins in the oral cavity, and special attention should bepaid to the specific flora of this cavity.

This study reviewed the current knowledge about thevarious microbial ecosystems of the upper part of the GI

tract and discussed their potential l ink to carcinogenesis.The overal l composition of the microbial communities, aswell as the presence or absence of “key species”, inrelation to carcinogenesis is addressed. Alterations in theoral microbiota can potential ly be used to predict the riskof cancer. Molecular advances and the further monitoringof the microbiota wil l increase our understanding of therole of the microbiota in carcinogenesis and open newperspectives for future therapeutic and prophylacticmodalities.

Key words: upper aerodigestive, microbiome, oral cavity,carcinogenesis.

1 0

FONDATION MÉRIEUX EVENT 201 8BETTER FOOD FOR BETTER HEALTH

Childhood Nutrition: building a healthy life6th editionLes Pensières Center for Global HealthVeyrier-du-Lac, France.20-22 March 201 8

HIGHLIGHTS 201 7MICROBIOTA CONGRESS PARTICIPATION

JANUARY:• Microbiome Drug Development Summit Europe, Paris, France.

FEBRUARY:• Probiota, Berl in, Germany.

MARCH :• Pharmabiotics event, Paris, France.Poster: Clinical Metagenomics for Evaluation ofChemotherapy Impact on Gut Microbiota.• BioEurope Spring, Barcelona, Spain.

APRIL:• AACR, Washington, USA.Poster: IMODI initiative: a novel holistic and integrative approach with patient-derived tumor models against pancreatic cancer.• Microbiome R&D & Business collaboration forum, Amsterdam, The Netherlands.Poster: The Staphylococcal-specific Antibiotic Debio 1450 Minimizes Disturbance to the Gut Microbiota in Mice.Poster: Cosmetic study: How to choose the appropriate area for skin flora analysis?

MAY:• Vitafoods, Geneva, Switzerland.

JUNE:• Spoilers in Foods, Quimper, France.Poster: Alterobio Environmental Microbiota In Food processing Factories: The Smoked Salmon Case Study.

JULY:• JOBIM, Li l le, France.Poster: BiomanTM: A user friendly interface for targeted metagenomic data visualization and analysis.

SEPTEMBER:• Rencontres de l 'Institut Mérieux, Le Microbiote, enjeux cliniques et sociétaux, organized by Mérieux Université,Tassin La Demi-Lune, France.

OCTOBER:• ILSI , Bruxelles, Belgium.• Recent Computational Advances in Metagenomics, Paris, France.• Targeting Microbiota, Berl in, Germany.

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REFERENCES

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AUTHORS

Alessandra DE MARTINOFrançoise LE VACONBéatrice HOUSEZ-FEVRIER

GRAPHISM & PHOTOGRAPHY

Thomas LEFEVREAlexia BOUTIN

Authors thank Chad COOK, Valérie LEYLDE and Hélène CHEVALLIER for writing support.

CONTACTS

Biofortis Mérieux NutriSciences - Europebiofortis-contact@mxns.com - www.biofortis-blog.com

+33 (0)2.40.20.57.99

Alessandra De MartinoScientist - Microbiome Expertalessandra.de.martino@mxns.com

Françoise Le VaconChief Scientific Officerfrancoise. le.vacon@mxns.com