Research of the Host-Microbe Interactomics Group

1. Innate defence mechanisms in the small intestine

Certain commensal and probiotic bacteria also engage in active cross-talk with the host epithelium to promote epithelial development, homeostasis and protection of barrier disruption by infection with pathogenic bacteria. At HMI, we identify and study molecular mechanisms by which probiotics and other commensal bacteria activate mechanisms that protect against epithelial permeability caused by pro-inflammatory cytokines or pathogens. Additionally we investigate the role and function of the RegIII family proteins expressed in the intestine in response to bacterial colonization  (Thesis Loonen), role of Aryl hydrocarbon receptor (Ahr)  and the role of the Muc2-layer, which mediates many interactions of the microbiota with the gut epithelium (link to project). Parts of this work are supported by the Top Institute Food and Nutrition.

2. Probiotic interactions with host cells.

Modulation of the immune system is one of the most plausible mechanistic concepts of probiotic function. In vitro studies suggest that probiotic bacteria stimulate several intestinal cell protective responses, including enhancement of epithelial barrier function, defensin production, mucin synthesis and secretion, inhibition of pathogen binding and cell survival and proliferation.To understand the mechanisms involved, detailed research is needed to determine the bacterial factors and cellular receptors responsible for the immunomodulatory effects of specific probiotic strains.  Our main interest is in the interaction of bacteria with dendritic cells (DC) which regulate both tolerance and adaptive responses in mucosal tissues. We have been investigating the role of innate receptors found on DC (thesis Meijerink) and the role of putative probiotic factors using defined mutants in vivo (link to project). Parts of this work are performed in collaboration with the Top Institute Food and Nutrition and with Jolanda van Bilsen (TNO) and NIZO Food Research. We are investigating functionality of next generation probiotics (clostridia and other butyrate-producing human commensal bacteria) with external partners.

3.

Host-Microbe interactions in health and disease: using the zebrafish model to study dysbiosis

The zebrafish is a unique model in that it is exposed to the outside world from fertilization onwards. Development of the animal and its immune system goes hand in hand with bacterial colonization. Disturbances of this development might lead to dysbiosis and increased susceptibility to disease later in life. What cells and mediators are involved in establishing homeostasis in the intestine? What are the influences of feed, antibiotics or pollutants on the microbiota and disease susceptibility? By making use of the early life transparency of the zebrafish combined with the availability of transgenic (immune cell) reporter fish we are currently investigating the role of cxcl8a and regulatory cytokines (IL22 and IL10) during development from eggs to larvae to juveniles in which the fish transition from animals that solely rely on innate immunity to fish that have both innate and adaptive immune function. We investigate the effect of feed, antibiotics and other water pollutants during this development on the host as well as its microbiota and aim to understand what processes might underly increased intestinal disease susceptibility.

Projects:

-NWO-TTW: Fishing for functional feeds: using the zebrafish as a screening model to assess novel fish feeds (Adria Lopez Nadal HMI, CBI, AFI)

-NWO-ENW: Keeping the peace at the microbial surface: how does the host control pathobionts (HMI)

-WIAS: It takes IL-22 to tango (Evelien Kidess, HMI)

-EWUU-CUCo grant: Defeating chronic pain

-Protein transition Biochemistry project: Establishing a multidisciplinary pipeline to assess protein functionality

-Protein transition project: Using the zebrafish to assess the effect of fermented feed on gut health and microbiota

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4. Discovery of novel antimicrobials

Resistance to multiple antibiotics has built up slowly over the past 20 years but has come to a head in the last five years. Consequently, we are seeing more frequent and persistent disease outbreaks caused by multi-resistant bacteria. Unless strategies for the development of alternative antibiotics are initiated soon, this will have an enormous social impact on the sustainability of other developments in modern medicine and quality of life worldwide. In this project we are aiming to develop novel inhibitors of the essential two-component signal transduction system YycFG (also known as WalKR) that is conserved in several Gram-positive bacterial pathogens, including Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis. Together with industry and other academic partners we are exploiting recently obtained three-dimensional structures of YycFG homologues and in silico structure based drug discovery to identify putative inhibitors.(link to project) Additionally we are continuing to investigate the role and function of YycFG in S. suis using genetic (transposing mutagenesis together with RNA sequencing or Tn-Seq) and biochemical approaches. We are also evaluating the antibiotic efficacy of antimicrobial frog peptides on a broad panel of bacterial pathogens together with the Medical Microbiology group of Erasmus University Medical Centre, Rotterdam, and are currently following up on lead antibiotics produced by pig microbiota (link to project) together with the group of Colin Hill at University College Cork, Ireland.

To search for novel antibiotics, we are part of National Center of One Health, Antimicrobial Resistance (NCOH-AMR)

5. Virulence factors of Streptococcus suis and disease pathogenesis.

Streptococcus suis is one of the most important pathogens affecting the swine industry and can cause septicemia, meningitis, pneumonia and arthritis in young pigs. S. suis has also been reported to cause sporadic cases of meningitis and sepsis in humans. Current vaccines only protect against a limited range of strains. At HMI we have studied the role of surface proteins in virulence and pathogenesis by comparing the behavior and properties of isogenic mutants in different experimental models (thesis Ferrando). Some of the surface proteins are part of two-component systems, attractive antimicrobial targets (link to project). We have unravelled the natural competence system of S. suis and have identified a short peptide that dramatically increases our ability to genetically transform S. suis. (link to article) We are investigating methods to control S. suis proliferation in pigs using natural antimicrobials produced by pig microbiota and will evaluate if such compounds to be used as pig feed supplements. Parts of our research are in collaboration with Astrid de Greeff at WBR, Lelystad.

We are currently coordinating an EU project PIGSs (Program for Innovative Global Prevention of Streptococcus suis) (link to PIGSs website)

6. Using -omics technologies and network biology to investigate host-microbe interactions

In this research we are developing networks and pathway models to investigate responses of intestinal epithelial cells and tissues to interactions with microbes, both probiotics and microbiota, also using animal models. Throughout the HMI projects, we apply transcriptomics, metabolomics and high-content microscopy approaches to investigate cellular and tissue responses to microbes. Ultimately the developed network models and reconstructed signalling pathway models will provide new insights into the regulatory events in cells and tissues and help to identify microbial and host molecules that mediate host-microbe interactions in health and disease.

7. Analysis of molecular mechanisms establishing microbiota-host interactions

At HMI, we are investigating the molecular mechanisms that mediate specific interactions between specific parts of the microbiota and their hosts using next generation sequencing and metabolic intestinal and systemic blood parameters using unbiased, holistic -omics technologies to search for correlations between abundance of specific microbial groups and health and disease of human and different animal hosts including pigs  and mice. Parts of this research are in collaboration with NIZO Food Research  and the Netherlands Metabolomics Centre. In another project we are investigating the effect of a few foods diets on the microbiota and behaviour of children showing ADHD symptoms.