# The French “Microbial Ecosystems & Meta-omics” (MEM) metaprogram from INRA

Sophie Schbath

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To cite this version:

Sophie Schbath. The French “Microbial Ecosystems & Meta-omics” (MEM) metaprogram from INRA.

Hbioinfo 2018, Nov 2018, Thessalonique, Greece. 25 diapos. hal-01954709

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The French
“Microbial Ecosystems & Meta-omics” (MEM)
metaprogram from INRA

Sophie SCHBATH

MalAGE, INRA Jouy-en-Josas, France

Thessalonica, Greece — November 16, 2018

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INRA
SCIENCE & IMPACT

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MaiAGE

MATHÉMATIQUES ET INFORMATIQUE APPLIQUÉES DU GÉNOME À L'ENVIRONNEMENT
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Earth is a microbial world

~ 50% of the biomass

~ 95 % of the
biosphere diversity

Normal microbial life =
communities i.e.
ecosystems

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# Microbial ecosystems are important

Provide services linked to agriculture, environment, nutrition and health

* **Agriculture**: production and environment

* Soil, plants, trees microbiomes for production, health & mitigation of climate change

* Animals microbiomes for production, health and decrease of antimicrobial-use and greenhouse gas

* Depollution, recycling, improved sustainability

* **Food chain**: safety and sustainability

* Food quality, preservation and safety

* Sustainability, waste reduction and conversion

* **Human**: health

* Health & disease (chronic non transmissible and infectious ones)

* Nutrition & preservation of health

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# The Human microbiome wave

**2005** Technological breakthrough: New generation sequencing (C. Venter)

**2005** Paris meeting (INRA sponsored): ~80 scientists including C. Fraser, E. Rubin, J. Weissenbach, J. Doré, S. D. Ehrlich, ... + funding agencies NIH, NSF, EU

**2007** Rockville meeting (co-sponsored by NIH & EU) => creation of IHMC

> "Participants agreed that a **consortium** should be formed with membership to **include funding agencies and Principal Investigators** of projects that have an interest in the **comprehensive assessment of the human microbiome and its impact on health and disease**."

**2007-2008** NIH Human Microbiome Project-NIH Jump start ; EU MetaHIT project

**2008:** Data analysis & coordination center (HMP)

**2009:** Canadian Human Microbiome Initiative (CIHR); Australian Jumpstart Human Microbiome Project

**2010:** Korean Microbiome Diversity using Korean Twin Cohort (NRFK)

**2011:** International Human Microbiome Standards (EU)

...

Brought a new vision for health and medicine
The Human microbiome & INRA

**2005** Technological breakthrough: New generation sequencing

**2005** Paris meeting (INRA sponsored): C. Fraser, E. Rubin, J. Weissenbach, J. Doré, S. D. Ehrlich

**2007** Rockville meeting (co-sponsored by NIH & EU) => creation of IHMC

"Participants agreed that a **consortium** should be formed with membership to **include funding agencies and Principal Investigators** of projects that have an interest in the **comprehensive assessment of the human microbiome and its impact on health and disease**."

**2007-2008** NIH Human Microbiome Project-NIH Jump start ; EU MetaHIT project

**2008:** Data analysis & coordination center (HMP)

**2009:** Canadian Human Microbiome Initiative (CIHR); Australian Jumpstart Human Microbiome Project

**2010:** Korean Microbiome Diversity using Korean Twin Cohort (NRFK)

**2011:** International Human Microbiome Standards (EU)

...

=> share with other studied biotopes
# INRA's METAPROGRAMS: overcoming disciplinary boundaries

## AAFCC

Adaptation of agriculture and forestry to climate change

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2011

## MEM

Microbial ecosystems and meta-omics

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2011

## SMACH

Sustainable management of crop health

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2011

## DIDIT

Determinants and impacts of the diets

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## OF&F

Organic Farming and Food
(becoming a MP in 2018, AgriBio started in 2006)

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## ECOSERV

Agriculture and forest ecosystem services

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## SELGEN

Genomic selection (Bovine, Wheat, others)

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## GISA

Integrated management of animal health

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## GLOFOODS

Transitions to global food security (CIRAD & INRA)

## Pluridisciplinarity – Agronomic issues - International
# Microbial Ecosystems and Meta-omics (MEM)

* A **multidisciplinary** program built on the strength in microbiology and involving mathematics

* To understand **functioning of the microbial ecosystems of agronomic interest**, from soils to humans, using meta-omics

* And to **optimize their services** through prediction and engineering
# MEM governance & priorities

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## MEM steering committee

## International SAB

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## Thematic groups

1. Create an interdisciplinary scientific community sharing thoughts, knowledge, resources and working on projects based on both **biology & mathematics**;

2. Develop common & accessible pipelines & analytic methods (for biology & math);

3. Go gradually **beyond descriptive approaches** (who is there) **toward functional** understanding (what do they do, which interactions within & with the environment), modeling, engineering to optimize the ecosystems' services;

4. Encourage and support integrated INRA projects;

5. Enhance visibility and **international positioning of INRA** in these fields of research.
# MEM budget and means

What is it ?

* **MEM budget is based on**

* Permanent staff salaries (main budget, often forgotten)

* Functioning: 1M€ to 700 000 € /year

* 2 cofunded PhD fellowships / year (covering 50% of the PhD salary)

* Recommendation for permanent positions

How does it
work

* **Support for**

* Projects: Calls, Key actions, integrated projects (incubated by MEM)

* Meetings & think-tanks, conferences

* Training

* Visits or short stays abroad (started 2017)

* Management

annual RCAM
workshop

* **Involves**

* 70 laboratories / teams from 11 INRA research divisions

* ~135 scientists

**=> Examples of achievements...**
Example 1, organize & ease metabarcoding

1. Enable easy access to sequencing facilities: SOPs, advices & low cost (20 €/sample)

2. Development of an analysis pipeline in a biologist friendly-environment

o Benchmarking of bioinformatics tools for metabarcoding

o Pipeline development in a Galaxy environment: FROGS*

o Training sessions from raw reads to (basic) statistical analyses and result interpretation. More than 12 3-days sessions of 10-12 persons.

3. Expand the choice of microbial barcodes : understudied phyla and development of functional markers => ongoing project

* Escudié et al. (2018) Bioinformatics -- frogs.toulouse.inra.fr

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## Example 1, barcodes for understudied species in Agri-systems

<figure><img src="image_21.png" /><figcaption>C. Mougel</figcaption></figure>

M. Buée

C. Vacher

M. Barret

S. Schbath

* ✓ IAM unit (Nancy): **Dikarya and Oomycota**

* ✓ IRHS units (Angers): **phytopathogens**

* ✓ CARRTEL unit (Thonon): **eukaryotic microplankton**

* ✓ BioGer Unit, (Versailles): **Fusarium** strains

* ✓ IGEPP (Rennes), LEM (Lyon), Agroecologie (Dijon): **bacteria**

* ✓ Agroecology (Dijon): **Glomeromycotina**

* ✓ BIOGECO(Bordeaux): **leaf yeasts**

* ✓ MAAGE unit (Jouy): **bioinformatics**

* ✓ GetPlaGe (Toulouse): **sequencing platform**

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### Mock communities (10 to 12 barcodes and associated primer pairs tested)

* about 250 strains for Fungi/Oomycota (genomic DNA)

* 54 bacterial strains (gDNA)

* 38 gDNA of EuK plankton

**Extension to food systems**: 10 additional laboratories involved
# Example 2, boosting metagenomic studies

## ☑ **Humans**: MetaHIT, Chinese and HMP studies

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1267

**10 Millions genes**
intestinal microbiota

Li, et al., Nature Biotechnol 2014

* Stratification of gut microbiota = predicts response to treatment or diet

## ☑ **Food - Cheeses**: CNIEL

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Almeida et al., BMC genomics 2014

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## ☐ **Animals**: all but one with international consortia

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184

**2.6 Millions genes**

Xiao et al., Nature Biotechnol 2015

287

**7.7 Millions genes**

Xiao, Estelle, et al., Nature Microbiol 2016

300

**9.7 Millions genes**

Calenge et al. unpublished

10

**13 Millions genes**

Li, ... Morgavi. under revision. bioRxiv

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Example 3, New statistical methods

* Latent Block Model for Overdispersed Count Data with Application in Microbial Ecology. Aubert, Schbath and Robin. Under revision for JRSS

➔ a biclustering model-based method allowing to study the interaction between the structure of microorganism communities and environnemental samples from an abundance matrix.

➔ **cobiclust** R package available at https://github.com/julieaubert/cobiclust and on CRAN

* Variational inference for probabilistic Poisson PCA. Chiquet, Mariadassou and Robin *Ann. Appl. Stat.*, 2018.

➔ a probabilistic PCA adapted to multivariate Poisson-log normal count data and allowing to account for covariates and offsets.

➔ **PLNModels** R package available at https://github.com/jchiquet/PLNmodels
## Example 4, Use of text-mining

Extraction of information from publications thanks to knowledge modelling, ontologies and text-mining approaches :

- Microbes

- Habitat

- Phenotype

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Florilege

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Ontology : http://agroportal.lirmm.fr/ontologies/ONTOBIOTOPE

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Florilege DB and web application http://migale.jouy.inra.fr/Florilege

- Taxon ↔ Habitat : 820 000 relations

- Taxon ↔ Phenotype : 86 000 relations

- Direct links with external public DB (PubMed, DSMZ, GenBank ...)

Chaix, Deléger, Bossy & Nédellec (2018). **Text mining tools for extracting information about microbial biodiversity in food. Food Microbiology.**
And now ?

* MEM after 7 years

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✓ Changes mind and work practices

(Maths:Bio; 75% MEM project with international partners)

✓ Increased % of INRA publications on MEM topics, more collaborative publications, 68% in journals of exceptional & excellent reputations

✓ 28 patents, 5 start-ups

* Assessment of INRA's metaprograms Feb 2018

* 2018: institutional reflexion to launch new metaprograms
  → **from MEM to « Holobiont, the host and its microbiota »**

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* No national strategic agenda on Microbiomes

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Food security, sustainable agriculture and forestry, marine,
maritime and inland water research and the bioeconomy

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* **International Bioeconomy Forum** (launched on Nov 2017)

Flexible **multilateral platform** whereby **European and global R&I partners** would gather **to discuss and act on common challenges** in the bioeconomy, such as the **microbiome**... the IBF will be used as a platform to **share ideas and experiences** on bioeconomy policies, strategies and actions, **fostering collaboration and joint activities** that will promote innovation in key sectors.

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Feb 2018: submission of Coordination Support Action projects ⇔ Microbiome working group

“Towards a **coordinated microbiome R&I** activities in the **food system** to support (EU and) **international bioeconomy goals**”
Microbiome Support

➔ Exchange knowledge across the _scientific and political community_ and ensure an efficient use of the available resources

➔ Improve coherence between national and EU microbiome research and facilitate alignment of international research agendas

➔ Establish international agreed microbiome definition, best practices and standards

➔ Improve the international cooperation, creating the basis for joint international partnerships

<figure><img src="image_36.png" /><figcaption>A. Sessitch</figcaption></figure>

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AUSTRIAN INSTITUTE
OF TECHNOLOGY

<figure><img src="image_38.png" /><figcaption>E. Maguin</figcaption></figure>

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More specific European & international initiatives

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European Plant Science Organization

http://www.epsoweb.org/

○ independent academic organization that represents more than 220 research institutes, departments and universities from 31 countries in Europe and beyond.

○ EPSO's mission is to improve the impact and visibility of plant science in Europe

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**Working group on microbiome**

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2 Leaders from PhytoMic network

<figure><img src="image_44.png" /><figcaption>Marc Buée</figcaption></figure>

<figure><img src="image_45.png" /><figcaption>Corinne Vacher</figcaption></figure>

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International Alliance for Phytobiomes Research

http://www.phytobiomesalliance.org/

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2 Leaders from our PhytoMic network

<figure><img src="image_48.png" /><figcaption>K. Eversole</figcaption></figure>

Eversole Associates
Enabling Science & Technology

<figure><img src="image_49.png" /><figcaption>Corinne Vacher</figcaption></figure>

<caption>Christophe Mougel</caption>
# Phytobiomes Conference 2018

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4-6 December 2018
Montpellier – France
www.phytobiomesconference.org

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## Main Scientific topics

* Microbial community assembly and function

* Impact of microbiota on plant fitness

* Network analyses within the phytobiome system

* Modeling

* Data - framework, tools and resources, big data

* Genetic linkages

* Engineering to improve carbon sequestration

* Interactions within phytobiomes for abiotic stress

* Engineering microbes and microbial communities - including genome/gene editing

* Screening for microbes

* Precision agriculture

* Fertilizer, nutrient, and chemical input efficiency

* Translating complexity into products

* Regulatory requirements (EFSA, EPA, ...)

* Greenhouse & Field trials

* Industry research needs

→ Early bird registration: 15 September 2018

→ Abstract submission for a talk: 31 August 2018
Conclusion, a time of opportunities

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INRA's metaprogramm on microbial ecosystems

- Create an internal scientific dynamic and ....

- ... foster a pluri-disciplinary community

- Will shift to the more focus holobiont concept
for next generation of MP

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European Commission level

- International Bioeconomy Forum / WG microbiome / *Microbiome Support*

- Common strategic agenda

- Work on standards

- Recommendations for future actions

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European & international initiatives

- EPSO & International phytobiomes Alliance

- ERA-Net INTIMIC : Diet-microbiota-health => 11 projects, knowledge PF

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Thank you!

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# Bi-clustering of overdispersed count data: LBM

## Latent Block Model:

### Assumptions

$(Z_i) \sim \mathcal{M}(1, \pi = (\pi_1, \dots, \pi_K)) (W_j) \sim \mathcal{M}(1, \rho = (\rho_1, \dots, \rho_G))$

Latent variables $(Z_i)$ and $(W_j)$ are independent

The random variables $Y_{ij}$ are independent conditionally on labels

### Model

$(Y_{ij}), i = 1, \dots, n \text{ et } j = 1, \dots, m$ matrix of observations.

$$Y_{ij} | (Z_{ik} = 1, W_{jg} = 1) \sim f(\cdot; \mu_i, \nu_j, \alpha_{kg})$$

* $\mu_i$: mean level of presence of one particular bacteria

* $\nu_j$: scale factor correcting for sampling effort (around 1)

* $\alpha_{kg}$: interaction level between bacteria and sampling units within the $(k, g)$ group

## Poisson-Gamma Latent Block Model:

$$Y_{ijr} | (Z_{ik} = 1, W_{jg} = 1) \sim \mathcal{P}(\mu_i, \nu_{jr}, U_{ijr}, \alpha_{kg})$$

$$\text{with } U_{ijr} \sim \text{Gamma}(a, a)$$
# Probabilistic PCA for multivariate Poisson-log normal counts

## Hierarchical Model

$$ \mathbf{z} \sim \mathcal{N}(\mu, \Sigma) $$

Basis

$$ \lambda_j | \mathbf{z} = e^{z_j} $$

Average count of species j

$$ \mathbf{Y}_j | \mathbf{z} \sim \mathcal{P}(e^{z_j}) $$

Observed count of species j
Example 4, Pathobiome concept

2013 Think tank => multidiscipline to address animal and plant health taking into account the biotic environment of pathogens (pathologists, infectiologists, microbial ecologists, mathematics, etc).

<figure><img src="image_58.png" /><figcaption>Muriel Vayssier
Animal Sc Div.</figcaption></figure>

Frontiers in
CELLULAR AND INFECTION MICROBIOLOGY

REVIEW ARTICLE

published: 06 March 2014
doi: 10.3389/fimbio.2014.00029

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Shifting the paradigm from pathogens to pathobiome: new concepts in the light of meta-omics

Muriel Vayssier-Taussat¹*, Emmanuel Albina²,³,⁴, Christine Citti⁵, Jean-François Cosson⁶,

Marie-Agnès Jacques⁷, Marc-Henri Lebrun⁸, Yves Le Loir²,¹⁰, Mylène Ogliastro¹¹, Marie-Agnès Petit¹²,

Philippe Roumagnac¹³ and Thierry Candresse¹⁴

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@gr_pathobiome

2 international meetings

2015, march 2018
# MEM activities

## Scientific impetus

* INRA think tank: 6 (pathobiome and phytoMic emerged)

* INRA, National & international meetings: 20

* Networks: 5 on going

* Continuing education: bioinformatics & microbial ecology

* Science popularization: 5

## Research projects

* Call for projects: 35 funded projects (all maths & biology)

* Key actions: 20

* PhD fellowships: 14 (directly supported by MEM)

* Short international missions: 10 (2017 & 2018)