The Future of Microbiome Research

Program Director, Human Microbiome Project

Presentation Title
Challenges and Priorities for the Next 10 years of Human Microbiome Research

Abstract
The human microbiome field has seen tremendous investment and growth, especially in the
last 10-20 years. For example, the US National Institutes of Health invested $215M over
2007-2016 in the Human Microbiome Project to develop the research toolbox for this field
with an additional $880M over this same period in individual studies of the role of the
microbiome in over 100 different classes of disease. However, the number of successful
microbiome-based interventions for disease remain limited. I posit that our fundamental
approach to the microbiome may need to be recast and that an ecological approach may
provide better insights into the role of the microbiome in human health and disease.

 


 

Chief Scientific Officer at Kaleido Biosciences

Presentation Title
A Chemistry-Driven Approach to Leveraging the Potential of the Microbiome to Treat
Disease and Improve Human Health

Abstract

  • Why glycans are the superior modality for therapeutic modulation of the microbiome
  • How we systematically synthesize differentiated glycans to systematically span the
    modulation space
  •  Our now clinically validated platform from in vivo to response in patients
  •  How we use the GRAS status for accelerated clinical development by only filing for
    IND at phase 2/3
  •  What data we have from the clinic and what the therapeutic opportunities are

 


 

Assistant Professor
Vrije Universiteit Amsterdam

Presentation Title
On the Future of Clinical Research Using Pharmabiotics

Abstract
Although the gut microbiota has been studied intensively for the last decades, clinical trials
focusing on gut microbiota intervention using probiotics are still in their infancy. Probiotic
products and their effects are inherently heterogeneous, hampering a proper comparison
between clinical trials. In this lecture, factors underlying this heterogeneity will be discussed.
Moreover, possible solutions will be provided with respect to the design of clinical trials to
increase the success rate for reaching statistical significance and the development of new,
rationally designed, probiotic products.

 


 

Presentation Title
A Prototype Pharmabiotic for the Treatment of Phenylketonuria

Abstract
Phenylalanine hydroxylase (PAH) deficiency, historically known as phenylketonuria, is a
genetic disorder of metabolism affecting approximately 1 in 10,000 to 15,000 persons
worldwide. Non-functional PAH enzyme results in supraphysiologic blood phenylalanine
concentration, which if untreated at early ages, causes permanent cognitive delays. Current
standards of care include severe dietary protein restriction with close monitoring of
phenylalanine intake and tyrosine supplementation. Another treatment is supplementation
with PAH cofactor (BH4, Kuvan), but is effective in only 20-30% of PAH patients and does
not eliminate dietary restriction. Palynziq is a recently approved enzyme replacement
therapy, but because it is a non-human protein, carries significant risk of anaphylactic
reactions. A targeted, gastrointestinal pharmabiotic approach for the treatment of PAH
deficiency represents a novel way forward. We have developed and provisionally patented a
prototype pharmabiotic for PAH deficiency, which is a genetically modified Lactobacillus
helveticus strain expressing human phenylalanine hydroxylase”. Lactobacillus helveticus is a
GRAS gram-positive bacterial species commonly formulated in commercially marketed
probiotics. A cDNA for human PAH was amplified and inserted into a gram-neutral shuttle
vector to create a novel plasmid, LiLi5. The identity of the LiLi5 plasmid was confirmed by
restriction enzyme digest and sequencing of the cDNA insert. We created a new
transformation protocol to successfully transform LiLi5 into L. helveticus and generate a
novel strain of Lactobacillus, which was named “HELin”. PCR-based detection confirmed the
presence of the human PAH cDNA in HELin. HELin can be optimized, tested and
formulated into a pharmabiotic to treat phenylalanine hydroxylase deficiency. The product
could be formulated into a capsule, yogurt, or slurry for oral administration. The pharmabiotic
bacteria is expected to colonize a patient’s small intestine and provide an exogenous source
of the deficient protein, allowing for greater dietary variation and increased quality of life for
patients with PAH deficiency.

 


 

Presentation Title
Introduction of Million Microbiome of Humans Project (MMHP)

Abstract

From MetaHIT (Metagenomics of the Human Intestinal Tract) and HMP (Human Microbiome
Project) to culturomics studies, reference datasets have always been a major theme for
metagenomic studies. Metagenome-wide Association Studies (MWAS) based on such
references offered a data-driven approach to identify new biomarkers, including those that
have not been isolated in culture. Samples across geography, diseases, body sites, and with
interventions, would help scientists to converge on a more comprehensive picture of the
microbiome. As the cost for whole genome drops, we also have high hopes for M-GWAS
(Metagenome-Genome-wide Association Studies). The metagenomic field would not fall
behind human genomics and single-cell studies regarding international consortium and
sample sizes. More details on how to join the Million Microbiome of Humans Project (MMHP)
will be released soon.

 


 

Presentation Title
Digging for Diamonds: Lactobacillus casei AMBR2 as Novel Live Biotherapeutic Product for
the Upper Respiratory Tract.

Abstract
Chronic rhinosinusitis (CRS) is one of the most common upper respiratory tract (URT)
diseases with a major impact on public health. The exact role of bacteria in the disease
pathology is still controversial and current treatment options often fail. In this study, we
aimed to analyze the URT microbiota to better understand the difference in potential health-
promoting and pathogenic bacteria in CRS patients versus healthy controls, and to develop
new treatment strategies based on beneficial bacteria from the URT. We demonstrated with
16S rRNA amplicon sequencing analysis that taxa from the well-documented beneficial
Lactobacillus genus are low-abundant but important species of the healthy URT since their
prevalence was decreased with almost 40% in the URT of CRS patients compared to
healthy controls. Several URT-specific Lactobacillus isolates were cultured, characterized,
and further explored for their genetic and functional properties related to adaptation to the
URT. Catalase genes were found in the identified Lactobacillus taxa, which is a unique
feature within this mostly facultative anaerobic genus. Moreover, one of our isolated strains,
Lactobacillus casei AMBR2, contained unique fimbriae enabling strong adherence to URT
epithelium, inhibited the growth and virulence of several URT pathogens. In a preclinical trial
in healthy individuals, the safety of this strain in a nasal formulation was tested, as well as
the capacity of the strain to colonize the URT. The spray was well-tolerated and no major
complaints were observed. Furthermore, the strain was found to be able to temporally
colonize the URT after nasal administration. This study demonstrates that administration of
the specifically selected L. casei AMBR2 might hold promise as a live biotherapeutic product
for direct nasal and other URT applications.

 


 

Professor of Clinical Microbiology
University of Milan

Presentation Title
Nasal Microbiome: Connection with Respiratory Diseases and Novel Pharmabiotics Approaches

Abstract
The nasal microbiota includes a wide variety of potential pathogenic and harmless bacteria.
This diverse nature may be attributable to localized factors (temperature and humidity) and
position in the respiratory tract. Authors have recently observed that the anterior nares had
decreased levels of microbiome biodiversity in comparison with the middle meatus. The
microbiome of the anterior nares in healthy adults has been observed to be dominated by 3
phyla: Actinobacteria, Firmicutes, and Proteobacteria. Disturbances of nasal microbiome can
lead to allergic rhinitis and chronic rhinosinusitis. Local administration of selected probiotics
have been seen to improve otitis media and pharyngotonsillitis by also acting against biofilm
formation of respiratory pathogens.

 


 

Presentation Title
Engineering Living Medicines for Chronic Diseases

Abstract
As the molecular mechanisms underlying the associations between the microbiome and
diseases are discovered, delivering defined activities to gut will become an increasingly
important therapeutic modality. A key challenge for microbiome therapeutics is delivering
predictable, high doses of therapeutics strains despite widely varying patient microbiomes.
We have developed a suite of synthetic biology tools that enable the programing of
therapeutic activities into the most abundant genus of gut bacteria, Bacteroides. Our
therapeutic Bacteroides strains are engineered to consume a rare carbohydrate, porphyran,
so that even within a complex community we can exclusively feed them with a prebiotic. By
creating this exclusive niche, we can colonize diverse, and even resistant, microbiotas at a
predictable level that is tunable with porphyran dosing. To avoid the uncontrolled release of
engineered strains we have further modified the strains to rely on porphyran for function of
essential genes, so that strains are only viable in the subject during porphyran dosing. We
are applying our platform for robustly and reversibly colonizing the gut with engineered
bacteria to treating enteric hyperoxaluria, a chronic disease where over absorption of oxalate
in the colon can result in recurrent kidney stones. Inspired by natural oxalate degrading
bacteria often found in the gut at low levels, we have engineered rapid oxalate degradation
into our robustly colonizing Bacteroides strain. When introduced in rat and pig models of
enteric hyperoxaluria, our strain successfully reduces urine oxalate. We are currently
working to bring this therapeutic into the clinic and are investigating treatment of other
microbiome associated disease.

 


 

Presentation Title
Akkermansia muciniphila, the Next Generation of Beneficial Microbes to Fight
Cardiometabolic Disorders

Abstract
A-Mansia is a Belgian microbiome spinoff company based on discoveries made by the
founding scientists Prof. Willem M. de Vos (Wageningen University -The Netherlands) &
Prof. Patrice D. Cani (UCLouvain – Belgium). In 2004, Akkermansia muciniphila MucT
(Akkermansia) was isolated from human gut by Pr. W.M. de Vos team’s – Laboratory of
Microbiology, Wageningen University & Research Center, Netherlands1. Then, Pr. P.D. Cani
team’s – UCLouvain, Metabolism and Nutrition Research Group, LDRI, Belgium – discovered
that murine models of obesity and/or type 2 diabetes were characterized by a lower
abundance of Akkermansia. In addition, they found strong correlations between the
presence of Akkermansia and lower cardiometabolic risk factors². Both researchers decided
to collaborate in order to produce this anaerobic bacterium for preclinical investigations and
decipher its potential health effects on preclinical models. Besides the numerous correlations
observed, this collaboration led to several scientific articles demonstrating: (i) a large body
of evidence of the causal beneficial impact of this bacterium in a variety of preclinical
models, (ii) the ability to produce a bacteria compatible and safe for human use³ and (iii)
accomplished the first proofof-concept study using Akkermansia in humans4. It’s against that
stimulating background with strong scientific evidences and know how that the A-mansia
company was born. Its objective is to launch in the market dietary supplements comprising
Akkermansia to tackle cardiometabolic disorders.

 


 

Image result for gregory lambert 

Presentation Title

Hafnia Alvei 4597™ – Naturally Modulating the Appetite via the Microbiome

Abstract

TargEDys is a French clinical stage biotech company aiming to control metabolic disease by modulating the appetite through an intervention on the microbiome. TargEDys’ innovative, satiety inducing technology (ProbioSatys®), is based on a unique understanding of appetite regulation by the microbiome at the molecular level. Bacteria can send signals of satiety to the brain from the gut by molecularly mimicking satiety hormones, thus activating natural satiety pathways. The basis of the technology is a commensal, enterobacteria probiotic strain, Hafnia alvei HA4597™, that produces the ClpB protein, a mimetic of the satiety hormone α-MSH. The pre-clinical data have demonstrated the beneficial anti-obesity effects of Hafnia alvei 4597™ in mice. Treatment with Hafnia alvei 4597™ was associated with decreased body weight and fat mass gain along with reduced food intake as well as positive effects on glycemia and OGTT.

A randomised, multicentric, double-blind, placebo controlled clinical trial in 240 subjects has been completed. The trial met the primary endpoint:  statistical difference in the proportion of subjects who lost at least 3% of body weight at 12 weeks. Amongst other findings, the mechanism of action is confirmed by achieving secondary endpoints such as an increase in the feeling of fullness in the verum group. This talk covers ProbioSatys’® journey from its preclinical and clinical stage to commercialized product, EnteroSatys®, including formulation, manufacturing and control. First results of clinical trial will be presented and discussed.

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