DISCOVERING CAUSES, DECIPHERING FUNCTIONS. Opening new prophylactic, therapeutic and diagnostic avenues.
Understanding, predicting and manipulating host-microbiota ecosystems
100,000 billion cells, 200 cell types and 25,000 genes in humans; 1 quadrillion microbes, over 1,000 species and 3.3 million genes in microbiota. There can be no doubt about it; we are no longer organisms, but ecosystems, fruit of the symbiosis between our cells and microbes (bacteria, yeasts, fungi and viruses) that inhabit our skin and mucous membranes: the gastrointestinal tract, eyes, mouth, vagina and respiratory tract. Discovery after discovery, microbiota reveals the many positive effects it has on our physiology; it protects us against pathogens (by depriving them of nutrients, producing bactericidal compounds, strengthening our epithelial barrier, etc.), contributes to the synthesis of vitamins, to the breaking down of food into nutrients and energy, the development of our immune system, the list goes on. Microbiota dysfunctions (dysbiosis) can be observed in diseases as diverse as obesity, allergies, inflammatory bowel disease, hepatic encephalopathy, type 2 diabetes, autism, etc.
As always when exploring a new world, these findings, in turn, raise many questions: how does microbiota shape our immune system? In how many diseases is this dysbiosis found? Are they the cause or the consequence of these diseases? Which bacterial populations and biological mechanisms are affected? How can we take advantage of it?
At the intersection of medicine and health, BIOASTER and its partners are now trying to better understand, predict and manipulate host-microbiota ecosystems using new biology tools such as omics analysis, biocomputing and gnotobiology.
An ecological approach
Developments in metagenomic analyses have greatly increased scientific knowledge on the composition of microbiota. Just like our fingerprints, our gut microbiota is unique because 50% of microbial species are unique to each individual. It is dominated by four large phyla of bacteria (Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria). The genetic and microbial diversities of this bacterial population are lower in diabetic patients or those with inflammatory bowel disease.
However, this initial inventory does not completely reflects the complexity of the microbiota. Our gut microbiota alone is home to hundreds of different bacterial species, including true symbionts and pathobionts (very few). Some of these bacteria circulate freely in the colon, while others are attached to food particles or combine with mucus to form biofilms. These bacteria communicate with each other (by exchanging genes and secreting metabolites) and with their host (via a multitude of signals and receptors). Their fermentation also produces gases (H2, CO2, CH4) and a large number of chemical compounds. Finally, while dysbiosis is seemingly involved in an increasing number of diseases, we are still unable to go beyond the correlation stage.
In order to uncover new prophylactic, diagnostic and therapeutic strategies, the “Microbiota” programme is implementing a ecological approach . By combining meta-omics, microbiology, biological samples, imaging and predictive models, BIOASTER with its academic and industrial partners are:
- Exploring host-microbiota interactions when host are healthy but also during diseases (infections, metabolic diseases and chronic inflammations) as well as when hosts are under therapeutic treatment (antimicrobials and vaccines) or following food consumption (pre- and probiotics).
- Measuring the impact on microbial ecology, how the different microbiota and host physiology function.
- Assessing the potential of biomarkers for diagnostic, prognostic or predictive purposes.
New in vitro models
Nearly 70% of the bacteria that make up human microbiota are uncultivable and many of them are strictly anaerobic (so can only be cultivated without oxygen). These hurdles have led scientists to look into meta-genomics and in vivo models. To date, few cell culture systems have been developed and while in vitro models of the digestive tract can be used to mimic one or more stages of digestion (in the stomach, small intestine or colon) they are nevertheless incapable of reproducing the complexity of host-microbiota interactions.
BIOASTER is now developing models that will accelerate the validation of hypotheses generated by meta-omics and high-throughput analyses. The objective is to develop next-generation platforms for phenotypic screening, co-culture systems for human cells and microbes (essential for studying the relationship between commensal bacteria and host cells) and new gut-on-a-chip models.
Innovative and standardised in vivo models
As with meta-omic analyses, gnotobiotics is a key technological tool for studying the microbiota. So many recent discoveries have been made using germ-free mice (animals without microbiota born under caesarean section and raised in sterile conditions) or gnotoxenic mice (inoculation of one or more microbial microflora in the digestive tract of these mice).
With the progress of genetic engineering, these models have become increasingly sophisticated. Today most mouse strains (isogenic, knock-out, knock-in) may result in germ-free mice. Once re-colonised via controlled intestinal microflora, these animal models can be used to measure the impact of various factors (food, toxic compounds, treatments, bacterial, pathogenic strains, etc.) on microflora and intestinal mucosa.
Today, the program is attempting to respond to the new challenges of gnotobiotics: the lack of axenic models for human diseases, improving existing models and the necessary standardization of these models (“isobiotic” models of a minimal phenotypic variability in which highly stable microbial flora that transfer their genes horizontally and vertically are implanted). Thanks to close collaborations with BIOASTER "preclinical models and imaging" technology unit and its sate of the art laboratory equipment, the “Microbiota” programme is today well positioned to contribute to this field by responding to the quality standards of the industry.
For better understanding watch the lastest video 'technology designed by BIOASTER' entitled ANOXIC plateform:
Immunobiotics: the impact of probiotic bacteria on the immune response
Today, scientists still find very difficult to predict the impact of probiotics on the complex microbial communities that our bodies host. In 2013, with its academic and industrial partners (Institut Pasteur, Imagine and Danone Research), BIOASTER implemented an R&D programme that aimed at measuring the impact of various probiotics on the host immune response (resistance to respiratory tract infections, response to vaccines and the potential occurrence of allergies).
The results of this programme, which are expected to be released in 2017, should enable the targets of these probiotics to be identified and, in return, those bacterial strains with a favourable immune profile to be selected.